Master Validation Plan
The Ultimate Guide to
FDA, GMP, and GLP Compliance
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Pharmaceutical
Master Validation Plan
The Ultimate Guide to
FDA, GMP, and GLP Compliance
Syed Imtiaz Haider, Ph.D.
ST. LUCIE PRES S
A CRC Press Company
Boca Raton London New York Washington, D.C.
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Every effort has been made to ensure that the contents of this generic validation master plan are accurate and that recommendations are appropriate and made in good faith. The author accepts no responsibility for inaccuracies or actions taken by companies subsequent to these recommendations. Library of Congress Cataloging-in-Publication …show more content…
Data
Haider, Syed Imtiaz.
Pharmaceutical master validation plan : the ultimate guide to FDA, GMP, and GLP compliance / by Syed Imtiaz Haider.
p. cm.
Includes bibliographical references and index.
ISBN 1-57444-330-5 (alk. paper)
1. Pharmaceutical technology—Quality control. 2. Pharmaceutical industry—Quality control. I. Title.
[DNLM: 1. Drug Industry—standards. 2. Drug and Narcotic Control. 3. Facility
Regulation and Control. 4. Guideline Adherence—organization & administration. 5.
Quality Control. 6. Technology, Pharmaceutical—standards. QV 736 H149p 2001]
RS192 .H3533 2001
615'.19'021873—dc21
2001048618
This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the authors and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.
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Visit the CRC Press Web site at www.crcpress.com
© 2002 by CRC Press LLC
St. Lucie Press is an imprint of CRC Press LLC
No claim to original U.S. Government works
International Standard Book Number 1-57444-330-5
Library of Congress Card Number 2001048618
Printed in the United States of America 1 2 3 4 5 6 7 8 9 0
Printed on acid-free paper
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LIMITED WARRANTY
CRC Press LLC warrants the physical disk(s) enclosed herein to be free of defects in materials and workmanship for a period of thirty days from the date of purchase. If within the warranty period
CRC Press LLC receives written notification of defects in materials or workmanship, and such notification is determined by CRC Press LLC to be correct, CRC Press LLC will replace the defective disk(s). The entire and exclusive liability and remedy for breach of this Limited Warranty shall be limited to replacement of defective disk(s) and shall not include or extend to any claim for or right to cover any other damages, including but not limited to, loss of profit, data, or use of the software, or special, incidental, or consequential damages or other similar claims, even if CRC Press LLC has been specifically advised of the possibility of such damages. In no event will the liability of CRC Press
LLC for any damages to you or any other person ever exceed the lower suggested list price or actual price paid for the software, regardless of any form of the claim.
CRC Press LLC specifically disclaims all other warranties, express or implied, including but not limited to, any implied warranty of merchantability or fitness for a particular purpose. Specifically,
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Warranty covering the physical disk(s) only (and not the software) and is otherwise expressly and specifically disclaimed.
Since some states do not allow the exclusion of incidental or consequential damages, or the limitation on how long an implied warranty lasts, some of the above may not apply to you.
DISCLAIMER OF WARRANTY AND LIMITS OF LIABILITY
The author(s) of this book have used their best efforts in preparing this material. These efforts include the development, research, and testing of the theories and programs to determine their effectiveness.
Neither the author(s) nor the publisher make warranties of any kind, express or implied, with regard to these programs or the documentation contained in this book, including without limitation warranties of merchantability or fitness for a particular purpose. No liability is accepted in any event for any damages, including incidental or consequential damages, lost profits, costs of lost data or program material, or otherwise in connection with or arising out of the furnishing, performance, or use of the programs in this book.
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DEDICATION
This book is dedicated to the loving memory of my mother,
Khursheedun-nissa, whose encouragement and love have added substantial value to my career.
vi
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PREFACE
The regulatory guidelines such as those of the FDA, Current Good Manufacturing Practices (cGMP) for Pharmaceuticals, and Good Laboratory
Practices (GLP) require comprehensively documented systems. The guidelines mentioned above provide only a set of rules to be followed and leave the specificity of the working documents to the individual companies.
The purpose of this book is to provide a generic format for a Master
Validation Plan, also often called a Validation Master Plan (VMP), using a pharmaceutical manufacturing site with both sterile and non-sterile operations as the case facility. The intent is to show basic format and samples of contents for all the sections of the plan, because it provides a road map for validation to establish FDA requirements master validation procedures, validation programmes, execution protocols, and resources planning and scheduling.
The pharmaceutical, medical device, and biotech industries are regulated worldwide to be in compliance with cGMP and GLP principles. Each company is required to create a VMP to qualify its equipment, utilities, buildings, and personnel. The template VMP available enables the end users to understand the principles and elements of a VMP and provides documentation language that is generic to very specific depending on the depth of the requirements.
Compliance with FDA regulations by the health care industry over the past decade has been a major goal, especially for those companies intending to export their product to the U.S. market. As a result, the FDA inspects nearly 300 companies throughout the world every year for cGMP and GLP compliance, but only five or six are able to seek approval for exportation. One reason for this is the absence or inadequacy of a VMP.
The key benefits of a VMP include, but are not limited to:
Ⅲ Minimize noncompliance
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viii Ⅲ Pharmaceutical Master Validation Plan
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Reduce rejected lots
Avoid recalled lots
Helps in new drug approval
Satisfactory inspections
Corporate image
Financial gain
Secure third-party contracts
Corporate legal protection
Utility cost reduction
Minimize capital expenditures
Fewer complaints
Reduced testing
Improved employee awareness
The Validation Master Plan on CD-ROM is a valuable tool for those companies that are in a process of developing or revising a VMP to achieve
FDA, GMP, and GLP compliance. The documentation package is especially relevant to quality assurance (QA) personnel, engineers, utilities engineers, computer engineers, validation designers, internal and external auditors, and to anyone interested in developing a qualification documentation matrix. The VMP provides administrative solutions for management, both in text and software.
The author believes that following the broadly based example of a
Validation Master Plan, both new and experienced companies can benefit and enhance their existing documentation of a Validation Master Plan to meet FDA and other regulatory requirements worldwide.
Syed Imtiaz Haider, Ph.D.
September 2001
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ACKNOWLEDGMENTS
I would like to thank friends and colleagues, especially Javed Zamir, for their help and encouragement in this endeavor and for creating the professional environment that demanded that this book be developed.
I would like to thank the staff of CRC Press, particularly Drew Gierman and Gail Renard for their patience and diligence in the production of this work.
ix
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ABOUT THE AUTHOR
Syed Imtiaz Haider has a Ph.D. in chemistry and is a quality assurance specialist with more than 12 years of experience in pharmaceutical validation, in-process control, and auditing. He has more than 40 research publications in international refereed journals dealing with compounds of pharmaceutical interest, their isolation, purification, and structure development. Dr. Haider is a professional consultant, technical writer, and author of more than 2000 Standard Operating Procedures based on FDA regulations, ISO 9001, and ISO 14000; a Standard Certified Lead Auditor of IRCA; and registered provisional auditor of EARA. He has written more than ten manuals for multidisciplinary industries. Dr. Haider has also written
ISO 9001:2000 Document Development Compliance Manual: A Complete
Guide and CD-ROM, published by CRC Press, Boca Raton, FL, and holds a copyright certificate of registration on an electronic documentation package on ISO 14001 from the Canadian Intellectual Property Office.
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PROLOGUE
The purpose of this book is to provide a generic template for a Validation
Master Plan (VMP), using a broadly based pharmaceutical facility as an example. The contents of the VMP are based on a hypothetical, newly constructed ABC Pharmaceutical facility. The facility is comprised of three buildings: A, B, and C.
Ⅲ Building A is dedicated to the manufacture of dry oral products.
Ⅲ Building B is designed to manufacture liquid and semisolid oral products. Ⅲ Building C is constructed to manufacture injectables in ampoules, vials, and disposable ready-to-use syringes, and lyophilized products in vials.
The information provided in this introduction is intended to help those who use this book and its CD-ROM understand the basic elements of a
VMP; download the electronic files provided on the CD-ROM on a personal computer; and execute the desired changes or directly adopt the contents for the development of a VMP in accordance with the operational requirements of their companies.
VALIDATION MASTER PLAN
What is a Validation Master Plan? There is no official definition; however, based on the interpretation of FDA regulatory guidelines on current Good
Manufacturing Practice (cGMP), Good Laboratory Practice, and process validation, a suitable definition may be described as:
xiii
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xiv Ⅲ Pharmaceutical Master Validation Plan
A comprehensive document describing the applicable validation requirements for a given facility, and providing a plan for meeting those requirements. The VMP provides a “road map” for validation, to establish a sequence of events followed by facilities audits and inspections. The benefits of a VMP are not limited to proactive regulatory compliance but help in the prevention of omissions and inappropriate or laborious testing, scheduling and tracking of tasks, identification of personnel qualifications, and human resource optimization. The overall program gains regulatory and management credibility and helps to avoid unforeseen delays in facility start-up operations for commercial production. The key benefits involved are:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Minimize noncompliance costs
Reduce rework
Reduce rejected lots
Avoid recalled lots
Helps in new drug approval
Satisfactory inspections
Corporate image
Financial gain
Secure third-party contracts
Corporate legal protection
The observations made during the execution of the VMP pr ovide strength to significantly reduce the regulatory risks related to the systems and initiation of the proactive corrective actions required. The plan provides visibility for the completion of individual tasks and assures system evaluation, process validation, equipment validation, facility and utilities qualification, documentation, environmental control, and monitoring; implementation and execution of the VMP assures process reproducibility control over the applicable changes and modifications as a result in facilities, equipment, personnel, and materials.
WRITING A VALIDATION MASTER PLAN
The VMP can be written for a new or existing facility. The following unique information should be established as a minimal requirement.
For a new facility, this information is readily available and the scope of the work is easily defined. However, an existing facility may have to be assessed for vulnerability prior to planning.
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Ⅲ xv
Information
Facility specifications
Utilities specification
HVAC specifications
Major equipment list/specs.
List of major SOPs
Descriptions of processes
Personnel resumes
Design review documents
Major purchase orders
Equipment manuals
Review of audit citations
Review of past validation
Physical inspection of facility/equipment
New Facility
Existing Facility
*
*
*
*
*
*
*
*
*
*
—
—
—
*
*
*
*
*
*
*
*
*
*
*
*
*
Note: — = Not applicable.
Vulnerability Assessments
The vulnerability assessment is an organized review of validation-related vulnerabilities concerning the facility. The above objective is best achieved by an organizational multidisciplinary task force. The internal audits and past 483s should be reviewed. The existing validation documentation should focus, in addition, on the inspection of the physical facility and critical equipment.
DECISION MAKING
The development of a VMP requires several decisions. If the facility is new, due consideration is given to determine, on time, the target dates for routine production to ensure completion of validation for facility approval; otherwise manufacturing at risk is the alternative choice. The deadline determination provides ample opportunity to perform validation of utilities, critical equipment installation, and qualification prior to construction work. In addition, it provides a sufficient time frame to identify the critical processes and steps involved. The parameters critical for each step shall be established. The critical equipment required shall be determined. Critical processes, steps involved, parameters, and equipment are identified. For existing facilities, establish the criteria for revalidation based on known vulnerabilities and engineering projects in progress.
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xvi Ⅲ Pharmaceutical Master Validation Plan
In general, a key decision should be taken regarding development of the multidisciplinary team supporting the quality matrix of the VMP (i.e., adequacy of in-house personnel or is contract help necessary). The availability of validation supporting procedures is also essential. Responsibility and authority for the generation of pr otocols and their pre- and post-approval should be clear. The mechanism for reviewing and routing protocols shall be clear, including types of protocols and formats; where possible, equipment may be grouped under specific systems. The group responsible for the execution of protocols shall be identified. Above all, the final acceptance of the facility should be after the formal review by the quality function responsible.
The validation of utilities should ideally commence prior to that of support process equipment, and installation qualification prior to the operational qualification.
Define whether the facility is a new or existing one. Identify types of products or materials to be produced. Establish if any outside facility is involved as part of plan.
RESOURCE REQUIREMENT ESTIMATES
The effective execution of the VMP is based on how precisely the man-hour requirements are calculated for each task. Use input from experienced validation and engineering personnel. Consideration should be given to the time frame for protocol preparation, review, correction, and approval. Consider the analysis involved, the test equipment, and the time frame for procurement.
ELEMENTS OF VALIDATION MASTER PLAN
The elements described in the VMP are not the policy requirements.
However, they can be manipulated according to individual needs.
PLAN APPROVAL
Formal approval of the plan, indicating the top-level management for each function, is essential to share the responsibility. The VMP shall be supported with approval signatures from multidisciplinary functions, including
Engineering, Manufacturing, Quality Control, Quality Assurance, and Validation at a …show more content…
minimum.
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REASONS FOR REVISION
At the end of approvals, indicate reasons for revisions with dates for the circumstances requiring revision and reapproval.
1. Introduction. The VMP should have well-defined limits pertaining to the facility. The context of the plan should include a description of the project, definitions, validation team members, and their responsibilities. 2. Concept of qualification/validation. This takes into consideration the concept of validation life cycle for the company’s facilities, equipment and processes, documentation format, and numbering system.
3. Revalidation. Revalidation criteria shall be established and defined for facilities, equipment, processes, and utilities.
4. Facility description. The facility description addresses locations, numbers of employees covered and uncovered in area, specificity of processes and line capacities, etc.
5. Description of building. The facility description considers:
a. Facility size
b. Details of physical construction
c. Critical design criteria
d. Defined activity
e. Defined personnel flow (where applicable)
6. Equipment description. The major or critical equipment shall be identified by equipment name or asset control number. There should be a brief summary of the most relevant equipment attributes, including a brief summary of process applications if possible.
7. HVAC description. The points to be considered for utilities and
HVAC descriptions should include identification sources for all product contact utilities and all product contact utilities applications. The air handling system supporting controlled areas should be identified with air classification for all applicable areas, including diagrams or descriptions of air flow directions, design, etc.
8. Utilities description. The description of utilities shall be defined for their final quality and, where necessary, the surface quality, particularly where the product is in direct contact with the surface.
The following utilities are the most pertinent but the list is not limited to:
Deionized water
Purified water
Water for injection
Chilled water
Pure steam
Compressed air
Nitrogen
Carbon dioxide
Electric power
Potable water
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9. Validation program overview. Describe the validation group organization to establish the responsibilities of each group and/or individual. The organization of the system documents should be defined. Define project management responsibility, design review responsibility, classification of equipment, and general understanding of overall certification package (i.e., IQ, OQ, and PQ). Define contents of validation reports. Briefly describe the required protocols and their contents.
10. Calibration program summary. The instrument calibration program should describe calibration policy for validation of test equipment, pre- and post-calibration, and NIST traceability of calibration standards. The responsibility of calibration shall be defined.
11. Preventive maintenance program summary. The preventive maintenance program should be summarized for the facility with responsibility for tracking.
12. Key SOPs. The list of key standard operation procedures (SOPs) shall be included with a remark to be updated. Key procedures such as internal audit should be highlighted. Identify applicable process-related documents.
13. Validation of building. Define test functions and acceptance criteria for building finishes.
14. Validation of utility systems. Define test functions and acceptance criteria for the utilities, including workmanship.
15. Process description: dry products. The description of the processes should include a brief summary and flow diagrams for the steps involved, and describe control variables and measured responses as follows:
Process Flow Tablets
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Addition of raw materials (actives and excepients)
Pre-blending
Granulation
Drying
Sizing
Addition of lubricants and disintegrates
Blending
Tableting
Coating
Blistering
Boxing
Cartoning
Identify the product characteristics impacted at each process step and the parameters requiring validation.
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Ⅲ xix
16. Process description: liquid and semisolid products. Apply a similar approach as defined in Step 15 and as appropriate to the process requirement. 17. Process description: parenterals. Apply a similar approach as defined in Step 15 and as appropriate to the process requirement.
18. Qualification of process equipment. Define test functions and acceptance criteria for major equipment. A comprehensive list identifying the protocols required shall be finalized, or alternatively, shall be provided by the validation program overview in Step 9.
19. Validation of support processes. Define test functions and acceptance criteria for critical validation support processes such as washing of components, sterilization of components, depyrogenation, etc.
20. Quality assurance/control laboratory validation. Describe the validation approach for the laboratory equipment and test methods.
Define test functions and acceptance criteria.
21. cGMP procedures and programs. Define the following programs: engineering change control, calibration, preventive maintenance, personal training, facility cleaning and sanitization, environmental monitoring, HEPA filter integrity testing, etc.
22. Validation schedule. Provide time line chart for the on-time completion of validation tasks of equipment, utilities, processes, cleaning etc., to ensure compliance with government regulations, quality, and cost reduction.
23. Drawings. Identify all key drawings related to the civil layout, utilities, personnel flow, materials flow, etc. Assign a number to each drawing.
CD-ROM
An electronic copy of the generic Validation Master Plan is provided. See the inside back cover of this book for the CD-ROM.
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VALIDATION MASTER PLAN
APPROVAL PAGE
Issued on: mm/dd/yyyy
Written By
Supersedes: mm/dd/yyyy
Signature & Date
Name
Designation
Department
Checked & Agreed By
Signature & Date
Name
Designation
Department
Reviewed By
Signature & Date
Name
Designation
Department
Approved By
Signature & Date
Name
Designation
Department
Reasons for Revision mm/dd/yyyy First time issued for ABC Pharmaceutical
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ABOUT THE BOOK
This book and CD-ROM take into account all major international regulations, such as FDA, cGMP, GLP, GCP and industry standard ISO 9000, to be in compliance with documentation guidelines.
No other book in print deals exclusively with the key elements of a Validation Master Plan for a pharmaceutical plant and provides a hands-on template to be tailor made to achieve documentation compliance for FDA inspection.
The Validation Master Plan (VMP) is written to provide explicit instructions on how to achieve it for anyone responsible for writing and executing a VMP for drug, drug-device combination, diagnostic, pharmaceutical, biotechnology, and bulk pharmaceutical chemicals products. Included is the ready-to-use template that one can immediately use as one’s own without reinventing the wheel, thus saving time and money without missing any critical element.
This book provides instant answers to validation engineers, validation specialists, quality professionals, quality assurance auditors, and protocol writers regarding what should be made part of the VMP and how
to enhance productivity.
Introduction
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Validation Master Plan
Writing a Validation Master Plan
Vulnerability assessments
Decision making
Disclaimer
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Resource requirement estimates
Elements of Validation Master Plan
CD-ROM
Acknowledgment
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xxii Ⅲ Pharmaceutical Master Validation Plan
Master Validation Plan
Plan approval
Reasons for revision
Introduction
Project description
What is a Validation Master Plan
Scope of Validation Master Plan
Definition for the term validation
Validation team member
Validation team responsibility
Concept of qualification/validation
Fundamentals
Concept of a validation life cycle
Elements of validation
Documentation format of qualification programs
Numbering system
Revalidation
Facility description
Description of building
Dry Production facility
Liquid and semisolid production facility
Parenterals production facility
Equipment description
Dry production
Liquid and semi-solid production
Parenterals production
Over printing area
Quality assurance (in-process)
Product development laboratories
HVAC description
Dry production facility
Liquid and semi-solid production facility
Parenterals production facility
Over printing area
Quality control
Quality assurance (in-process)
Product development laboratories
Utilities description
Validation program overview
Validation project management
Validation responsibilities
Design and validability review
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Enhanced turn-over package
Installation qualification protocols
Operational qualification protocols
Change control initiation
Cycle development
Performance qualification protocol
Process validation protocols
Validation final reports
Validation package
Certificate for use in manufacturing
Required protocols and procedures for dry production
Required protocols and procedures for liquid and semisolid products Required protocols and procedures for parenterals production
Calibration program summary
Preventive maintenance program summary
Key SOPs
Validation of building
Test functions and acceptance criteria
Civil work
Drainage system
Validation of utility systems
Test functions and acceptance criteria
Plant steam
Pure steam
Water for injection
Compressed air
Nitrogen (N2)
Carbon dioxide (CO2)
Heating ventilation and air conditioning (HVAC)
Emergency power
Process description: dry products
Process flow, variables, and responses: tablets
Process flow, variables, and responses: powder for suspension
Process flow, variables, and responses: capsules
Process description: liquids and semisolid products
Process flow, variables, and responses: syrups, suspension, and drops products
Process flow, variables, and responses: cream, ointment, and suppository products
Process description: parenterals product
Process flow, variables, and responses: aseptic fill products
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xxiv Ⅲ Pharmaceutical Master Validation Plan
Process flow, variables, and responses: aseptic fill ready-to-use disposable syringes
Process flow, variables, and responses: terminal sterilization products Process flow, variables, and responses: lyophilized products
Qualification of process equipment test functions and acceptance criteria Commuting mill
Oven
V-shell blender
Tablet compression
Capsulation
Powder filling
Capsule polisher
Tablet coating
Syrup manufacturing vessel
Suspension manufacturing vessel
Drops manufacturing vessel
Mixer
Emulsifying mixer
Filter press
Cream/ointment/suppository manufacturing vessel
Syrup, suspension, and drop filling machine
Cream and ointment filling machine
Suppository filling machine
Labeling machine
Capping machine
Cartonator
Shrink wrapping machine
Over printing machine
Trays and rack washer
Autoclave (steam sterilizer)
Hot air tunnel (dry heat sterilizer)
Vials/ampoules washing machine
Vials/ampoules/syringes filling
Freeze dryer (lyophilizer)
Laminar flow unit
Pass-through
Validation of support processes test functions and acceptance criteria Washing of components
Sterilization of components
Depyrogenation of components
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Aseptic filling validation (media fill studies)
Cross-contamination control
Computerized pharmaceutical system
Quality assurance/control laboratory validation
Laboratory equipment qualification
Computer-related systems in QA/QC cGMP procedures and program
Engineering change control
Calibration
Preventive maintenance program
Standard operating procedures (SOPs)
Facility cleaning and sanitization
Environmental monitoring program
HEPA filter integrity testing
Filter integrity testing
Label control program cGMP training
Equipment logbooks, status tags, and room clearance
Validation files
Drawings/Layouts
Dry production facility
Liquid and semisolid production facility
Parenterals production facility
Deionized water system
HVAC
Water for injection
Steam distribution
Compressed air distribution
Nitrogen distribution
Drainage system
Personnel flow
Materials flow
Electrical drawings
Equipment installation drawings
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CONTENTS
Preface .................................................................................... vii
Prologue................................................................................. xiii
Validation Master Plan Approval Page .................................... xx
1 Introduction..................................................................................1
1.1
1.2
1.3
1.4
1.5
1.6
2
Project Description ................................................................................... 1
What Is a Validation Master Plan?........................................................... 2
Scope of a Validation Master Plan.......................................................... 2
Definition of the Term Validation ........................................................... 2
Validation Team Members ....................................................................... 3
Validation Team Responsibilities ............................................................. 3
Concept of Qualification/Validation ...........................................9
2.1
2.2
2.3
2.4
2.5
Fundamentals ............................................................................................ 9
Concept of a Validation Life Cycle ....................................................... 10
Elements of Qualification/Validation..................................................... 14
Documentation Format of Qualification Programs.............................. 31
Numbering System ................................................................................. 32
3
Revalidation ................................................................................35
4
Facility Description ....................................................................37
4.1 Line Capacities........................................................................................ 38
5
Description of Building .............................................................43
5.1 Dry Production Facility: Building A...................................................... 44
5.2 Liquid and Semisolid Production Facility: Building B ........................ 45
5.3 Parenterals Production Facility: Building C.......................................... 46
6
Equipment Description..............................................................47
6.1
6.2
6.3
6.4
Dry Production: Building A................................................................... 47
Liquid and Semisolid Production: Building B...................................... 49
Parenterals Production: Building C....................................................... 51
Over-Printing Area.................................................................................. 53
xxvii
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xxviii Ⅲ Pharmaceutical Master Validation Plan
6.5 Quality Control ....................................................................................... 53
6.6 Quality Assurance (In-Process) ............................................................. 54
6.7 Product Development Laboratories....................................................... 55
7
HVAC Description.......................................................................57
7.1
7.2
7.3
7.4
7.5
7.6
7.7
8
Utilities Descriptions..................................................................67
8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
8.9
8.10
8.11
9
Dry Production Facility: Building A...................................................... 57
Liquid and Semisolid Production Facility: Building B ........................ 60
Parenterals Production Facility: Building C.......................................... 62
Over-Printing Area.................................................................................. 64
Quality Control ....................................................................................... 65
Quality Assurance (In-Process) ............................................................. 66
Product Development Laboratories....................................................... 66
Deionized Water (DI Water).................................................................. 67
Purified Water ......................................................................................... 67
Water for Injection (WFI) ...................................................................... 67
Chilled Water .......................................................................................... 68
Pure Steam .............................................................................................. 68
Compressed Air ...................................................................................... 68
Nitrogen (N2) .......................................................................................... 68
Carbon Dioxide (CO2) ........................................................................... 68
Electric Power......................................................................................... 69
Sanitary Water ......................................................................................... 69
HVAC (Heating, Ventilation, and Air Conditioning) System ............... 69
Validation Program Overview ...................................................71
9.1
9.2
9.3
9.4
9.5
9.6
9.7
9.8
9.9
9.10
9.11
9.12
9.13
9.14
Validation Project Management: Organization ..................................... 71
Validation Responsibilities...................................................................... 72
Design and Validability Review............................................................. 72
Validation Documents ............................................................................ 74
Installation Qualification Protocols ....................................................... 75
Operational Qualification Protocols...................................................... 76
Change Control Initiation ...................................................................... 77
Cycle Development ................................................................................ 77
Performance Qualification Protocols .................................................... 77
Process Validation Protocols.................................................................. 78
Validation Final Reports ......................................................................... 78
Validation Package ................................................................................. 78
Certification for Use in Manufacturing ................................................. 79
Required Protocols and Procedures for Dry Production:
Building A ............................................................................................... 79
9.15 Required Protocols and Procedures for Liquid and Semisolid
Production: Building B........................................................................... 80
9.16 Required Protocols and Procedures for Parenterals Production:
Building C ............................................................................................... 81
10
Calibration Program Summary .................................................83
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Ⅲ xxix
11
Preventive Maintenance Program Summary ...........................85
12
Key Standard Operating Procedures (SOPs) ...........................87
13
Validation of Building ................................................................89
13.1
13.2
14
Validation of Utility Systems .....................................................91
14.1
14.2
14.3
14.4
14.5
14.6
14.7
14.8
15
15.3
16.2
Flow, Variables, and Responses: Tablets ........................... 102
Flow, Variables, and Responses: for Suspensions .................................................................... 103
Flow, Variables, and Responses: Capsules ........................ 104
Process Flow, Variables, and Responses: Syrup, Suspension, and Drop Products ............................................................................ 106
Process Flow, Variables, and Responses: Cream, Ointment, and Suppository Products ................................................................. 107
Process Description for Parenterals Production Facility:
Building C..................................................................................109
17.1
17.2
17.3
17.4
18
Process
Process
Powder
Process
Process Description for Liquid and Semisolid Production
Facility: Building B ...................................................................105
16.1
17
Plant Steam ........................................................................................... 91
Pure Steam............................................................................................ 92
Water for Injection (WFI) .................................................................... 93
Compressed Air .................................................................................... 95
Nitrogen (N2) ........................................................................................ 96
Carbon Dioxide (CO2) ......................................................................... 97
Heating, Ventilation, and Air Conditioning (HVAC).......................... 98
Emergency Power (Standby Generator)............................................. 99
Process Description for Dry Production Facility:
Building A..................................................................................101
15.1
15.2
16
Civil Work ............................................................................................. 89
Drainage System................................................................................... 90
Process Flow, Variables, and Responses: Aseptic Fill Products..... 110
Process Flow, Variables, and Responses: Ready-to-Use
Disposable Syringes ........................................................................... 111
Process Flow, Variables, and Responses: Terminal Sterilization
Products .............................................................................................. 112
Process Flow, Variables, and Responses: Lyophilized Products .... 113
Qualification of Process Equipment.......................................115
18.1
18.2
18.3
18.4
18.5
18.6
18.7
18.8
Commuting Mill.................................................................................. 115
Dryer ................................................................................................... 116
V-Shell Blender................................................................................... 117
Tablet Compression ........................................................................... 118
Capsulation ......................................................................................... 119
Powder Filling .................................................................................... 119
Capsule Polisher................................................................................. 120
Tablet Coating .................................................................................... 121
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Ⅲ Pharmaceutical Master Validation Plan
18.9
18.10
18.11
18.12
18.13
18.14
18.15
18.16
18.17
18.18
18.19
18.20
18.21
18.22
18.23
18.24
18.25
18.26
18.27
18.28
18.29
18.30
18.31
19
Validation of Support Processes .............................................147
19.1
19.2
19.3
19.4
19.5
19.6
20
Washing of Components ................................................................... 147
Sterilization of Components .............................................................. 148
Depyrogenation of Components ...................................................... 150
Aseptic Filling Validation (Media Fill Studies)................................. 151
Cross-Contamination Control ............................................................ 152
Computerized Pharmaceutical System.............................................. 153
Quality Assurance/Control Laboratory Validation ................155
20.1
20.2
21
Syrup Manufacturing Vessel .............................................................. 122
Suspension Manufacturing Vessel ..................................................... 123
Drops Manufacturing Vessel.............................................................. 124
Mixer ................................................................................................... 125
Emulsifying Mixer .............................................................................. 126
Filter Press .......................................................................................... 127
Cream/Ointment/Suppository Manufacturing Vessel....................... 128
Syrup, Suspension, and Drop Filling Machine ................................ 129
Cream and Ointment Filling Machine .............................................. 130
Suppository Filling Machine.............................................................. 130
Labeling Machine ............................................................................... 131
Capping Machine ............................................................................... 132
Cartonator ........................................................................................... 133
Shrink-Wrapping Machine ................................................................. 134
Over-Printing Machine....................................................................... 134
Trays and Rack Washer ..................................................................... 135
Autoclave (Steam Sterilizer) .............................................................. 136
Hot Air Tunnel (Dry Heat Sterilizer)................................................ 138
Vials/Ampoules Washing Machine.................................................... 139
Vials/Ampoules/Syringes Filling Machine ........................................ 140
Freeze Dryer (Lyophilizer) ................................................................ 141
Laminar Flow Unit ............................................................................. 143
Pass-Through ..................................................................................... 144
Laboratory Equipment Qualification................................................. 155
Computer-Related Systems in the QA/QC Laboratory.................... 156
cGMP Procedures and Programs ............................................157
21.1
21.2
21.3
21.4
21.5
21.6
21.7
21.8
21.9
21.10
21.11
21.12
Engineering Change Control ............................................................. 157
Calibration........................................................................................... 157
Preventive Maintenance Program ..................................................... 158
Standard Operating Procedure (SOPs)............................................. 158
Facility Cleaning and Sanitization..................................................... 159
Environmental Monitoring Program ................................................. 159
HEPA Filter Integrity Testing............................................................. 159
Filter Integrity Testing........................................................................ 160
Label Control Program ...................................................................... 160 cGMP Training.................................................................................... 161
Equipment Logbook, Status Tags, and Room Clearance Checklists.... 161
Validation Files ................................................................................... 161
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22
Validation Schedule ..................................................................163
23
Drawings for ABC Pharmaceutical Plant ...............................165
Recommended Reading....................................................................169
Index..................................................................................................171
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SL3305_C01_fm Page 1 Thursday, November 8, 2001 3:09 PM
1
INTRODUCTION
1.1
PROJECT DESCRIPTION
This Validation Master Plan (VMP) specifies and coordinates all qualification/validation activities to ensure the production of pharmaceutical products according to accepted international standards. It also specifies the responsibilities for validation procedures and helps to plan the necessary activities.
The plant is designed to produce oral solid dosage forms as well as liquid dosage forms, ointments, creams, suppositories, and sterile injectable products.
The production of each product group is divided into the processing stages listed below. The general production stages for all products are:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Receipt of raw materials and sampling
Interim storage of raw materials
Weighing
Manufacturing
Packaging
Storage of finished product
Dispatch
1
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2 Ⅲ Pharmaceutical Master Validation Plan
To ensure the manufacturing of pharmaceutical products in ABC Pharmaceutical according to international standards, there are several guidelines that are considered for the planning, construction, start-up, and validation of the buildings, equipment, and processes.
1.2
WHAT IS A VALIDATION MASTER PLAN?
A Validation Master Plan (VMP) is a comprehensive document describing the applicable validation requirements for the facility, and providing a plan for meeting those requirements.
1.3
SCOPE OF A VALIDATION MASTER PLAN
The Validation Master Plan (VMP) includes all relevant aspects relating to the production of pharmaceuticals in the production facility at ABC Pharmaceutical. The principles of validation, the organization of qualification and validation, and the design and nomenclature of the documentation and equipment are also described. The VMP covers all facilities used in the production of tablets, liquids, ointments, creams, suppositories, and sterile products; the facilities for storing raw materials, interim and finished products, storage, services, and the rooms for staff.
1.4
DEFINITION OF THE TERM VALIDATION
Validation is documented evidence that provides a high degree of assurance that a specific process will consistently produce a product that meets its predetermined specifications and quality attributes.
After the requirement for each aspect is determined, the responsible engineers complete the design and it is again reviewed by the validation team. After the approved designs are constructed and/or installed, the validation cycle continues with the preparation and execution of the validation documents.
Validation is a systematic approach to gathering and analyzing sufficient data that will give reasonable assurance (documented evidence), based on scientific judgment, that a process, when operating within specified parameters, will consistently produce results within predetermined specifications.
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Introduction
˙1.5
Ⅲ 3
VALIDATION TEAM MEMBERS
Members
Validation Manager,
Quality Assurance Department
Member from Production
Member from Engineering (Utilities)
Qualification a
Note: Qualification must be in accordance with the job requirement in combination with experience. Member from Calibration Laboratory
Member from Quality Control
Laboratory
Member from Maintenance
Member from HVAC Department
Member from Product Development
Laboratory
a
The resumes of validation team members are presented in a separate folder, including contract help.
1.6
VALIDATION TEAM RESPONSIBILITIES
Validation is a team effort that generally requires the involvement and close interaction of Quality Assurance, Production, Packaging, and Maintenance with other appropriate support such as Product Development and Quality Control. The validation team should include representatives from the above-mentioned departments to provide the necessary expertise and guidance.
The validation activities within the validation life cycle should be carried out according to the scheme shown in Figure 1.1. The documentation of the validation process is carried out in the form of programs that must be developed by the qualification/validation teams. These programs must be approved by the review team. After approval, the validation activities can start and a report of the activities must be produced. The approval of this report must be given by the same people who approved the program.
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4 Ⅲ Pharmaceutical Master Validation Plan
ValidationTeam
(Review-Team)
ValidationRepresentative
QualificationTeam
ProcessValidationTeam
CleaningValidationTeam
ComputerValidationTeam
External
Validation
Service
Figure 1.1 Organization chart.
If test procedures do not fulfill acceptance criteria, the review team must decide whether or not tests must be repeated or test specifications must be edited. The review team can decide whether or not test results, even if they will not fulfill acceptance criteria, should be accepted as
“within specification.” (See Figure 1.2.)
The teams shown in the organization chart (Figure 1.1) should consist of personnel in the following positions:
Validation team (Review team):
Head of validation
Head of quality assurance
Validation representatives
Validation representative:
Person appointed by the validation team
Qualification/validation teams:
Personnel from different manufacturing areas. The size of the teams varies with the scope of the activities necessary. Personnel from external validation services may be included.
External validation service:
External qualified personnel who support the qualification/validation teams if necessary.
Control of Validation Documents
The person identified for overall validation activities during the validation process is responsible for validation documents. Other departments have
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Introduction
Ⅲ 5
Work Out the ValidationProgram
Team
Testing +
Approving
ReviewTeam
Editing
ValidationTeam
No
OK?
Yes
Carry Out the ValidationProgram
Team
Yes
Acceptance
Criteria
Fulfilled?
No
Check of Test
Specification
ReviewTeam
Repeat Test
Procedure?
Yes
No
No
Approval
of Reports
ReviewTeam
Edit Test
Specifications?
Yes
Figure 1.2 Testing and approving procedures.
access to these documents during the validation process so that they can further develop validation documentation. At the end of all validation activities, the documents are stored and controlled by the validation responsible. The updating of documentation is done during the Change or Revalidation procedure. This is also valid for documents from external validation services. The validation responsible is responsible for the distribution of updated documents.
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6 Ⅲ Pharmaceutical Master Validation Plan
The Engineering department is responsible for the technical documentation, for example, manuals, inspection reports, maintenance reports, specification sheets, etc. These documents are stored and updated by personnel from this department.
Quality Assurance
Validation officers from Quality Assurance (QA) coordinate the entire validation process by scheduling meetings and discussions with the validation team, preparing the validation protocols, monitoring the validation process, compiling and analyzing validation data and test results, and preparing the Final Report. All documentation associated with validation should be reviewed by the QA Manager for completeness and compliance with cGMP requirements.
Production
A validation team member from the Production department is responsible to participate in performing the validation steps during manufacturing processes and equipment qualification. This department should prepare the necessary SOPs for the new process or equipment and assist in the collection of validation data.
Packaging
A validation team member from the Packaging department is responsible to participate in performing the validation steps during packaging processes and equipment qualification. The Packaging department should prepare the necessary SOPs for the new packaging process or equipment and assist in the collection of validation data.
Utilities/Calibration/HVAC
A validation team member from the Maintenance department participates in performing the validation; defining the necessary equipment specifications, limitations, capacity, calibration, and maintenance requirements; and providing the necessary training on the proper operation and maintenance of the equipment. The Maintenance department should be responsible for providing the necessary utilities and equipment accessories.
In some cases, the Maintenance department is required to participate in equipment installation and operational qualifi cation and provide technical support to ensure proper and efficient function during the validation process.
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Introduction
Ⅲ 7
Quality Control
A validation team member from the Quality Control department is responsible for providing the necessary support for sampling, testing, and reporting of test results for validation. A support group in Quality Control should also perform the microbiological testing and environmental monitoring during the validation process.
Product Development Laboratory
A validation team member from Product Development Laboratories is responsible for defining the process (new product or process) to be validated and for providing technical assistance to the validation team by defining specifications, limits, and manufacturing methods.
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2
CONCEPT OF
QUALIFICATION/VALIDATION
2.1
FUNDAMENTALS
The aim of production facilities and processes qualification/validation in the ABC Pharmaceutical facility is to establish and provide documentary evidence that:
Ⅲ The facilities, equipment, and processes have been designed in accordance with the requirements of current GMP.
Ⅲ The facilities and the equipment have been built and installed in compliance with their design specifications.
Ⅲ The facilities and equipment operate in accordance with their design specifications to repeatedly and reliably produce a finished product of the required quality.
To fulfill these requirements, a complete program for validation has been developed for ABC Pharmaceutical Company to ensure that all processes and equipment affecting the quality, integrity, safety, and efficacy of the pharmaceutical product are qualified and validated.
With the successful conclusion of validation, the ABC Pharmaceutical
Company management can prove that all pharmaceutical products produced in the validated plant are unobjectionable, suitable for use, and correspond to the requirements of the product licence.
The concept of validation in this master plan covers the following fields of activity.
Ⅲ Qualification of buildings, rooms, and supply systems
Ⅲ Qualification of equipment and service units
Ⅲ Validation of computer systems
9
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10 Ⅲ Pharmaceutical Master Validation Plan
Ⅲ Validation of production processes
Ⅲ Validation of cleaning processes
Ⅲ Periodic revalidation within the scope of a change control plan
All necessary activities and responsibilities for the qualification and validation are controlled and specified in this Validation Master Plan. Every step of the described validation program for facilities, equipment, processes, process controls, and cleaning is in accordance with the current
European Community Guidelines for GMP and FDA, and the cGMP guideline for finished pharmaceutical manufacturers. All requirements in these directives are fulfilled in this validation process.
In manufacturing facilities, validation test procedures are used to validate equipment and processes that may influence product quality. The tests for validation are used in accordance with approved written qualification procedures. The approval for these procedures is given by representatives from Quality Management, Production, and Engineering. During realization of this program, all activities will be documented so that the plant operates in accordance with the requirements of cGMP and within design specifications. At the end of the program, a review team will verify and approve the documented results.
The Validation Report will be the final document of all validation activities. The Validation Report includes the reports for:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Qualification
Computer validation
Process validation
Cleaning validation
To ensure a continuous validation status of facilities, processes, and process controls, continuous monitoring of the normal production conditions is necessary — as is the maintenance, calibration, and revalidation of the validated systems.
2.2
2.2.1
CONCEPT OF A VALIDATION LIFE CYCLE
Prospective Validation Life Cycle
Establishing documented evidence prior to process implementation that a system does what it proposed to do based on preplanned protocols.
The life cycle for prospective validation is divided into the following steps (Figure 2.1):
1. Validation Master Plan (VMP)
2. Design Qualification (DQ)
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Concept of Qualification/Validation
3.
4.
5.
6.
7.
8.
9.
10.
11.
Ⅲ 11
Risk Analysis (RA)
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
Process Validation (PV)
Cleaning Validation (CLV)
Computer Validation (CV)
Validation Report (VR)
Revalidation (ReV)
Each prospective validation step will be described in Qualification/Validation documents. In these documents, except for the Validation Master
Plan and the Validation Report, the test methods for validation and acceptance criteria for the results are specified. Also described are whether the equipment has to be prepared for the test method and whether the original status of the equipment has to be restored after testing.
VALIDATION MASTER PLAN
Risk
Analysis
Design
Qualification
Revalidation
Installation
Qualification
Operational
Qualification
Monitoring
Maintenance
ChangeControl
Performance
Qualification
Cleaning
Validation
Process
Validation
Computer
Validation
VALIDATION REPORT
Figure 2.1 Prospective validation life cycle.
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12 Ⅲ Pharmaceutical Master Validation Plan
2.2.2
Retrospective Validation Life Cycle
The retrospective validation is used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process. Validation of these facilities, processes, and process controls is possible using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do.
Therefore, this type of validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of product, operating processes, or equipment. In each case of retrospective validation it must be decided which elements of the validation life cycle (Figure 2.2) should be used. In general, the design qualification is left out of the retrospective life cycle.
Actual
Survey
VALIDATION MASTER PLAN
Risk
Analysis
Revalidation
Installation
Qualification
Monitoring
Maintenance
ChangeControl
Operational
Qualification
Performance
Qualification
Cleaning
Validation
Process
Validation
VALIDATION REPORT
Figure 2.2 Retrospective validation life cycle.
Computer
Validation
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Concept of Qualification/Validation
Ⅲ 13
The life cycle for retrospective validation is divided into the following steps:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
2.2.3
Actual survey of facilities, processes, and process controls
Validation Master Plan (VMP)
Design Qualification (DQ)
Risk Analysis (RA)
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
Process Validation (PV)
Cleaning Validation (CLV)
Computer Validation (CV)
Validation Report (VR)
Revalidation (ReV)
Concurrent Validation Life Cycle
Concurrent validation is used for establishing documented evidence that a facility and processes do what they purport to do, based on information generated during actual imputation of the process.
The life cycle for concurrent validation is divided into the following steps (Figure 2.3):
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Validation Master Plan (VMP)
Design Qualification (DQ)
Risk Analysis (RA)
Installation Qualification (IQ)
Operational Qualification (OQ)
Performance Qualification (PQ)
Process Validation (PV)
Cleaning Validation (CLV)
Computer Validation (CV)
Validation Report (VR)
Revalidation (ReV)
Each concurrent validation step will be described in Qualification/Validation documents. In these documents, except for the Validation Master
Plan and the Validation Report, the test methods for validation and acceptance criteria for the results are specified. Also described are whether the equipment has to be prepared for the test method and whether the original status of the equipment has to be restored after testing.
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14 Ⅲ Pharmaceutical Master Validation Plan
VALIDATION MASTER PLAN
Design
Qualification
Revalidation
Installation
Qualification
Monitoring
Operational
Maintenance
Qualification
ChangeControl
Performance
Qualification
Cleaning
Validation
Process
Validation
Computer
Validation
VALIDATION REPORT
Figure 2.3 Concurrent validation life cycle.
2.3
2.3.1
2.3.1.1
ELEMENTS OF QUALIFICATION/VALIDATION
Design Qualification (DQ)
Definition
During design qualification (DQ), it is documented that the design aspects of the ABC Pharmaceutical plant have been checked and approved. The design qualification contains a plant description and shows that the plant design agrees with the design specifications of the customer. Design aspects that were not defined during design specification and that are not yet defined (i.e., when design qualification begins) must be listed and evaluated with respect to their influence on product quality.
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Concept of Qualification/Validation
Ⅲ 15
Within the design qualification process, the design is checked to ensure that the important aspects of GMP are fulfilled and compliance with these important GMP aspects is documented. In the definition of the design qualification as well as in the further stages of the DQ process, all qualified personnel from various departments of the company must be involved.
The involvement of qualified personnel is important in the process of design qualification as well as in the definition of tests that must be performed; for example, checking the technical and phar maceutical demands. In subsequent stages of the validation process, the involvement of these qualified personnel will not be required to such a large extent.
In this Validation Master Plan, Chapter 9 shows the qualification matrix.
This matrix indicates the facilities for which a design qualification must be produced. Normally, when not otherwise specified, a design qualification is produced for all buildings, rooms, and process plants. However, when plants are to be validated retrospectively, no design qualification process occurs.
2.3.1.2
Contents
The Design Qualification should be divided into the following sections:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
History of DQ
Fundamentals
Purpose
Implementation procedure
Acceptance criteria
Tests specification
Summary of DQ evaluation
Additional design aspects
The basis of the DQ is the design specification of ABC Pharmaceutical.
The DQ is done by the personnel responsible from the ABC Pharmaceutical Company and the plant designers. The design specifi cations demanded by the customer are compared with the actual design of the plant. Written evidence of this comparison is produced which confirms whether or not the actual design agreed with the customer’s design specifications. Once the DQ is approved, the status of the design specifications is frozen. From this point on, the DQ and the specifications are under the control of change management.
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16 Ⅲ Pharmaceutical Master Validation Plan
2.3.2
Risk Analysis (RA)
2.3.2.1
Definition
The purpose of validation is to obtain written evidence that processes and equipment work within their specifications to produce products of the demanded quality. However, when working with processes and equipment, there are always risks that may or may not be acceptable.
To prove whether or not possible risks are acceptable for the product quality, a risk analysis (RA) must be done. The purpose of the RA is to identify critical and noncritical parts of processes and equipment. This risk analysis also identifies the activities necessary for validation, maintenance, and calibration.
The RA must be done for prospective as well as retrospective validation processes. For a realistic opinion of possible risks to be obtained and to cover the most relevant aspects, it is necessary to involve qualified personnel with different specialist knowledge in the process of RA. For example, Quality
Control personnel, Production personnel, Engineering personnel, etc.
In this Validation Master Plan, Chapter 9 shows the qualification matrix.
This matrix indicates the processes and parts of the plant for which an
RA must be produced.
2.3.2.2
Contents
The risk analysis should be divided into the following sections:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
History of RA
Fundamentals
Purpose
Implementation procedure
Participants
Risk analysis
2.3.2.3
Risk Analysis Procedure
The RA is systematically carried out by personnel/departments specified in Section 1.5 of this master plan. Documents used for the analysis of processes and equipment might include:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
P&I diagrams
System descriptions
Manufacturer’s documentation
Recordings from logbooks, batch documents, etc. (for plants in use)
Literature
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Concept of Qualification/Validation
Ⅲ 17
The RA procedure is divided into the following steps:
1.
2.
3.
4.
5.
6.
List of all parts of the plant and their functions
Classification (critical or noncritical)
Reason for classification
Possible influence on quality parameters
Estimation of failure probability
List of measurements taken
2.3.3
Installation Qualification (IQ)
2.3.3.1
Definition
In the installation qualification (IQ) process, written evidence is given that all parts of the equipment are installed according to the equipment supplier’s and purchase specifications. For complicated or large pieces of equipment, it may be decided to undertake a predelivery check of the equipment at the supplier’s assembly facility. This predelivery check will also be part of the IQ. It is documented that the operating criteria for the equipment, as installed, are in compliance with the P&I diagrams, plant functional specifications, and process flow diagrams.
The IQ represents the status of the plant where the completeness and correctness of all required documents are checked. At this point, if necessary, documents must be completed and corrected.
In the case of retrospective validation, processes and purchase specifications as well as manuals from the manufacturer of equipment are rarely available. Therefore, the IQ is, for many parts, equivalent to the actual survey of the plant and uncompleted documentation can be replaced by the IQ documentation.
The IQ refers as often as possible to engineering documents (e.g., P&I diagrams, plant functional specifications, process flow diagrams, inventory lists, etc.) to avoid redundant documentation and to minimize the expenditure of updating.
2.3.3.2
Contents
The IQ procedure is divided into the following steps:
1.
2.
3.
4.
5.
6.
History of the IQ
Fundamentals
Purpose
Implementation procedure
Identification of signatures
Acceptance criteria
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18 Ⅲ Pharmaceutical Master Validation Plan
7. Description of the systems
8. Specification of tests
9. Results of the tests
The specifications of the test procedures should be divided into the following sections:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Check completeness and current status of documentation
Check delivered equipment from manufacturer
Check if all parts of the plant are according to their specifications
Check the identity of all parts of the plant
Visual check of complete and craftsmanship installation of all parts of the plant
Ⅲ Check if materials used are within their specifications
2.3.3.3
IQ Process and Documentation
In the IQ process, the first documents to be written are the IQ programs.
Persons responsible for the release of IQ programs are identified in
Chapter 9. An auditor and a witness carry out the test procedures given in the approved IQ programs. During the test procedures, the auditor will decide whether or not the tests’ acceptance criteria are fulfilled. The witness certifies by signature that the test procedures are carried out by the auditor in accordance with their test specifications. If the IQ programs are filled in with all results of the test procedures, they become the IQ report. The persons named in Section 1.5 will approve the IQ reports again, and they become the final IQ documents.
2.3.4
2.3.4.1
Operational Qualification (OQ)
Definition
During the OQ process, documented evidence is given that all parts of the plant and equipment work within their specifications and process parameters are within the acceptance criteria. Process controls that are part of the equipment (e.g., PLC [programmable logic controller]) will be qualified during the OQ process. Computerized process controls (i.e., for complex processes) should be qualified in the Computer Validation (CV) process. To ensure that the systems tested during OQ are doing what they are believed to do, a simulation of normal production conditions must be done.
The given definition of OQ is valid for retrospective validation as well as for prospective validation.
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Concept of Qualification/Validation
Ⅲ 19
SOPs for use, maintenance, calibration, and cleaning of the plant must be developed during the OQ process, as well as schedules for maintenance and calibration. Each OQ document contains a list of required SOPs for the use of the plant. At this point, training of the technical staff of the plant should take place. The training must be documented and checked using prepared forms. Within the OQ process, the calibration of measuring and controlling devices must be checked. Critical parameters and circumstances identified in the risk analysis (RA) must be checked for conformity to the acceptance criteria.
The OQ refers as often as possible to start-up protocols and engineering documents (e.g., P&I diagrams, plant functional specifications, process flow diagrams, inventory lists, etc.) to avoid redundant documentation and to minimize the expenditure of updating.
2.3.4.2
Contents
The OQ procedure is divided into the following steps:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
History of the OQ
Fundamentals
Purpose
Implementation procedure
Description of the systems
Measuring instruments
Services of the processes
Consumables
Specification of tests
Results of the tests
Malfunction protocol
To avoid extensive documentation, the specifications of the test procedures in OQ should be divided into sub-sections as in the IQ procedure.
An example of some essential sections is given below.
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Purpose of test specification
Required equipment
Preparative measures
Testing procedures
Acceptance criteria
Data to be recorded
Additional measures
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20 Ⅲ Pharmaceutical Master Validation Plan
2.3.4.3
OQ Process and Documentation
To start the OQ process for a given part of the plant, it is necessary that the IQ process for this part has been completed. As in the IQ process, the first documents that must be written in the OQ process are the OQ programs. The persons named in Section 1.5 and Chapter 9 give the approval/release of these OQ programs. The test procedures given in the approved OQ programs are carried out by an auditor and a witness. During test procedures, the auditor will decide whether or not the tests acceptance criteria are fulfilled. The witness certifies by signature that the test procedures are carried out by the auditor in accordance with their test specifications. If the OQ programs are filled in with all results of the test procedures, they become the OQ report. The OQ reports will be approved again by the persons named in Section 1.5 and
Chapter 9 and they become the final OQ document.
2.3.5
2.3.5.1
Performance Qualification (PQ)
Definition
The PQ process provides documented evidence that all parts of the plant and the processes validated produce products of the specified quality under conditions of normal production for a longer period of time. It is shown that product quality is within the specifications as long as the quality of raw materials stays within specification. The PQ includes critical variable studies, for example, by simulating conditions of upper and lower processing, processing at the operating limits of the equipment, or circumstances like worst-case conditions. It is shown that such conditions should not necessarily induce process or product failure.
In contrast to the OQ procedures where all parts of the plant and equipment are qualified separately, the PQ procedures qualify the entire plant with respect to the production process. The definition given for PQ is valid for retrospective validation as well as for prospective validation.
While carrying out PQ processes, all necessary SOPs (e.g., for the use or cleaning of the plant) should be approved. Values of critical and noncritical process parameters recorded during PQ must be collected to evaluate the efficiency and performance of the plant.
In this Validation Master Plan, the qualification matrix is presented in
Chapter 9. This matrix indicates processes and parts of the plant for which a PQ must be produced.
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2.3.5.2
Ⅲ 21
Contents
The PQ procedure is divided into the following steps:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
History of the PQ
Fundamentals
Purpose
Implementation procedure
Description of the systems
Measuring instruments
Services of the processes
Consumables
Specification of tests
Results of the tests
Malfunction protocol
For the same reasons as in the OQ, the specifications of the PQ test procedures should be divided into sub-sections. Some essential sections are listed below.
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Purpose of test specification
Required equipment
Preparative measures
Testing procedures
Acceptance criteria
Data to be recorded
Additional measures
2.3.5.3
PQ Process and Documentation
The OQ procedures must be completed before starting the PQ process.
The PQ process and documentation are carried out in a similar manner to the OQ process. As in OQ documentation, the PQ documents are the
PQ programs, the PQ report, and the approved final PQ document. With this, document qualification of the plant is completed.
At this point, a summary of the activities during DQ, RA, IQ, OQ, and PQ must be written and qualification activities remaining open should be listed.
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22 Ⅲ Pharmaceutical Master Validation Plan
2.3.6
2.3.6.1
Process Validation (PV)
Definition
Process Validation (PV) ensures and provides documented evidence that processes within their specified design parameters are capable of repeatedly and reliably producing a finished product of predetermined quality.
The PV process is divided into the steps shown in Figure 2.4. First, a plan for the process validation must be developed. This process validation plan (PV plan) regulates the validation procedures for the manufacturing processes for each product. The process validation program is a single document and contains the specifications and test procedures for each single product. The process validation report contains the results of each validation program. In contrast to PQ documentation, where the program and report are together in one document, the validation program and report of PV are stated in two different documents. A summary of all PV activities is given in the final PV document at the end of the PV process.
Process validation plan
(PV-plan)
PVprogram 1
PVprogram 2
PVprogram 3
PV- report 1
PV- report 2
PV- report 3
Final PV document Figure 2.4 The PV process.
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2.3.6.2
Ⅲ 23
Contents of PV Plan
The PV plan contains several essential sections, for example, the points listed below:
Ⅲ Which manufacturing processes must be validated (product matrix)
Ⅲ Which kind of validation (prospective, retrospective, or concurrent) must be done
Ⅲ Schedule of the validation of product processes
Ⅲ Number of batches that must be used for validation (normally 3 to
10 batches of the quantity assigned for production)
Ⅲ Responsibilities
2.3.6.3
Contents of PV Program
The following points should be included in the Process Validation program:
Ⅲ History of development and a description of the product (if available, the development report would be useful)
Ⅲ A manufacturing procedure and flowchart of the manufacturing process Ⅲ A list of all equipment required for production
Ⅲ A list of production stages that may be critical for product quality
Ⅲ A schedule for PV test procedures
Ⅲ A detailed description for all test procedures, including:
– Sampling procedure
– Labeling of the samples
– Test procedure
– Evaluation procedure
– Specifications for the intermediate and finished products
– Acceptance criteria
Ⅲ Responsibilities
2.3.6.4
PV Process and Documentation
All qualification procedures for equipment and services of the manufacturing process must be completed before starting the PV process. A manufacturing process achieves the status of “validated” if all batches defined in the PV plan fulfill the specifications for the intermediate and finished products.
Schedules and other requirements for the PV process and documentation are stated in the PV plan document.
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24 Ⅲ Pharmaceutical Master Validation Plan
2.3.7
2.3.7.1
Cleaning Validation (CLV)
Definition
During the CLV process, written evidence is given that specified cleaning procedures will lead to reliable and repeatable results in the cleaning of surfaces with and without contact with the product. It is shown that the following criteria will be fulfilled if cleaning procedures are used as specified in cleaning SOPs:
Ⅲ The concentration of active substances on product contact surfaces will not exceed specified limits.
Ⅲ The concentration of highly active substances (e.g., hormones or cytostatics) on surfaces without contact with the product will not exceed specified limits.
Ⅲ The concentration of other pharmacologically active substances (e.g., process and cleaning materials or disinfectants) in the product to follow will not exceed specified limits
Ⅲ The number of germs on product contact surfaces will not exceed specified limits.
The procedures within the CLV process must be specified in a CLV plan. Cleaning procedures for products and processes that are very similar do not need to be individually validated. It is acceptable to select a representative range of similar products and processes and then to justify a validation program that addresses the critical issues relating to the selected products and processes. A single validation study can be carried out that takes into account the relevant criteria. This practice is termed
“bracketing.” The criteria for the bracketing of products and processes must be given in the CLV plan.
For nondedicated multi-purpose equipment (i.e., equipment for the production of products from different defined product groups), the cleaning procedures must be validated for each and every product group. For single-purpose equipment (i.e., equipment for the production of one single product), it is acceptable to visually confirm that the equipment is clean after batch-to-batch cleaning procedures. The validation of these procedures is not necessary, but it must be established that the equipment is microbiologically clean after these cleaning procedures and the stability of the product due to the reduced cleaning. For products that decompose into intermediate or final products, acceptance criteria for the concentration of degradation product on the equipment inside surface must be given to ensure that all validation requirements are fulfilled. The development and
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Concept of Qualification/Validation
Ⅲ 25
validation of cleaning procedures are usually part of product development and therefore should be validated prospectively.
Figure 2.5 illustrates the steps of the CLV process. The different programs represent the selected brackets of products.
2.3.7.2
Contents of CLV Plan
The CLV plan should contain essential sections for example the points listed below:
Ⅲ Which manufacturing processes must be validated (product matrix)
Ⅲ Which kind of validation (prospective, retrospective or concurrent) must be done
Ⅲ Schedule of the validation of product processes
Ⅲ Number of batches that must be used for validation (normally three to ten batches of the quantity assigned for production)
Ⅲ Responsibilities
Cleaning
validation plan
(CLV-plan)
CLVprogram 1
CLVprogram 2
CLVprogram 3
CLV- report 1
CLV- report 2
CLV- report 3
Final CLV document Figure 2.5 The CLV process.
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26 Ⅲ Pharmaceutical Master Validation Plan
2.3.7.3
Contents of CLV Program
The following points should be included in the Cleaning Validation program:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Purpose of validation
Responsibilities
Composition of the product (formulation)
A short master formula
A description of:
– Substance that should be detected
– Cleaning procedure
– Sampling method
– Analytical method used
– Evaluation method used for the result
– Acceptance criteria
Description of the plant to be cleaned and of the sampling locations
Description of the sampling procedure
Time between end of production and sampling
Number of test runs (test runs must be performed by qualified personnel only)
Description of procedures necessary in the case of exceeded acceptance criteria
As in the PV process, the CLV program and CLV report are two separate documents. A final CLV document summarizes the results of all CLV activities. 2.3.7.4
Bracketing of Products and Equipment
As shown above, similar products can be validated together on the same equipment by selecting representative products for the validation procedure (“bracketing”). The Cleaning Validation procedures must be carried out according to the critical parameters of these products.
Criteria for the selection of a representative range of similar products include: Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Identical dosage form
Identical manufacturing process
Similar formulation
Properties of active substances
Similar therapeutical efficacy
Toxicity
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Concept of Qualification/Validation
Ⅲ 27
As with similar products, the production plants should be divided into similar plants. Plants with similar layouts and functionalities should be selected, and representative plants should be used to carry out the Cleaning
Validation procedures. Essential for this type of bracketing is that the selected plants will be cleaned in exactly the same way, that is, according to the same cleaning SOP.
2.3.8
Computer Validation (CV)
Validation of computerized systems differs from the validation processes previously described because of the complexity and key-function in the process controls of such systems. Therefore, computer validation has a special life cycle (system development life cycle [SDLC]) that contains the hardware and the software. The sub-sections of the SDLC are similar to the subsections of the life cycles for prospective/retrospective validation processes.
2.3.8.1
Definition
The CV provides documented evidence that processes controlled by computerized systems are checkable and produce the specified product quality repeatedly and reliably.
The life cycle for computer validation (SDLC) contains planning, specification, programming, testing, start-up, documentation, operation, checking, and changing. To validate the software according to the requirements given above, the following activities should be part of the SDLC:
Ⅲ Documentation
– Project plan/application
– Quality plan
– User requirements
– Functional specifications
– User manual
– System operator manual
Ⅲ SDLC document standards
Ⅲ Risk analysis
Ⅲ Coding modules/setting of parameters/configuration
Ⅲ Planning and performing module and integration tests
Ⅲ Software installation
Ⅲ Planning and performing acceptance tests
Ⅲ Validation report/release
Ⅲ Putting out of action
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28 Ⅲ Pharmaceutical Master Validation Plan
The comprehensive activities that must be considered for the points listed above include:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Management of configuration
Failure investigation and corrective activities
Change control
Training
Responsibilities
Planning and performing of audits
Planning and performing of reviews
The life cycle for the hardware is divided into the following steps:
1. Obtaining and Installation
2. Operation
3. Putting out of action
The physical conditions in the computer systems’ surroundings could have an effect on the operation. Therefore, these conditions must be controlled or protective measures must be taken. The physical quantities that must be controlled include:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Temperature
Humidity
Voltage stability
Smoke
Controls and protective measures must be considered during planning or modification of all rooms with computerized systems for the following factors: Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Aggressive gases
Voltage fluctuation
Flash of lightning
Fire
Water
Vibration
Electrostatic charge
The range of controls and protective measures should be specified for each system separately according to the sensitivity of the system and the associated risk.
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Concept of Qualification/Validation
Ⅲ 29
The Validation Report is the final document of all validation activities.
It summarizes the essential parts of the activities and marks the end of the validation process. Separate reports for the validation sub-sections listed below must be written.
2.3.9
Validation Report
2.3.9.1
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Definition
Qualification
Process validation
Cleaning validation
Computer validation
Includes: DQ, RA, IQ, OQ, PQ
PV
CLV
CV
The Validation Report refers to these sub-sections.
2.3.9.2
Contents
A detailed discussion of the following points should be included in the
Validation Report:
1. Changes and deviations of the qualification/validation activities from the documentation must be listed. The measures taken instead must be justified and incomplete measures must be listed.
2. Critical points found during qualification/validation that are not included in the risk analysis must be listed and the measures taken described. 3. The Validation Report must include an overview of all documentation, including appendices.
4. At the end of the Validation Report, a statement must be given as to whether or not the equipment and the processes have the status
“qualified/validated.”
2.3.10
General Acceptance Criteria
The general acceptance criteria for the tests during IQ, OQ, and PQ processes are listed in subsequent chapters. Specific acceptance criteria that belong to individual test procedures are listed in each separate qualification document.
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30 Ⅲ Pharmaceutical Master Validation Plan
2.3.10.1
Installation Qualification
1. All parts of the plant must be produced and installed according to approved documents from the manufacturer. These could be:
a. Process and service flow sheets
b. Construction/P&I diagrams
c. Layout and installation specifications
d. Manufacturer’s manuals and statements
2. All documents listed must be available.
3. All critical parameters, equipment models, capacity, and material must be checked and proved against approved construction and order specifications.
4. The performance of electrical devices must be checked.
5. Manuals and lists of spare parts must be available.
6. Results of equipment test runs by the manufacturer must be satisfactory. 2.3.10.2
Operational Qualification
1. Tests must be done according to approved plans for testing and using suitable test procedures.
2. Automatic systems (e.g., locks, alarms, or timers) that are connected to systems to be validated must work according to their approved design specifications.
3. All systems and equipment parts must work reliably under normal plant operating conditions.
4. The operating status of systems that contain programmable process controls as part of the equipment must be equivalent to the status defined in the program.
5. Indicating and recording instruments used in test procedures and normal operation must be calibrated by qualified personnel.
6. The first draft of SOPs for normal operation, control, and maintenance must be available.
7. The first calibration of measurement and control devices must be checked. 8. Operational staff must be trained in their areas of responsibility.
2.3.10.3
Performance Qualification
1. The system must operate within the specifications for a longer period of time.
2. Samples must have the specified quality.
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Concept of Qualification/Validation
2.4
Ⅲ 31
DOCUMENTATION FORMAT OF QUALIFICATION
PROGRAM
2.4.1
The Coversheet
The coversheets of the different qualification programs should be designed as follows.
The header contains the name of the pharmaceutical manufacturer, the specific plant name, and the document number.
ABC
ABC Pharmaceutical Company
Doc.-No.:
Each coversheet should contain the following points below the header:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Title
Area of application
Number of pages
Version number
The author as well as the person approving the document should be named in the next section of the coversheet. The position of these persons should also be given. All following pages should contain the number of pages and the current page number within the header.
2.4.2
Document Structure
The documentation of each qualification procedure is divided into two sections. The first section is a general section that includes, for example, the coversheet, the history, the table of contents, and all other points except for the test specifications and the results of the tests. The second section includes the test specifications and the results of the tests. Each test specification should be listed in the table of contents.
2.4.2.1
Header Test Specification
The structure of the test specification header is the same as the header of the general section except for the number of pages. The pages of each test specification should be counted separately so that the page number
Z represents the pages of a single test specification.
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32 Ⅲ Pharmaceutical Master Validation Plan
2.4.3
Change of Documents
If it is necessary to edit or remove test specifications from the documentation, this should be done according to the following procedure.
1. The version number of the test specification should be increased by one after the specification is edited (i.e., version V01 becomes version V02).
2. The results of the test should be updated.
3. The version number of the general section should be increased by one.
4. The history should be updated.
5. The table of contents should be updated.
6. The changes should be approved by qualified personnel by signature on a new coversheet. (The approval is valid for the changes only.)
Each qualification document could contain sections/specifications with different version numbers.
2.5
2.5.1
NUMBERING SYSTEM
Numbering System for Equipment
To identify the main parts of the plant and equipment, a numbering system is used based on the ABC Pharmaceutical Equipment Code.
2.5.2
Numbering System for Validation/Qualification Documentation
The purpose of a numbering system for the documentation is to ensure an unambiguous identification of each validation/qualification document produced within the field of application of the Validation Master Plan.
The document number is a combination of letters and numbers with a length of 10 or 11 characters. An example of such a document number might be:
MM001IQ.V01 or RO001CLP.D01
The letters in the first and second positions represent the area that is covered by the document (e.g., qualification of rooms or validation of liquids). A legend for the first two letters is given below:
Rooms
Manufacturing machines
= RO
= MM
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Concept of Qualification/Validation
Liquid dosage forms
Creams/ointments/suppositories
Solid dosage forms
Cleaning
Computer systems
Service units
=
=
=
=
=
=
Ⅲ 33
LI
CR/OT/ST
SO
CL
CS
SU
The next three positions represent a serial number for the document.
This number should be assigned according to the chronological order of documentation development.
The sixth through eighth positions represent the type of document
(e.g., a specification or a performance qualification). A legend is given below: Validation master plan
Specification
Risk analysis
Design qualification
Installation qualification
Operational qualification
Performance qualification
Validation report
Process validation plan
Process validation program
Cleaning validation plan
Cleaning validation program
Computer validation plan
=
=
=
=
=
=
=
=
=
=
=
=
=
VMP
SP
RA
DQ
IQ
OQ
PQ
VR
PVP
PPG
CLP
CPG
CVP
The first place to the right of the dot shows whether it is a version or a draft version of the document:
Version
Draft version
= V
= D
The subsequent two characters identify the serial number of the version or draft version.
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3
REVALIDATION
The revalidation process is essential to maintain the validated status of the plant, equipment, manufacturing processes, and computer systems. It should be as important as calibration and maintenance.
Possible reasons for starting the revalidation process include:
1. The transfer of a product from one plant to another
2. Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality
3. The necessity of periodic checking of the validation results
Note to point 1: For the transfer of a product from one plant to another qualified production plant, it is essential to revalidate the entire manufacturing process in the new plant. It is possible that several new critical or noncritical parameters must be determined.
Note to point 2: In the case of the following changes, revalidation might be necessary:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Changes in the plant
Changes in product composition
Changes in manufacturing processes
Changes in the packaging materials
Changes to computer systems
Changes in the cleaning processes or agents
Changes which may affect the quality and efficacy of product
The scope of revalidation procedures depends on the extent of the changes and the effect upon the product.
Note to point 3: Periodic revalidation must be done to ensure that no unintentional changes were made and to prove that the results of the previous validation procedures are still valid.
35
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36 Ⅲ Pharmaceutical Master Validation Plan
The period of time between the revalidation activities is fixed by the review team. The members of this team should consider the following questions: 1.
2.
3.
4.
Are the manufacturing processes sterile, or not?
Are the results of the plant (product, performance) expected?
Are maintenance and calibrating procedures carried out regularly?
What are the critical stages of the processes?
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4
FACILITY DESCRIPTION
ABC Pharmaceutical is a medium-sized pharmaceutical industry in New
York state and employs approximately 500 employees. The plant intends to produce millions of units annually. The annual sales of the plant are above U.S. $200 million. The total covered area is 50,000 square feet. ABC
Pharmaceutical places basic emphasis on the concept of quality and on strict compliance with the rules of current Good Manufacturing Practice
(cGMP) in all steps of manufacturing, shipping, and marketing.
The Head Office of ABC Pharmaceutical is located at Kennedy Airport
Road, approximately 60 km east of New York City, New York, U.S.A.
Building “A” of ABC Pharmaceutical is designed to manufacture dry oral products. The conventional pharmaceutical dosage forms include tablets, capsules, and powders for suspension.
Building “B” of ABC Pharmaceutical is designed to manufacture liquids and semisolid products. The conventional pharmaceutical dosage forms include drops, syrups, suspensions, creams/ointments, and suppositories.
Building “C” is designed to manufacture injectables in ampoules, vials, and disposable ready-to-use syringes, and lyophilized products in vials.
The products manufactured are shipped in market packages to customers worldwide.
The plant operations are administered through the Administration
Division, Quality Affairs Division, and Technical Affairs Division as below:
Quality Affairs Division
Ⅲ Quality Assurance
Ⅲ Quality Control
Ⅲ Product Development Laboratory
Ⅲ Registration
Technical Affairs Division
Ⅲ Production
Ⅲ Packaging
37
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38 Ⅲ Pharmaceutical Master Validation Plan
Ⅲ Materials Planning
Ⅲ Maintenance
Ⅲ Shipping
Ⅲ Purchasing
Administration Division
Ⅲ Marketing
Ⅲ Personnel
Ⅲ Accounts
Ⅲ Management Information System
4.1
LINE CAPACITIES
Production line capacities for ABC Pharmaceutical would be as follows in the different dosage forms:
Ⅲ The capsule line, with an annual production capacity of about 50 million capsules.
Ⅲ The tablets line, with an annual production capacity of about 1 billion tablets. Ⅲ The powder for suspension line, with an annual production capacity of about 3 million bottles.
Ⅲ The syrup and suspension line, with an annual production capacity of about 60 million bottles.
Ⅲ The drops line, with an annual production capacity of about 10 million bottles.
Ⅲ The cream and ointment line, with an annual production capacity of about 15 million tubes.
Ⅲ The suppositories line, with an annual production capacity of about
20 million suppositories.
Ⅲ The injectable line, with the following annual production capacity of
– Ampoules
12 million
– Disposable syringes
5 million
– Lyophilized vials
3 million
– Vials
10 million
The following is a detailed description of ABC Pharmaceutical, which in addition to the warehouse, reception, and cafeteria, consists of three buildings A, B, and C:
A: Dry products
B: Liquids and semisolid products
C: Parenteral products
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Facility Description
Ⅲ 39
The buildings can be divided into three sections:
1. Description of building
2. Description of equipment
3. Description of process
4.1.1
Building Description
The design and material selection will be done according to cGMP regulations. All walls and ceilings inside the production area are designed as recommended by cGMP, and cleanroom walls and ceilings are designed as cleanroom sandwich steel panels with a chemical-resistant coating and nonporous surfaces. The panel joints are sealed with silicon or acrylic sealants. The wall bases as well as the floor are covered with seamless epoxy coating. For room specifications, climate, and utilities, refer to
Chapter 5:
1. Building for dry production
2. Building for liquid and semisolid production
3. Building for parenterals production
4.1.2
Equipment Description
This section provides facility, HVAC, and major equipment descriptions for the following areas of all three manufacturing buildings.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
4.1.3
Equipment for dry production
Equipment for liquid and semisolid production
Equipment for parenterals production
HVAC of dry production area
HVAC of liquid and semisolid production area
HVAC of parenterals production area
Raw material stores and weighing area
Over-printing
Quality Control
Quality Assurance (in-process)
Product Development Laboratory
Process Description
This description provides a summary of process steps and control parameters for the following dosage forms:
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40 Ⅲ Pharmaceutical Master Validation Plan
1.
2.
3.
4.
5.
6.
7.
8.
9.
Tablets
Capsules
Powder for suspensions
Drops
Syrups
Suspensions
Creams/ointments
Suppositories
Injectables
a. Aseptic fill (ampoules/vials/syringes)
b. Terminally sterilized (ampoules/vials)
c. Lyophilized (vials)
The pharmaceutical products of ABC Pharmaceutical include the following dosage forms and processes.
4.1.3.1
Dry Oral Production
The conventional pharmaceutical products include the following dosage forms and processes.
4.1.3.2
Tablets
Capsules
Milling
Blending
Compression
Blistering
Packing
Milling
Blending
Capsulation
Blistering
Packing
Powder for
Suspensions
Mixing
Filling
Packing
Liquids and Semisolid Oral Production
The conventional pharmaceutical products include the following dosage forms and processes.
Syrups
Drops
Suppositories
Creams/Ointments
Mixing
Filling
Packing
Mixing
Filling
Packing
Compounding
Filling
Packing
Compounding
Filling
Packing
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Facility Description
4.1.3.3
Ⅲ 41
Injectables
Aseptic Fill
Amp./Vials
Terminally Sterilized
Amp./Vials
Lyophilized
Vials
Ready-to-Use
Disposable
Syringes
Solution preparation Sterile filtration
Aseptic
filling/sealing
Leak test
Optical checking
Solution preparation Filtration
Filling/sealing
Solution preparation Sterile filtration
Aseptic filling
Solution preparation Sterile filtration
Aseptic filling
Steam sterilization
Leak test
Stoppering
Inspection
Labeling/packing
Optical checking
Pre-stoppering
Shelf chamber loading Lyophilization
Labeling/packing
Freezing
Sublimation
Desorption
Full stoppering
Chamber
unloading
Container sealing
Optical checking
Labeling/packing
Plunger rod assembly Blister packing
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5
DESCRIPTION OF BUILDING
43
Area
Room No.
Area
Area Requirement
Room No.
Civil
Activity
Activity
RH
Temp.
Floor
Construction
Covering
5.1 DRY PRODUCTION FACILITY: BUILDING A
Lux
Sound
Level
Gases
Wall
Construction
Covering
Water
Steam
Ceiling
Construction
Covering
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44 Ⅲ Pharmaceutical Master Validation Plan
Area
Room No.
Area
Area Requirement
Room No.
Civil
Activity
Activity
RH
Temp.
Floor
Construction
Covering
Lux
Sound
Level
Gases
Wall
Construction
Covering
5.2 LIQUID AND SEMISOLID PRODUCTION FACILITY: BUILDING B
Water
Steam
Ceiling
Construction
Covering
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Description of Building
Ⅲ 45
Area
Room No.
Area
Area Requirement
Room No.
Civil
Activity
Activity
RH
Temp.
Floor
Construction
Covering
Lux
Sound
Level
Gases
Wall
Construction
Covering
5.3 PARENTERALS PRODUCTION FACILITY: BUILDING C
Water
Steam
Ceiling
Construction
Covering
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46 Ⅲ Pharmaceutical Master Validation Plan
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6
EQUIPMENT DESCRIPTION
6.1
DRY PRODUCTION: BUILDING A
Stores and Weighing Area
Location
Equipment Name
Capacity
Manufacturer
Weighing scale
Weighing station (LF)
Mixing/Blending/Sieving
Location
Room No.
Equipment Name
Manufacturer
Granulation machine
Milling machine
Sieving machine
Blender
47
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48 Ⅲ Pharmaceutical Master Validation Plan
Encapsulation
Location
Room No.
Equipment Name
Manufacturer
Capsule filling machine
Capsule sorting machine
Hard gelatin capsule polisher
Capsule Blistering
Location
Room No.
Equipment Name
Manufacturer
Thermoform blister machine
Tablets Compression
Location
Room No.
Equipment Name
Manufacturer
Compression machine
Sugar/Film Coating
Location
Room No.
Equipment Name
Air pressure pump
Cota 60”
Coating pan
Manufacturer
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Ⅲ 49
Powder Filling
Location
Room No.
Equipment Name
Manufacturer
Powder filling machine
Capping machine
Labeling and Cartoning Area
Location
Room No.
Equipment Name
Manufacturer
Labeling machine
Cartoning machine
6.2
LIQUID AND SEMISOLID PRODUCTION:
BUILDING B
Stores and Weighing Area
Location
Room No.
Equipment Name
Manufacturer
Weighing cabinet (balance)
Weighing station
Syrups/Suspensions/Drops Manufacturing
Location
Room No.
Equipment Name
Syrup manufacturing tank
Filter press
Suspension manufacturing tank
Drops manufacturing vessel
Manufacturer
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50 Ⅲ Pharmaceutical Master Validation Plan
Syrups/Suspensions/Drops Fill and Pack
Location
Room No.
Equipment Name
Manufacturer
Syrup filling machine
Capping machine
Labeling machine
Cartonator
Shrink-wrapping machine
Suspension filling machine
Capping machine
Labeling machine
Cartonator
Shrink-wrapping machine
Drops filling machine
Capping machine
Labeling machine
Cartonator
Creams/Ointments and Suppository Manufacturing
Location
Room No.
Equipment Name
Manufacturer
Manufacturing vessel
Homogenizing machine
Transfer pump
Creams/Ointments and Suppository Fill and Pack
Location
Room No.
Equipment Name
Cream filling and packing machine
Cartonator
Ointment filling and packing machine
Cartonator
Suppository filling and packing machine Manufacturer
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Ⅲ 51
6.3
PARENTERALS PRODUCTION: BUILDING C
Solution Preparation
Location
Room No.
Equipment Name
Manufacturer
Mobile vessel - 500 liter
Integrity testing
Ampoule/Vial Washing and Dry Heat Sterilization
Location
Room No.
Equipment Name
Manufacturer
Washing machine for amp./vials
Hot sterilization tunnel
Aseptic Filling for Ampoules and Vials
Location
Room No.
Equipment Name
Manufacturer
Vial filling and closing machine
Ampoule filling and sealing machine
Laminar flow unit
Steam Sterilization (Autoclave)
Location
Room No.
Equipment Name
Steam sterilizer (autoclave)
Manufacturer
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52 Ⅲ Pharmaceutical Master Validation Plan
Syringe Preparation and Filling
Location
Room No.
Equipment Name
Manufacturer
Laminar flow unit
Filling and closing machine for syringes
Freeze Drying
Location
Room No.
Equipment Name
Manufacturer
Freeze dryer
Rotary table
Automatic loading/unloading system
Automatic vial closing machine
Buffer and feeding equip. for bottles
Control panel for freeze dryer
Ampoule Coding
Location
Room No.
Equipment Name
Manufacturer
Automatic ampoule coding machine
Packing
Location
Room No.
Equipment Name
Labeling machine for amp./vials
Rotary infeed table
Inspection machine for amp./vials
Manufacturer
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Ⅲ 53
6.4
Location
Room No.
OVER-PRINTING AREA
Equipment Name
Manufacturer
Labels/Box printing machine
Leaflet folding machine
Aluminum foil and PVC printing machine
6.5
Location
Room No.
QUALITY CONTROL
Equipment Name
Autoclave
Hot air sterilizer
Laminar air flow
Incubator
Refrigerator pH meter
Microscope
Water bath
Compact sterility tester
Analytical balance; Min. 0.5 g,
Max. 3100 g
Analytical balance
Distillation unit
Hot plate
Vortex mixer
UV-VIS spectrophotometer
UV-VIS spectrophotometer w/auto sampler IR spectrophotometer
Luminescence spectrometer
Dissolution apparatus
Potentiometer
Moisture analyzer
Manufacturer
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54 Ⅲ Pharmaceutical Master Validation Plan
Location
Room No.
Equipment Name
Manufacturer
HPLC
HPLC
Refractometer
Conductivity meter pH meter
Polarimeter
Friability tester
Viscometer
Suppository hardness tester
Suppository melting tester
Antibiotic zone reader
Air sampler
Centrifuge
Muffle furnace
6.6
Location
Room No.
QUALITY ASSURANCE (IN-PROCESS)
Equipment Name
Analytical balance
Torque tester
Leak test chamber
Tablet/capsule testing system
Friabilater
Disintegration unit
Analytical balance
Moisture analyzer pH meter
Manufacturer
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Ⅲ 55
6.7
PRODUCT DEVELOPMENT LABORATORIES
Location
Room No.
Equipment Name
Granulator
Oven
Granulator
Compression machine
Sugar coating pan
Blister machine
Digital pH meter
Granulate flow tester
Particle size analyzer
Hardness tester
Manufacturer
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7
HVAC DESCRIPTION
7.1
DRY PRODUCTION FACILITY: BUILDING A
Stores and Weighing Area
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Weighing scale
Weighing station (LF)
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
A:BLU 30
20
1440
Blending/Sieving
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Granulation machine
Mill/Sieve
Pneumatic conveyor
Bin weighing station
Tumbler
Drum emptying station
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
A:BLU 30
20
4160
57
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58 Ⅲ Pharmaceutical Master Validation Plan
Encapsulation
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Capsule filling machine
Capsule sorting machine Hard gelatin capsule polisher AHU
No.
Min. Air
Change
Air Flow
(m3/h)
A:BLU 30
20
2880
Capsules Blistering
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Thermoform machine
Cartonator
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
A:BLU 30
20
6720
Tablet Compression
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
Compression machine
Compression machine
Compression machine
A:BLU 20
A:BLU 30
A:BLU 30
20
20
20
1920
2880
2880
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HVAC Description
Ⅲ 59
Sugar/Film Coating
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Air pressure
Cota 60"
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
A:BLU 40
A:BLU 40
20
20
2520
2520
Powder Filling
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Powder filling
Capping machine
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
A:BLU 30
20
2880
Labeling and Cartoning Area
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Labeling machine
Rotary table
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
A:BLU 40
20
3840
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60 Ⅲ Pharmaceutical Master Validation Plan
7.2
LIQUID AND SEMISOLID PRODUCTION FACILITY:
BUILDING B
Stores and Weighing Area
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 30
20
1440
Equipment Name
Weighing cabinet (balance)
Weighing station
Syrups/Suspensions/Drops Manufacturing
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 30
B:BLU 30
B:BLU 10
20
20
20
2880
2880
2680
B:BLU 20
20
2550
Equipment Name
Syrup manufacturing tank
Filter press
Suspension manufacturing tank Drops manufacturing vessel Syrups/Suspensions/Drops Fill and Pack
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Syrup filling machine
Capping machine
Labeling machine
Cartonator
Shrink wrapping machine
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 40
20
3360
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HVAC Description
Location
Equipment Name
Suspension filling machine
Capping machine
Labeling machine
Cartonator
Shrink wrapping machine
Drops filling machine
Capping machine
Labeling machine
Cartonator
Ⅲ 61
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 30
20
3210
B:BLU 30
20
2880
Cream/Ointment and Suppository Manufacturing
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Manufacturing vessel
Homogenizing machine
Flux pump
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 20
20
2520
Cream/Ointment and Suppository Fill and Pack
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Cream filling and packing machine Cartonator
Ointment filling and packing machine
Cartonator
Suppository filling and packing machine
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 10
20
2960
B:BLU 10
20
2210
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62 Ⅲ Pharmaceutical Master Validation Plan
7.3
PARENTERALS PRODUCTION FACILITY: BUILDING C
Solution Preparation
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 50
20
2120
Equipment Name
Mobile vessel, 300 liter
Integrity testing
Ampoule/Vial Washing and Dry Heat Sterilization
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 50
20
5880
Equipment Name
Washing machine for amp./vial Hot sterilization tunnel
Aseptic Filling for Ampoules and Vials
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Vial filling and closing machine Ampoule filling and sealing machine
Laminar flow unit
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 50
30
2970
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HVAC Description
Ⅲ 63
Steam Sterilization (Autoclave)
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Steam sterilizer (autoclave)
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 50
30
2070
Syringe Preparation and Filling
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Laminar flow unit
Conveyors
Filling and closing machine for syringes
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 50
20
840
C:BLU 50
30
1620
Freeze Drying
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Freeze dryer technical area
Rotary table
Conveyor
Automatic loading/unloading system Automatic vial closing machine Buffer and feeding equipment for bottles
Control panel for freeze dryer
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 10
C:BLU 50
20
30
990
2700
C:BLU 50
20
720
C:BLU 10
20
1210
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64 Ⅲ Pharmaceutical Master Validation Plan
Ampoule Coding
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Automatic ampoule coding machine AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 50
20
550
Packing
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Conveyor belt
Labeling machine for amp./vial Rotary infeed table
Inspection machine for amp./vial 7.4
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
C:BLU 40
C:BLU 40
20
20
4500
4020
OVER-PRINTING AREA
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Labels/box printing machine Leaflet folding machine
Aluminum foil and PVC printing machine
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 10
20
3210
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HVAC Description
7.5
Ⅲ 65
QUALITY CONTROL
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Autoclave
Hot air sterilizer
Laminar air flow
Incubator
Refrigerator pH meter
Microscope
Water bath
Compact sterility tester
Analytical balance, min.
0.5 g, max. 3100 g
Analytical balance, min.
0.1 mg, max. 210 g
Distillation unit
Hot plate
Vortex mixer
UV-VIS spectrophotometer
IR spectrophotometer
Luminescence
spectrometer
Dissolution apparatus
Potentiometer
Moisture analyzer
HPLC
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 10
20
5040
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66 Ⅲ Pharmaceutical Master Validation Plan
7.6
QUALITY ASSURANCE, IN-PROCESS
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Analytical balance
Torque tester
Leak test chamber
Tablet/capsule testing system Friabilater
Disintegration unit
Analytical balance
Moisture analyzer pH Meter
7.7
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
B:BLU 10
20
2210
A:BLU 10
20
2210
PRODUCT DEVELOPMENT LABORATORIES
The HVAC system covering this area is controlled by air handling unit
(AHU) No.
Location
Equipment Name
Granulator
Oven
Granulator
Compression machine
Fette (single station)
Sugar coating pan
Blister machine
Krieger
Digital pH meter
Granulate flow tester
Particle size analyzer
Hardness tester
AHU
No.
Min. Air
Change
Air Flow
(m3/h)
BLU 15
20
4410
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8
UTILITIES DESCRIPTIONS
The major utilities involved in the routine operation of the plant are as follows: 8.1
DEIONIZED WATER (DI WATER)
DI water is produced using an XYZ rapid, high-performance, twin-bed deionizer. The plant consists of two glass-reinforced plastic pressure vessels that hold the ion exchange resins together with a process pump, pipe work, valves, flowmeters, and controls to enable the plant to produce high-quality deionized water and automatically regenerate the resins.
8.2
PURIFIED WATER
The water treatment plant produces Purified Water. The unit that fills the
1000-liter storage tank is located in building C first floor from where a loop will start to distribute water in building C. A separate distribution loop starts in building C and allows filling of tanks in buildings A and B.
8.3
WATER FOR INJECTION
The Water for Injection (WFI) is produced by an XYZ multi-effect water still (type 300-S), which is intended to produce pure, pyrogen-free distilled water from pretreated feed water by evaporating and condensing the feed water (i.e., DI Water). The water still consists of pressure vessels, five columns, and a condenser. The piping between the pressure vessels is stainless steel (S.S.) 316L.
The WFI distribution system (storage tanks, circulation pumps, pipework) is steam sterilized. The sterilization cycle is controlled and monitored by temperature indicators located at critical points.
67
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68 Ⅲ Pharmaceutical Master Validation Plan
8.4
CHILLED WATER
Two chillers (300-ton capacity each) provide Chilled Water for various air handling units and all machinery in need of chilled water. Another chiller
(15-ton capacity) provides chilled water to boiler, compressor, and deionized water plant.
8.5
PURE STEAM
Pure Steam is produced by an XYZ 1500-S pure steam generator. The generator is fed with deionized water that descends the inside tubes where it is converted into steam. The steam generator is located in building C first floor, from where the loop diverts to different use points; steam traps are installed to collect condensate when necessary. The quality of pure steam condensate is the same as for Water for Injection.
8.6
COMPRESSED AIR
The plant has two reciprocating oil-free compressors, with a total capacity of 20 m3/h. The oil-free Compressed Air is supplied to a stainless steel air receiver. The air then passes through the air filter along with the oil and water separator system and passes through the air dryer and is distributed through S.S. use points in the three buildings. Terminal sterile filtration (0.01 µm) is used at critical use points.
8.7
NITROGEN (N2)
Nitrogen is supplied by a membrane generator with a capacity of 20 m3/h and a minimum purity of 97%. Nitrogen is distributed by an S.S. 316L pipe network with TIG welding to all required use points. Nitrogen is utilized for the following:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Purging during solution preparation
Pressurizing process vessels for product transfer and filtration
Purging during filling of oxygen-sensitive products
Vacuum break during freeze drying
Removal of air during filling of liquids
8.8
CARBON DIOXIDE (CO2)
Carbon Dioxide is supplied in cylinders and distributed by stores from the gas cylinders storage area. Carbon dioxide is utilized during manufacturing of liquids for blanketing oxygen-sensitive products.
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Utilities Descriptions
8.9
Ⅲ 69
ELECTRIC POWER
ABC Pharmaceutical’s total peak power consumption is about 4000 kWh, and is obtained from Water and Electricity Supply Corporation, New York.
ABC Pharmaceutical also has three (2) standby generators totalling 4500
KVA, which are to be used during main power failure.
8.10
SANITARY WATER
ABC Pharmaceutical’s average water consumption (based on 3 months,
i.e., June, July, and August) is about 80,000 gal/day; the water obtained from Water and Electricity Supply Corporation, New York.
The water is stored in an underground tank having a capacity of
200,000 gal.
8.11
HVAC (HEATING, VENTILATION, AND
AIR-CONDITIONING) SYSTEM
Buildings A, B, and C of ABC Pharmaceutical have a total of 35 Air
Handling Units (AHUs). Each building has its own HVAC system with absolutely separate air handling units.
Building A
Building B
Building C
Dry production
Liquids and semisolid production
Parenterals production
No contamination is allowed between the three buildings. They are completely segregated.
All air handling units (AHUs) are intended to be in continuous operation. The AHU fans are equipped with built-in air flow measuring devices of the direct-read type (Q-nozzles). This will facilitate monitoring of the delivered air at remote locations. All exhaust fans are also provided with air flow measuring devices. Some of the parameters will be continuously monitored in the critical areas, as shown in the monitoring document.
Table 8.1, a monitoring document for buildings A, B, and C, respectively, provides the following information:
Room number
Activity
Cleanliness class
Pressure (Pascal)
Temperature (°C)
Relative humidity (%)
Number of air changes
AHU number
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70 Ⅲ Pharmaceutical Master Validation Plan
Table 8.1
Monitoring Document for HVAC System
Building A
Room
No.
Activity
Relative
Cleanness Pressure Temperature Humidity
(%)
Class
(Pascal)
(°C)
No. of
Air
Changes
AHU
No.
Relative
Cleanness Pressure Temperature Humidity
Class
(Pascal)
(°C)
(%)
No. of
Air
Changes
AHU
No.
Relative
Cleanness Pressure Temperature Humidity
Class
(Pascal)
(°C)
(%)
No. of
Air
Changes
AHU
No.
Building B
Room
No.
Activity
Building C
Room
No.
Activity
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9
VALIDATION PROGRAM
OVERVIEW
9.1
VALIDATION PROJECT MANAGEMENT:
ORGANIZATION
71
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72 Ⅲ Pharmaceutical Master Validation Plan
ABC QA / Plant
Design Qualification for
ABC Pharmaceuticals
Manufacturer
QA / Plant
Authorization
Primary Responsibilities
Validation Master Plan
Protocols Execution
IQ, OQ, PQ
Design Review/Approval
Documents Review/Approval
Analytical Testing
Microbiological Testing
HVAC Design
Architectural Design and Construction
ABC Pharma.
XYZ Consultants
ABC Pharmaceuticals
WYZ Consultants
Equipment
IQ / OQ
ABC Pharma.
Validation Team
QA Division / Plant
Validation Team
Preparation of
Validation Master Plan
Equipment, Facility,
Process
IQ, OQ, PQ
PQ/ Process
Qualification
ABC Pharma.
Validation
Team
Figure 9.1 The organization and responsibilities of the ABC Pharmaceutical validation. 9.2
VALIDATION RESPONSIBILITIES
The Validation Team has overall responsibility for validating the facility.
The Quality Assurance Manager has responsibility for approval of all validation protocols, final reports, standard operating procedures, chemical and microbiological testing, as well as other critical cGMP documentation.
9.3
DESIGN AND VALIDABILITY REVIEW
The validation of the ABC Pharmaceutical facility is to be started simultaneously with the initial conceptual design. At key stages throughout the
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Validation Program Overview
Ⅲ 73
design process, design review meetings are to be held to review and make key cGMP design decisions.
Through these design review meetings, cGMP and functionality requirements have and continue to be determined for each aspect of the facility, including: Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Architectural layout
Civil work execution
HVAC and cleanroom
Water for Injection/Purified water
Steam
Oil-free compressed air
Personnel and material flow
Mechanical equipment
Material receipt, storage, and shipping
Quality Assurance/Control testing and inspection
Drainage system
Process equipment design
Maintenance and calibration access
Emergency power
Safety engineering
Waste disposal
Class Equipment and Systems
1. Class I Equipment and Systems: systems representing processes, equipment, and areas with the highest degree of product quality and regulatory impact. For example:
a. Product/commodity sterilization and depyrogenation
b. Utilities utilized during manufacturing (e.g., distilled/deionized water facilities, compressed air, etc.)
c. HVAC system
2. Class II Equipment and Systems: systems representing processes, equipment, and areas with a high degree of product quality and impact, but which are established processes generally recognized as prevalent throughout the drug industry. For example:
a. Equipment used in product processing (e.g., manufacturing tanks, mixers, blenders, dryers, etc.)
b. Product fill/seal machines
c. Commodity washers
d. Granulators.
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74 Ⅲ Pharmaceutical Master Validation Plan
3. Class III Equipment and Systems: systems representing processes, equipment, and areas with a low regulatory and product impact.
For example:
a. Cap assemblers, cleaners, and washers
b. Drying equipment
c. Incubators
9.4
VALIDATION DOCUMENTS
Enhanced Turn-Over Package (ETOP)
The Enhanced Turn-Over Package (ETOP) consists of documentation binders or files that contain all relative design, installation, and testing documentation generated during the design and construction of a particular engineered system such as HVAC or Pure Steam. ETOPs serve to capture all engineering documentation generated throughout the design construction process.
This information is compiled into single-source packages, which then provide the foundation for Installation and Operational Qualification.
The Enhanced Turn-Over Package (ETOP) for each system contains all information relating to the following areas:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
General
Equipment
Piping
Instrumentation
Controls and automation
Electrical
Operating procedures
Maintenance procedures and schedules
Calibration procedures and schedules
Calibration specifications (accuracy requirements)
An Enhanced Turn-Over Package (ETOP) is prepared for each of the following systems:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Water for Injection (WFI) system
Pure steam
Plant steam
Drainage and waste decontamination system
Compressed gas system
Electrical system
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Validation Program Overview
Ⅲ 75
Ⅲ Building automation system
Ⅲ HVAC system
Ⅲ Civil work execution
Certification Package Requirements
The following table summarizes the documentation package requirements for each equipment system classification.
Equipment Class
Class I
Class II a 9.5
Certification Package Requirements a
IQ, OQ, and PQ
IQ and PQ
IQ = Installation Qualification; OQ = Operational Qualification; PQ = Performance Qualification
INSTALLATION QUALIFICATION PROTOCOLS
The Installation Qualification (IQ) verifies that the equipment or system and/or corresponding utilities are installed in accordance with design specifications, manufacturer recommendations, and cGMPs. In addition, the IQ will confirm that critical instruments are calibrated and that system components are properly identified. Any exceptions will be documented, corrected, and/or justified.
Where possible and applicable, pre-shipment inspection of equipment and documentation is included as part of the Installation Qualification.
Pre-shipment inspection can be performed along with vendor audits to address issues such as software development and quality assurance plans, operational reports, and specific vendor/purchaser inspection reports.
Typical Installation Qualification test functions include, but are not limited to, the following:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Manufacturer specifications
Purchase order specifications
Piping and installation drawing (P&ID)
Construction and installation
Test equipment calibration
Required spare parts
Cleaning/passivation
Weld inspection
System installation compliance to cGMPs
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The IQ is performed in accordance with a preapproved written protocol. The specific IQ attributes to be verified during the performance of the IQ protocol will be developed from system and component design criteria, cGMP requirements, and other specifying documentation. They, along with the acceptance criteria, will be approved as part of the protocol approval process.
9.6
OPERATIONAL QUALIFICATION PROTOCOLS
The Operational Qualification (OQ) verifies that the system or equipment operates in accordance with design specifications, manufacturer recommendations, and cGMPs. OQ testing is designed to simulate the full range of operating conditions to establish a system capabilities baseline and to ensure that the system operates as intended.
Operational Qualification test functions include, but are not limited to, the following:
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
Ⅲ
General operational and control verification
Functional testing of computer-related systems
Specific operational testing (generation of baseline data)
Utility system capability
Calibration of test equipment
Standard operating procedures (SOPs)
Maintenance procedures
Cleaning or sanitizing procedures
For equipment or systems controlled or monitored by a computerrelated system, the functional testing cycle approach to computer validation is included and performed as part of the Operational Qualification.
Functional testing verifies that the integrated hardware and software program perform in accordance with the functional specifications developed during the requirements phase.
The Operational Qualification is performed in accordance with a preapproved written protocol. The specific Operational Qualification attributes to be verified during the performance protocol will be developed from the design specifications, manufacturer documentation, cGMP requirements, and other specific documentation. They, along with the acceptance criteria, will be approved as part of the protocol approval process.
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Validation Program Overview
9.7
Ⅲ 77
CHANGE CONTROL INITIATION
Each system/equipment/process will be covered by the Engineering
Change Control program immediately following the completion of the OQ test functions. Any change(s) made to the system during OQ must be documented in the Final Report. Any engineering changes proposed after
OQ (i.e., during cycle development, performance qualification, or manufacturing) must be preapproved and follow the Engineering Change Control procedure.
If changes are made prior to approval of the Final Report, the Change
Control documentation must be included in the Validation Packages, and the change and its justification must be documented in the Final Report.
9.8
CYCLE DEVELOPMENT
Critical processes other than the actual product manufacturing process — such as sterilization, component washing, and equipment cleaning — require prevalidation cycle development work. This may include establishment of appropriate sterilization cycle types, cleaning agents, etc. This test work is performed during or after Operational Qualification.
Cycle Development does not have to be performed per a written procedure; however, the procedure and results of all work must be recorded in laboratory notebooks, performed in accordance with cGMP documentation practices and sound scientific methods, and retained as part of the Validation Package. At the completion of Cycle Development work, a brief Cycle Development Report will be prepared that identifies parameters having a high probability of successfully meeting the Performance Qualification requirements.
9.9
PERFORMANCE QUALIFICATION PROTOCOLS
Performance Qualification (PQ) verifies the performance of critical utility systems or processes. Critical utility systems such as WFI and Pure Steam are challenged throughout proposed operating ranges for extended periods of time, while an extensive program of quality monitoring is performed. Critical processes such as sterilization of components ar e challenged three (3) consecutive times under worst-case conditions.
Performance Qualification is carried out in accordance with a preapproved written protocol. The specific PQ attributes to be verified during the performance of the protocol will be developed from the finished product specifications, research and development data, cGMP requirements, and other specific documentation. They, along with the acceptance criteria, will be approved as part of the protocol approval process.
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9.10
PROCESS VALIDATION PROTOCOLS
Process Validation (PV) verifies the performance of the overall product manufacturing process. PV is performed on the entire product manufacturing process, which includes all support, processes, preparation of media, components, buffers, formulation, filtration, filling, and packaging.
During Process Validation, three (3) consecutive batches are manufactured, and all in-process and finished product specifications are verified at much higher than normal inspection quantities and frequencies. Critical parameters are set at different ranges during the manufacturing process to verify that the product consistently meets its predetermined quality specification over the range of critical parameter settings. Consequently, a proven acceptable range for each critical parameter is developed.
All equipment, processes, and quality assurance test procedures must be validated (or verified if using a compendial method) prior to the start of Process Validation.
Process Validation is performed in accordance with a preapproved written protocol. The specific PV attributes and process parameters to be verified during the performance of the protocol will be developed from the finished product specifications, research and development data, the manufacturing process capability, cGMP requirements, and other specific documentation. These, along with the acceptance criteria, will be approved as part of the protocol approval process.
9.11
VALIDATION FINAL REPORTS
The Final Report summarizes the results of the validation process and provides an analysis of the test data in support of the conclusion that the equipment or system demonstrates consistent performance within the established acceptance criteria. Deviations and/or exceptions to approved protocols, along with suitable explanations and justifications, are also documented in the Final Report.
9.12
VALIDATION PACKAGE
The Final Report, completed protocols, and all supporting documentation are then gathered into a Final Report Package for review, approval, and retention.
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Validation Program Overview
9.13
Ⅲ 79
CERTIFICATION FOR USE IN MANUFACTURING
Validation of a system/equipment/process will be considered complete when its respective protocols identified in the Validation Master Plan have been successfully implemented and the Final Report has been approved.
A system/equipment/process may be certified for use in manufacturing upon completion of the following.
Ⅲ Applicable protocols identified in the Validation Master Plan have been successfully completed and the Final Report has been approved. Ⅲ Applicable SOPs identified in the Validation Master Plan have been approved. Ⅲ Validation is complete for all utility systems that support the equipment or process, and for all equipment that supports a process.
Ⅲ All system/equipment/process instrumentation is still within calibration. 9.14
IQ
OQ
PQ
PV
PM
REQUIRED PROTOCOLS AND PROCEDURES FOR
DRY PRODUCTION: BUILDING A
Installation Qualification protocol
Operational Qualification protocol
Performance Qualification protocol
Process Validation protocol
Preventive Maintenance procedure
System/
Equipment
Compressed air
HVAC and monitoring system
Drainage system
Civil work
Emergency
power
Labeling
machine
Powder filling machine IQ
1
1
OQ
1
1
1
1
1
1
1
1
1
1
Protocols
PQ
CL
1
1
Final Report
Operating Procedure
Cleaning Procedure
Calibration Procedure
Computer Validation
OP
1
1
PM
1
1
SOPs
CL
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
FR
1
1
FR
OP
CL
CAL
CV
CAL
CV
1
1
1
1
1
1
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80 Ⅲ Pharmaceutical Master Validation Plan
System/
Equipment
Capsule filling machine Mill
Sifter
Granulation machine Blister machine
IQ
1
OQ
1
1
1
1
1
1
1
1
1
Protocols
PQ
CL
1
1
1
FR
1
OP
1
PM
1
SOPs
CL
1
CAL
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
CV
1
1
9.15 REQUIRED PROTOCOLS AND PROCEDURES FOR
LIQUID AND SEMISOLID PRODUCTION: BUILDING B
IQ
OQ
PQ
PV
PM
Installation Qualification protocol
Operational Qualification protocol
Performance Qualification protocol
Process Validation protocol
Preventive Maintenance procedure
System/
Equipment
Compressed air
HVAC and monitoring system
Drainage system
Civil work
Emergency
power
Labeling
machine
Syrup filling machine Capping machine Labeling machine Susp. filling machine Capping machine Labeling machine IQ
1
1
OQ
1
1
1
1
1
1
1
1
1
1
1
Protocols
PQ
CL
1
1
FR
1
1
FR
OP
CL
CAL
CV
Final Report
Operating Procedure
Cleaning Procedure
Calibration Procedure
Computer Validation
OP
1
1
PM
1
1
SOPs
CL
CAL
CV
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
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Validation Program Overview
System/
Equipment
Drops filling machine Capping machine Cream filling/ packaging machine
Ointment filling/ packaging machine
9.16
IQ
OQ
PQ
PV
PM
IQ
1
OQ
1
1
1
1
1
1
1
Protocols
PQ
CL
1
1
1
Ⅲ 81
FR
1
OP
1
PM
1
SOPs
CL
1
CAL
1
CV
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
REQUIRED PROTOCOLS AND PROCEDURES FOR
PARENTERALS PRODUCTION: BUILDING C
Installation Qualification protocol
Operational Qualification protocol
Performance Qualification protocol
Process Validation protocol
Preventive Maintenance procedure
System/
Equipment
Pure steam generator Water still
Compressed air
Nitrogen
HVAC and monitoring system
Drainage system
Emergency
power
Laminar flow units Automatic ampoule coding machine Filling and closing machine for syringes Autoclave
Protocols
PQ
CL
1
FR
OP
CL
CAL
CV
Final Report
Operating Procedure
Cleaning Procedure
Calibration Procedure
Computer Validation
FR
1
OP
1
PM
1
1
1
1
1
1
1
1
1
1
1
IQ
1
OQ
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
SOPs
CL
CAL
1
CV
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
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82 Ⅲ Pharmaceutical Master Validation Plan
System/
Equipment
Washing machine for ampoules and vials Hot sterilization tunnel Labeling machine for ampoules and vials Inspection machine for ampoules and vials Freeze dryer
Automatic vial filling and closing machine
Ampoule filling and sealing machine Manufacturing vessels Protocols
PQ
CL
1
1
FR
1
OP
1
PM
1
SOPs
CL
1
CAL
1
CV
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
IQ
1
OQ
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
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10
CALIBRATION PROGRAM
SUMMARY
Below is a summary of ABC Pharmaceutical’s Calibration Program, which is defined in related SOP(s).
1. All process and facility instruments are classified as to their calibration status into one of the three following categories:
a. Calibration
b. Preventive Maintenance
c. No Calibration/No Preventive Maintenance
2. All instruments providing critical process information necessary to make a quality determination are calibrated with the available standards. 3. ABC Pharmaceutical is in the process of procuring calibration standards. The Calibration Engineer will be responsible for scheduling, tracking, and maintenance of standards, records, etc. All standards will be traceable to NIST standards.
4. Pre- and post-calibration of instruments utilized in validation studies are performed to ensure data accuracy.
5. All instruments providing critical process information should be calibrated before performing the validation studies.
83
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11
PREVENTIVE MAINTENANCE
PROGRAM SUMMARY
Below is a summary of key points of ABC Pharmaceutical’s Preventive
Maintenance Program, which is defined in related SOP(s).
1. An appropriate Preventive Maintenance Program is defined for the equipment that will be checked at the time of validation.
2. The Supervisor of the related area and the Engineer concerned will sign the register and verify if repairs are required.
85
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12
KEY STANDARD OPERATING
PROCEDURES (SOPs)
Below is a list of key procedures for process operations and maintenance for ABC Pharmaceutical.
Description
Contractors qualification system
Raw material issuing system
Packaging material issuing system
Manufacturing procedures
Batch packaging record system
Equipment operating procedures
Equipment calibration procedures
Equipment maintenance procedures
Product release procedures
Handling of out-of-specification results
Complaints handling system
Change control system
Calibration procedures
A
SOPs
B
C
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
87
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13
VALIDATION OF BUILDING
13.1
CIVIL WORK
Test Functions
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Inspect the facility as per approved layout.
Inspect floors in each room.
Inspect painted surfaces in each room.
Perform dimensional testing for each room.
Inspect windows in each room, if any.
Inspect lights in each room.
Inspect utilities penetration into each room.
Inspect all drains.
Inspect all communicators.
Inspect all doors and interlocks.
Acceptance Criteria
1. The facility has been constructed in accordance with design specifications and cGMPs.
2. Doors open/close properly, and interlocks operate in accordance with design specifications.
3. Floor surfaces are smooth, and free of crevices, holes, and rough spots.
4. Painted surfaces are to have full and smooth coverage.
5. The length, width, and height of each room conform to the design specifications. 6. All windows are installed for easy cleaning, correct window type, and are sealed with smooth surfaces.
7. All lights switches operate; light is adequate at all workstations; and fixtures are flush mounted.
89
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8. All utilities penetrations are correctly installed, labeled, and sealed.
9. All drains are located according to the design specifications.
10. All communicators are correctly installed and sealed.
13.2
DRAINAGE SYSTEM
Test Functions
1.
2.
3.
4.
Inspect the drainage system as per the approved layout.
Inspect floor drain locations as per the approved design.
Check that process drains are segregated from the sanitary waste.
Ensure that process drains are provided with deep-seal traps.
Acceptance Criteria
1. The system is constructed and installed in accordance with design specifications, manufacturer recommendations, and cGMPs.
2. No open floor drains are to be located in Aseptic Core areas:
Classes 100, 10,000, and 100,000.
3. Process drains must be separated from sanitary waste drainage system. 4. Process drains must have adequate back-flow prevention devices
(deep-seal traps) at tie-in to sewer line.
5. Tie-in to sewer line must be located outside immediate building, away from the production area.
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14
VALIDATION
OF UTILITY SYSTEMS
This chapter provides a summary of the key validation test functions and acceptance criteria for each utility system. These are provided as a guideline for those involved in the validation of ABC Pharmaceutical. Approval of this Master Plan neither provides approval of these test functions and acceptance criteria nor does it limit the test functions and acceptance criteria included in any protocol. Final approval of test functions and acceptance criteria is made by approval of the Installation, Operational, and where applicable, Performance Qualification protocols.
14.1
PLANT STEAM
Test Functions
1. Perform Installation Qualification of deionizer and distillation equipment, holding tanks, clean steam generator, and distribution system. 2. Complete and document all required pre-start-up maintenance procedures (including cleaning).
3. Perform general operational controls verification testing.
4. Operate system throughout the range of operating design specifications or range of intended use.
5. Confirm that the pressure-reducing regulators in the sub-branches are set at the predetermined operating pressure ±2 psi.
6. Verify that the system has adequate steam capacity during peak hours of operation. Confirm that the steam pressure is within 5 psi of the recommended operating pressure.
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7. Record the range of all process or equipment parameters (set points, pressure, timing sequences, etc.) verified during operational and performance qualification testing.
8. Test the water produced by the system to ensure adequate conductivity. 9. Check that the holding tank water quality does not change adversely during storage in holding tanks.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. System regulators must operate within ±2 psi of design levels.
5. The system capacity must be sufficient to operate all systems at peak demand periods.
14.2
PURE STEAM
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout range of operating design specifications or range of intended use.
4. Verify that clean steam is fed by a purified water system or WFI system. 5. Confirm that the pressure-reducing regulators in the sub-branches are set at the predetermined operating pressure ±2 psi.
6. Verify that the system has adequate steam capacity during peak hours of operation. Confirm that the steam pressure is within 5 psi of the recommended operating pressure.
7. Operate the system per applicable SOPs. Perform sampling as per the sampling procedure and schedule. Test steam condensate samples for conformance to current USP Water for Injection monograph
(also endotoxin, sterility).
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Validation of Utility Systems
Ⅲ 93
8. Record the range of all process or equipment parameters (set points, pressure, timing sequences, etc.) verified during Operational and Performance Qualification testing.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The system capacity must be sufficient to operate all systems at peak demand periods.
5. Operate the system per applicable SOPs. Perform sampling over a 1-month period as per the sampling procedure and schedule.
Test samples for conformance to current USP Water for Injection monograph. 6. All samples must meet following criteria:
a. Chemical Testing. Test samples must meet the acceptance criteria of the chemical tests as described in USP 24 Monograph on
Water for Injection.
b. Bacteriological Purity. All samples must contain no more than
10 cfu/100 ml; no pseudomonas or coliform are detected.
c. Endotoxins. Less than 0.25 EU/ml.
14.3
WATER FOR INJECTION (WFI)
Test Functions
1. Perform Installation Qualification. Verify piping, fittings, proper dimensions, drawings, wiring, PC software, calibration, and quality of materials.
2. Check flow rates, low volume of water supply, excessive pressure drop, resistivity drops below set point, and temperature drop or increase beyond set level.
3. Perform general operational controls verification testing.
4. Operate system throughout the range of operating design specifications or range of intended use.
5. System regulators must operate within ±2 psi of design level.
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6. Operate the system per applicable SOPs. Perform sampling over a 1-month period per the sampling procedure and schedule. Test samples for conformance to current USP Water for Injection monograph, microbial content, and endotoxin content. Identify all morphologically distinct colony forming units (CFUs) to at least the genus level.
7. Measure the flow rate and calculate the velocity of the water, or measure the velocity directly at a point between the last use point and the storage tank.
8. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualification testing.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The system flow rate must be in compliance with design specifications.
5. All samples must meet the following criteria:
a. Chemical Testing. Test samples must meet the acceptance criteria of the chemical tests as described in USP 24 Monograph on
Water for Injection.
b. Bacteriological Purity. All samples must contain no more than
10 cfu/100 ml; no pseudomonas or coliform are detected.
c. Endotoxins. All samples must contain no more than 0.25 EU/ml.
d. Physical Properties. The temperature of the hot Water for Injection must be greater than 80°C.
e. Particulate Matter. Small Volume Injection: The Small Volume
Injection meets the requirements of the test if the average number of particles it contains is not more than 10,000 per container that are equal to or greater than 10 µm in effective spherical diameter and not more than 1000 per container equal to or greater than 25 µm in effective spherical diameter.
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Validation of Utility Systems
14.4
Ⅲ 95
COMPRESSED AIR
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the compressed air system is capable of supplying pressurized compressed air to all use points. Perform an operational test of the distribution system and pressure regulators by monitoring the pressure output at the respective use points.
5. Perform a capacity test to verify that the system is capable of supplying the required gas, pressure, and flow rate at each use point.
6. Verify that in-line filters are integrity tested. Confirm that all documentation clearly indicates acceptable test results.
7. Perform dew point measurement.
8. Perform hydrocarbon content measurement.
9. Perform viable particulate count, microbiological at critical use points after sterile filters (refer to Federal Standard 209E).
10. Identification of oxygen content.
11. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualifications testing.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls, alarms, and interlocks operate in accordance with design specifications.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The compressed air distribution system must consistently deliver pressurized compressed air to the use points at the design pressure as specified.
5. All in-line filters are integrity tested and qualify per manufacturer’s operating specifications.
6. Dew point must be <0° or lower.
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7. Hydrocarbon content must be ≤1 ppm.
8. Viable particulate must be ≤1.0 cfu/10 ft3.
9. Nonviable particulate counts must be ≤100/ft3 of 0.5 µ or larger at all critical use points.
14.5
NITROGEN (N2)
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the nitrogen gas system is capable of supplying pressurized nitrogen to all use points. Perform an operational test of the distribution system and pressure regulators by monitoring the pressure output at the respective use points.
5. Perform a capacity test to verify that the system is capable of supplying the required gas, pressure, and flow rate at each use point.
6. Verify that the filters are integrity tested. Confirm that all documentation clearly indicates acceptable test results.
7. Perform dew point measurement.
8. Perform hydrocarbon content measurement.
9. Perform nitrogen gas identification (USP 24 Monograph).
10. Check bioburden if necessary.
11. Record the range of all process or equipment parameters (set points, pressure, timing sequences, etc.) verified during Operational and Performance Qualifications testing.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls, alarms, and interlocks operate in accordance with design specifications.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The nitrogen distribution system must consistently deliver pressurized nitrogen to the use points at the design pressure specified.
5. All filters are integrity tested and qualified per manufacturer operating specifications.
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6. Dew point must be –20°C or lower.
7. Hydrocarbon level must be ≤1 ppm.
8. Gas quality must conform to the USP 24 Monograph for nitrogen purity. 9. The microbiological test must meet the approved specification requirements. 14.6
CARBON DIOXIDE (CO2)
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the carbon dioxide gas system is capable of supplying pressurized carbon dioxide to all use points. Perform an operational test of the distribution system and pressure regulators by monitoring the pressure output at the respective use points.
5. Perform a capacity test to verify that the system is capable of supplying the required gas, pressure, and flow rate at each use point.
6. Verify that the filters are integrity tested. Confirm that all documentation clearly indicates acceptable test results.
7. Perform dew point measurement.
8. Perform hydrocarbon content measurement.
9. Perform viable particulate count (microbiological particulates).
10. Perform nonviable particulate count.
11. Perform CO2 gas identification (USP 24 Monograph)
12. Record the range of all process or equipment parameters (set points, pressure, timing sequences, etc.) verified during operational and performance qualifications testing.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls, alarms, and interlocks operate in accordance with design specifications.
3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The carbon dioxide distribution system must consistently deliver pressurized carbon dioxide to the use points at the design pressure specified. SL3305_C14_fm Page 98 Thursday, November 8, 2001 3:21 PM
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5. All filters are integrity tested and qualified per manufacturer’s operating specifications.
6. Dew point must be –20°C or lower.
7. Hydrocarbon level must be ≤1 ppm.
8. Viable particulates must be ≤1.0 cfu per 10 ft3.
9. Nonviable particulate counts must be ≤100/ft3 at 0.5 µ or larger.
10. Gas quality must conform to USP 24 Monograph for carbon dioxide purity. 14.7 HEATING, VENTILATION, AND AIR CONDITIONING
(HVAC)
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Integrity test all HEPA filters with dioctylphthalate (DOP) smoke
(0.3 µ).
5. Measure the average face velocity of each terminal HEPA filter.
Measure the average velocity 1 ft above the workspace, exposed product areas, or exposed component areas in all Class 100 laminar flow rooms or areas.
6. Verify that system air flows have been balanced to within ±10% of design criteria.
7. Verify that directional air flows are consistent with design drawings by verifying relative differential air pressures.
8. Verify that each room maintains the design temperature range for three (3) consecutive days.
9. Verify that each room maintains the design relative humidity range for three (3) consecutive days.
10. Verify that air flow patterns within Class 100 laminar flow areas are nonturbulent and unidirectional by performing smoke-stick air flow studies and recording the test on videotape.
11. Verify that rooms identified with particulate classifications are certified per Federal Standard 209E for their respective classification
(Class 100, 10,000, and 100,000).
12. Verify that AHUs, fans, and heat exchangers operate per design ratings. 13. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, etc.) verified during operational and performance qualifications testing.
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Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. HEPA filters are 99.99% efficient when tested with DOP smoke
(0.3 µ).
5. All terminal HEPA filter face velocity measurements are within ±30% of the average filter velocity.
6. The average face velocity of terminal HEPA filters servicing Class
100 laminar flow rooms is 90 ft/min ±20%, with no points below
75 ft/min or above 105 ft/min.
7. All room supply, exhaust, and return flow rates must be within
±10% of design flow rates.
8. Directional air flows (as determined by room differential pressure) must be consistent with design drawings.
9. Each room must maintain the design temperature range for three
(3) consecutive days.
10. Each room must maintain the design relative humidity range for three (3) consecutive days.
11. Air flow in Class 100 laminar flow areas must be nonturbulent and unidirectional, as demonstrated by smoke-stick studies.
12. All classified rooms are certified to meet their particulate classification per Federal Standard 209E.
13. AHU, fan, and heat exchanger operations must meet or exceed their respective design ratings.
14.8
EMERGENCY POWER (STANDBY GENERATOR)
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that the emergency power generation system has adequate power to provide all intended users upon normal power source interruption. SL3305_C14_fm Page 100 Thursday, November 8, 2001 3:21 PM
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5. Record the range of all process or equipment parameters (set points, etc.) verified during operational and performance qualifications testing.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. All intended users must operate under normal power source interruption conditions.
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15
PROCESS DESCRIPTION FOR
DRY PRODUCTION FACILITY:
BUILDING A
101
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15.1
PROCESS FLOW, VARIABLES, AND RESPONSES: TABLETS
Process Flow
Control Variables
Measured Responses
*Screen Type
*Screen Size
*Granules Size
Distribution
Blender
*Load Size
*rpm
*Blending Time
*Blend Uniformity
*Flow Characteristics
Tableting
*Compression Rate
*Granules Feed Rate
*Fill-O-Matic Speed
*Weight Variation
*Friability
*Hardness
*Thickness
*Dissolution
Addition of Raw Materials
Active
Excipients
Sizing
Mill / Sieve
Addition of Raw Materials
Lubricants
Disintegrants
Blending
High-Speed Rotary Machine
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Process Description for Dry Production Facility: Building A
15.2
Ⅲ 103
PROCESS FLOW, VARIABLES, AND RESPONSES:
POWDER FOR SUSPENSIONS
Process Flow
Control Variables
Measured Responses
*Screen Type
*Screen Size
*Granules Size
Distribution
*Load Size
*rpm
*Blending Time
*Blend Uniformity
*Moisture Content
*Filling Machine Speed
*Flow Characteristics
*Weight Variation
Addition of Raw Materials
Active
Excipients
Sizing
Mill / Sieve
Blending
Blender
Filling
Automatic Powder Filling
Machine
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15.3
PROCESS FLOW, VARIABLES, AND RESPONSES:
CAPSULES
Process Flow
Control Variables
Measured Responses
* Load Size
* rpm
* Mixing Time
* Mixing Uniformity
*Load Size
*rpm
*Blending Time
*Blend Uniformity
*Flow Characteristics
*Capsulation Speed
*Powder Feed Rate
*Weight Variation
*Disintegration Time
*Locking
Addition of Raw Materials
Active
Excipients
Mixing
Mixer
Addition of Raw Materials
Lubricants
Disintegrants
Blending
Blender
Capsulating
High-Speed Capsulation
Machine
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16
PROCESS DESCRIPTION FOR
LIQUID AND SEMISOLID
PRODUCTION FACILITY:
BUILDING B
105
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16.1 PROCESS FLOW, VARIABLES, AND RESPONSES:
SYRUP, SUSPENSION, AND DROP PRODUCTS
Process Flow
Control Variables
Measured Responses
*Mixing Time
*rpm
*Temperature
*Final Volume
*Clarity
*Viscosity
*Assay
*Mesh Size
*Filter Integrity
*Clarity
*Filling Machine Speed
*Volume
Addition of Raw Materials
Active
Excipients
Mixing
Jacketed Vessel with Variable
Speed Mixer
Filtration
Filter Press / Cartridge Filter /
Nylon Filter
Filling
Automatic Filling Machine
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Process Description for Liquid and Semisolid Production Facility: Building B
16.2
Ⅲ 107
PROCESS FLOW, VARIABLES, AND RESPONSES: CREAM,
OINTMENT, AND SUPPOSITORY PRODUCTS
Process Flow
Control Variables
Measured Responses
*Mixing Time
*rpm
*Temperature
*Amount of Stiffening Agent
*Final Volume
*Clarity
*Viscosity
*Assay
*Filling Machine Speed
*Volume Variation
Addition of Raw Materials
Active
Excipients
Mixing
Jacketed Vessel with Variable
Speed Mixer
Filling
Automatic Filling Machine
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17
PROCESS DESCRIPTION FOR
PARENTERALS PRODUCTION
FACILITY: BUILDING C
109
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17.1 PROCESS FLOW, VARIABLES, AND RESPONSES:
ASEPTIC FILL PRODUCTS
Process Flow
Control Variables
Measured Responses
Issuance of raw and packaging material
Addition of raw material
Active
Non-active
Medium
Water for injection
Steam sterilization
Pressure vessel/ filling and filtration assembly/stoppers and seals/gowning Mixing
Pressure vessel
Ampoules/vials washing * Temperature
* pH
* Conductivity
* AMC
* Time and temperature of steam sterilizer
* Time and temperature printout or graph
* Mixing time
* rpm
* Temperature
* Final volume
* pH
* Clarity
* Temperature
* Pressure
* Washing cycle
(sequence and time)
Ampoules/vials hot air sterilization
Filtration
Filtration assembly and 0.22-µ filter
Aseptic filling
Automatic filling and sealing machine
In-line filtration
Gassing
Leak test
Inspection of filled ampoules/vials Labeling/packing
* Time and temperature of dry heat sterilizer
* Time and temperature printout or graph
* Pressure
* Filter integrity test * Machine speed
* Pressure
* Flow rate
* Filter integrity test
* In-process checks
* Environment monitoring
* Air sampling and gloves print for microbial counts
* Temperature
* Pressure
* Vacuum
* Inspection of attributes
* Chemical and microbiological analysis
*In-process checks
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Process Description for Parenterals Production Facility: Building C
17.2
Ⅲ 111
PROCESS FLOW, VARIABLES, AND RESPONSES:
READY-TO-USE DISPOSABLE SYRINGES
Process Flow
Control Variables
Measured Responses
* Temperature
* pH
* Conductivity
* AMC
* Time and temperature of steam sterilizer
* Time and temperature printout or graph
* Mixing time
* rpm
* Temperature
* Final volume
* pH
* Clarity
* Pressure
* Filter integrity test
* Machine speed
* Pressure
* Flow rate
* Filter integrity test
* In-process checks
* Environment monitoring
* Air sampling and gloves print for microbial counts
Issuance of raw and packaging material
Addition of raw material
Active
Non-active
Medium
Water for injection
Steam sterilization
Pressure vessel
Filling and filtration assembly Gowning
Mixing
Pressure vessel
Sterile syringes
Filtration
Filtration assembly and 0.22-µ filter
Aseptic filling
Automatic syringe filling
Stoppering machine
In-line filtration
Gassing
Leak test
Inspection of filled syringes
Plunger rod assembly
Blister packing
* Temperature
* Pressure
* Vacuum
* Inspection of attributes
* Chemical and microbiological analysis
* In-process checks
* Final identity
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17.3
PROCESS FLOW, VARIABLES, AND RESPONSES:
TERMINAL STERILIZATION PRODUCTS
Process Flow
Control Variables
Measured Responses
Issuance of raw and packaging material
Addition of raw material
Active
Non-active
Medium
Water for injection
* Temperature
Steam sterilization
Pressure vessel
Filling and filtration assembly Gowning
* Time and temperature of steam sterilizer
* Mixing time
* rpm
* Temperature
* Final volume
Mixing
Pressure vessel
* pH
* Conductivity
* AMC
* Time and temperature printout or graph
* pH
* Clarity
* Temperature
* Pressure
* Washing cycle
(sequence and time)
Ampoules/vials washing Ampoules/vials sterilization * Time and temp. of dry heat sterilizer
* Time and temperature printout or graph
* Pressure
* Filter integrity test
* Machine speed
* Pressure
* Flow rate
* Filter integrity test
* In-process checks
* Environment monitoring
* Air sampling and gloves print for microbial counts
* Time and temperature of steam sterilizer
* Time and temperature printout or graph
* F sub-zero
Filtration
Filtration assembly and 0.22-µ filter
Filling/sealing
Automatic filling/ sealing machine
In-line filtration
Gassing
Leak test
Steam sterilization of filled ampoules/ vials * Temperature
* Pressure
Inspection of filled ampoules/vials Labeling/packing
* Vacuum
* Inspection of attributes
* Chemical and microbiological analysis
* In-process checks
* Final identity
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Process Description for Parenterals Production Facility: Building C
17.4
Ⅲ 113
PROCESS FLOW, VARIABLES, AND RESPONSES:
LYOPHILIZED PRODUCTS
Process Flow
Control Variables
Measured Responses
Issuance of raw and packaging material
Addition of raw material/Active Non Active
Medium
Water for injection
Steam sterilization
Pressure vessel
Filling and filtration assembly/Gowning Mixing
Pressure vessel
* Temperature
* pH
* Conductivity
* AMC
* Time and temperature of steam sterilizer
* Time and temperature printout or graph
* Mixing time
* rpm
* Temperature
* pH
* Clarity
* Final volume
Vial washing * Temperature
* Pressure
* Washing cycle
(sequence and time)
Vial sterilization/depyrogenation through dry heat sterilizer
Filtration
Filtration assembly and 0.22-µ filter
Aseptic filling
Automatic filling
In-line filtration
Gassing
Partial stoppering
Shelf loading
Lyophilization
Freezing
Sublimation
Freeze drying
Full stoppering
Vial sealing
Inspection of filled vials Labeling/Packing
Stopper and caps
Sterilization through steam sterilizer
* Time and temperature of dry and moist heat sterilizer
* Time and temperature printout or graph
* Pressure
* Filter integrity test
* Machine speed
* Pressure
* Flow rate
* Filter integrity test
* In-process checks
* Environment monitoring
* Air sampling and gloves print for microbial counts
* Shelf temp.
* Product temp.
* Freezing temp.
* Freezing time
* Vacuum level
* Time, temperature, and vacuum printout and graph
* Machine speed
* Inspection of attributes
* Moisture contents
* Cake uniformity
* Reconstitution time
* Chemical and microbiological assay
* In-process checks
* Final identity
SL3305_C17_fm Page 114 Thursday, November 8, 2001 3:23 PM
SL3305_C18_fm Page 115 Thursday, November 8, 2001 3:24 PM
18
QUALIFICATION OF PROCESS
EQUIPMENT
18.1
COMMUTING MILL
Test Functions
1. Perform Installation Qualification. Verify equipment identification, required documents, utilities, manual, and drawings.
2. Perform general operational controls verification testing. Verify calibration requirements.
3. Operate system throughout the range of operating design specifications or range of intended use. Verify switches and push-buttons, motor speed, empty and loaded mill, rotor blade arrow directions, auger speed arrow direction, rotor blade rotation speeds, and auger feed speed.
4. Verify that all safety devices are operating as specified in the manual. 5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates and the oxidizing effect of the air is minimal.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform the particle size test to check the fineness of each product as per product specification.
115
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Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General alarms and controls operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices operate as specified in the manual.
5. The quality of lubricants is adequate, and their storage is dry and cool. 6. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
7. The particle size of the mill granules should meet specifications.
18.2
DRYER
Test Functions
1. Perform Installation Qualification. Verify equipment identification, required documents, utilities, manual, and drawings.
2. Perform general operational controls verification testing. Verify calibration requirements.
3. Operate system throughout the range of operating design specifications or range of intended use. Verify switches and push-buttons, open-door leaks, differential pressure, timer operations, circulation air flow, exhaust air flow, high-temperature limit, and oven-door opening. 4. Verify that all safety devices of oven drying ar e operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control. 7. Perform studies to check the moisture removal on each product as per SOP.
8. Perform the study for establishing the drying time as per acceptable moisture level.
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Qualification of Process Equipment
Ⅲ 117
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General alarms and controls operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices operate as specified in the manual.
5. The quality of lubricants is adequate, and their storage is dry and cool. 6. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
7. The moisture level should meet specifications.
18.3
V-SHELL BLENDER
Test Functions
1. Perform Installation Qualification. Verify equipment identification, required documents, utilities, manual, and drawings.
2. Verify components material.
3. Verify equipment safety features.
4. Operate the blender throughout the range of operating design specifications or range of intended use.
5. Verify equipment switches, push-buttons, rotation direction, and motor fixed speed.
6. Perform the assay to check the content uniformity on blended granules at different locations.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General alarms and controls operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices operate as specified in the manual.
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5. The quality of lubricants is adequate and the lubricants are properly stored. 6. Unauthorized changes to cycle parameters are not allowed without supervisory control or password.
7. Assay results should be within the specifications.
18.4
TABLET COMPRESSION
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that all safety devices of the tablet press are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
7. Perform capability and consistency studies to check the weight variation of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. The machine must be in statistical control as per capability and consistency studies.
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Qualification of Process Equipment
18.5
Ⅲ 119
CAPSULATION
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that all safety devices on the capsulation machine are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform capability and consistency studies to check the weight variation of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Machine must be in statistical control as per capability and consistency studies.
18.6
POWDER FILLING
Test Functions
1. Perform Installation Qualification.
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2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that all safety devices of the powder filling machine are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform capability and consistency studies to check the weight variation of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to the manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Machine must be in statistical control as per capability and consistency studies.
18.7
CAPSULE POLISHER
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
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4. Verify that all safety devices of the capsule polisher are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform studies to check the capsule polishing of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General alarms and controls operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices operate as specified in the manual.
5. The quality of lubricants is adequate and as per supplier’s recommendation. 6. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
7. The machine must be in statistical control as per study.
18.8
TABLET COATING
Test Functions
1. Perform Installation Qualification. Verify equipment identification, required documents, utilities, component materials, drawings, and manuals. 2. Perform general operational controls verification testing. Verify coating pan motor, supply blower, exhaust motor, and spray system.
3. Operate system throughout the range of operating design specifications or range of intended use. Verify switches and push-buttons, rotator direction, motor variable speed, supply temperature, differential pressure, and pan air flow.
4. Verify that all safety devices are operating as specified in the manual. SL3305_C18_fm Page 122 Thursday, November 8, 2001 3:24 PM
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5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform physical attribute characteristic studies to check the uniformity of the coating on each product as per SOP and acceptance criteria. Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General alarms and controls operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices operate as specified in the manual.
5. The quality of lubricants is adequate and their storage as recommended by the manufacturer.
6. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
7. Coating must be in compliance with SOP and acceptable quality levels. 18.9
SYRUP MANUFACTURING VESSEL
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of mixing speed, temperature, and vacuum, or the range of intended use.
4. Verify that all safety devices of vessel are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
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7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Assay the final mix to check the content uniformity of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Assay results should meet specifications.
18.10
SUSPENSION MANUFACTURING VESSEL
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of mixing speed, temperature, and vacuum and homogenization, or the range of intended use.
4. Verify that all safety devices of the vessel are operating as specified in the manual.
6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Assay the final mix to check the content uniformity of each product as per SOP.
9. Perform particle size distribution and re-suspendibility tests over the final blend as per SOP.
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Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Assay results and re-suspendibility should meet specifications.
18.11
DROPS MANUFACTURING VESSEL
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of mixing speed, temperature, and vacuum, or the range of intended use.
4. Verify that all safety devices of the vessel are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Assay the final mix to check the content uniformity of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
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2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Assay results should meet specifications.
18.12
MIXER
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of mixing speed or range of intended use.
4. Verify that all safety devices of the mixer are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Assay the mixed blend to check the content uniformity of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
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5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Assay results should meet specifications.
18.13
EMULSIFYING MIXER
Test Functions
1. Perform Installation Qualification. Verify equipment identification, required documents, utilities, component materials, drawings, and manuals. 2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications, or range of intended use, at fixed speed. Verify switches and push-buttons, rotator direction, and motor variable speed.
4. Verify that all safety devices of the emulsifying mixer are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform globule size assay to check the uniformity of emulsification on each product blend as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General alarms and controls operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices operate as specified in the manual.
5. The quality of lubricants is adequate and their storage is according to manufacturer recommendations.
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6. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
7. The machine must be in statistical control as per capability study.
8. Assay results should meet specifications.
18.14
FILTER PRESS
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of vacuum operating design specifications or range of intended use.
4. Verify that all safety devices of filter press are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform visual inspection under magnification to check the clarity of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Visual inspection results must meet product specifications.
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18.15
CREAM/OINTMENT/SUPPOSITORY
MANUFACTURING VESSEL
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of mixing speed, temperature, and vacuum, or the range of intended use.
4. Verify that all safety devices of vessel are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform assay of final mix to check the content uniformity of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Assay results should meet specifications.
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18.16 SYRUP, SUSPENSION,
AND DROP FILLING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use (e.g., different packages).
4. Verify that all safety devices of vessel are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform capability studies to check the volume variation on each size of product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. The machine must be in statistical control as per capability study.
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18.17
CREAM AND OINTMENT FILLING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that all safety devices of filling machine are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform capability studies to check the weight variation of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. The machine must be in statistical control as per capability study.
18.18
SUPPOSITORY FILLING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
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3. Operate system throughout the range of operating design specifications of mixing speed, temperature, fill volume/weight, or the range of intended use.
4. Verify that all safety devices of the suppository filling machine are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform capability and consistency studies to check the weight variation of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be as per manufacturer recommendations. 7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Machine must be in statistical control as per capability and consistency studies.
18.19
LABELING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of speed, temperature, and vacuum, or the range of intended use.
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4. Verify that all safety devices of labeling machine are operating as specified in the manual.
5. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
6. Perform inspection to check the labeling on each pr oduct as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices must operate as specified in the manual.
5. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
6. The labeling is performed in accordance with the acceptance criteria. 18.20
CAPPING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of speed, or the range of intended use.
4. Verify that all safety devices of capping machine are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform the torque test on different bottle sizes and check the capping on each product as per SOP.
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Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be according to manufacturer recommendations.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. Torque of the caps should meet specifications.
18.21
CARTONATOR
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of feeding speed, or the range of intended use.
4. Verify that all safety devices of cartonator are operating as specified in the manual.
5. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
6. Check that change parts of each size are available.
7. Perform inspection to check the cartoning on each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
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4. Safety devices must operate as specified in the manual.
5. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
6. The cartoning operation meets the acceptance criteria.
18.22
SHRINK-WRAPPING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of shrink-wrapping speed, temperature, and vacuum, or the range of intended use.
4. Verify that all safety devices of the shrink-wrapping machine are operating as specified in the manual.
5. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
6. Perform inspection to check the shrink-wrapping on each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
6. The shrink-wrapping operation meets the acceptance criteria.
18.23
OVER-PRINTING MACHINE
Test Functions
1. Perform Installation Qualification
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications of printing speed, or the range of intended use.
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4. Verify that all safety devices of the over-printing machine are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Perform inspection to check the over-printing on each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The over-printing operation meets the acceptance criteria.
18.24
TRAYS AND RACK WASHER
Test Functions
1. Perform Installation Qualification. Verify equipment identification, required documents, utilities, components material, drawings, and manuals. 2. Perform general operational controls verification testing. Check header drive circulation pump, rinse pump, detergent pump, exhaust fan, and drying fan.
3. Operate system throughout the range of operating design specifications or range of intended use at fixed speed. Verify switches and push-buttons and calibration requirements.
4. Verify that all safety devices of tray/rack washer are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
7. Perform the study to check the time of washing and detergent contamination on each product as per SOP.
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Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General alarms and controls operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The safety devices operate as specified in the manual.
5. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
6. The tray and rack washer operation shall meet the acceptance criteria. 18.25
AUTOCLAVE (STEAM STERILIZER)
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Perform vacuum pump evacuation rate test to verify that the vacuum pump evacuates the chamber at the rate specified.
5. Perform chamber vacuum and positive pressure integrity verification studies to verify that the chamber does not leak.
6. Perform controller security challenges to verify that sterilization cycle parameters cannot be altered without appropriate supervisory control. 7. Take pressure and temperature measurements to verify that the steam is 100% saturated during the dwell period.
8. Perform simulated steam supply failures to verify that the controller either resets the dwell timer or stops incrementing upon a drop in temperature below the set point.
9. Perform three (3) empty chamber heat distribution studies to determine the thermal characteristics of the sterilization cycles. A
Kaye Validator equipped with thermocouples shall be used to map the internal chamber temperatures.
10. Perform three (3) loaded chamber heat penetration studies to determine the coolest point within a specified load and configuration. A Kaye Validator equipped with thermocouple-probed containers will be used to provide an equal representation among layers in the chamber.
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11. Perform microbiological challenge studies to determine the degree of process lethality provided by the sterilization cycle. The microorganisms most frequently utilized to challenge steam sterilization cycles are Bacillus Stearothermophilus and Clostridium Sporogenes of 106 population.
A Kaye Validator equipped with thermocouple-probed containers and the containers previously inoculated with the biological indicator will be positioned in the detected cool points of the load configuration. After the sterilization cycle is complete, the inoculated containers are recovered and subjected to microbiological test procedures.
12. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during operational and performance qualifications testing.
13. Air filters must be tested for integrity.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The vacuum pump evacuates the chamber to the target pressure at a rate equal to or greater than specified.
5. The average chamber leak rate is in accordance with the manufacturer recommendations.
6. Unauthorized changes to cycle parameters are not allowed without supervisory control or password.
7. The temperature and pressure during the dwell period must indicate 100% saturated steam.
8. The controller must either reset the dwell timer or stop incrementing upon a drop in temperature below the set point.
9. The chamber temperature recorded by the sterilizer temperature control system must be within ±0.5°C of the set point during the stabilized portion of the dwell period.
10. The maximum temperature deviation from the mean chamber temperature at any one print interval during the stabilized dwell period is within ±0.5°C.
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11. Heat distribution thermocouples at each 1-minute print interval must be within ±1.0°C of the mean chamber temperature of all distribution thermocouples during the dwell period after stabilization.
12. The slowest-to-heat location (coolest point) in each test run must receive an F0 (121°C) of at least 20 minutes, as calculated during the dwell period only.
13. A minimum Solution Microbiological Challenge Spore Log Reduction (SLR) of equal to or greater than 6 must be shown for each run.
14. Air filters must pass integrity test.
18.26
HOT AIR TUNNEL (DRY HEAT STERILIZER)
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Document the system operation, including performance checks of safety interlocks and values of operating parameters, during a minimum of three (3) consecutive acceptable runs.
5. Verify that particulate levels within the chamber are within acceptable limits.
6. Perform three (3) empty chamber heat distribution studies to determine the thermal characteristics of the sterilization cycles. A
Kaye Validator equipped with thermocouples should be used to map the internal chamber temperatures.
7. Perform three (3) loaded chamber heat penetration studies to verify that the temperature distribution is uniform for the load configuration, and that all measured points within each load configuration receive thermal treatment sufficient for depyrogenation and sterilization. A Kaye Validator equipped with thermocouple-probed containers shall be used to provide an equal representation among layers in the chamber.
8. Perform microbiological challenge test. Confirm through laboratory testing that all endotoxin samples in each load are reduced by a minimum of 3 logs. Endotoxin reduction of 3 logs or greater will also ensure a greater than 12 log reduction of biological organisms.
9. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualifications testing.
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Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. All monitoring and functional testing of the system will be completed and approved. The Performance Qualification will document that the system is capable of operating within specified parameters and is ready for validation.
5. The endotoxin content of all endotoxin indicators must be reduced to levels of <0.025 EU (or undetectable), or at least demonstrate a minimum 3 log reduction for three (3) consecutive runs.
6. Positive control for endotoxin indicator must yield a minimum of
1000 EU.
7. Negative control for endotoxin indicator must be <0.03 EU/ml.
8. Temperature distribution thermocouples in the heat penetration and distribution test studies for three (3) consecutive runs must be within ±5°C of the set point temperature during the dwell period.
9. All thermocouples within the load must be at or above 250°C.
10. Testing is to be repeated until a minimum of three (3) consecutive tests meet requirements.
11. All test instruments used during the Performance Qualification shall be calibrated and certified using NIST traceable standards.
12. FH(250°C) shall be calculated.
18.27
VIALS/AMPOULES WASHING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Three (3) sets of vials will be spiked with an NaCl solution, dried, and then washed. Baseline data will be established using unwashed, NaCl-spiked bottles. The washed vials will be tested for conductivity (NaCl), particulate count (WFI), and concentrations of the three solutions. Also, one load will be run with all vials in
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5.
6.
7.
8.
the load spiked with fluorescent dye. These vials will be inspected for dye residue.
Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualifications testing.
The pressure/temperature of cleaning media (DIW, WFI, compressed air) must be documented.
Machine speed (amp/min or vials/min) and exposure time of cleaning media must be documented.
All in-line filters are to be tested for integrity.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. No dye residue is detected at >1 ppb in any of the washed vials.
5. The rinse solution from each washed, NaCl-spiked vial must have a conductivity <1 µmho.
6. The rinse solution from each washed, NaCl-spiked vial must have no precipitate when tested per USP 24 Monograph for Sodium
Chloride.
7. Both the rinse solutions from the NaCl-spiked and unspiked vials must have particulate counts that meet the specifications listed in
USP 24, Physical Test, Particulate Matter in Injections.
8. The rinse solutions from the NaCl-spiked and unspiked vials must meet the specifications for Water for Injection listed in USP 24
Monograph for Water for Injection.
9. The rinse solutions from the unspiked vials must contain no more than 0.25 EU/ml.
18.28
AMPOULES/VIALS/SYRINGES FILLING MACHINE
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
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3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that all safety devices of ampoules, vials, and syringes filling machine are operating as specified in the manual.
5. Verify that recommended lubricants are used during machine operation. 6. Verify that all lubricants such as oil and grease are kept in clean, sealed containers so that no dust or moisture penetrates, and that the oxidizing effect of the air is minimal.
7. Perform controller security challenges to verify that specified parameters cannot be altered without appropriate supervisory control.
8. Perform capability studies to check the volume variation of each product as per SOP.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Safety devices must operate as specified in the manual.
5. The recommended lubricants must be used as specified in the manual. 6. The storage location of the lubricants must be dry and cool.
7. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
8. The machine must be in statistical control as per capability studies.
18.29
FREEZE DRYER (LYOPHILIZER)
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Perform vacuum pump evacuation rate test to verify that the vacuum pump evacuates the chamber at the rate specified.
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5. Perform chamber vacuum and positive pressure integrity verification studies to verify that the chamber does not leak.
6. Perform controller security challenges to verify that lyophilization cycle parameters cannot be altered without appropriate supervisory control. 7. Upon completion of the filling operation, the product is placed on the shelves in the lyophilizer. A number of temperature probes should be placed in product vials located throughout the batch.
The temperature probes can be placed at multiple positions in a select number of vials. Having probes at these positions will yield results indicating that the entire batch of product is at the same temperature. 8. Verify that the temperature throughout the chamber is maintained at set point(s). Gather baseline data on time vs. temperature profile in the event of a power failure.
9. Record the range of all process or equipment parameters (set points, flow rates, speeds, timing sequences, concentrations, etc.) verified during operational and performance qualifications testing.
10. Heat distribution study should be performed (3 consecutive runs) with documentation for pressure, temperature set points, and exposure time.
11. WFI conductivity, flow rate, temperature, and pressure should be checked. 12. N2 filter should be tested for integrity.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. The vacuum pump must evacuate the chamber to the target pressure at a rate equal to or greater than specified.
5. The average chamber leak rate must be in accordance with the manufacturer recommendations.
6. Unauthorized changes to cycle parameters must not be allowed without supervisory control or password.
7. All temperature monitoring points (thermocouples) are maintained within a specified range during the specified testing period.
8. F0 (121°C) of at least 20 minutes.
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9. Water for Injection (WFI) must meet specifications.
10. N2 filter must pass the integrity test.
18.30
LAMINAR FLOW UNIT
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Integrity test all HEPA filters with dioctylphthalate (DOP) smoke.
5. Measure the average face velocity of each terminal HEPA filter.
Measure the average velocity 1 ft above the workspace, exposed product areas, or exposed component areas in all Class 100 laminar flow rooms or areas.
6. Verify that system air flows have been balanced to within ±10% of design criteria.
7. Verify that air flow patterns within Class 100 laminar flow areas are nonturbulent and unidirectional by performing smoke-stick air flow studies and recording the test on videotape.
8. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Operational and Performance Qualifications testing.
9. Verification of particle count (Class 100).
10. Verification of decontamination time.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. HEPA filters are 99.99% efficient when tested with DOP smoke.
5. All terminal HEPA filter face velocity measurements are within ±30% of the average filter velocity.
6. The average face velocity of terminal HEPA filters servicing Class
100 laminar flow rooms is 90 ft/min ±20% with no points below
75 ft/min or above 105 ft/min.
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7. Directional air flows (as determined by room differential pressure) must be consistent with design drawings.
8. Each room must maintain the design temperature range.
9. Air flow in Class 100 laminar flow areas must be nonturbulent and unidirectional, as demonstrated by smoke-stick studies.
10. AHU, fans, and heat exchanger operations meet or exceed their respective design ratings.
11. Particle count must meet specifications.
18.31
PASS-THROUGH
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
4. Verify that both doors of the pass- through cannot be open simultaneously. 5. Verify that directional air flows are consistent with design drawings by verifying relative differential air pressures.
6. Verify air flow patterns by performing smoke-stick air flow studies and recording the test on videotape.
7. Integrity test HEPA filter with dioctylpthalate (DOP) smoke.
8. Particle count test (Class 100).
9. Air velocity.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specifications throughout the operating range or range of intended use.
4. Both doors of the pass-through should not be open simultaneously.
5. Pass-through shall be under positive pressure in relation to adjacent areas of other than an equal or higher Class 100 classification. In sterile powder handling areas, an airlock must be under negative pressure to prevent the movement of dust from one sterile area to another.
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6. Air flow in Class 100 pass-through must be outward directional, as demonstrated by smoke-stick studies.
7. HEPA filter is 99.99% efficient when tested with DOP smoke.
8. Particle count must meet specifications.
9. Face velocity = 0.45 ±20%.
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19
VALIDATION OF SUPPORT
PROCESSES
19.1
WASHING OF COMPONENTS
The washing of components will be validated for each load configuration in the vial washer. Cycle Development Testing and Performance Qualification testing will qualify each washing process. A separate performance qualification and cycle development testing report will be written for each load configuration. The processes will be considered validated when the acceptance criteria is met for three (3) successful consecutive runs.
Cycle Development Testing
Perform one or more cycle development test runs with vials to determine appropriate time for each cycle (wash and rinse), temperature for each cycle, load size, WFI supply pressure, and air supply pressure.
Performance Qualification Test Functions
1. Identify and document the quantity and placement of vials in the load configuration. Determine load configuration from Cycle Development Test studies.
2. Prepare a full load of vials spiked with dye. Wash the vials as per the proposed operating procedure. Inspect each vial for dye residue.
3. Spike three (3) sets of vials with NaCl solution. Allow vials to dry and then wash them per the proposed procedure. Baseline data will be established using unwashed, NaCl-spiked vials. Test the washed vials for conductivity (NaCl) and particulate count (WFI).
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Acceptance Criteria
1. No dye residue is detected at >1 ppb in any of the washed vials.
2. The rinse solution from each washed, NaCl-spiked vial must have a conductivity <2 µmho.
3. The rinse solution from each washed, NaCl-spiked vial must have no precipitate when tested per USP 24 Monograph for Sodium
Chloride.
4. Both the rinse solutions from the NaCl-spiked and unspiked vials must have particulate counts that meet the specifications listed in
USP 24 Monograph for Physical Test, and Particulate Matter in
Injections.
5. The rinse solutions from the NaCl spiked and unspiked vials must meet the specifications for Water for Injection listed in USP 24
Monograph for Water for Injection.
6. The rinse solutions from the unspiked vials must have no more than 0.25 EU/ml.
19.2
STERILIZATION OF COMPONENTS
The sterilization of components and equipment will be validated for each load configuration using the cGMP autoclave. Cycle Development Testing and Performance Qualification Testing will qualify each sterilization process. A separate Performance Qualification and Cycle Development Testing
Report will be written for each load configuration. The process will be considered validated when the acceptance criteria is met for three (3) successful consecutive runs.
Cycle Development Testing
Perform one or more cycle development test runs used in the load configuration to determine appropriate cycle type, temperature and dwell period, hard-to-heat items or areas, load item preparation, and minimum and maximum load configurations.
Performance Qualification Test Functions
1. Identify and document the quantity, placement, and physical description of each component to be included in the load configuration. Determine the load configuration from Cycle Development
Test studies.
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2. Perform load and chamber temperature mapping and verify that the temperature distribution in the chamber is uniform for the load configuration, and that all measured points within the load configuration receive thermal treatment sufficient for sterilization. Perform three (3) runs on the maximum load and a minimum of three
(3) runs on the minimum load.
3. Perform microbiological challenge studies using the Overkill
Approach Sterilization Validation. Place Bacillus stearothermophilus spores throughout the load configuration, at points where steam penetration may be incomplete, and at hard-to-heat locations.
Perform a minimum of three (3) runs on the maximum load configuration and a minimum of three (3) runs on the minimum load configuration. Perform spore quantification verification on each manufacturer’s lot of spore strips or suspensions. Perform microbiological challenge studies simultaneously with loaded chamber heat penetration and distribution studies.
4. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during cycle Development and Performance Qualifications testing.
Acceptance Criteria
1. During load and chamber temperature mapping, the maximum load configuration, the mean of the F 0 values from the single slowest-to-heat point from each of the three (3) test runs minus 3 standard deviations of the these three F0 values must be greater than 20 min.
2. During load and chamber temperature mapping, the minimum load configuration, the mean of the F0 values from the single slowestto-heat point from each of the three (3) test runs minus 3 standard deviations of the these three F0 values must be greater than 20 min.
3. During microbiological challenge studies, all Bacillus stearothermophilus spore strips/suspensions must show negative test for the growth of B. stearothermophilus.
4. During microbiological challenge studies, positive controls for the
B. stearothermophilus spore strips/suspensions must test positive for the growth of B. stearothermophilus.
5. During Microbiological Challenge studies, spore strips/suspension quantification test must indicate that the population of each manufacturer’s lot of spore strips/suspensions is within ±50% of their labeled population.
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19.3
DEPYROGENATION OF COMPONENTS
The depyrogenation of components will be validated for each load configuration using the depyrogenation hot air sterilization tunnel. Cycle
Development Testing and Performance Qualification Testing will qualify each depyrogenation process. A separate Performance Qualification and
Cycle Development Testing Report will be written for each load configuration. The processes will be considered validated when the acceptance criteria is met for three (3) successful consecutive runs.
Cycle Development Testing
Perform one or more cycle development test runs with item used in the load configuration to determine appropriate cycle type, temperature and dwell period, hard-to-heat items or areas, load item preparation, and minimum and maximum load configurations.
Performance Qualification Test Functions
1. Identify and document the quantity, placement, and physical description of each component to be included in the load configuration. Determine load configurations from Cycle Development
Test studies.
2. Perform load and chamber temperature mapping and verify that the temperature distribution in the chamber is uniform for the load configuration, and that all measured points within the load configuration receive thermal treatment sufficient for depyrogenation.
Perform three (3) runs on the maximum load and a minimum of three (3) runs on the minimum load.
3. Perform pyrogen challenge studies and verify through laboratory testing that the endotoxin contents of all indicators in each load are reduced by a minimum of 3 logs. Endotoxin reduction of 3 logs or greater will also ensure a greater than 12 log reduction of biological organisms.
4. Record the range of all process or equipment parameters (set points, flow rates, timing sequences, concentrations, etc.) verified during Cycle Development and Performance Qualifications Testing.
Acceptance Criteria
1. Temperature distribution thermocouples in the heat penetration and distribution test studies for three (3) consecutive runs must be within ±5°C of the mean chamber temperature during the dwell period at any one print interval.
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2. During heat penetration studies, all thermocouples must receive a minimum temperature of 250°C. FH (250°C) must be calculated.
3. The endotoxin content of all endotoxin indicators must be reduced to levels of <0.025 EU (or undetectable), or at least demonstrate a minimum of 3 log reduction for three (3) consecutive runs at half-cycle. 4. Positive controls for endotoxin indicators must yield a minimum of 1000 EU.
5. Negative controls for endotoxin indicators must be <0.03 EU/ml.
19.4
ASEPTIC FILLING VALIDATION (MEDIA FILL STUDIES)
Protocols will be developed to demonstrate that the product is aseptically filled into a final dosage container. These studies will consist of exposing media capable of supporting a broad spectrum of microbiological growth to all operations and procedures normally performed during the manufacturing process. Vials will be filled at the normal working volume. Each study will include filling approximately 3000 vials/ampoules. The vials/ampoules will be incubated at 20 to 25°C for 14 days.
“Worst-case,” challenges such as personnel breaks, equipment adjustments, and additional personnel in the fill room will be incorporated into all media fill studies. Stoppers and vials or ampoules will be sterilized.
The time between sterilization and the start of the first media fill will be the maximum validated storage time for sterile stoppers, vials, and ampoules, provided the media fills meet all other acceptance criteria.
All environmental monitoring supplies will be growth promoted on the release date and fill date. Agar strips will be growth promoted after being exposed to the same environmental conditions as those experienced during the fill. Growth promotion will be performed for organisms required by USP 24 Monograph for Indigenous Organisms and Anaerobes using vials/ampoules collected during the fill and upon completion of the 14-day incubation period.
The protocol will include acceptance criteria for sterility assurance level and growth promotion.
Also included will be details of data collection, growth promotion sampling, environmental and personnel monitoring schedule, personnel movement documentation, incubation time and temperature, etc.
Acceptance Criteria
Upon successful completion (end-point contamination level of not more than 0.1%) of three (3) consecutive media fills for the vial/stopper combination and ampoules, the aseptic process will be considered validated.
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19.5
CROSS-CONTAMINATION CONTROL
Test Functions
1. Verification of HVAC design, zoning of air handling units, airlocks, room pressure differentials, recirculation vs. once-through air handling systems, room air distribution, use of HEPA filters on main return ducts to air handling plants, supply and return duct work, fresh air intakes and exhaust for buildings A, B, and C.
2. Verification of materials and product dispersal around manufacturing facility in buildings A, B, and C.
3. Verification of spread of materials and products during maintenance and cleaning of environmental and process air handling plant and equipment. 4. Verification of containment of materials and products during processing. 5. Verification of dust collection system as per design.
6. Verification of movement of personnel, gowning, and laundry as per design.
7. Verification of utilities design, mix-up, identification, check valves, and back-flow prevention.
8. Verification of facility design, architectural finishes, and room layout.
9. Verification of equipment design, construction materials, clean in-place (CIP) units where possible, and cleaning out-of-place practice. 10. Verification of cross-contamination prevention by performing air sampling and machine swabs.
11. Verification of prevention of cross-contamination by cleaning system validation.
12. Verification of prevention of cross-contamination through residual analysis of finished products.
13. Verification of pallets transfer and interlocks as per design.
Acceptance Criteria
1. The system is installed in accordance with design specifications based on manufacturer recommendations and cGMP guidelines and documented.
2. Materials and product dispersal around manufacturing facility in buildings A, B, and C with design specification.
3. Spread of materials and products during maintenance and cleaning of environmental and process air handling plant and equipment is maintained and demonstrated through environmental monitoring.
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4. Containment of materials and products during processing is demonstrated through environmental monitoring.
5. Dust collection system operates in accordance with design specifications throughout the operating range or range of intended use.
6. General control of movement of personnel, gowning, and laundry is demonstrated through SOP compliance and training.
7. General controls, alarms, identification, and interlocks operate in accordance with design specifications.
8. Facility construction and architectural finishes demonstrate adherence to specifications and cGMPs.
9. Equipment design, construction materials, CIP, and cleaning out-of-place practice are in compliance with cGMPs.
10. Air sampling and machine swabs results meet the acceptance criteria established.
11. Area/equipment cleaned in accordance with the written SOPs and meet the acceptance criteria.
12. The pallet transfer units and interlocks operate as per design and in accordance with the written SOPs.
19.6
COMPUTERIZED PHARMACEUTICAL SYSTEM
Test Functions
1. Perform Installation Qualification.
2. Confirm that hardware and software descriptions are available.
3. Confirm that the documentation is appropriate, up-to-date, relevant, and complete.
4. Verify the digital transmission inputs and outputs as appropriate.
5. Verify analog transmission inputs and outputs as appropriate.
6. Verify data entry and boundary testing as appropriate.
7. Verify access control testing as appropriate.
8. Verify SOPs for operation, maintenance, and change control.
9. Verify training records.
10. Verify system recovery procedure.
Acceptance Criteria
1. The system is installed in accordance with design specifications based on manufacturer recommendations and cGMP guidelines.
Instruments are calibrated, identified, and entered into the calibration program.
2. Hardware and software systems are verified as per manual.
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3. The documentation is appropriate, up-to-date, relevant, and complete as per protocol.
4. The digital transmission inputs and outputs are verified.
5. The analog transmission inputs and outputs are verified.
6. The data entry and boundary testing meets the specification design.
7. The access control testing meets the specification design.
8. SOPs are available for operation, maintenance, and change control.
9. Training records are available.
10. System recovery procedure is available.
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20
QUALITY
ASSURANCE/CONTROL
LABORATORY VALIDATION
The Quality Assurance/Control Laboratory serves one of the most critical functions in the ABC Pharmaceutical facility. Consequently, a comprehensive validation program will be initially performed for procedures and equipment used for all products, as well as any analytical procedures required for the first scheduled product. Thereafter, the analytical methods requirements and resulting validation will be evaluated and performed as necessary for each new product.
The Quality Assurance/Control staff will evaluate in detail the analytical requirements and the procedures. Where applicable, the validated laboratory equipment and analytical methods will be utilized.
Equipment and methods will be operated/performed in accordance with cGMPs. Instruments will be calibrated, automatic analyzers and equipment will be qualified; computer-related systems will be validated; analytical methods from USP/NF will be verified; and glassware preparation, media preparation, and noncompendial methods will be validated.
20.1
LABORATORY EQUIPMENT QUALIFICATION
Laboratory equipment such as incubators, refrigerators, laminar flow hoods, depyrogenation ovens, sterilizers, etc., will be qualified using the same approach as that used for process equipment and utility systems.
The processes of sterilization and depyrogenation of laboratory equipment and microbiological media will be validated using the same approach as that used for production processes. Test functions and acceptance
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criteria for these validation protocols are summarized in Chapter 19.2 and
19.3, respectively.
Automatic analyzers will be qualified by performance of Installation and Operation Qualifications. The purpose of the qualification for automatic analyzers is the same as that for any other piece of cGMP equipment: to verify that it has been installed and operates in accordance with design specifications, manufacturer recommendations, and cGMPs.
Test Functions
1. Perform Installation Qualification.
2. Perform general operational controls verification testing.
3. Operate system throughout the range of operating design specifications or range of intended use.
Acceptance Criteria
1. The system is installed in accordance with design specifications, manufacturer recommendations, and cGMPs. Instruments are calibrated, identified, and entered into the calibration program.
2. General controls and alarms operate in accordance with design specifications. 3. The system operates in accordance with design specification throughout the operating range of intended use.
20.2
COMPUTER-RELATED SYSTEMS USED
IN THE QA/QC LABORATORY
Computer-related systems used in the laboratory for control of automatic analyzers and/or laboratory information management systems will be validated; however, additional emphasis will be placed on the following specific concerns:
Ⅲ Authorization for data entry
Ⅲ Features to prevent deletion of data (changes must be made as amendments; deletion of data is not permitted)
Ⅲ Security of the database (database must be as tamper-proof as possible) Ⅲ Procedures for ensuring the validity of the data
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21 cGMP PROCEDURES
AND PROGRAMS
21.1
ENGINEERING CHANGE CONTROL
Change Control will be written to ensure that systems and processes remain in a state of validation. The procedure outlines steps to follow when a change is proposed. The change control program ensures that proposed changes are reviewed and approved by appropriate departmental representatives prior to initiating changes. The review also defines the required tests and documentation to be performed to verify that the system, equipment, and process remain in a validated state.
21.2
CALIBRATION
The calibration program will ensure that all critical instruments used are maintained in a calibrated state. Specific acceptance criteria limits will be established based on system and processing requirements.
Periodic calibration orders generated by the calibration program will contain information such as department, location, accuracy, data sheet number, SOP number, etc. needed by the calibration technician. Instrumentation in this program will include, but is not limited to, timers, monitoring probes (temperature, relative humidity, etc.), pressure gauges, balances, etc.
Each instrument will be placed in one of three categories: Critical,
Non-critical, and Convenience. A critical instrument is one whose failure or precision directly affects the quality, purity, and/or integrity of the product. A non-critical instrument does not fall into the Critical category, but can be used in troubleshooting, mainting, controlling, or monitoring
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a process or test that is potentially hazardous. A Convenience instrument is any instrument that does not fall into the Critical or Non-critical category.
Instrument calibrations are required at intervals based on the criticality of the instruments, instrument capability, and instrument calibration history. An instrument will also be calibrated following the repair of the instrument, following the repair of the system that the instrument is monitoring/controlling, if the repair could have affected the instrument accuracy, and/or after installing the instrument into a system. All equipment used to perform calibrations will be calibrated to standards traceable to the National Institute of Standards and Technology (NIST) or other approved standards and maintain the following:
Ⅲ Standards
Ⅲ Instrument numbering system
Ⅲ Instrument calibration files
21.3
PREVENTIVE MAINTENANCE PROGRAM
A preventive maintenance program is developed and implemented to maintain production systems in proper working condition and reduce equipment malfunctions.
The manufacturer’s specifications, past experience, and history of the equipment will be used to establish the preventive maintenance schedule.
Procedures will be developed for issuing work orders, performing the maintenance work, documenting the work in the proper logbooks and files, frequency of performing preventive maintenance, reviewing the impact of maintenance on validation state, etc.
21.4
STANDARD OPERATING PROCEDURES (SOPs)
The standard operating procedure (SOP) system is established, procedure number WXY-001 “for Preparation, Approval and Issue of Standard Operating Procedure.” The procedure includes instructions for preparation, review, approval, issuance, control, modification, and document retention.
The modification to procedure WXY-001 will include establishment of the review and approval.
All new procedures will be written to address all activities performed in the facility, including documentation systems, raw materials handling and control, personnel movement, equipment operation, product formulation, handling and testing, etc.
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21.5
Ⅲ 159
FACILITY CLEANING AND SANITIZATION
A comprehensive Facility Cleaning and Sanitization Program with an initial schedule for each room will be developed, with procedures based on the initial sanitization validation results, the criticality of operation performed in each area, and the frequency of use. The initial schedule will be modified as necessary based on routine environmental monitoring. The environmental monitoring results will be compared against alert and action levels.
The program will include a schedule for rotation of sanitizing agents to prevent the proliferation of resistant organisms in the facility. Cleaning and sanitizing will be documented in logbooks, the status of each room will be marked, and all cleaning will be performed per written procedures
(SOPs). Sanitizing agents will be routinely monitored for bacterial contamination. Logbooks will be periodically reviewed by Quality Assurance.
21.6
ENVIRONMENTAL MONITORING PROGRAM
A comprehensive Environmental Monitoring Program will be developed to ensure that the environmental conditions are maintained within validated limits. The program will include critical utility systems, microbiological testing areas, and manufacturing areas. Parameters that may affect the integrity of the product or manufacturing process, personnel safety, or the cleaning and sanitization program will be monitored. These parameters include nonviable particulate, bioburden, purity, identity, temperature and relative humidity.
Most of the testing procedures required for this program will be adapted from Quality Assurance and Quality Control procedures. The existing analytical and microbiological procedures have been validated or verified.
Any additional analytical or microbiological test procedures will be validated or verified.
Alert and action levels for each parameter in each area or critical utility will be established based on the results from validation testing, compendia requirements, and cGMPs. Area or room limits will be based on the environmental data collected during the validation of the aseptic filling process validation. Specific action plans will be developed for addressing excursions beyond alert and action limits for each area or utility.
21.7
HEPA FILTER INTEGRITY TESTING
A procedure will be developed that identifies the certification requirements for all High Efficiency Particulate Air (HEPA) filters in the Injectable facility.
This will include HEPA filters mounted in ceilings, flow hoods, biosafety
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cabinets, cleanroom vacuum cleaners, microbiology testing rooms, and air handling units. HEPA filters will be certified by the DOP test method for proper face velocity profile, velocity at the workspace, and integrity. HEPA filters will be initially tested as part of the installation, and all test documentation will be verified and included in the Validation Package for the HVAC system, biosafety cabinets, and laminar flow hoods. Terminal
HEPA filters servicing Class 100 areas will be certified more frequently than those in Class 1000 or greater areas.
21.8
FILTER INTEGRITY TESTING
A filter testing procedure will be developed to ensure that bacterial retentive air and liquid filters are integrity tested and replaced as necessary.
This program will include those filters not directly in the process stream, such as vent filters on tanks and autoclaves, and compressed gas filters.
This procedure will include filter integrity testing instructions, schedules, and acceptable test results.
Filters that are directly in the process stream, such as product sterilizing filters and media sterilizing filters, will be tested before and after the processing of each batch and documented in the actual batch production records.
The automatic filter integrity tester will be operationally qualified, and all test parameters and acceptable test results will be verified in the
Operational and Performance Qualifications of the equipment, for example, the Sterilizing Filter and the Media Preparation System.
21.9
LABEL CONTROL PROGRAM
The label control program and procedure includes labeling requirements.
The program is structured to ensure the following:
Ⅲ Issuance is strictly controlled and performed by authorized personnel only.
Ⅲ Labeling materials issued are carefully examined for identity and conformity to the labeling specified in the batch production record for the product being labeled.
Ⅲ Reconciliation of quantities issued, used, and returned, as well as investigation of any discrepancies.
Ⅲ Excess labeling bearing lot numbers is destroyed.
Ⅲ Returned labeling is stored in a manner to prevent mix-ups and provide proper identification.
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21.10
Ⅲ 161
cGMP TRAINING
A GMP training system which ensures that all personnel are trained in current Good Manufacturing Practices as required by Title 21 CFR Part
211.25 (a) will be developed in all operations that they are required to perform. The program will be designed so that training is performed and/or coordinated by the Quality Assurance Manager. All training will be documented and retained in a training file.
21.11 EQUIPMENT LOGBOOKS, STATUS TAGS,
AND ROOM CLEARANCE CHECKLISTS
A system for determining the day-to-day status of critical systems, areas, and activities will be developed. Activities such as batch pr oduction, cleaning, preventive maintenance, calibration, load sterilization, etc. will be controlled and documented by procedure in logbooks and reviewed and filed as critical processing documentation.
Status tags will be utilized to indicate the status, such as under cleaning, clean, in-process, quarantine, released, etc. Procedures will be developed for the placement and removal of status tags.
A checklist will be developed to establish proper room clearance prior to initiating a production batch. Checklist development, handling, control, and review will be incorporated into procedures for ongoing control.
21.12
VALIDATION FILES
A program to ensure control of critical system documentation will be established. The files will be controlled by QA. Validation and centralized for easy retrieval. Equipment validation data such as operating and service manuals, purchase orders, manufacturer specifications, as-built drawings and schematics, spare parts lists, and any other information pertaining to the system will be included in the file. Separate validation files for Facility,
Systems, and Process validation of each product, including all related data, will be maintained. Procedures will be developed to create files for new equipment, update information for existing equipment, control, removal, and return of information, etc.
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22
VALIDATION SCHEDULE
Validation schedule is the last but not the least important component of overall validation activity. The validation schedule prepared for ABC
Pharmaceutical Industries defines a time line chart for the execution of
IQ, OQ, PQ, PV, CLV, etc., to attain sufficient documented evidence to give reasonable assurance that the process under consideration does and/or will do what it purports to do.
Description of
Room Equipment/Facility/Utilities/
No.
Process/Cleaning
Validation
Requirement
IQ/OQ/PQ/PV/CLV etc. Year
Quarter
1Q
2Q
3Q
4Q
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23
DRAWINGS FOR ABC
PHARMACEUTICAL PLANT
165
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166 Ⅲ Pharmaceutical Master Validation Plan
S. No.
1
2
3
4
5
6
7
8
Description
Drawing No.
Machine Layout
Building A
Building B
Building C
Machine - 01
Machine - 02
Machine - 03
Civil Layout
Building A
Building B
Building C
Civil - 01
Civil - 02
Civil - 03
Nitrogen Piping Layout
Building A
Building B
Building C
Piping - 01
Piping - 02
Piping - 03
Chilled Water Piping Layout
Building A
Building B
Building C
Piping - 01
Piping - 02
Piping - 03
Steam Piping Layout
Building A
Building B
Building C
Piping - 01
Piping - 02
Piping - 03
Hot Water Piping Layout
Building A
Building B
Building C
Piping - 01
Piping - 02
Piping - 03
Compressed Air Piping Layout
Building A
Building B
Building C
Piping - 01
Piping - 02
Piping - 03
Deionized Water Piping Layout
Building A
Building B
Building C
Water - 01
Water - 02
Water - 03
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Drawings for ABC Pharmaceutical Plant
S. No.
9
10
Description
Ⅲ 167
Drawing No.
Water for Injection Piping Layout
Building C
Water - 01
HVAC
GA & Ducting Layout
Building A
Building B
Building C
HVAC - 01
HVAC - 02
HVAC - 03
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RECOMMENDED READING
Baker, G.S. and Rhodes, C.T., Modern Pharmaceutics, Marcel Dekker, New York, 1996.
Berry, I.R. and Harpaz, D., Validation of Bulk Pharmaceutical Chemicals, Interpharm
Press, Buffalo Grove, IL, 1997.
Berry, I.R. and Nash, R.A., Pharmaceutical Process Validation, Marcel Dekker,
New York, 1993.
British Pharmacopoeia, 1993.
Carleton, F.J. and Agalloco, J.P, Validation of Aseptic Pharmaceutical Processes, Marcel
Dekker, New York, 1986.
Cloud, P., How to Develop and Manage Qualification Protocols for FDA Compliance,
Interpharm Press, Buffalo Grove, IL, 1999.
Cloud, P., Pharmaceutical Equipment Validation Qualification, Interpharm Press,
Buffalo Grove, IL, 1998.
Commission of the European Communities, The Rules Governing Medicinal Products in the European Community, Vol. 4, Guide to II / 2244 / 87-EN, Rev. 3, January 1989.
DeSain, C., Documentation Basics That Support Good Manufacturing Practices,
Advanstar Communications, Cleveland, OH, 1993.
Development Pharmaceutics and Process Validation, CPMP, 1988.
European Community, Good Manufacturing Practice for Medical Products, 1992.
FIP, Guidelines for Good Validation Practice, 1988.
Gibson, W. and Evans, K.P., Validation Fundamentals How to, What to, When to
Validate, Interpharm Press, Buffalo, Grove, IL, 1998.
Guide to Inspection of High Purity Water System, Interpharm Press, Buffalo Grove,
IL, 1993.
Guide to Inspection of Microbiological Pharmaceutical Quality Control Laboratories,
Interpharm Press, Buffalo Grove, IL, 1993.
Guideline of the Commission for Principles of Good Manufacturing Practice for Medical
Products, Directive 91/356/EEC, 1991.
Huber, L., Validation and Qualification in Analytical Laboratories, Interpharm Press,
Buffalo Grove, IL, 1998.
Huber, L., Validation of Computerized Analytical System, Interpharm Press, Buffalo
Grove, IL, 2000.
Isaacs, A., Validating machinery with electronic control systems, Manufacturing Chemist, p. 19, February 1992.
ISPE, Bulk Pharmaceutical Chemicals, 1996.
ISPE, Oral Solid Dosage Forms, 1997.
Knapp, J.Z. and Kushner, H.K., generalized methodology for evaluation of parenteral inspection, J. Parenteral Drug Assoc., Vol. 34 (I), January–February 1980).
Loftus, B.T and Nash, R.A., Pharmaceutical Process Validation, Marcel Dekker,
New York, 1984.
Parenteral Drug Association, Validation of Dry Heat Process Used for Sterilization and
Depyrogeneration, Technical Report No. 3, 1981.
169
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170 Ⅲ Pharmaceutical Master Validation Plan
PIC, Principles of Qualification and Validation in Pharmaceutical Manufacture, PIC
Document PH 1/96, 1996.
PMA’s Computer Systems Validation Committee, Computer system validation — staying current: introduction, Pharm. Technol., 13(5), 60, 1989.
PMA’s Computer Systems Validation Committee, Validation concepts for computer systems used in the manufacture of drug products, Pharm. Technol., 10(5),
24, 1986.
Stokes, T., Branning, R.C., Chapman, K.G., Hamblock, H., and Trill, A.J., Good Computer
Validation Practices: Common Sense Implementation, Interpharm Press, Buffalo
Grove, IL, 1994.
United States Pharmacopoeia 24, 2000.
Validation Documentation Inspection Guide, Interpharm Press, Buffalo Grove, IL, 1993.
WHO, Guidelines on the Validation of Manufacturing Process, 1996.
Wingate, G., Validating Automated Manufacturing and Laboratory Applications: Putting
Principles into Practice, Interpharm Press. Buffalo Grove, IL, 1997.
SL3305_Index_fm Page 171 Thursday, November 8, 2001 3:31 PM
INDEX
A
Air, compressed, 68
Air-conditioning, see HVAC system
Aseptic fill products, process flow, variables, responses, 110
Autoclave
performance qualification of, 148–149 qualification of, 136–138
B
Bracketing, products and equipment,
26–27
Building(s) description of, 39, 44–46 validation of, 89–90
C
Calibration program, 83, 157–158 validation team member from, 6
Capping machine, qualification of,
132–133
Capsulation, qualification of, 119
Capsule(s), process flow, variables, responses, 104
Capsule polisher, qualification of,
120–121
Carbon dioxide, 68 validation of, 97–98
Cartonater, qualification of, 133–134
Certification, for use in manufacturing, 79
Certification package requirements, 75
Chilled water, 68
Civil work, 89–90
Class I equipment, 73
Class II equipment, 73
Class III equipment, 73
Cleaning/sanitization, facility, 159
Cleaning validation, 24–27
Commuting mill, qualification of,
115–116
Compressed air, 68 validation of, 95–96
Computer systems, in quality control/assurance laboratory,
156
Computer validation, 27–29
Computerized pharmaceutical system,
153–154
Coversheet, 31
Cream/ointment filling machine, qualification of, 130
Cross-contamination control, 152–153
Current good manufacturing practice
(cGMP), xiii, 37, 76 calibration in, 157–158
Engineering Change Control in, 157 environmental monitoring system in,
159
equipment logbooks in, 161 facility cleaning and sanitization in,
159
filter testing in, 160
HEPA filter testing in, 159–160 label control program in, 160 preventive maintenance in, 158 room clearance checklists in, 161 standard operating procedures in, 158 status tags in, 161 training in, 161 validation files in, 161
Cycle development, 77
Cycle development testing, see specific equipment D
Decision-making, xv–xvi
Deionized water, 67
Design, validation, 72–74
171
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172 Ⅲ Pharmaceutical Master Validation Plan
Design qualification, 14–15
Disposable syringe(s), process flow, variables, responses, 111
Document control, validation team, 4–6
Document structure, 31
Drainage system, facility, 90
Drop(s), process flow, variables, responses, 106
Drop filling machine, qualification of, 129
Drop manufacturing vessel, qualification of, 124–125
Dry heat sterilizer, qualification of,
138–139
Dry production, 40 building description for, 44 equipment description for, 47–49
HVAC description for, 57–59 process description for, 101–104 protocols and procedures for, 79–80
Dryer, qualification of, 116–117
E
Electric power, 69
Emergency power, validation of, 99–100
Emulsifying mixer, qualification of,
126–127
Engineering Change Control in, 157
Engineering Change Control program, 77
Enhanced Turn-Over Package (ETOP),
74–75
Environmental monitoring system, 159
Equipment
certification package requirements for,
75
classification of, 73–74 description of, see Equipment description numbering system for, 32 process, qualification of, 115–145 autoclave, 136–138 capping machine, 132–133 capsulation machine, 119 capsule polisher, 120–121 cartonater, 133–134 commuting mill, 115–116 cream/ointment filling machine,
130
drop filling machine, 129
drop manufacturing vessel,
124–125
dry heat sterilizer, 138–139 dryer, 116–117 emulsifying mixer, 126–127 filter press, 127 freeze dryer, 141–143 labeling machine, 131–132 laminar flow units, 143–144 lyophilizer, 141–143 mixer, 125–126 overprinting machine, 134–135 pass-through, 144–145 powder filling machine, 119–120 semisolids manufacturing vessel,
128
shrink-wrapping machine, 134 steam sterilizer, 136–138 suppository filling machine,
130–131
suspension filling machine, 129 suspension manufacturing vessel,
123–124
syrup filling machine, 129 syrup manufacturing vessel,
122–123
tablet coating machine, 121–122 tablet compression machine, 118 tray and rack washer, 135–136
V-shell blender, 117–118 vials/ampoules/syringes filling machine, 140–141 vials/ampoules washer, 139–140
Equipment description, 39 dry production, 47–49 liquid and semisolid production, 49–50 overprinting, 53 parenterals production, 51–53 product development laboratories, 55 quality assurance, 54 quality control, 53–54
Equipment logbooks, 161
F
Facility
cleaning and sanitization of, 159 description of, 37–38 building(s), 39
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Index
equipment, 39 process, 39–42 drawings of, 166–167 line capacity of, 38–39
Filling equipment, qualification of cream/ointment filling machine, 130 drop filling machine, 129 powder filling machine, 119–120 suppository filling machine, 130–131 suspension filling machine, 129 syrup filling machine, 129 vials/ampoules/syringes filling machine, 140–141
Filling process validation, 151
Filter press, qualification of, 127
Filter testing, 159–160, 160
Final Report, 78
Final Report Package, 78
Freeze dryer, qualification of, 141–143
G
Good laboratory practice, xiii
H
Heating, ventilation, and air-conditioning, see HVAC system HEPA filter testing, 159–160
Hot air tunnel performance qualification of, 150–151 qualification of, 138–139
HVAC system, 69–70 description of, see HVAC system description monitoring document for, 70 validation of, 98–99 validation team member for, 6
HVAC system description for dry production, 57–59 for liquid and semisolid production,
60–61
for overprinting area, 64 for parenterals production, 62–64 for product development laboratory,
66
for quality assurance, 66 for quality control, 65
Ⅲ 173
I
Injectables production, 41
Installation Qualification, 17–18, 74–75 general acceptance criteria for, 30 protocols for, 75–76
L
Label control program, 160
Labeling machine, qualification of,
131–132
Laminar flow unit, qualification of,
143–144
Line capacity, 38–39
Liquids and semisolids production, 40 building description for, 45 equipment description for, 49–50 equipment validation of, see
Equipment
HVAC description for, 60–61 process description for, 105–107 protocols and procedures for, 80–81
Lyophilized products, process flow, variables, responses, 113
Lyophilizer, qualification of, 141–143
M
Maintenance, preventive, 85
Media fill studies, 151
Mixer, qualification of, 125–126
N
Nitrogen, 68 validation of, 96–97
Numbering system, 32–33
O
Ointments, process flow, variables, responses, 107
Operational Qualification, 18–20, 74–75 general acceptance criteria for, 30 protocols for, 76
Overprinting area equipment description for, 53
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174 Ⅲ Pharmaceutical Master Validation Plan
HVAC description for, 64
Overprinting machine, qualification of,
134–135
P
Packaging, validation team member from, 6
Parenterals production building description for, 46 equipment description for, 51–53
HVAC description for, 62–64 process descriptions for, 109–113 protocols and procedures for, 81–82
Pass-through equipment, qualification of,
144–145
Performance Qualification, 20–21 general acceptance criteria for, 30 protocols for, 77 for support processes, 147–154
Plant steam, validation of, 91–92
Powder filling, qualification of, 119–120
Powder for suspensions, process flow, variables, responses, 103
Power, see Electric power; Emergency power Preventive maintenance program, 85, 158
Process description, 39–42, see also Dry production; Liquids and semisolids production;
Parenterals production
Process equipment, see Equipment
Process Validation, 22–23 protocols for, 78, see also Dry production; Liquids and semisolids production;
Parenterals production
Product development laboratory equipment description for, 55
HVAC description for, 66 validation team member from, 7
Production
dry oral, 40 injectables, 41 liquid and semisolid oral, 40 validation team member from, 6
Pure steam, 68 validation of, 92–93
Purified water, 67
Q
Qualification, see Validation/qualification
Quality assurance computer related systems used in, 156 equipment description for, 54
HVAC description for, 66 qualification of laboratory equipment for, 155–156 validation of, 155 validation team member from, 6
Quality Assurance Manager, 72
Quality control computer related systems used in, 156 equipment description for, 53–54
HVAC description for, 65 qualification of laboratory equipment for, 155–156 validation of, 155 validation team member from, 7
R
Resource requirement estimates, xvi
Revalidation, reasons for, 35–36
Revisions, reasons for, xvii–xix
Risk analysis, 16–17
Room clearance checklists, 161
S
Sanitary water, 69
Semisolids manufacturing vessel, qualification of, 128
Semisolids production, see Liquids and semisolids production
Shrink-wrapping machine, qualification of, 134
Standard operating procedures, key, 87
Standard operating procedures (SOPs),
158
Status tags, 161
Steam, pure, 68
Steam utilities, validation of, 91–93
Sterilization process hot air, validation of, 150–151 steam, validation of, 148–149
Sterilization products, process flow, variables, responses, 112
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Index
Support process validation, 147–154
Suppository(ies), process flow, variables, responses, 107
Suppository filling machine, qualification of, 130–131
Suspension(s), process flow, variables, responses, 106
Suspension filling machine, qualification of, 129
Suspension manufacturing vessel, qualification of, 123–124
Syringe(s), process flow, variables, responses, 111
Syringe filling machine, qualification of,
140–141
Syrup(s), process flow, variables, responses, 106
Syrup filling machine, qualification of,
129
Syrup manufacturing vessel, qualification of, 122–123
System development life cycle (SDLC),
27–29
T
Tablet(s), process flow, variables, responses, 102
Tablet coating, qualification of, 121–122
Tablet compression, qualification of, 118
Terminal sterilization products, process flow, variables, responses, 112
Test specification header, 31
Title 21 CFR Part 211.25 (a), 161
Tray and rack washer, qualification of,
135–136
U
Utility description carbon dioxide, 68 chilled water, 68 compressed air, 68 deionized water, 67 electric power, 69 heating, ventilation and air-conditioning, 69–70 nitrogen, 68 pure steam, 68
Ⅲ 175
purified water, 67 sanitary water, 69 water for injection, 67
Utility system validation carbon dioxide, 97–98 compressed air, 95–96 emergency power, 99–100
HVAC, 98–99 nitrogen, 96–97 plant steam, 91–92 pure steam, 92–93 team member for, 6 water for injection, 93–94
V
V-shell blender, qualification of, 117–118
Validation, definition of, 2
Validation documents, 74–75
Validation files, 161
Validation life cycle concurrent, 13–14 prospective, 10–11 retrospective, 12–13
Validation master plan, 2, see also
Validation/qualification
approval of, xvi approval page for, xx benefits of, xiv
CD-ROM copy of, xix in decision-making, xv–xvi elements of, xvi
FDA definition of, xiii–xiv resource requirement estimates in, xvi revision of, xvii–xix, see also
Revalidation
scope of, 2 vulnerability assessment of, xv writing, xiv–xv
Validation process, 72–74, 78 in certification for use in manufacturing, 79
Cycle development, 77 dry production protocols and procedures, 79–80
Engineering Change Control program,
77
Installation Qualification protocols,
75–76
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176 Ⅲ Pharmaceutical Master Validation Plan liquid and semisolid production protocols and procedures,
80–81
Operational Qualification protocols,
76
parenterals production protocols and procedures, 81–82
Performance Qualification protocols,
77
reporting, 78
Validation project management, 71–72
Validation/qualification
acceptance criteria in, 29–30, see also specific process or equipment cleaning, 24–27 computer, 27–29 concept of, 9–10 design, 14–15 documentation changes in, 32 documentation format for, 31–32 documentation numbering system for,
32–33
general acceptance criteria in, 29–30, see also specific process or equipment installation, 17–18 numbering system in, 32–33 operational, 18–20 performance, 20–21 process, 22–23 reporting, 29 risk analysis, 16–17 of support processes, 147–154
Validation report, 29
Validation schedule, 163
Validation team document control by, 4–6 members of, 3 organization chart of, 4 packaging member of, 6 product development laboratory member of, 7 production member of, 6 quality assurance member of, 6 quality control member of, 7 responsibilities of, 3–7, 72 in testing and procedure approval, 5 utilities/calibration/HVAC member of,
6
Ventilation, see HVAC system
Vial/ampoule/syringe filling machine, qualification of, 140–141
Vial/ampoule washer performance qualification of,
147–148
qualification of, 139–140
W
Washer(s)
tray and rack, , qualification of,
135–136
validation of, 147–148 vials/ampoules, qualification of,
139–140
Water consumption, 69
Water production, 67–68 validation of, 93–94