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FDA Denis Kluba

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FDA Denis Kluba

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    1. 1 ??FDA?????? Denis Kluba ?? ??? ??

    2. 2 ??Table Of Contents ???? CGMP?????? ??????? ???? ???????? ??????? ????????? ?????? ???? ???? ??? ??

    3. 3 Part One: What is Validation?

    4. 4 What is Validation? For this Seminar??? it refers to two things: 1. The USA FDA requirements that must be met in order to successfully and continually sell drug products in the USA 2. Activities that will contribute to the success of the company in the manufacture of drug products

    5. 5 Validation

    6. 6 Validation Is.....

    7. 7 To Consistently Produce A Desired Known Product Why Do We Validate?

    8. 8 How Do We Validate? Details Will Follow But This is the General Model

    9. 9 First three steps to CGMP compliance document document document

    10. 10 Boundaries of Validation

    11. 11 Validation Life Cycle Approach

    12. 12 Validation Life Cycle Approach

    13. 13 Benefits of Validation Increased Throughput Reduction In Rejections and Reworks Reduction In Utility Costs Avoidance Of Capital Expenditures Fewer Complaints About Process Related Failures Reduced Testing – In-process and Finished Goods More Rapid / Accurate Investigations Into Process Upsets More Rapid and Reliable Startup Of New Equipment Easier Scale-up From Development Work Easier Maintenance Of The Equipment Improved Employee Awareness Of Processes More Rapid Automation

    14. 14 Elements Of Contemporary Validation In The US Equipment Calibration - Process and Validation Equipment Equipment Qualification - Installation and Operational Process Development Process Documentation Performance Qualification - "Validation" Maintenance of Validation - Process and Equipment Change Control

    15. 15 cGMP and ISO-9000 - Similarities Aimed at Quality Require Documentation Require Specific Quality Program QA and QC Included

    16. 16 cGMP and ISO-9000 - Differences cGMP Aimed at Product ISO-9000 Includes Design and Service, as well cGMP Covers Activities Directly Related to Manufacturing ISO-9000 Covers Broader Range of Activities (e.g.. Purchasing) cGMP Requires Formal Validation ISO-9000 Requires Applicable Statistical Methods

    17. 17 Benefits of the Systems Approach to Validation More Rigorous Control Over Operations Centralized Planning for all Validation Related Aspects Ties Existing Sub-elements into Cohesive System Establishes Validation as a Program, not a Project Provides for Continuity of Approach Affirms Validation as a Discipline Much like Others Allows For Personnel Growth within the Validation Expertise Usually Results in Centralization of Validation Expertise More Compatible with the Accomplishment of a Corporate??? Objective for Validation

    18. 18 The Validation Program Establish Goals and Objectives as to What Must be Validated Qualify or Re-qualify the Equipment Establish Validation Protocols for each, and obtain Approval of the Protocols Establish Personnel Requirements and Training Records Procedure Design and Conduct Experiments. Collect Data Evaluate the Data Prepare Summary Reports Outlining the Results of the Experiments. Obtain the Necessary Approvals Establish and Maintain Validation Files Including Raw Data Institute a Change Control Procedure to Insure the Ongoing Acceptability of the Work The validation program is not planned and carried out in a vacuum. It must emphasize design criteria and specifications initially and gradually progress through the test phase to establish operating requirements and procedures. The validation program is not planned and carried out in a vacuum. It must emphasize design criteria and specifications initially and gradually progress through the test phase to establish operating requirements and procedures.

    19. 19 Part Two: GMP Requirements

    20. 20 GMP requirements Part 211: Current good manufacturing practice for finished pharmaceuticals   §211.68 - Automatic, mechanical, and electronic equipment.   §211.84 - Testing and approval or rejection of components, drug product containers, and closures.   §211.110 - Sampling and testing of in-process materials and drug products.   §211.113 - Control of microbiological contamination.   §211.165 - Testing and release for distribution.   §211.166 - Stability testing.

    21. 21 cGMP in the Pharmaceutical Industry GMP is the abbreviation of “Good Manufacturing Practice” which is adopted by the medical and health related industries including the pharmaceutical industry in an effort to maintain the highest standards of quality in the development, manufacture and control of medicinal products. Since the industry standards are subject to continuous improvement, the letter ‘c’ in the abbreviation “cGMP” refers more specifically to the current or the latest version of the GMP requirements.

    22. 22 Regulatory Requirements for Validation..... The requirement of process validation is implicit in the language of 21 CFR 211.100 of the Current Good Manufacturing regulations which states: “There shall be written procedures for product and process control to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess."

    23. 23 GMP Regulatory Requirements for Cleaning Validation 1978 cGMP Regulations (part 211.67(a)) Equipment cleaning and maintenance states: “Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements”.

    24. 24 GMP Regulatory Requirements for Test Method Validation Laboratory Controls 21 CFR 211.165(e) states: The accuracy, sensitivity, specificity and reproducibility of test methods employed by the firm shall be established and documented. Such validation and documentation may be accomplished in accordance with Part 211.194(a)(2).

    25. 25 GMP Regulatory Requirements for Test Method Validation Part 211.194(a)(2) states: A statement of each method used. . . shall indicate the location of data that establish that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested. The suitability of all testing methods used shall be verified under actual conditions of use.

    26. 26 GMP Regulatory Requirements for Test Method Validation U.S. Federal Court decision: United States vs Barr Labs Cleaning Validation: . . . it was ruled for cleaning to be effective, the specific test methods had to be shown to be effective.

    27. 27 PROCESS VALIDATION 21 CFR 211.110 “such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product”

    28. 28 Part Three: History and Expectations As applied by the FDA and Implemented by Industry

    29. 29 History and expectations Learn for the experiences of the USA manufacturers and industry organizations Current applications Past citations Industry guidelines ICH Q7A ISPE PDA Etc.

    30. 30 Validation Targets Early Years Sterilization Aseptic Operations Middle Years Non-sterile Processes Oral Dosage Forms Recent Years Biological Processes Bulk Organic Synthesis Developmental and Pilot Operations Supporting Services Currently Total Operations Review by Systems Quality System Production System Laboratory Controls Packaging and Labeling, Materials and Facilities Equipment Manufacturing. The trend in recent years has been to expand validation activities backwards both time-wise and process-wise. In other words, validation is now being performed both early in the drug development process and nearer the beginning of the production process. This trend has paralleled the trend toward a systems or Life Cycle approach to validation.The trend in recent years has been to expand validation activities backwards both time-wise and process-wise. In other words, validation is now being performed both early in the drug development process and nearer the beginning of the production process. This trend has paralleled the trend toward a systems or Life Cycle approach to validation.

    31. 31 History of Validation Validation in The Early Years - 1972 to 1978 Regulatory Based to Satisfy FDA Pressures Defensive to Protect Product Line Validation in Its' Adolescence - 1978 To 1983 Primarily Defensive Some Efforts at Process Optimization Includes Some Peripheral Concerns Validation in the US Today - 1983 to Present Non- Regulatory in Many Areas Geared Towards Optimization and focused on Systems

    32. 32 "validation" vs. "VALIDATION" "validation" Defensive Testing Oriented Costly Quality Control Narrow Focus Big "V" vs. little "v" - the difference is obvious. How to get there is with the Life-cycle or systems approach. Then Validation becomes not an event, but a state, that is a state of control over the process. Initially, validation encompassed only the "testing" of the system, process or product. Contemporary Validation encompasses a system of inter-related practices which, in combination, provide regulatory compliance in addition to other advantages.Big "V" vs. little "v" - the difference is obvious. How to get there is with the Life-cycle or systems approach. Then Validation becomes not an event, but a state, that is a state of control over the process. Initially, validation encompassed only the "testing" of the system, process or product. Contemporary Validation encompasses a system of inter-related practices which, in combination, provide regulatory compliance in addition to other advantages.

    33. 33 Elements of Contemporary Validation in the US Equipment Calibration - Process and Validation Equipment Equipment Qualification - Installation and Operational Process Development Process Documentation Performance Qualification - "Validation" Maintenance of Validation - Process and Equipment Change Control

    34. 34 Expectations Validation is a Program not a Project Validation Contributes to the Stability of the Operations Validation is not Someone Else's Job!

    35. 35 Part Four: Validation An Overview

    36. 36 Who Validates?

    37. 37 Validation

    38. 38 Validation

    39. 39 Validation The objective of these two slides is to indicate the concept of validation as one which involves the entire life of the project, thus the term "Life-cycle". A plant or process cannot be validated if it is not designed and installed properly. There must be design reviews by people who know the process and inspections of the equipment and facility as they are constructed and installed. Many different groups must become involved in the program. Although the team leader may be from manufacturing (as is usually the case at Roche in the bulk manufacturing area), the other team members are equally important. It must be a team effort. The objective of these two slides is to indicate the concept of validation as one which involves the entire life of the project, thus the term "Life-cycle". A plant or process cannot be validated if it is not designed and installed properly. There must be design reviews by people who know the process and inspections of the equipment and facility as they are constructed and installed. Many different groups must become involved in the program. Although the team leader may be from manufacturing (as is usually the case at Roche in the bulk manufacturing area), the other team members are equally important. It must be a team effort.

    40. 40 Write Protocols

    41. 41 Example Data Sheets

    42. 42 Conduct Testing

    43. 43 Installation Qualification (IQ) IQ documents that system is installed in accordance with approved design, specification and regulatory codes manufacturers installation recommendation have been taken into consideration IQs implemented concurrently with construction of each system

    44. 44 Operational Qualification (OQ) OQ documents that the equipment: can operate as designed and intended is capable of repeatable operation over the entire operating range of process variables OQ executed when equipment can be started up

    45. 45 Process Qualification (PQ) PQ documents critical systems which can be challenged test procedures product quality attributes to be evaluated acceptance criteria alert/action levels system validated under "worst case conditions" generally 3 consecutive successful runs required

    46. 46 Definition of Process Validation Validation is: Documented evidence that provides a high degree of assurance that a specific process will consistently produce a product of a certain predetermined quality. THE DEFINITION OF PROCESS VALIDATION HAS CHANGED FROM:" PROOF THAT A PROCESS DOES WHAT IT PURPORTS TO DO. " TO THE MORE ACCEPTED DEFINITION CONTAINED IN THE FDA'S GUIDELINES ON PROCESS VALIDATION. THE KEY DIFFERENCES ARE THAT WHEREAS THE OLDER DEFINITION EMPHASIZED THE TESTING APPROACH TO VALIDATION, THE NEWER DEFINITION REQUIRES A SYSTEMS APPROACH, INCLUDING EMPHASIS ON DESIGN AND OPERATION, AS WELL AS TESTING.THE DEFINITION OF PROCESS VALIDATION HAS CHANGED FROM:" PROOF THAT A PROCESS DOES WHAT IT PURPORTS TO DO. " TO THE MORE ACCEPTED DEFINITION CONTAINED IN THE FDA'S GUIDELINES ON PROCESS VALIDATION. THE KEY DIFFERENCES ARE THAT WHEREAS THE OLDER DEFINITION EMPHASIZED THE TESTING APPROACH TO VALIDATION, THE NEWER DEFINITION REQUIRES A SYSTEMS APPROACH, INCLUDING EMPHASIS ON DESIGN AND OPERATION, AS WELL AS TESTING.

    47. 47 Definition of Process Validation In addition to documented evidence that a process will perform reliably and repeatedly, validation, in its highest form, provides an understanding of why.

    48. 48 Stages of the Life-Cycle Even the R&D phase is important, because it defines the requirements of the product and process. In each succeeding step, the system becomes better and better defined and is subject to stricter and stricter controls. The operational phase (SOPs/maintenance) may be considered the most critical phase of validation. After all, this is the phase where the product is made. This is the phase which operator and mechanics control.Even the R&D phase is important, because it defines the requirements of the product and process. In each succeeding step, the system becomes better and better defined and is subject to stricter and stricter controls. The operational phase (SOPs/maintenance) may be considered the most critical phase of validation. After all, this is the phase where the product is made. This is the phase which operator and mechanics control.

    49. 49 Benefits of Validation Increased Throughput Reduction in Rejections and Reworks Reduction in Utility Costs Avoidance Of Capital Expenditures Fewer Complaints About Process Related Failures Reduced Testing – In-process and Finished Goods More Rapid / Accurate Investigations Into Process Upsets More Rapid and Reliable Startup Of New Equipment Easier Scale-up From Development Work Easier Maintenance Of The Equipment Improved Employee Awareness Of Processes More Rapid Automation

    50. 50 Documentation of Validation Master Plan Protocol Data Sheets Report Procedures The key to modern validation is documentation. Much of what we now do is a repeat of what might be considered good engineering and construction practices. The problem in the past is, that although these practices were carried out, they were often not properly documented and maintained, resulting in the loss of valuable information. The validation program ensures that this information gets into the hands of the operating (manufacturing, QC, QA, Tech. Services) people who run the process after engineering has moved on.The key to modern validation is documentation. Much of what we now do is a repeat of what might be considered good engineering and construction practices. The problem in the past is, that although these practices were carried out, they were often not properly documented and maintained, resulting in the loss of valuable information. The validation program ensures that this information gets into the hands of the operating (manufacturing, QC, QA, Tech. Services) people who run the process after engineering has moved on.

    51. 51 Validation Protocols Provide an Outline of the Validation Effort Include a Clear Definition of What Will Be Validated Is Uniquely Identified Is Dated Approved By Competent Individuals In Responsible Areas Are Suitable For Review By Regulatory Agencies Although not strictly required by the GMPs, the protocol has become a necessary part of a solid validation program. It not only plans the testing phase, but provides the background necessary to understand the system. In doing so, it becomes the foundation for future operating and maintenance procedures. Although not strictly required by the GMPs, the protocol has become a necessary part of a solid validation program. It not only plans the testing phase, but provides the background necessary to understand the system. In doing so, it becomes the foundation for future operating and maintenance procedures.

    52. 52 Validation Protocol Essential Elements Introduction/Abstract Description of Process or System Test Plan Responsibilities Acceptance Criteria Approvals Append Data Sheets, Etc. The introduction or abstract may be short, explain the location of the system and the purpose of the protocol. The description is important as it serves to familiarize the responsible team members so that they may plan and review the test program. The results of the test program are judged against the acceptance criteria. These should be clear and unambiguous, so that review and approval of the final report is expedited. Data sheets and other records to be filled out during testing should also be prepared up front so that they may be reviewed for completeness.The introduction or abstract may be short, explain the location of the system and the purpose of the protocol. The description is important as it serves to familiarize the responsible team members so that they may plan and review the test program. The results of the test program are judged against the acceptance criteria. These should be clear and unambiguous, so that review and approval of the final report is expedited. Data sheets and other records to be filled out during testing should also be prepared up front so that they may be reviewed for completeness.

    53. 53 Validation Reports – Functions Restrict to One Task or Subject Has a Unique Identification Is Dated Formally Reviewed and Approved Identifies Protocol(s) Used in the Study Is Suitable for Review by FDA

    54. 54 Validation Report - Contents Abstract Or Summary Conclusion Plan Of Study Experimental Results Conclusions Protocol Reference Diagrams Any Miscellaneous Information Approvals The report is the ultimate record. It should contain the protocol, and thus, a complete but concise description of the system. Sketches and drawings, both of the system and the experimental design , are valuable. The objective is to provide a ready reference for future understanding, operating and troubleshooting of the system. It may become the system "bible", so to speak. A summary section, with data tables, but not complete raw data, may serve for initial presentation to the FDA. Include lab results and all completed data sheets in the main report. These should be signed off according to cGMP.The report is the ultimate record. It should contain the protocol, and thus, a complete but concise description of the system. Sketches and drawings, both of the system and the experimental design , are valuable. The objective is to provide a ready reference for future understanding, operating and troubleshooting of the system. It may become the system "bible", so to speak. A summary section, with data tables, but not complete raw data, may serve for initial presentation to the FDA. Include lab results and all completed data sheets in the main report. These should be signed off according to cGMP.

    55. 55 Installation Qualification (IQ) IQ Documents That The: System is Installed in Accordance with Approved Design, Specifications and Regulatory Codes Manufacturers Installation Recommendations have been taken into Consideration IQ is Implemented Concurrently with Construction of Each System IQ answers the questions: "What is the system, how and where is it documented, and has it been built and/or installed properly?" This can be a monumental task, especially in large plants. It requires an understanding of engineering and construction principles, the current state of the industry with regard to design and , of course, the cGMPs. Some IQ can be carried out by contractors or construction supervisors, if properly documented and audited. The validation team must determine the criticality of the data and whether 100% inspection is required. Examples include pressure testing, cleaning and passivation, receipt of materials, workmanship, HVAC balance, DOP testing, etc. The close link between engineering and validation reaches a high point during IQ. The following diagram indicates how these two activities interact starting with the inception of the project. Key engineering documents, drawings and specifications, are used in the field as a reference.. The validation team will audit or inspect to see that they are followed. The most often used drawing is the P&ID, example included. This will be taken to the field and marked up to indicate whether the installed system complies or not. Where it does not, a decision must be reached as to whether a field correction needs to be made or whether the drawing needs to be changed. When agreement is reached, the validation team will mark-up the field copy and sign it, indicating the accepted state of the installation. This is only done after field corrections are completed and inspected. The marked up and signed drawing becomes the reference for preparation of "as built" P&IDs. It becomes part of the validation record. In some critical systems (e.g.. WFI, clean rooms) other design drawings, such as piping isometrics or duct drawings might also be used in IQ. Some other typical data sheets used in IQ are also included. IQ answers the questions: "What is the system, how and where is it documented, and has it been built and/or installed properly?" This can be a monumental task, especially in large plants. It requires an understanding of engineering and construction principles, the current state of the industry with regard to design and , of course, the cGMPs. Some IQ can be carried out by contractors or construction supervisors, if properly documented and audited. The validation team must determine the criticality of the data and whether 100% inspection is required. Examples include pressure testing, cleaning and passivation, receipt of materials, workmanship, HVAC balance, DOP testing, etc. The close link between engineering and validation reaches a high point during IQ. The following diagram indicates how these two activities interact starting with the inception of the project. Key engineering documents, drawings and specifications, are used in the field as a reference.. The validation team will audit or inspect to see that they are followed. The most often used drawing is the P&ID, example included. This will be taken to the field and marked up to indicate whether the installed system complies or not. Where it does not, a decision must be reached as to whether a field correction needs to be made or whether the drawing needs to be changed. When agreement is reached, the validation team will mark-up the field copy and sign it, indicating the accepted state of the installation. This is only done after field corrections are completed and inspected. The marked up and signed drawing becomes the reference for preparation of "as built" P&IDs. It becomes part of the validation record. In some critical systems (e.g.. WFI, clean rooms) other design drawings, such as piping isometrics or duct drawings might also be used in IQ. Some other typical data sheets used in IQ are also included.

    56. 56 Design Documentation Design and Procurement Documentation Support of IQ: PFDs/P&IDs Critical System Installation Drawings (E.G. Water System Isometrics, Sanitary Duct Drawings) Purchase and Installation Specifications Vendor Manuals and Prints Computer Software Documentation The list is by no means complete, but is meant to alert designers/constructors as to the types of documentation required to support validation. Any given project may require additional documentation to support facility, equipment and support system qualification. Some of the above documents, particularly specifications and vendor literature, are also important in support of OQ. These tell the validation team what the capability of the equipment or system is intended to be, so that it may be tested.The list is by no means complete, but is meant to alert designers/constructors as to the types of documentation required to support validation. Any given project may require additional documentation to support facility, equipment and support system qualification. Some of the above documents, particularly specifications and vendor literature, are also important in support of OQ. These tell the validation team what the capability of the equipment or system is intended to be, so that it may be tested.

    57. 57 Construction Documentation Construction Documents In Support Of IQ: Slope Checks Piping Pressure Test Reports Motor Checkout Reports Weld Inspection Reports Cleaning, Passivation and Sanitization Procedures and Reports HVAC Test and Balance Reports Other Appropriate Construction Documentation

    58. 58 The P&ID Process Equipment Support Vessels Interconnecting Lines Utility Lines Instruments/Instrument Functions Schematic No Scale - Not Spatially Precise Shows Relationships and Relative Position For most systems the P&ID is the only drawing necessary to check out a field installation. All members of the validation team should familiarize themselves with this type of document and learn how to read it and use it.For most systems the P&ID is the only drawing necessary to check out a field installation. All members of the validation team should familiarize themselves with this type of document and learn how to read it and use it.

    59. 59 Operational Qualification (OQ) OQ Documents That The Equipment: Can Operate as Designed and Intended Is Capable of Repeatable Operation Over the Entire Operating Range of Process Variables OQ Implemented After Equipment has been Started Up or Commissioned OQ should begin after the system has been started up and/or commissioned. This may be called pre-Q and involves the proper application of power, leak checking, lubrication, coolant addition, etc. These activities are best carried out by construction or maintenance crews. The validation team, unless specifically charged to do so, should not be expected to perform start-up. The real reasons for OQ are to run the equipment through its paces for comparison with operating specs. This is generally not done with product, but makes use of water or a placebo. Often, operating parameters which are not subject to specification (e.g. heat up rate) will also be checked during OQ to establish baseline date for future system evaluation. Several OQ data sheets of various kinds are included. A non conformance report triggers corrective action, or at least establishes a record, where a system may not meet spec.OQ should begin after the system has been started up and/or commissioned. This may be called pre-Q and involves the proper application of power, leak checking, lubrication, coolant addition, etc. These activities are best carried out by construction or maintenance crews. The validation team, unless specifically charged to do so, should not be expected to perform start-up. The real reasons for OQ are to run the equipment through its paces for comparison with operating specs. This is generally not done with product, but makes use of water or a placebo. Often, operating parameters which are not subject to specification (e.g. heat up rate) will also be checked during OQ to establish baseline date for future system evaluation. Several OQ data sheets of various kinds are included. A non conformance report triggers corrective action, or at least establishes a record, where a system may not meet spec.

    60. 60 Process Qualification (PQ) PQ Documents That: Processes Operate as Required at the Normal Operating Limits of Critical Parameters Systems Operate Consistently and Reliably Appropriate Challenges Are Employed

    61. 61 Review and Approvals Design Drawings and Specifications Master Plan Protocols Reports Procedures

    62. 62 Part Five: Validation Master Planning

    63. 63 Planning “If you don’t know where you are going, you are likely to end up someplace else!” - Lewis Carroll Like any other important activity in a complex organization validation must be managed. This is especially true given the multi-disciplined nature of many validation activities.

    64. 64 Existing Plants The same level of management is necessary for the validation of an existing facility, whether fully validated or not. Validation is easier when it is an integral part of the day-to-day operation of the facility.

    65. 65 Master Plan Defines and Establishes the Validation Approach and the Acceptance Criteria

    66. 66 Facilities, Processes or Products What needs to be done? Who will do it? How will they do it? How long will it take? How much will it cost?

    67. 67 Master Plan - General Introduction to Facility Purpose and Design Intent Facility/Process Description Process Control Considerations System Definitions Planning/Scheduling

    68. 68 Master Plan - Why Project Familiarization/Training Management Introduction FDA Introduction/Familiarization Validation Program Foundation Basic Procedures Protocol Outlines/Bases Resource Planning/Scheduling Contract Execution Interaction Codifies Prior Decisions Structures Validation Activities Facilitates Regulatory Compliance Useful in Regulatory and Client Interactions Use With 3rd Parties Convertible Into Drug Master File Internal Audit Preparation

    69. 69 Master Plan - What Introduction Facility / Process / Product Description Process Control Considerations System Definition Protocol Outlines/Acceptance Criteria Formats SOPs Planning/Scheduling

    70. 70 Master Plan - Getting Started Facility Layout Process Description(s) Product Description(s) Equipment List Utility List Controlled Environment Requirements Control Philosophy Schedule

    71. 71 Master Plan – Facility Description Layout/Equipment Arrangement People/Material/Component Flow Controlled Environments Materials of Construction Sketches

    72. 72 Master Plan - Process Description Major Process Steps Block Diagram Process Flow Diagram(s) Utilities (WFI, DI, CIP, Etc.) Major Support Equipment (Autoclaves, Ovens, Etc.)

    73. 73 Master Plan - Process Control General Architecture Central/Distributed Control System PLCs/Individual Control Systems Building Automation System Higher Level Systems (LIMS, EBR, Etc.) Integrate into other Sections if Minimal

    74. 74 Master Plan - Validated Systems Lists Of Systems To Be Validated General Acceptance Criteria Specific Acceptance Criteria Basic Protocol Outlines

    75. 75 Master Plan - Procedures and Formats Protocol Format SOP Format Basic Procedures Validation Program Responsibilities Calibration Change Control List Of SOPs

    76. 76 Master Plan - Planning and Scheduling Manpower Resources Document Preparation Field Execution Calibration Lab Support Test & Balance/Filter Certification Start-Up/Commissioning

    77. 77 Master Plan - Focus Sterile Products Facility Emphasis On Facility and Environment People, Component, Product Flows Automation May Or May Not Be Central Support Systems Critical (Autoclaves, Ovens, WFI, Etc.)

    78. 78 Master Plan - Focus Solids Facility In-process Controls Tests Examinations to be Conducted on Appropriate Samples of In-process Materials of Each Batch

    79. 79 Master Plan - Focus API Facility Emphasis On Chemical Process Identify API Step Cross-contamination Control, if Appropriate Automation Critical Cleaning Critical In Multi-product Facilities

    80. 80 Master Plan - Focus CIM Systems Emphasis on Functional Requirements System Structure Communication Routing

    81. 81 Master Plan - Focus Anything Unusual Areas that are Unique to Your Process Emphases on the Philosophy for Controls (Procedural and Automation)

    82. 82 Part Six: Methods of Performing Validation Including Document Requirements, Formats and Approvals

    83. 83 Qualification Combine I/OQ into Single Document Add PQ for Smaller Projects I/OQ is Sometimes 90% of the Overall Effort, but Receives Only 10% of the Investigators Attention Review Contractor Proposals Closely

    84. 84 Design Qualification Useful on Larger Projects Critiques Design from an Operability & Validation Perspective Reduces Costs of Correcting Errors Required in Device Regulations

    85. 85 Installation/Operational Qualification Checklist Format Preferred Avoid Arbitrary Criteria Convey Requirements to Suppliers in Specifications Check at Vendor and Reconfirm on Site Focus on Accuracy of Collected Documentation Test to Manufacturer’s Specifications if the Detailed Process Needs are Vague

    86. 86 Performance Qualification Use Generic Protocols [“Terminal Sterilization” rather than “Sterilization of xxxxx Vials, Autoclave 6, Building 4”] Use Quantitative Criteria [“RSD Maximum of 4.5%” Rather Than “Must Demonstrate a Uniform Mix”] Use Meaningful Criteria [“3 Log Reduction in Endotoxin” Rather Than “8 Minutes At 300 C”]

    87. 87 Validation as discussed in Q7A Should extend to those operations determined to be critical to the quality and purity of the API Critical parameters/attributes are normally identified during the development stage or from historical data, along with ranges necessary for reproducible operations

    88. 88 Prospective Validation Q7A Normally performed for all API processes Validation of API process should be completed before commercial distribution of the final drug product manufactured from that API

    89. 89 Concurrent Validation Q7A Conducted when data from replicate production runs are unavailable: Limited number of API batches produced API batches produced infrequently API batches produced by a validated process that has been modified

    90. 90 Concurrent Validation Q7A Batches can be released and used in production of drug products for commercial distribution based on thorough monitoring and testing of the API batches

    91. 91 Retrospective Validation Q7A Exception for well established processes used without significant changes to API quality due to changes in: Raw materials Equipment Systems Facilities Production Process

    92. 92 Retrospective Validation Q7A May be used where: Critical quality attributes and critical process parameters have been identified Appropriate in-process acceptance criteria and controls have been established

    93. 93 Retrospective Validation Q7A May be used where (Continued): Process/product failures attributed mostly to operator error or sporadic equipment failures unrelated to equipment suitability Impurity profiles have been established for existing API

    94. 94 Validation Q7A Validation is NOT for exploration to design a process. It is for showing that an already established process does what it is supposed to do. Validation approaches, protocols, execution, and reports are fully described. Different from drug manufacturing: Only critical processes are usually validated, e.g.. at the following points of the processing: - significant impurities may be introduced or removed - no significant impurities will be removed - all essential structural elements of the API are present

    95. 95 New Equipment/System Milestones

    96. 96 Commissioning/Qualification Transformation

    97. 97 Qualification Program

    98. 98 Qualification Program Attributes Completion Of Commissioning. Test Protocol(s) With Pre-determined Acceptance Criteria Covering Installation and Operation. Execution Under Pre-approved Procedures For: Protocol and Report Development Documentation Practices Change Control (Pre-approval Of Changes) Investigations (Deviations) Approvals

    99. 99 Commissioning Program Attributes Ability to ‘Fix’ Equipment/System as Required (Design Intent). Documented Activities. Tests That Have Pre-determined Expectations. Execution Under Pre-approved Procedures For: Test Plan Development Test Execution Documentation Practices Change Management (Documented Audit Trail for Changes, including Approvals) Approvals

    100. 100 Proposed Qualification Program

    101. 101 Test Documentation

    102. 102 PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF THE VALIDATION TEAM Writing and approving the Master Plan. Writing protocols Providing validation engineers Providing supervisory assistance Generation of summary reports Preparation of designated Standard Operating Procedures (SOP). Training to construction and operation personnel as needed for the validation activities. Review, assistance and support as outlined in the project approach section of this Master Plan for the Engineering/Construction/Validation interface.

    103. 103 PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF THE GENERAL CONTRACTOR Reviewing and approving the Master Plan and appropriate protocols. Review, approval and implementation of Validation’s checklists. Establish and maintain the document control procedures and administration for this project. Transmission of all design drawings, specifications, purchase documents and vendor literature Execution of the Protocols as defined. Assembly of the turn-over and construction support documentation. Coordination of Calibration, certification activities and supervision of the subcontractors execution of validation activities. Support activities as outlined in the project approach section of the Master Plan for the Engineering/Construction/Validation interface.

    104. 104 PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF ENGINEERING CONTRACTOR Write up the Basis of Design for all systems and sections of the facility and have them approved by the responsible operations personnel. Preparation of all design drawings and specifications necessary for the completion of the scope of work by Validation. Support activities as outlined in the project approach section of the Master Plan for the Engineering/Construction/Validation interface. Reviewing and approving the Master Plan.

    105. 105 PROJECT RESPONSIBILITIES THE RESPONSIBILITIES OF OPERATIONS Supplying all procedures and documentation necessary for the generation of the Master Plan and execution of the protocols. Reviewing and approving the Basis of Design and the Master Plan and all other documentation such as protocols, the executed protocol data packages and the final reports produced by Validation. Preparation of designated Operation, Calibration, and Maintenance Standard Operating Procedures (SOP). Providing personnel, when necessary, to assist in the sampling and operating of equipment and equipment systems during the execution of qualification studies. Coordination of all other Validation Team requirements and responsibilities. Providing Validation personnel with adequate office and specified Quality Control laboratory support and test methods as required for the execution of the scope of work. Support activities as outlined in the project approach Section of the Master Plan for the Engineering/Construction/Validation interface.

    106. 106 List and Compare Break Down of Scope Categorize the Packages Keep Like Items Together Define Boundaries

    107. 107 Integrated E,P,C,V,SI Timeline Research and Development: Process Requirements, Critical Process Parameters, Cleaning Toxicology, Analytical Testing Conceptual Design: Project Approach and Integration Plan Basic Engineering: Review of critical systems and philosophies Detailed Engineering: Validation/GMP Input, Procurement, Vendor documents, Specifications, Acceptance Criteria, P/Os, Drawings, FAT & VTOP Construction: FAT/SAT, Training, Installation Qualification, Ongoing Audit/Review, SOPs, “As-built Drawings”Research and Development: Process Requirements, Critical Process Parameters, Cleaning Toxicology, Analytical Testing Conceptual Design: Project Approach and Integration Plan Basic Engineering: Review of critical systems and philosophies Detailed Engineering: Validation/GMP Input, Procurement, Vendor documents, Specifications, Acceptance Criteria, P/Os, Drawings, FAT & VTOP Construction: FAT/SAT, Training, Installation Qualification, Ongoing Audit/Review, SOPs, “As-built Drawings”

    108. 108 Integrated Validation The purpose of integrated validation is to provide assurance and documented evidence that a facility will consistently produce pharmaceutical substances which meet the owner’s specifications that are their interpretation of the regulatory requirements for the products they are going to manufacture. Integrated validation will assure that the equipment and facilities are installed, constructed and operate per the manufacturing requirements and that they provide an environmentally and physically safe work area for employees. Integrated validation requires all vendors and suppliers of equipment, contractors and sub contractors responsible for construction and installation of plant systems and equipment, all departments and disciplines which are confronted with cGMP requirements to participate and understand their role in the implementation of the regulatory requirements of the operation. Integrated validation incorporates the use of the expertise and documentation of skilled personnel hired to perform functions in a project and to transfer the necessary technology to the on going operations. The integrated validation will be organized following the modular or system approach, mimicking the design methods used, when performing Installation Qualification (IQ) and Operational Qualification (OQ). What follows is an outline of a methodology using integrated validation at an inspected and qualified facility. The methodology developed in the project is the methodology still in place for both on-going operations and new projects.

    109. 109 Develop Standard IQ Protocol Write One IQ Protocol that is General and has a Method of Being Uniquely Identified so Specific Attachments for Qualification can be Attached Develop Appropriate Checkout Sheets Accept Vendor Documentation Accept Contractor Verification

    110. 110 Documentation Clear, Concise Prose Tables and Drawings, Rather than Words Summaries not Narratives Plagiarism Should Be Encouraged Put Repetitive Elements in Procedures Don’t Rewrite War and Peace

    111. 111 Approvals Minimize the Number of Approvers Maximum of 4-6 Must Include the “Quality Control Unit” Approvers Must Have Technical Understanding

    112. 112 Approach to IQ Verification The Appropriate Engineer to Walk Down and “Red Line” the P&IDs Validation Personnel to Develop Checkout Sheets from Engineering Drawings and Specifications Vendor Documentation for Their Specific Required Specifications of Their System or Equipment Contactor Verification of Installation per Vendor Requirements or Drawings

    113. 113 Approach to IQ Verification Terminations and Connections Verified per Contractor Verification Forms or Checkout Sheets CM to Verifies the System was Checked and No Blind Flanges, Start Up Strainers or other Temporary Items were Found or were Identified as Necessary For OQ.

    114. 114 Approach to IQ Verification CM verifies that all extraneous tags are removed - electrical and mechanical CM verifies that the identification of all items is correct and completed Proper safety and caution notices are placed on pressurized lines and rotating equipment. Restriction notices for the module or System are in place.

    115. 115 Approach to IQ Verification Overall installation was found correct: Correct Ordering Inlet/Outlet Damping Distances (if applicable) Accessibility for Operation Accessibility for Maintenance Dead Ends / Insertion Depth Freedom for Expansion (No Stress) All Internal Equipment Components Installed where Required All Manual Equipment is Functional

    116. 116 Develop Standard OQ Protocol Write One OQ Protocol for Each Type of Package that is General and Has a Method of being Uniquely Identified so Specific Attachments for Qualification can be Attached Develop Appropriate Checkout Sheets Follow the FAT Model Define Test to Assure Operational Requirements are Met

    117. 117 Transition IQ to OQ Verification by Validation of the Completion of IQ or Authority to Proceed with OQ Pre-OQ Verifications Calibration Start-Up/Commissioning Documentation Complete Vendor Start-Up Procedures Identified Qualified Personnel Identified Exceptions/Deviations Noted and Approved

    118. 118 Pre-OQ Verification Report For Completion of the Building and/or Area and the Required Support Areas or Systems are Attached or Referenced in PRE-OQ Checkout Sheet. Required Package Start-Up Preparation is Performed (If Applicable). Cleaning of Area / Room and Equipment Externals is Completed. Inspection of Equipment Internals is Completed (If Applicable). An Appropriate Safety Inspection has been Performed and Found Acceptable for OQ Activities. The Device Calibrations are Complete and the Calibration Data Documented in the Appropriate System.

    119. 119 Pre-OQ Verification Confirmation of Availability of the Tag Checkout Forms, Loop Tuning Checkout Sheets and 72 Hour Motor Runs and Checkout Sheets. BOPs To Be Tested are Identified, Downloaded and Ready to be Started. BOP Requirement Specifications and Test Matrices are Available. Sequence of BOPs to be Tested are Identified. BOP Test Procedures are Available for Each "Typical" Package. Partial Recipes - Water are Identified, Downloaded and Ready to be Started. Synthetic Recipes - Water are Identified, Downloaded and Ready to be Started

    120. 120 Calibration Calibration of all Instruments which Require Calibration will be Performed. A List by Module or System of all Instruments that Must be Calibrated which belong to the Package will be Prepared and Attached to the Package OQ Protocol. This List will Identify the Instruments which Require Calibration as well as the Applicable Calibration SOPs. Confirmed on Package Pre-OQ

    121. 121 Start-Up/Commissioning All Systems and Equipment in a Package to be Started Up will be Identified. Procedures to Perform Start-Up/Commissioning will be Written and Approved Adjustments and/or Modifications will be Allowed And Documented Appropriately

    122. 122 Vendor Start-Up Vendor Start-Up Procedures and Requirements will be Met and Verified by CM Documentation will be Part of the Protocol

    123. 123 Procedures Written Procedures for all Operational Functions will be in Place in at Least Draft Form before OQ Begins Approved Procedures for Support Packages will be in Place Before Operational or Follow on Packages Proceed with OQ

    124. 124 Qualified personnel Personnel Performing the Required Functions will have Verification of Their Ability to do the Qualification Work. Training Records Education Resumes Contractor Certifications Etc.

    125. 125 Tag Checkout The main objective of tag checkout is to test the communication and correctness of an input signal from a calibrated field device to the computer console and an output signal from the computer console to a calibrated field device. Specific procedures are developed for Tag Checking of Instruments which are DCS or FMS controlled. Depending on the Instrument type, one of the following forms will be completed for each of the Instrument Tags: - "VFD controlled motors"; - "Analog Inputs"; - "Analog Outputs"; - "Digital Inputs"; - "Digital Outputs"; - "One Speed Motor"; - "Two speed Motor". The appropriate procedure to follow when performing Tag Checkouts, is described on the forms mentioned above. A list of instruments to be tag checked will be attached to the package OQ Protocol. The completion of Instrument tag checkout for a specific package is confirmed on package OQ Checkout Sheet.

    126. 126 Construction Cleaning - Process & Facility A reference to the construction cleaning - process and facility (external equipment, pipe lines, vessel internals, miscellaneous construction equipment removed, etc...) applicable to the proposed package will be confirmed on the OQ Checkout Sheet. The cleaning will be completed by the responsible contractors and verified by Construction Management/Start up.

    127. 127 Loop Tuning The objective of loop tuning is to adjust a controller in order to make it able to maintain process variable stability under any combination of internal or external disturbances which may reasonably occur to the process. The control loops will be tuned according to a SOP and may be performed more than once and at several stages of OQ in order to fine tune the controller. A list of the controllers to be tuned will be attached to the package OQ Protocol.

    128. 128 Execution Use Appropriately Trained Operational Personnel Use Validation Teams for Larger Tasks Maintain Some Internal Expertise Use Contractors for Peak Demand and Special Tasks Use Prepared Forms For Data Gathering

    129. 129 BOP Testing Each BOP for each typical package will be operated and tested for proper performance within the package. Where possible, the performance of the individual components of the package or module will be tested using water as the process media. Documentation of performance will be recorded, where possible, via the DCS and acceptance provided by a sign off, on hard copy, by the performer and the user, if required. Additional testing results will also be recorded directly on the testing procedure being part of the OQ Protocol for that package. The package specific OQ Protocol will list the BOPs that are applicable to the package. The documentation of testing compliance is reported on OQ Checkout Sheet and confirmed on OQ Summary

    130. 130 72 Hour Test The 72 hour run in of rotating equipment will be performed per a specific SOP. Results will be documented on the appropriate checkout sheet performed for recording 72 hour test. The documentation of testing compliance is reported on OQ Checkout Sheet and confirmed on OQ Summary

    131. 131 Partial Recipe Testing - Water Each Partial Recipe for the package will be operated and tuned for proper performance within the package. The capacity of the components of the package will be tested for the ranges outlined in the specifications. These ranges will be listed in the package OQ Protocol. Documentation of performance will be recorded, where possible, via the DCS and acceptance provided by a sign off, on hard copy, by the qualification team , if required. The documentation of testing compliance is reported on OQ Checkout Sheet and confirmed on OQ Summary. Additional testing results will also be recorded directly on the testing procedure being part of the OQ Protocol for that package.

    132. 132 OQ Checkout and Summary Complete the Package OQ Checkout Sheet which documents the hand over of the package from the qualification team to the user in order to certify: The required package preparation for operational condition runs is performed. Equipment calibration is complete and calibration data documented. Tag checkout is completed and documented Loop tuning is completed and documented 72 hour run test is completed and documented. Water batch testing is completed and documented. Safety inspection has been performed and found acceptable for operational runs. Passivation procedure is available (if applicable). Availability of instrument calibration SOPs is noted and referenced within the system. Availability of maintenance SOPs is noted and referenced within the system. Availability of the operating procedures is noted. Specific sequence of BOPs to be tested for operational runs is identified. Partial recipes for operational runs are identified, downloaded and ready to be started. Availability of approved cleaning SOPs are noted for rooms and equipment which are not cleaned through automated controlled cleaning procedures and that the cleaning is performed.

    133. 133 Methods of Performing Validation The above methodology was followed in detail to achieve an efficiency that allowed the facility to quickly start production and to expand the operations under controlled procedures.

    134. 134 Part Seven: Technical Content Requirements

    135. 135 Process Parameters Diagram

    136. 136 Validation Protocol Provide an outline of the validation effort Include a clear definition of what will be validated Is uniquely identified Is dated Approved by competent individuals in responsible areas Are suitable for review by regulatory agencies Introduction/abstract Description of process or system Responsibilities Challenge criteria Acceptance criteria Append data sheets, etc.

    137. 137 Operational Qualification (OQ) OQ documents that the equipment: Can operate as designed and intended Is capable of repeatable operation over the entire operating range of process variables OQ implemented after equipment has been started up or commissioned

    138. 138 PAR Approach To Process Validation This is perhaps the most important concept in process validation. It is necessary for the developmental function to participate fully in guiding the validation on the production scale. In the developmental phase, the control parameters which are critical to the process and the quality of the product are determined. Some of these, such as solvent quality, agitation rate, etc. may be fixed. Others may be variable over an acceptable range. This is important to the production scale , so that production has the greatest degree of flexibility in running the process. Development should attempt to learn as much about the effects of the process control parameters as possible. Edge of failure need not be reached as long as a firm understanding of the PAR is gained. In addition, developmental work is needed to explore the effects that the process parameters have on each other. Does running at high temperature and high pH have a detrimental effect, whereas independently they are OK?This is perhaps the most important concept in process validation. It is necessary for the developmental function to participate fully in guiding the validation on the production scale. In the developmental phase, the control parameters which are critical to the process and the quality of the product are determined. Some of these, such as solvent quality, agitation rate, etc. may be fixed. Others may be variable over an acceptable range. This is important to the production scale , so that production has the greatest degree of flexibility in running the process. Development should attempt to learn as much about the effects of the process control parameters as possible. Edge of failure need not be reached as long as a firm understanding of the PAR is gained. In addition, developmental work is needed to explore the effects that the process parameters have on each other. Does running at high temperature and high pH have a detrimental effect, whereas independently they are OK?

    139. 139 Process Qualification (PQ) PQ documents that: Processes operate as required at the normal operating limits of critical parameters Systems operate consistently and reliably Appropriate challenges are employed

    140. 140 Automation / System Integration Business Management Automation = SAP, MRP, People softBusiness Management Automation = SAP, MRP, People soft

    141. 141 IQ Verification Engineering Documentation Engineering Drawings Equipment and Filter List Instrument List and Calibration Construction Completion SOPs Review Room Finishes (optional) Lubricant List Trainings Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Room Air Changes Power Failure Air Flow Direction Air Make-up HEPA Filter Integrity Test Report Air Balance Report Monitoring of Environmental Conditions Qualification Test Equipment and Instruments Variance Summary Report

    142. 142 IQ Verification Engineering Documentation Engineering Drawings Utilities List Dust Collectors Inspection Spare Parts List SOPs Reviews Preventive Maintenance Program Instruments Calibration / Certification Records Variance Summary Report OQ Verification Alarm System Verification Dust Collectors Motors Checkout Back Flow Prevention Dust Collection Capture Velocity at Use Point Variance Summary Report

    143. 143 IQ Verification Engineering Drawings Engineering Specifications Room Design Verification Utilities List Preventive Maintenance Program Variance Summary Report OQ Verification Checkout: Drawings, Specification, Instrument, Equipment and Utilities Room Layout is effective for material and personnel flow Room Surfaces meet the specifications and designed to be easily sanitized and clean Floor,Walls and Ceiling finish meet specifications Variance Summary Report

    144. 144 PQ Verification Evaluation and Selection of Chemical Solution or Agent Determination of label validity or concentration Application of analytical methods Chemical Solution or Agent residual Compatibility with surfaces Methods of cleaning application Frequency of use Effectiveness and Reproducibility of the cleaning process Non-toxic Chemical Solution or Agent Documentation of the obtained results SOPs preparation Training Variance Summary Report

    145. 145 IQ Verification Engineering Documentation Equipment and Filter List Instrument List and Calibrations Lubricant List Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Pump Checkouts Filter Integrity Test Report System Operational Data Qualification Test Equipment and Instruments Variance Summary Report PQ Verification Bioburden & Endotoxin Washing Test & Inspection Qualification Test Equipment Variance Summary Report

    146. 146 IQ Verification Engineering Documentation Equipment and Filter List Instrument List and Calibrations Lubricant List Material Product Contact Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Equipment Operational Data Qualification Test Equipment and Instruments Variance Summary Report PQ Verification Heat Distribution Cycles Heat Penetration Cycles Process Parameters Load Configuration and Thermocouple Placement Qualification Test Equipment Variance Summary Report

    147. 147 IQ Verification Engineering Documentation Equipment and Filter List Instrument List and Calibrations Lubricant List Material Product Contact Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Sensors Operation Equipment Operational Data Qualification Test Equipment and Instruments Variance Summary Report PQ Verification Process Parameters Particulate Test Product in process checkout Qualification Test Equipment Variance Summary Report

    148. 148 IQ Verification Engineering Documentation Equipment and Filter List Instrument List and Calibrations Lubricant List Material Product Contact Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Sensors Operation Equipment Operational Data Qualification Test Equipment and Instruments Variance Summary Report PQ Verification Leak Test & Inspection Product in process checkout Particulate Test Qualification Test Equipment Variance Summary Report

    149. 149 IQ Verification Engineering Documentation Equipment and Filter List Instrument List and Calibrations Lubricant List Material Product Contact Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Sensors Operation Equipment Operational Data Qualification Test Equipment and Instruments Variance Summary Report PQ Verification Torque Test & Inspection Product in process checkout Qualification Test Equipment Variance Summary Report

    150. 150 IQ Verification Engineering Documentation Equipment and Filter List Instrument List and Calibrations Lubricant List Material Product Contact Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Equipment Operational Data Qualification Test Equipment and Instruments Variance Summary Report

    151. 151 IQ Verification Engineering Documentation Equipment List Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Equipment Operational Data Qualification Test Equipment and Instruments Variance Summary Report

    152. 152 IQ Verification Engineering Documentation Equipment List Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Equipment Operational Data Qualification Test Equipment and Instruments Variance Summary Report

    153. 153 IQ Verification Station Drawings Utilities Environmental Conditions Inspector List SOPs & Trainings Review Variance Summary Report OQ Verification Sampling Plan Inspection Test Data Analysis Qualification Test Equipment and Instruments Variance Summary Report

    154. 154 IQ Verification Engineering Documentation Material in Product Contact Engineering Drawings Equipment and Filter List Utilities SOPs & Trainings Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Agitator Checkout and minimum operational volume Pump and Spray ball Checkout Pressure and Vacuum Test Heating and Cooling Test Filter Integrity Test Report Qualification Test Equipment and Instruments Variance Summary Report

    155. 155 IQ Verification Engineering Documentation Equipment and Filter List Material in Product Contact Lubricant List Instrument & Calibration List Utilities Loop Verification SOPs & Trainings Review Piping System Cleaning and Flushing Checklist Welding and Passivation Reports Variance Summary Report OQ Verification Piping System Leak Test Application Software Audit Security Capability Emergency Power Cycle Control Studies Cycle Monitoring Qualification Test Equipment and Instruments Variance Summary Report PQ Verification Cycle Monitoring and Microbial Test Detergent & Active Ingredient residue Variance Summary Report

    156. 156 IQ Verification Engineering Documentation Equipment and Filter List Material in Product Contact Lubricant List Utilization List Instrument & Calibration List Utilities SOPs & Trainings Review Piping System Cleaning and Flushing Checklist Passivation Reports Piping Leak Test Report Variance Summary Report OQ Verification SIP OQ Log Sheet Digistrip Data Logger Recording SIP Station Diagram Qualification Test Equipment and Instruments Variance Summary Report PQ Verification SIP Cycle Monitoring Temperature Analysis and Microbial Checkout Clean Steam Analysis Qualification Test Equipment and Instruments Variance Summary Report

    157. 157 IQ Verification Engineering Documentation Engineering Drawings Electrical Utility SOPs Review Environmental Conditions Installation Verification Configuration & Wiring Checkout Software Verification Radio Frequency and Electromagnetic Interference Tests Variance Summary Report OQ Verification Functional Verification Alarm Test Security Test Input/Output Verification Power Failure Test Reports Verification Load and Backup Test Variance Summary Report

    158. 158 IQ Verification Engineering Documentation Engineering Drawings Equipment and Filter List Lubricant List Material Product Contact Utilities SOPs Review Training Records Variance Summary Report OQ Verification Controls Verification Instrument Checkout Functional Verification Alarm Test Power Failure Test Operational Settings Documentation Variance Summary Report

    159. 159 IQ Verification System Related Manuals Critical Equipment Installation Configuration Verification Power & Fusing Hardware Maintenance Software Program Version Software Configuration SOPs Review System Securities Software Backup and Archiving Provisions Variance Summary Report OQ Verification Functional Branching Test Functional Key Availability and Operational Test Field Specification Tests Power Failure Test Printing Verification Variance Summary Report

    160. 160 PQ Verification Setting Parameters Checkout Speed Verification Reject Station Test Equipment Functional Verification Sampling Plan Inspection Qualification Equipment and Instruments Variance Summary Report

    161. 161 IQ Verification Engineering Documentation Engineering Drawings Equipment List Instrument List and Calibration Lubricant List Electrical Utility SOPs Review Variance Summary Report OQ Verification Control Verification Instrument Checkout Digistrip Data Logger Recording Qualification Test Equipment and Instruments Variance Summary Report

    162. 162 IQ Verification Engineering Documentation Engineering Drawings Equipment List Instrument List and Calibration Electrical Utility SOPs Review Variance Summary Report OQ Verification Control Verification Instrument Checkout Digistrip Data Logger Recording Qualification Test Equipment and Instruments Variance Summary Report

    163. 163 IQ Verification Engineering Documentation Construction Completion Engineering Drawings Equipment and Filter List Instruments List SOPs Reviews Preventive Maintenance Program Variance Summary Report OQ Verification Qualification Test Equipment and Instruments Use Points Utilization List Use Point Pressure Testing Operational Performance Checkout System Functional Checkout Hydrocarbons Verification Test Dew Point Record Viable and Non Viable Particulate Test Variance Summary Report

    164. 164 IQ Verification Construction Completion Engineering Documentation Engineering Drawings Equipment and Filter List Specifications Instruments List and Calibrations Spare Parts List SOPs Review Preventive Maintenance Program Trainings Variance Summary Report OQ Verification Major Equipment Performance Checkout Controls Verification Instrument Functionality Verification Piping Cleaning System and Flushing Steam Supply Pressure Verification Alarm & Interlock System Verification Test Supply for all Use Points Steam Quality Verification Variance Summary Report

    165. 165 IQ Verification Engineering Documentation Engineering Drawings Equipment and Filter List Instrument List and Calibrations Lubricant List Construction Completion Utilities SOPs & Trainings Review In Process Maintenance List Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Utilization List Pump Checkouts Filter Integrity Test Report System and Loop Operational Data and Monitoring Qualification Test Equipment and Instruments Variance Summary Report PQ Verification Sampling Plan Water Quality Report Variance Summary Report

    166. 166 IQ Verification Engineering Documentation Engineering Drawings Major Equipment Specification & Calibrations Lubricant List Filters List and Specifications Utilities List SOPs Trainings & Review Preventive Maintenance Program Variance Summary Report OQ Verification Control System Checkouts Major Equipment Checkout Filter Integrity Test Report Sanitization Program Variance Summary Report PQ Verification Sampling Plan Water Quality Verification Variance Summary Report

    167. 167 IQ Verification Construction Completion Engineering Documentation Engineering Drawings Utilities List Equipment Specifications Spare Parts List Instruments Calibrations SOPs Reviews Preventive Maintenance Program Variance Summary Report OQ Verification Utilization List System Operational Data and Monitoring Qualification Test for Equipment and Instruments Alarms Verification System Flush Verification Use Points Sampling Plan Quality Tests Variance Summary Report

    168. 168 Chromatography – Validation Considerations Column Packing Pressure Flow Rate pH Buffer Concentration HETP Efficiency

    169. 169 Bioreactions - Validation Considerations Cell Line Integrity Temperature pH Agitation Dissolved Oxygen Maintenance Of Sterility Mutation

    170. 170 Organic Synthesis Design & Construction -Reactor - Pumps -Agitator -Materials Of Construction -Controls -Jacket Services -Venting -Cleaning Operation -Temperature -Agitation Rate -Pressure -Raw Materials -Step Times -Concentration of Reagents -Yield -Impurities

    171. 171 Purification and Drying Operation -Agitation Rate -Time -Temperature -Ph -Drying Temperature Distribution -Dryer Air Flow -Activated Carbon Type & Mesh

    172. 172 Multi-product Facility: Areas of Concern People and Material Flow Cross-contamination Cleaning Validation Cleanability Environmental Contamination Lubricant Contamination Housekeeping Written Procedures/Records Equipment Qualification Technology Transfer Process Validation Analytical Method Validation API Impurity Profiles (Identify > 0.1%) Computer System Validation

    173. 173 People Must Be Considered In Design Phase Presented In Master Plan Direction Of Movement Validated Gowning Procedures Documentation Of Training

    174. 174 Material Flow Clean Vs. "Dirty" Corridors Methods For Moving Equipment Storage and Staging Areas Decontamination Areas Tagging/Labeling Procedures

    175. 175 Equipment - Primarily a Cleaning Validation Concern, But Want to Ensure Gasket Materials, O-rings, Etc,. will not be a Source for Cross -Contamination Utilities- Multipurpose HVAC - Easiest Way for Contaminants to be Dispersed Throughout a Facility Cross-Contamination

    176. 176 Cross-Contamination: Utilities Direct Connection Check Valves Backflow Preventers Interlocked Valves Alarms Indirect Connections Proper Safeguards SOPs

    177. 177 Part Eight: Execution

    178. 178 HVAC Validation IQ - During Construction Phase OQ TAB Report Retest Critical Areas DOP Testing Laminar Flow Pressure Differentials BAS (Separate Validation Program?) Environmental Baseline

    179. 179 Environmental Baseline Test HVAC System Operation As An Integrated System Temperature, Humidity * Bioburden * Non Biological Particulate 30 Days (Typical) - OQ 30 Days (Typical) - PQ

    180. 180 Air System Qualification Pressure Differential Air Changes Flow Patterns Sound Level Lighting Temperature Relative Humidity HEPA Filter Qualification Non-viable Counts

    181. 181 HEPA Filter Qualification DOP or Alternative testing Velocity Testing Recommended Practices: - Laminar Flow - Testing Clean Rooms - HEPA Filters Dioctyl phthalate aerosol particle size is around 0.3 micrometers. It is the traditional material used to challenge HEPA filters, which are better than 99.9% effective in removing particles of this size. This activity requires a scanning photometer is usually left to specialists. Velocity testing should follow IES standards. These require a HEPA filter to be checked within one foot of its face, at several different spots. The IES standards listed are available from the: Institute for Environmental Sciences Mount Prospect, IL 60056 312-255-1561 It is valuable to understand these and to require certifying contractors to comply with them.Dioctyl phthalate aerosol particle size is around 0.3 micrometers. It is the traditional material used to challenge HEPA filters, which are better than 99.9% effective in removing particles of this size. This activity requires a scanning photometer is usually left to specialists. Velocity testing should follow IES standards. These require a HEPA filter to be checked within one foot of its face, at several different spots. The IES standards listed are available from the: Institute for Environmental Sciences Mount Prospect, IL 60056 312-255-1561 It is valuable to understand these and to require certifying contractors to comply with them.

    182. 182 Non-viable monitoring hiac-royco climet met-one particle measurement systems etc.

    183. 183 Viable Organisms Monitoring Slit To Agar Swabs RCS Sampler Settling Plates Anderson Sampler Sartorius Sampler Rodac Plates

    184. 184 Cleaning Validation GOAL: Confirm the effectiveness of the cleaning procedures CIP (Clean In Place) Manual Cleaning

    185. 185 What Items are being Removed Active Ingredients Decomposition Products Excipients Detergent/Cleaning Agents Microbial Contamination Endotoxin Particulate Sanitizing Agents Lubricants

    186. 186

    187. 187 Sampling Methods Swabs in Open Areas Swabs in Inaccessible Areas Step Rinses Final Rinse Placebo Product Next Production Lot Visual Examination

    188. 188 Priority Of Cleaning Validation All Products Least Soluble Most Potent Most Toxic Least Soluble and Most Potent (or Most Toxic) Hardest To Clean Family Approach New Products

    189. 189 Limitation Of Rinse Sampling Only Valid When Applied To Highly Soluble Contaminant Requires Rigorous Qualification of Cleaning Solution Requires Rigorous Qualification of Mechanical Systems (Especially Spray Coverage) “Baby in the Bathwater”

    190. 190 “Baby in the Bathwater” The Cleanliness of the Bathwater (rinse sample) may not be Indicative of the Cleanliness of the Baby Contaminants may be Poorly Soluble in the Cleaning Solution Cleaning Solution may not Contact all Contaminated Areas Both Cleaning and Evaluation Methods may be Inadequate

    191. 191 Permissible Residuals LTD - Lowest Therapeutic Dose TIEL - Toxicologically Insignificant Exposure Limit PIEL - Pharmacologically Insignificant Exposure Limit Lowest Marketed Dose NOEL - No Observable Effect Limit EPA, OSHA, USDA, Other Published Limits Log Reduction “None Detectable”

    192. 192 WFI Design Recommendations Polished Stainless Proper Piping System Sloping Machine Welding Flush Type Diaphragm Seals Rupture Discs Diaphragm Valves Temperature Record For Critical Points WFI Pressure Higher than Cooling Water Pressure Low Flow and Low Temperature Alarms "6d Rule" Turbulent Flow Of these, there are some differences for Purified Water. The WFI standards consider the highly corrosive nature of hot pure water. Since Purified water is ambient, design specs are not so stringent. Nevertheless, the quality of installation for Purified Water should not be taken lightly. Polished stainless tubing is the recommended material. Purified Water systems have made use of sanitary design plastic systems (e.g.. , PVDF, SaniTech) PVC is not recommended and industrial PE and other plasticsOf these, there are some differences for Purified Water. The WFI standards consider the highly corrosive nature of hot pure water. Since Purified water is ambient, design specs are not so stringent. Nevertheless, the quality of installation for Purified Water should not be taken lightly. Polished stainless tubing is the recommended material. Purified Water systems have made use of sanitary design plastic systems (e.g.. , PVDF, SaniTech) PVC is not recommended and industrial PE and other plastics

    193. 193 The '6d' Rule "The system shall be constructed with minimal distance (no greater than six pipe diameters) as measured from the end of the leg to the point of connection to the adjoining header.”

    194. 194 Turbulence "Rule Of Thumb" 5 Ft./Sec. Applies To Lines 1" - 2" Diameter Design Recommendation to Ensure Adequate Turbulence Reynolds Number at least 20,000 Turbulence, as measured by Reynolds number, is important because of the difference in flow pattern between turbulent and laminar flow. The fluid velocity profile in laminar flow is parabolic, that is flow is fastest in the center of the pipe, diminishing as it approaches the walls. Along the walls there is a region of virtual stagnation, known as a boundary layer, which can harbor microbial growth. This then becomes a "biofilm". In turbulent flow the velocity profile is flat, with velocity near the walls nearly the same as in the center. In addition, turbulent flow is highly mixed, with eddies and currents across the profile. The boundary layer is very thin, inadequate to harbor microorganisms. Turbulence may be calculated by measuring velocity with a flow meter, or by estimating velocity from the pump curve. Cooling is a special problem with hot WFI. It is important that terminal heat exchangers, as shown in the first figure following, do not act as dead legs. Thus they must be designed for a constant flow, through, when not in use. The second figure shows a system where a cold loop is kept in constant use. Note that the storage tank is maintained hot. The cold loop is affixed with a dual purpose heat exchanger to heat the loop to sanitizing temperatures on a regular basis, when not in use. Experience has shown that a daily sanitization of four hours at 80 C is adequate to maintain microbial quality. It is not necessary to dump the water in the cold loop under these conditions. Turbulence, as measured by Reynolds number, is important because of the difference in flow pattern between turbulent and laminar flow. The fluid velocity profile in laminar flow is parabolic, that is flow is fastest in the center of the pipe, diminishing as it approaches the walls. Along the walls there is a region of virtual stagnation, known as a boundary layer, which can harbor microbial growth. This then becomes a "biofilm". In turbulent flow the velocity profile is flat, with velocity near the walls nearly the same as in the center. In addition, turbulent flow is highly mixed, with eddies and currents across the profile. The boundary layer is very thin, inadequate to harbor microorganisms. Turbulence may be calculated by measuring velocity with a flow meter, or by estimating velocity from the pump curve. Cooling is a special problem with hot WFI. It is important that terminal heat exchangers, as shown in the first figure following, do not act as dead legs. Thus they must be designed for a constant flow, through, when not in use. The second figure shows a system where a cold loop is kept in constant use. Note that the storage tank is maintained hot. The cold loop is affixed with a dual purpose heat exchanger to heat the loop to sanitizing temperatures on a regular basis, when not in use. Experience has shown that a daily sanitization of four hours at 80 C is adequate to maintain microbial quality. It is not necessary to dump the water in the cold loop under these conditions.

    195. 195 Water System Operational Qualification Capacity Resistivity Feedwater Quality Temperature Control Flow Rate Frequency Of Sanitization Frequency Of Regeneration

    196. 196 Water System Performance Qualification Minimum 30 Day Sampling (60 Days Referred) Every Use Point Once/Wk Sample Every Working Day Minimum Allowable Operating Conditions Temperature Sanitization / Regeneration Frequency Emphasis On Micro Testing Establish Action / Alert Limits

    197. 197 Execution Use Calibrates equipment (both on the System and the Validation/Commissioning Testing Equipment) Use process instruments Use qualified personnel and procedures The Validation is intended to prove the Reliability and Consistency of the Process not to be a Detailed Academic Study.

    198. 198 Part Nine: Flow of Work

    199. 199 Integrated E,P,C,V,SI Timeline Research and Development: Process Requirements, Critical Process Parameters, Cleaning Toxicology, Analytical Testing Conceptual Design: Project Approach and Integration Plan Basic Engineering: Review of critical systems and philosophies Detailed Engineering: Validation/GMP Input, Procurement, Vendor documents, Specifications, Acceptance Criteria, P/Os, Drawings, FAT & VTOP Construction: FAT/SAT, Training, Installation Qualification, Ongoing Audit/Review, SOPs, “As-built Drawings”Research and Development: Process Requirements, Critical Process Parameters, Cleaning Toxicology, Analytical Testing Conceptual Design: Project Approach and Integration Plan Basic Engineering: Review of critical systems and philosophies Detailed Engineering: Validation/GMP Input, Procurement, Vendor documents, Specifications, Acceptance Criteria, P/Os, Drawings, FAT & VTOP Construction: FAT/SAT, Training, Installation Qualification, Ongoing Audit/Review, SOPs, “As-built Drawings”

    200. 200 Flow of work Research Data/Product Specifications and Requirements Facility and Equipment Specifications and Requirements Validation Master Planning Writing Protocols Execution of Protocols Summary Reports Maintenance of Validation

    201. 201 Summary Reports

    202. 202 Evaluating the Data

    203. 203 Summary reports A written report that summarizes the validation study, including any data gathered under amendments to the protocol. Any out of parameter data should be identified and fully explained. If data is acceptable, the summary report is approved or “certified” by the same departments (preferably individuals) that approved the protocol.

    204. 204 Summary reports Data, Analysis and results – (Procedure, documentation, Acceptance Criteria, IQ, OQ and/or PQ Analysis) The procedure followed to validate the system will be briefly described and the results obtained summarized. Usually the IQ analysis will be listed using a tabulated form that reflects the results. The OQ and/or PQ analysis must be written in concise detailed form (tabulated, results list, graphs, etc.) and the specific results compared with the acceptance criteria will be presented. In addition, any deviations in terms of procedure or results from those originally defined in the protocol will be documented and discussed as to their impact upon the validation study.

    205. 205 Summary reports It is recommended that all Validation Summary Reports will be in the first section of the validation package file or Binder. The validation package binder will have the following sections: First Section - Summary Report Second Section - IQ/OQ/PQ Protocol (original written document) Third Section - IQ/OQ/PQ Execution (raw data and documentation) Fourth Section - Standard Operating Procedures (when applicable) Fifth Section - General Additional Information (when applicable)

    206. 206 Storage and Usage

    207. 207 Where Is The Validation Data Kept?

    208. 208 Documentation: Records of . . .

    209. 209 Storage and Usage Controlled for Security Available for Review Part of the Operations

    210. 210 Part Ten: Change Control

    211. 211 Change Control "Who needs it? The process is validated. Just read the report." Change Control Necessary To Perpetuate Validation When should change control begin? - After the validation report is approved? - After qualification? - Before qualification begins? A workable way to institute change control is to use it informally during qualification. As such, it must be strictly controlled by the validation team. The informal program does not require the same level of review as in an operating plant. Any changes made during IQ or OQ will be documented in the validation report and on "as built" drawings. These, of course, will be approved. Once qualification is complete, the formal change control program may take effect. A workable way to institute change control is to use it informally during qualification. As such, it must be strictly controlled by the validation team. The informal program does not require the same level of review as in an operating plant. Any changes made during IQ or OQ will be documented in the validation report and on "as built" drawings. These, of course, will be approved. Once qualification is complete, the formal change control program may take effect.

    212. 212 Planned Changes Propose Change, Document Reason (Manufacturing, Development, Etc.) File Formal Request Determine Need For Validation Of Process With Change Implemented Implement Change Execute and Report Validation Testing Review and Approve Update Drawings, SOPs and Operating Records

    213. 213 Emergency Changes Only To Save Product In Process Impound Product Pending Evaluation Of Change Document Change - Formal Request Form Determine Need For Validation Of Change Determine If Change Should Be Permanent Validation Testing, If Necessary Accept Or Reject Impounded Product Update Drawings and Procedures, As Required Responsibility for making emergency changes must be assigned in an SOP. Like for like replacements are not considered changes. An example change control SOP is included. Change control must cover process, equipment and material changes.Responsibility for making emergency changes must be assigned in an SOP. Like for like replacements are not considered changes. An example change control SOP is included. Change control must cover process, equipment and material changes.

    214. 214 Change Control Systems Needed To Assure That : All Changes Are Reviewed and Approved Changes Potentially Affecting Product Specifications, Controls, and/or Processing Parameters Are Reacted to Appropriately No Unintentional Changes Are Made

    215. 215 Change Control Change = A Planned or Unplanned Alteration or Replacement of: Buildings/Facilities Equipment Production Process Controls and Procedures Storage & Distribution Procedures Regulatory Commitments Master Formulas Etc.

    216. 216 Change Control Substances Raw Materials Synthesis Purification Solvents

    217. 217 Change Control Products Excipients Equipment Operating Principles

    218. 218 Master & Batch Formulas Sops - Written Procedure Specifications (Changes beyond filed/validated parameters) Test Procedures

    219. 219 Change Control An Effective System Facilitates Change in Support of Continuous Improvement. Assures Change is Thoroughly Reviewed and Documented in a Traceable Manner, Providing a Complete Historical Record

    220. 220 Change Control Changes Made Outside of a Change Control Process May Result in Processes and/or Products Outside of: Validated Ranges Application Commitments Bioburden Limits New (Undocumented) Process

    221. 221 Change Control Require Approval of Authorized Personnel 21CFR211.22(c) Quality Unit Responsible

    222. 222 Change Control A Written Change Control Procedure Is Required All Changes Must Be Documented System Should Manage All Documents That Control Operations and Quality Functions Best to Tie in Annual Reviews and Internal Audits

    223. 223 Establish Change Control Procedures Identify and Address Significant Process Changes Equipment SOPs Manufacturing Instructions Environment Any Aspect That May Affect the State of the Process All of these items are addressed through the change control but not necessarily in one procedure.All of these items are addressed through the change control but not necessarily in one procedure.

    224. 224 Maintaining a Validated Process Proposed Changes to CGMPs Link Change Control With Revalidation

    225. 225 Maintaining a Validated Process Process Validation - Establish Change Control Procedures Identify and Address Significant Process Changes Equipment SOPs Manufacturing Instructions Environment Any Aspect that May Affect the State of the Process

    226. 226 PROCESS VALIDATION Document All Changes, Any Revalidation Performed and/or Rationale When Revalidation Deemed Unnecessary Annual Process Reviews: Process Changes; Production Problems; Production Failures

    227. 227 CGMP Annual Review 21 CFR 211.180(e) Requires a Retrospective Overall Evaluation of the Adequacy of the Quality Standards At Least Annually Drug Products Directly Impacted Drug Substances Impacted Per Preamble (1978)

    228. 228 CGMP Annual Review ‘95 Retrospective Review Representative # of Batches for Ea. Product If Check Reveals an Adverse Quality Go to 100% Review Computers Use Encouraged As a Compliment to Human Judgment & Intervention

    229. 229 CGMP Annual Review ‘95 Proposed Revisions -Validation Implement Revalidation Procedures Whenever There Are Changes, Including Reprocessing, That Could Affect Product Effectiveness or Characteristics

    230. 230 Planned Changes Propose Change, Document Reason (Manufacturing, Development, Etc.) File Formal Request Determine Need For Validation Of Process With Change Implemented Implement Change Execute and Report Validation Testing Review and Approve Update Drawings, SOPs and Operating Records

    231. 231 Emergency Changes Only To Save Product In Process Impound Product Pending Evaluation Of Change Document Change - Formal Request Form Determine Need For Validation Of Change Determine If Change Should Be Permanent Validation Testing, If Necessary Accept Or Reject Impounded Product Update Drawings and Procedures, As Required Responsibility for making emergency changes must be assigned in an SOP. Like for like replacements are not considered changes. An example change control SOP is included. Change control must cover process, equipment and material changes.Responsibility for making emergency changes must be assigned in an SOP. Like for like replacements are not considered changes. An example change control SOP is included. Change control must cover process, equipment and material changes.

    232. 232 Part Eleven: Revalidation, etc Calibration Program Preventative Maintenance Change Control Program Software Equipment Logs SOPs Regular QA Reviews

    233. 233 Revalidation Validation of a Previously Validated System that has been Changed or Modified Need to perform is Established in the Change Control Program Event Based Time Based

    234. 234 Calibration Define Critical Process Variables - Effect On Quality - Effect On Yield Or Accountability - Effect On Operator Safety SOP - General Procedure For Critical Variables - Specific Procedure For Each Instrument - Acceptable Range Definition - Frequency Of Recalibration - Exception Reporting Traceability - NIST Traceable Standards - Recalibration Of Standards Definition of critical process variables is a joint effort involving development, QA, production, maintenance, etc. Always ask, "Does it effect the safety or efficacy of the product?" Non-critical or reference instruments are usually not recorded and are not part of the batch record. They still need to be calibrated, but not against NIST standards, and not as often as critical instruments. NIST is National Institute of Standards and Testing, formerly the Nation Bureau of Standards. NIST traceable standards can be purchased or are available at contract laboratories who subscribe to NIST.Definition of critical process variables is a joint effort involving development, QA, production, maintenance, etc. Always ask, "Does it effect the safety or efficacy of the product?" Non-critical or reference instruments are usually not recorded and are not part of the batch record. They still need to be calibrated, but not against NIST standards, and not as often as critical instruments. NIST is National Institute of Standards and Testing, formerly the Nation Bureau of Standards. NIST traceable standards can be purchased or are available at contract laboratories who subscribe to NIST.

    235. 235 Essential Parts of a Calibration Program Statement Of Purpose and Scope Criteria For Training Personnel Written Calibration Procedures Metrology Laboratory Calibration Records System For Instrument Recall For Calibration Alert Procedure For Out Of Calibration Instruments

    236. 236 Maintenance

    237. 237 Preventative Maintenance

    238. 238 Software Changes made to correct errors and faults in the software are corrective maintenance. Changes made to the software to improve the performance, maintainability, or other attributes of the software system are perfective maintenance. Software changes to make the software system usable in a changed environment are adaptive maintenance. When changes are made to a software system, either during initial development or during post release maintenance, sufficient regression analysis and testing should be conducted to demonstrate that portions of the software not involved in the change were not adversely impacted. This is in addition to testing that evaluates the correctness of the implemented change(s).

    239. 239 Equipment Logs A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.

    240. 240 SOPs Established to Ensure that Activities are Performed the Same Way at all Times Periodic Review and Updating Defined Approval Process, which includes Signatory Responsibility Training on the SOP Content A System of Archiving and Version Control

    241. 241 Regular QA Reviews There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.

    242. 242 Regular QA Reviews All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow up.

    243. 243 QA Reviews 21 CFR 211.180(e), General requirements [Subpart J - Records and Reports] The cGMP regulations call for at least an annual evaluation of each drug product's quality standards to determine the need for changes in product specifications or manufacturing or control procedures. The rule also requires firms to establish and follow written procedures for conducting those evaluations. Such an evaluation would be incomplete if the standard operating procedures for production and process controls were themselves not reviewed. During Your establishment inspections, when auditing for compliance with section 211.180, determine if the firm has established, and is following, those evaluation procedures. Also check to see if the procedures call for reviewing SOPs.

    244. 244 Part Twelve: SHOWSTOPPERS

    245. 245 SHOWSTOPPERS General Quality Assurance The failure to have written procedures in place that have been approved by the quality unit. Personnel performing critical operations who lack adequate training or experience The failure to have a quality unit review for product release that includes review of failures, yield discrepancies, and deviations from procedures.

    246. 246 SHOWSTOPPERS Laboratory Controls Analytical method not validated Not Stability Indicating Related compounds not distinguished Failure to test finished product Stability program inadequate/not observed Poor investigation of out of spec. findings Analysts and/or equipment not qualified Preservative/media effectiveness testing

    247. 247 SHOWSTOPPERS Facilities and Equipment No cleaning validation No environmental monitoring Obvious avenues of contamination Equipment operating parameters not documented Batch size exceeds capacity of equipment Water and air systems not validated

    248. 248 SHOWSTOPPERS Production and Process Controls Process not validated Components not independently check weighed Process deviations and rejected products not adequately controlled/investigated Yields not checked or investigated if out of range Reprocessing without approval or control

    249. 249 SHOWSTOPPERS Packaging and Labeling Failure to check incoming labels against masters or specifications Uncontrolled storage of labeling materials Inadequate clearance of lines Failure to electronically examine or visually double check finished package labeling, unless dedicated lines used

    250. 250 SHOWSTOPPERS Records and Reports Master/batch records that fail to include substantial information required by rules Inability to trace products to materials Failure to investigate complaints and provide appropriate follow up. Missing records for critical operations Falsification of production or control records

    251. 251 Myth #1 Validation is a project related activity, which once completed can be largely ignored.

    252. 252 Truth Validation is a journey, not a destination! Validation is best performed when it is practiced in a life-cycle model, using a cradle-to-grave approach. This provides the maximum benefit in compliance and finance.

    253. 253 Myth #2 Validation can be accomplished by a small cadre of individuals with minimal intrusion on the rest of the organization

    254. 254 Truth Validation is everyone’s job. Each portion of the organization must contribute to the overall effort to insure success. No single organization unit can hope to satisfy all the requirements [and reap the benefits] alone.

    255. 255 Myth #3 Too much is made of validation in this industry. If we are GMP compliant, follow procedures and make quality products, we shouldn’t have to spend as much time, money and energy on validation!

    256. 256 Truth Absolutely correct. Validation doesn’t replace the need to do any of those things, it merely helps us do them in a more structured way. It’s not the tail which is wagging the dog, it is part of the dog!

    257. 257 Some References used by an API Manufacturer Guideline on General Principles & Process Validation FDA – May 1987 Pharmaceutical Inspection Convention (PIC) “Internationally Harmonized Guide for Active Pharmaceutical Ingredients” 9/97 ICH-Q7A “Guide to the Inspection of Bulk Pharmaceutical Chemicals” FDA –1994 FDA Compliance Programs: Bulk Pharmaceutical Chemicals 7356.002F Sterile Drug Process Inspections 7356.002F Drug Product cGMPs 1978 preamble EPA Standards for potable water (at minimum) “Bulk Pharmaceutical Chemicals Baseline? Guide” ISPE – 6/96

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