Introduction to GMPs and Validation WILLIAM GARVEY AND ASSOCIATES

Transcription

1 Introduction to GMPs and Validation WILLIAM GARVEY AND ASSOCIATES William Garvey and Associates LLC 2016

2 Introduction About your instructor William (Bill) Garvey Important regulations and events Good Manufacturing Practices (GMP) Validation project management

3 William (Bill) Garvey Over 35 years pharmaceutical industry experience Qualification and validation Facility design and construction Quality Assurance (QA) GMP compliance 1980 BS degree, Northeastern University, Boston, MA

4 William (Bill) Garvey Began career with DuPont Pharmaceuticals Began to work in validation Previous employers Biogen Fluor Corporation Pfizer Inc Merck KGaA

5 William (Bill) Garvey Worked closely with US FDA to solve problems in US generic drug industry

6 Important regulations and events EARLY HISTORY TO MODERN DAY

7 US Pharmacopeia (USP) Eleven physicians meet in Washington, D.C. to establish the U.S. Pharmacopeia (USP) A private organization USP standards are legally enforceable Must comply with USP to sell drug products in US

8 Pure Food and Drug Act Established uniform standards for drugs Defined adulterated and misbranded

9 Federal Food, Drug and Cosmetic Act Basic US food and drug law Replaced earlier 1906 Act Drugs must be safe and effective Labeling and packaging must be truthful and informative Authority for factory inspections

10 Kefauver-Harris Drug Amendments Additional laws added to FD&C Act of 1938 Result of thalidomide Good Manufacturing Practices (GMPs) Facility registration

11 Large Volume Parenteral (LVP) Regulations FDA regulations issued in 1976, but never approved Result of contaminated LVPs Informal start for process validation Common validation testing and acceptance criteria established

12 GMP Regulations Much more specific than 1962 regulations Reduce confusion and inconsistent interpretations Process validation requirements implied

13 Guidelines on Principles of Process Validation Issued by FDA in May 1987 Formal start of qualification and validation High degree of assurance that drug products consistently meet all specifications

14 Good Manufacturing Practices (GMP) INTRODUCTION AND IMPORTANT CONCEPTS

15 Good Manufacturing Practices FDA regulations all drug companies must follow A system to control drug product manufacturing Assure product identity, quality, strength and purity

16 Good Manufacturing Practices Assure batch-to-batch uniformity Prevent, detect and correct errors during manufacturing and testing Increase productivity Non-specific and interpretive

17 Why were GMPs created? GMPs (and drug regulations in general) resulted from US and foreign tragedy Sulfanilamide (1938) Thalidomide (1962) Tylenol capsules filled with potassium cyanide (1982) Tamper-resistant packaging

18 Why were GMPs created? Adulterated and misbranded drugs are public health hazards Widely distributed Consumed in large amounts in a short time Used by the sick - could worsen illness rather than cure it

19 FDA and GMP enforcement Periodic, unannounced plant inspections Delay approving New Drug Applications (NDA) Drug product purchase and testing Import alerts

20 How GMP can benefit Reduce manufacturing errors product rework is costly Batch records are important For process control For product investigations To investigate complaints To monitor product quality

21 How GMP can benefit Cleaning log books and equipment pre-use inspection Prevent contamination and crosscontamination Product investigations what was made before? And after?

22 How GMP can benefit Component, container and labeling records Identify batches where component was used Investigate surpluses or shortages Where did it go? Prevent label mix-ups correct product but incorrect label

23 How GMP can benefit Distribution records assist with product recalls Product complaints may indicate unknown problems Reserve samples are retested when investigating complaints

24 How GMP can benefit Equipment maintenance records Used for reliability analysis Establish maintenance schedules Maximize equipment uptime Manage spare parts inventory Maintain equipment validated state

25 GMP and yield calculation Calculate yield at critical process steps Compare to expected yield If % theoretical yield is incorrect, investigate something went wrong

26 GMP and label reconciliation Reconcile labels when labeling is complete If label and product counts do not agree, investigate Did labels get applied to the wrong product?

27 GMP and Standard Operating Procedures (SOP) Encourages management review and discussion Assures consistent operations The standard for GMP audits Used for employee training

28 GMP and second verification Critical process steps require verification by second person Reduce human error Intentional errors require cooperation of two individuals

29 GMP and process validation 1962 Process validation implied but not enforced 1976 LVP regulations issued informal start to validation 1978 Revised GMP regulations require validation for processes causing product variability

30 GMP and process validation 1978 Parenteral Drug Association (PDA) issues Technical Report 1, Validation of Moist Heat Sterilization Processes 1987 FDA issues Guidance on Principles of Process Validation 2011 FDA reissues 1987 Guidance validation now risk based

31 Introduction to validation BEST PRACTICES AND LESSONS LEARNED

32 Introduction to validation Validation project management Facility and equipment design Validation project risk Validation master plan Process validation (PV) Cleaning validation (CV)

33 Validation project management Companies of all types perform work Operations are repetitive Projects are temporary Projects are implemented to achieve company s strategic plan

34 Validation project management All validation activities are projects Defined start date Expected end date Rarely or never repeated

35 Qualification and validation Qualification and validation are Quality Assurance (QA) activities Verify and document that systems, equipment and processes agree with approved designs Correct installation Reliable and predictable operation Perform as expected

36 Validation and design Validation testing and acceptance criteria are based on design Design documents must be complete and comprehensive Detailed designs increase probability that validation project will be successful

37 Design phases Phase 1 Conceptual design Various alternatives are evaluated Phase 2 Preliminary engineering Prepare design documents used for Phase 3 Phase 3 Detailed engineering Construction contracts Equipment purchasing, fabrication, installation and testing

38 Design phases and validation Phase 3 Detailed engineering Verified during Installation Qualification (IQ) Phase 1 Phase 2 Preliminary engineering Verified during Operational Qualification (OQ) Phase 2 Phase 1 Conceptual design Verified during Performance Qualification (PQ) Phase 3

39 Facility and equipment design Design facilities, equipment, systems and processes to assure GMP compliance Product quality, purity, strength and identity Batch-to-batch uniformity

40 Recognized design standards ISPE Guidelines 3A Sanitary Standards ISO European Commission EudraLex United States Pharmacopeia (USP)

41 Common design documents Piping and instrumentation diagrams (P&IDs) HVAC air flow diagrams (AFDs) Equipment specifications and drawings Software user and functional specifications Control system drawings and panel layouts

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44 Design review Review design documents to verify equipment or system is Correctly designed for application Does not react with product Cleanable Easy to maintain and repair

45 Design review Experienced engineering companies and equipment suppliers rarely make design errors and omissions Common or mass-produced equipment rarely require thorough design review

46 FDA Field Management Directive-135 Pre-operational Reviews of Manufacturing Facilities Design review Pre-construction review Construction/equipment installation and qualification review Pre-production review

47 Design review Best for engineered or custom systems and equipment Assess design for effect on Product quality Batch-to-batch uniformity

48 Validation project risk Validation projects have two risks Regulatory/product risk Validation project risk Use a scoring system to assess risk Use subject matter experts (SME) to evaluate risk

49 Regulatory/product risk Risk assessment identifies high impact systems and equipment Product contact equipment Product contact utilities Process control systems Building floor plans Processes with substantial variability

50 Regulatory/product risk High impact systems require design review for GMP compliance Qualify and validate high impact systems Test and commission low or noimpact systems

51 Risk assessment - blender Qualify and validate? Yes. High impact system Product contact Operation must be reliable and controlled Content uniformity and batch-tobatch uniformity are important

52 Risk assessment - boiler Qualify and validate? No. Low impact system No product contact Test and commission only

53 Regulatory/product risk Comprehensive risk assessment not required for Common equipment Proven technologies Risk assessment required Equipment is used for other than intended purpose High value product or process

54 Validation project risk Validation project risks Delay project completion Increase costs Identify and control validation project risks to assure completion on schedule and at expected cost

55 Validation project risk Late protocol preparation, review and approval Late approval delays projects Facility construction and equipment installation will not wait for protocol approval

56 Validation project risk Unexpected system or equipment failure Overtesting or undertesting Testing must be beneficial and proportionate to risk Standard is high degree of assurance

57 Validation project risk Inexperienced or insufficient validation personnel Estimate labor hours to complete all validation activities Estimate may exceed available personnel to meet scheduled completion date

58 Validation project risk Incorrect acceptance criteria Frequent cause of test failures Test failures delay projects Do not approve acceptance criteria that system or equipment is not designed to meet

59 Validation project risk Identify and carefully manage project critical path Series of activities that determine project duration Activities with the least amount of scheduling flexibility Project management software can identify critical path

60 Validation project risk Water systems are frequently on the critical path Most widely used ingredient in pharmaceutical companies Water system delays could delay process and cleaning validation studies

61 Validation project management Validation projects have two risks Regulatory/product risk Project risk Design review reduces regulatory and product risk Project planning and control reduces validation project risk

62 Validation master plan A comprehensive validation document Evaluates facility validation, ISO and cgmp requirements Prepared during conceptual design or preliminary engineering Large or complicated projects only

63 Validation master plan Project description System and equipment descriptions Risk assessment results Planned tests and inspections Preliminary acceptance criteria

64 Validation master plan Identifies required SOPs Describes important programs Instrument calibration Employee training Change control Facility cleaning Includes selected design drawings Describes process validation

65 Process validation (PV or PPQ) Combines actual facility, utilities, equipment and trained personnel with the commercial manufacturing process, control procedures, and components to produce commercial batches

66 PV prerequisites Equipment and system validation SOPs Employee training Component/supplier qualification Test method validation Product development report

67 Process validation Usually three consecutive batches produced at commercial scale Increased sampling and testing No deliberate challenge to critical control parameters Unit operation PV is preferred PV failures should not occur

68 Cleaning validation (CV) A separate program with its own Validation Master Plan Essential for multi-product facilities Must prevent product crosscontamination

69 Cleaning validation (CV) Cleaning strategy and acceptance criteria must be scientific Matrix or worse-case methods are commonly used to simplify CV

70 Cleaning validation (CV) CV is evaluated during product and process development CV often begins during equipment OQ Riboflavin added to equipment then removal verified

71 Cleaning validation (CV) CV performed simultaneously with process validation Equipment visual inspection Final rinse testing Equipment surface testing for residual active ingredient

72 Summary - GMP Legal requirement intended to protect the public Prevents, detects and corrects manufacturing errors Increases productivity and reduces costs Requires system, equipment and process validation

73 Summary - Validation Validation activities are projects - manage to complete on schedule Review design documents to confirm GMP compliance Assess and manage regulatory/product and project risk Develop Validation Master Plan for large and complicated projects Process validation confirms GMP programs and systems are effective Cleaning validation prevents product cross-contamination

74 Questions?