PROCESS VALIDATION ROCHAPON WACHAROTAYANKUN, PH.D.

Transcription

1 Basic GMP Requirement PROCESS VALIDATION ROCHAPON WACHAROTAYANKUN, PH.D.

2 Topic Process validation What and Why? Principle of process validation Manufacturing process validation Aseptic process validation Other supportive process validation Rochapon W. 2

3 Key References PIC/S and EU GMP Annex 15: Qualification and Validation (Effective date 01 October 2015) Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft): A note for guidance for the manufacture of prequalified vaccines for supply to United Nations agencies, July, 2013 WHO/BS/ : WHO GMP for Biological Products Proposed replacement of: TRS 822, Annex 1 US FDA Guidance for Industry -Process Validation: General Principles and Practices, January 2011 ICH Q7 EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1: Guideline on process validation for finished products - information and data to be provided in regulatory submissions Rochapon W. 3

4 Definition of Process Validation (1/2) The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes ICH Q7 Guideline on process validation for finished products - information and data to be provided in regulatory submissions EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1 PIC/S and EU GMP Annex 15: Qualification and Validation (Effective date 01 October 2015) Rochapon W. 4

5 Definition (1/2) (Production) Process validation (PV) is the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a manufacturing process is capable of consistently delivering quality products. Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) A note for guidance for the manufacture of prequalified vaccines for supply to United Nations agencies July, 2013 Vaccine Quality and Regulations (VQR) Essential Medicines and Health Products World Health Organization (WHO), Geneva, Switzerland Rochapon W. 5

6 Why Process validation? Required by cgmp - essential element in assurance of drug quality Quality, safety, and efficacy are designed or built into the product. Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications. Assures consistency of production process Demonstrates the capability of the commercial manufacturing process to give a high degree of assurance of obtaining medicinal products meeting the required quality attributes of safety, purity, and efficacy on a continued basis. Rochapon W. 6

7 a meaningful process validation program based on the assumption that quality cannot be adequately assured merely by in-process and finished-product inspection and testing Offers assurance that a process is reasonably protected against sources of variability that could affect production output, cause supply problems, and negatively affect public health. Proves that in spite of changes in operational parameters through the necessary scale up of the production process, including new facilities and equipment, the product characteristics will not vary. Rochapon W. 7

8 Lifecycle Approach : from R&D through clinical trials to commercial scale process validation should not be viewed as a one-time event but rather as an activity that spans the product lifecycle linking product and process development, validation of commercial manufacturing process, and its maintenance during routine commercial production Life cycle approach Product and Process development ICH Q8(R2) Validation of commercial Mfg Maintenance during routine commercial production: On-going process verification R&D Clinical trial Phase I, II, III Submission Commercial Rochapon W. 8

9 Knowledge and Risk based approach Scientific Knowledge Product Process Risk based approach More scientific and risk based approach required for Process validation- another new paradigm Rochapon W. 9

10 Process validation (PV) stages ICH Q8-11 PV Stage II Process description Process characterization Raw/ starting materials Extractables,Leachables Seed bank Cell lines, Cell bank Analytical methods Validation of production steps or unit operations PV Stage I US FDA s Process design Definition of Operational Parameters at commercial scale Manufacturing of Consistency Lots Manufacturing of Clinical Phase Material Bracketing, Family and Matrix Validation Approach Documentation Requirements Personnel Training and Qualification Process Technology Transfer Legacy products Design and Execution of Process Validation Studies Deviations Management Final report Change control Revalidation program Continual monitoring PV Stage III US FDA s Continued Process Verification US FDA s Process Qualification * Quality Risk Management applied Rochapon W. 10

11 CPP, CQA, Control strategy Critical process parameter (CPP): A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8) Critical quality attribute (CQA): A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (ICH Q8) Control strategy: A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to active substance and finished product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10) Rochapon W. 11

12 Quality Risk Management: applied through Life cycle Critical quality attributes (CQA) identification Critical process parameters (CPP) identification Developing Control strategy including Process validation Various tools can be applied: FMEA HACCP etc. Rochapon W. 12

13 From Stephan Krause, Medimmune, 2013 Rochapon W. 13

14 Process development, commercial manufacturing capabilities, and the quality system must be integrated in order to achieve effective and compliant commercial operations Process validation starts before consistency lots are produced, and continues during the commercial stage during which the knowledge of the product and process will continue to increase...interdisciplinary approach incorporating expertise from various disciplines (e.g., Engineering, Chemistry, Microbiology, Statistics, Manufacturing, QC and QA). with full support by upper management. Rochapon W. Validation of Production Processes for Vaccines for WHO Prequalification: Compliance Expectations (Draft) 14

15 Rochapon W. 15

16 Common Sequence of Process Validation Activities (based on PDA s Common Timing of PV Enablers and Deliverables to Validation Stage Activities) Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) Rochapon W. 16

17 Validation strategy Prospective validation Validation carried out before routine production of products intended for sale. Gold standard for both Traditional and Enhanced Mfg process Concurrent validation Validation carried out in EXCEPTIONAL CIRCUMSTANCES, justified on the basis of significant patient benefit, where the validation protocol is executed concurrently with commercialisation of the validation batches. Retrospective validation Existing process(es) in use but no formally documented process validation - Not acceptable Not always magic number of THREE! Statistically sound number Bracketing approach possible Rochapon W. 17

18 Manufacturing process validation approach Traditional approach Prospective Process Validation Normally performed when the pharmaceutical development and/or process development is concluded, after scale-up to production scale and prior to marketing of the finished product. statistically sound number of PV batches, No. of batches depends on Process variability, complexity of the process/ product and experience of manufacturer but should generally be a minimum of 3 batches. PV protocol includes Critical Quality Attributes, Critical Process Parameter and non CQA, non CPP to be monitored, etc. PIC/S EU GMP :Annex 15 Rochapon W. 18

19 Continuous process verification approach- An alternative approach to Traditional process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8) May be applicable for product developed by Quality by design (QbD), Continuous process Required scientific control strategy, Involve monitoring of critical processing steps, and end point testing of current production, to show that manufacturing process is in state of control Hybrid approach Apply Traditional and Continuous verification approach for different steps PIC/S EU GMP :Annex 15 Rochapon W. 19

20 Design space verification Normally developed at laboratory or pilot scale. During scale-up, commercial process is conducted and validated in a specific area of the design space, defined as the target interval or Normal Operating Range (NOR). During product lifecycle, moving from one area to another within the design space (i.e. change in the NOR) may represent higher or unknown risks not previously identified during initial establishment of the design space. For this reason and depending on how the design space was originally established and how the process was validated, there will be situations where it will be necessary to confirm the suitability of the design space and verify that all product quality attributes are still being met in the new area of operation within the design space. Rochapon W. 20

21 Other requirements prior to PV Equipment, facilities, utilities and systems used for process validation should be qualified. Test methods should be validated for their intended use. Batches manufactured by trained personnel if done by R&D, production personnel should be involved Qualified Raw mat,. Packaging mat. Quality Risk Management applied Rochapon W. 21

22 On-going Process Verification Ongoing Process Verification during Lifecycle Used throughout product lifecycle to support validated status of the product as documented in the Product Quality Review. Incremental changes over time considered and the need for any additional actions, e.g. enhanced sampling, should be assessed. PIC/S EU GMP :Annex 15 Rochapon W. 22

23 Manufacturing processes requiring validation Rochapon W. 23

24 Process Validation : What to validate and when? All product attributes and operational parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. This will contribute to identify critical operational parameters. Therefore, PV activities may focus on those processes which pose the greatest risk. Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) Rochapon W. 24

25 Production processes to be validated (1/2) All critical biological processes are subject to process validation. inoculation, multiplication, fermentation, cell disruption, inactivation, purification, virus removal, removal of toxic and harmful additives, filtration, formulation, aseptic filling, etc. WHO GMP for Biological Products Proposed replacement of: TRS 822, Annex 1 Rochapon W. 25

26 Production processes to be validated (2/2) Some manufacturing processes requiring validation covered in this WHO document: Fermentation Harvesting Purification Viral Clearance Inactivation Blending & Formulation Lyophilization Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) Rochapon W. 26

27 Manufacturing control parameters to be validated may include: specific addition sequences, mixing speeds, time and temperature controls, limits of light exposure, containment and cleaning procedures. WHO GMP for Biological Products Proposed replacement of: TRS 822, Annex 1 Rochapon W. 27

28 Biosafety concern Critical processes for inactivation or elimination of potentially harmful microorganisms of Biosafety Risk Group 2 or above, including genetically modified ones, are subject to validation. After initial validation, Continued process verification to be implemented WHO GMP for Biological Products Proposed replacement of: TRS 822, Annex 1 Rochapon W. 28

29 Process Revalidation May be triggered immediately by a process change, as part of the change control system. In addition, because of the variability of processes, products and methods, process revalidation may be conducted at predetermined regular intervals according to risk considerations. A detailed review of all changes, trends and deviations occurring within a defined time period (e.g. 1 year, based on the regular Product Quality Review) may require process revalidation. Rochapon W. 29

30 Other Supportive Critical Processes requiring Validation (1/2) Cleaning of product contact equipment Sanitization of areas Depyrogenation Sterilization Aseptic Filling or encapsulation process of Final Product Utilities, facility and equipment qualification, analytical assay validation, and validation of computerized systems Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) Rochapon W. 30

31 PIC/S 007-6: Aseptic Process Validation Validation of aseptic processes relies upon Prospective, Concurrent and Retrospective validation (not recommended for APV) Re-validation It is Sum total of all validation data providing the necessary level of assurance for aseptically produced products. Rochapon W. 31

32 2.3.3 Prospective studies Aseptic Process Validation: Prospective studies IQ/OQ of new or renovated facilities Product simulation studies (Media Fills) Prospective process validation with original product Rochapon W. 32

33 2.3.4 Concurrent validation Aseptic Process Validation: Concurrent validation Concurrent validation Qualified facilities and equipment Product simulation studies Concurrent process validation with product during routine production Rochapon W. 33

34 2.3.5 RE-VALIDATION Disinfection procedure Monitoring Environment Container / closure cleaning & sterilisation Equipment cleaning & Sterilisation Aseptic Process Validation: Re-validation Re-validation after Changes Regular performance of process simulation studies (Media Fills) Regular integrity testing of product filters, container/ closures, vent filters Routine maintenance and requalification of equipment eg.autoclave, HVAC, Oven, Water systems, etc. Sterility testing Rochapon W. 34

35 2.3.8 Process simulation studies (Media fills) Simulating the whole process in order to evaluate the sterility confidence of the process. Process simulation studies include formulation (compounding), filtration and filling with suitable media. Simulations made to ensure that the regular process for commercial batches repeatedly and reliably produces the finished product of the required quality. However, each process simulation trial is unique and so it is not possible to extrapolate these results directly to actual production contamination rates. Rochapon W. Formulation Using suitable media Filtration Ensure that Filling Regular process is REPEATEDLY and RELIABLY produced product of REQUIRED UALITY 35

36 Process simulation test -Media Fills To verify WEAK points in the chains of linked factors/ activities/ processes Rochapon W. 36

37 Other Supportive Critical Processes requiring Validation (2/2) The integrity and specified hold times of containers used to store intermediate products should be validated unless such intermediate products are freshly prepared and used immediately, as appropriate. Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) Rochapon W. 37

38 WHO Pre-Qualification process Expectations During the manufacturing of Phase 3 clinical material, consistency lots (i.e. PV lots) will be produced as part of adequate validation studies. Validation studies be reviewed in detail by NRA and NCL of country of origin before granting the marketing authorization of the product. Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) Rochapon W. 38

39 WHO PQ process focuses on adequacy of the following aspects: Inclusion of Risk assessment in validation studies, Conformance of current validation activities, Policies for routine validation and revalidation Change control and Deviation management Critical validation deviations like failure to have cleaning validation of critical steps, inactivation validation, uncontrolled risk of cross-contamination, etc. Continued process verification through trend analysis. Validation of Production Processes for Vaccines for WHO Prequalification- Compliance Expectations (Draft) Rochapon W. 39

40 Q&A Rochapon W. 40