Critical process for vaccine manufacturing and process validation

Transcription

1 Critical process for vaccine manufacturing and process validation Inactivation Influenza Vaccine Production Project The Government Pharmaceutical Organization Presented by Ms RATSAMIKORN SINGCHAREON and Ms THANAWAN SRINANG

2 OUTLINE Vaccine Development Stages & Life Cycle Definition of Process Validation Process Design Process Performance Qualification (PPQ) PPQ of GPO s Upstream Process of Influenza Vaccine Production Conclusion

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7 Process Validation Definition Process Validation Quality, safety & efficacy are designed into the product Quality cannot be assured by only in-process or release test Establish product quality attributes Establish process parameters and their criticality Define variability and limits for process parameters Demonstrate product suitability under routine production conditions: In process testing at critical steps Release testing of finished material Scale up process, and verify/demonstrate comparability of product under routine production conditions Documentation: Development Report, Quality Risk Assessment

8 Process Design 8

9 Process Design

10 Process Design

11 Risk Assessments

12 Process Performance Qualification The PPQ protocol should specify the manufacturing conditions, controls, testing and expected outcomes (FDA Guidance on Process Validation, Jan 2011) How will control of the process be demonstrated? CPPs must meet specification All in-process controls, critical quality attributes and release specifications must be met Acceptance criteria for additional characterization testing must be met Deviation to the procedures must be recorded on the data record forms. (A WHO guide to GMP requirements, Part2, 1997)

13 Documentation

14 Process Performance Qualification Protocol Responsibilities Training Description of facilities/equipment Raw materials Analytical Methods Operating parameters/limits Testing (in-process, release, characterization) Sampling plan Acceptance criteria Data collection/evaluation

15 Process Matrix

16 PPQ of GPO s Upstream Process of Influenza Vaccine Production

17 Inactivated Influenza Vaccine (GPO) Trivalent vaccine consists of 3 strains; H1N1, H3N2, and B- strain recommended for southern hemisphere Product name: Tri Fluvac (Seasonal Inactivated Influenza Vaccine) Type: Split inactivated influenza viral particles Detergent: Splitting by using TritonX-100 Inactivating agent: Formalin 2-dose, 4-dose vial, & Pre-filled syringe (@Industrial scale)

18 PROCESS FLOW VQE DAY11 INOCULATION INCUBATION HARVEST ULTRAFILTRATION 500 KDa Inoculum preparation EID 50 = 2-5 logeid 50 /0.2 ml Operational parameter WHO recommended strains for Southern Hemisphere In Process Control - Infectivity - Vol. of Inoculation Infectivity of WS - Temp. - Time - Humidity - Vol. ALF - Temp. - Time - Mw Cut off - Pressure inlet - Flow rate 1) HA titer 2) Protein content 3) Ovalbumin content 4) Endotoxin content 5) Bioburden 6) volume of harvested ALF/egg 1) HA titer 2) Protein content 3) Ovalbumin content 4) Endotoxin content

19 PROCESS FLOW Operational parameter In Process Control ULTRA CENTRIFUGATION DIAFILTRATION (1) SPLITTING DIAFILTRATION (2) INACTIVATION& STERILE FILTRATION MVB - Speed - Temp. - Time - Flow rate - Sucrose content - Mw Cut off - Pressure inlet - Flow rate - Temp. - Time - Splitting agent conc. - Mw Cut off - Pressure inlet - Flow rate - Final Conc. - Temp - Time - Pressure inlet - Filtration time - Flow rate 1) HA titer 2) Protein content 3) Ovalbumin content 4) Endotoxin content 5) Fraction analysis 1) HA titer 2) HA Content 3) Protein content 4) Bioburden 5) SDS-PAGE/Western blot 6) GFC 1) HA Content 2) Protein content 3) Bioburden 4) SDS-PAGE/Western blot 5) TritonX-100 content 1) Integrity test 2) EM 3) Sterility

20 Establish quality attribute, process parameters & their criticality Critical Process step Setting Parameter Rationale Testing 1) Harvest Impurity (Toxicity) and Yield To obtain the quality of ALF and yield of virus 2) Ultracentrifugation Purity To obtain highly purity of whole virus 3) Splitting Viral splitting To obtain the split vaccine 4) Inactivation Effective of Inactivation To ensure that the MVB has no live virus and remained in the product 5) Sterile filtration Sterility To ensure that the MVB of split virus is sterilized 1.1) HA test 1.2) Protein content 1.3) Endotoxin 2.1) Impurity clearance 2.2) Impurity content such as limit of Endotoxin, Ovalbumin 3.1) Degree of virus disruption: EM, GFC 4.1) Inactivation kinetic 4.2) Adventitious agent such as ALV, ADV, and Mycoplasma 5.1) Bacterial Challenge test of filter 5.2) Environment monitoring 5.3) Process simulation test

21 Acceptance criteria (1) No Process Test Acceptance criteria 1 Harvest Endotoxin content xxxx IU/ml 2 Ultracentrifugation Fractionation assay: OD280, HA titer, Ovalbumin, & Endotoxin content The fractionation of influenza virus shall be well separated from the fraction of egg-derived protein Content ratio of ovalbumin and total protein Content ratio of endotoxin and total protein Content ratio of HA content and total protein xxxx µg ovalbumin/µg protein xxxx IU/µg protein xxxx µg HA/µg protein

22 Acceptance criteria (2) No Process Test Acceptance criteria 3 Splitting Fractionation test XXXXXXXX 4 Inactivation Inactivation time course Absence viable virus after starting inactivation 5 MVB Preparation Integrity testing Passed Sterility testing No evidence of microbiological shall be found Process Simulation Test Passed Bacterial Challenge Passed Test Inactivation Test Absence viable virus Fractionation Test xxxxxxx

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24 Conclusion Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled. [CFR 21 Part 820.3(z)] Providing documented evidence that specific system will consistently produce an outcome meeting predetermined specifications The more understanding of process we have, the better we understand the variability of the process, and its impact on product quality attributes

25 Thank you so much for your attention