PIC/S Guide to GMP PE009-13 Key Changes to Annex 2 – Manufacture of Biological Medicinal Substances and Products for Human Use Francesco Cicirello GMP Inspector Manufacturing Quality Branch June 2018
Key changes to Annex 2: M ajor re-write to provide clarification on existing GM Ps and new technologies Guidance for application of GM P to starting materials Emphasis on controlling adventitious agents, TSE and zoonotic diseases Part A: General Guidance Part B: Specific guidance for selected product types 1
Scope of Annex 2 Table 1. Illustrative guide to manufacturing activities within the scope of Annex 2 • Clarification of the application of GM P to Type and Example Application of this guide to manufacturing steps shown in source of product grey biological substances and products material 1. Animal or Heparins, Collection of Cutting, Isolation and Formulation, • M aster Cell Banks, Working Cell Banks, plant sources: insulin, plant, organ, mixing, and / purification filling 3 non- enzymes, tissue or fluid or initial transgenic proteins, processing etc. allergen extract, ATMPs • Collection of plant, tissue or fluid immunosera 2. Virus or Viral or bacterial Establishment & Cell culture Inactivation Formulation, • GM P applies to all steps in grey bacteria / vaccines; maintenance of and/or when filling fermentation / enzymes, MCB4, WCB, fermentation applicable, • Sponsors – refer to TGA website for cell culture proteins MVS, WVS isolation and purification evidence requirements 3. Recombinant Establishment & Cell culture Isolation, Formulation, Biotechnolog products, MAb, maintenance of and /or purification, filling • y allergens, MCB and WCB, fermentation modification M anufacturers – should hold fermentation/ vaccines Gene MSL, WSL cell culture Therapy (viral evidence of GM P for the materials and non-viral vectors, you source plasmids) 4. Animal Recombinant Master and Collection, Isolation, Formulation, sources: proteins, working cutting, purification filling transgenic ATMPs transgenic bank mixing, and/or and initial modification processing 2
5. Plant Recombinant Master and Growing, Initial Formulation, harvesting 5 sources: proteins, working extraction, filling transgenic vaccines, transgenic bank isolation, allergen purification, modification 6. Human Urine derived Collection of Mixing, and/or Isolation and Formulation, fluid 6 sources enzymes, initial purification filling hormones processing 7. Human Gene therapy: Donation, Manufacture Ex-vivo Formulation, vector 7 and and/or animal genetically procurement genetic filling sources modified cells and testing of cell modification of starting tissue / purification cells, Currently regulated with cells8 and Establish processing, MCB, WCB or primary cell lot the Australian code of Somatic cell Donation, Establish Cell isolation, Formulation, therapy procurement MCB, WCB or culture combination, and testing of primary cell lot purification, fill GM P (2013) starting tissue / or cell pool combination cells 8 with non- cellular components Tissue Donation, Initial Cell isolation, Formulation, engineered procurement processing, culture, combination, products and testing of isolation and purification, fill starting tissue / purification, combination cells 8 establish with non- MCB, WCB, cellular primary cell lot components or cell pool 3 See section B1 for the extent to which GMP principles apply. 4 See section on ‘Seed lot and cell bank system’ for the extent to which GMP applies. 5 In the EEA: HMPC guideline on Good Agricultural and Collection Practice - EMEA/HMPC/246816/2005 may be applied to growing, harvesting and initial processing in open fields. 6 For principles of GMP apply, see explanatory text in ‘Scope’. 7 Where these are viral vectors, the main controls are as for virus manufacture (row 2). 8 In the EEA, human tissues and cells must comply with Directive 3
Heads up: PIC/S Annex 2 Revision • Working Group established to revise the Annex 2 (M anufacture of biological medicinal products for human use) of the Guide to Good M anufacturing Practice of M edicinal Products PE 009-13 (Annexes) • TGA (chair), WHO and EM A amongst participants • Objectives: � The revision of the requirements for ATM Ps will remain an integral part to the existing GM P guidelines and will not be a standalone guide � The WG will draft a separate Annex specific to ATM P and align the existing Annex 2 to the EU for remaining products � Efforts will be made, with the aim at maintaining as close harmonisation as possible, to use the language of the “Guidelines on Good M anufacturing Practice (GM P) specific to Advanced Therapy M edicinal Products (ATM P)” where possible. PIC/ S and WG represented stakeholder’s concerns will guide the final language. � Efforts will be made to accommodate language that address challenges such as “diffuse manufacturing” � Efforts will be made to accommodate language that will permit the standard to facilitate cross border movement of ATM P . The standard will aim to be bridging across the expectations for these products through all jurisdictions, even the ones that will not formally adopt it 4
PIC/S Guide to GMP PE009-13 Key Changes to Annex 11– Computerised Systems Francesco Cicirello GM P Inspector M anufacturing Quality Branch June 2018
Annex 11: What’s new? Scope Suppliers and Service Providers Applies to all forms of computerized systems (CS) in Quality/ technical Agreements GM P environment. software applications validated and IT infrastructure Audits of service suppliers visible qualified. Focus on QRM CS lifecycle management. Review and approval of supplied documentation Roles and Responsibilities 6
Annex 11: What’s new? Validation Data Integrity IT support Life-cycle approach Data accuracy, audit trails, and security Back-up and archiving System inventory list Data migration controls Incident management – RCA & CAPA URS for each system - traceability matrix Electronic Signatures Business continuity System parameter limits, data limits and error Checks on back-up handling Periodic Review Change Control 7
Annex 11: What’s gone? • Retrospective Validation – Annex 11 originated in 1992 Validation – Retrospective validation allowed manufacturers to validate existing systems – All systems in use today should be validated Retrospective validation not permitted • Parallel testing – Not widely adopted – Allows increased focus of resources on new system Parallel testing not required 8
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