TGA Manufacturing Principles Update Adoption of PIC/S Guide to GMP PE009-13 & beyond Neale Baldwin Senior GMP Inspector Manufacturing Quality Branch 22 August 2018
Overview • Why adopt updates to GMP? • Update Processes: – EMA process – PIC/S process – TGA process • Future Revisions – PE009-14 – PE009-?? Manufacturing Principles Update 1
Why adopt the latest PIC/S Guide to GMP? • TGA play an active role in update to PIC/S GMP Guidance documents • GMPs are routinely updated in response to identified risks: – Risks to patient health – Ambiguity leading to misinterpretation and compliance risks – Technological changes • Relevant to TGA’s Mutual Recognition Agreements with other regulators • Provides assurance of equivalence to international markets • GMP, science and innovation never stands still. TGA Manufacturing Principle Updates 2
TGA GMP Update Process TGA consults Comments Regulatory External Adoption of Establish with TIWGG on considered and Develop gap Impact communications new internal project draft Gap final Gap analysis Statement strategy Manufacturing team Analysis Analysis (OBPR) developed Principles document endorsed TGA Manufacturing Principles Update 3
Gap Analysis PE 009-13 PE 009-08 Nature of Estimated impact significance of impact Nil 1. ORGANISING AND PLANNING FOR New clause, but equivalent requirements provided in PE009-8 Clarification of Annex 15§2. existing QUALIFICATION AND VALIDATION requirements, PLANNING FOR VALIDATION no change to 1.1 All qualification and validation interpretation . activities should be planned and take the 2. All validation activities should be planned. The key elements life cycle of facilities, equipment, utilities, of a validation programme should be clearly defined and process and product into consideration. documented in a validation master plan (VMP) or equivalent documents. Expanded planning section in PE009-13 However, this section provides additional clarification to that included within PE009-8 TGA Manufacturing Principles Update 4
Gap Analysis PE 009-13 PE 009-08 Nature of Estimated impact significance of impact 5.21 A process validation protocol should New clause, but equivalent requirements provided in PE009-8 Introduction Nil for some Annex 15§6. of new manufacturers; be prepared which defines the critical minor for some. terminology process parameters (CPP), critical quality This clause introduces the terms CPP and CQA in line with ICH (CPP and CQA) attributes (CQA) and the associated Q11 terminology. While the terminology may be more into validation acceptance criteria which should be based systems. prescriptive, the process of identifying critical steps (that directly on development data or documented influence the critical attributes of the product) and acceptance process knowledge. criteria remain very similar to existing methods and expectations. (Note that these concepts already exist for API manufacturers) 6. A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria. 5 TGA Manufacturing Principles Update
Adoption Plan – Examples Between 1 January and Between 1 July 2018 and PIC/S GMP Requirement From 1 January 2019 30 June 2018 31 December 2018 Part I, Chapter 1 Clause 1.6 Management Approved policy Initial management review Full implementation meetings held. Reviews Documented assessment of which data will be collated Mechanisms for resolving and reported. issues formalised and implemented Commenced amending and drafting procedures Schedule for management reviews finalised. Commenced training staff in Management Reviews • Refer TGA website for guidance for deficiency reporting during the Transition period 6 TGA Manufacturing Principles Update
Adoption Plan – Examples Between 1 January and Between 1 July 2018 and PIC/S GMP Requirement From 1 January 2019 30 June 2018 31 December 2018 Part I, Chapter 7 Outsourced activities Approved policy Approved procedures Full implementation Commenced drafting Commenced All outsourced activities Medium Risk Item procedures amending/drafting new approved and covered contracts by an appropriate Risk assess/Determine list of contract. all service providers implicated. Develop priority list for evaluation and approval of providers. • Refer TGA website for guidance for deficiency reporting during the Transition period 7 TGA Manufacturing Principles Update
TGA Adoption Timeline for PE009-13 September November 2017 1 January 2018 31 June 2018 1 January 2019 Ongoing 2017 • 2nd notification •Adopt New GMP for industry Guide 1 st notification • • Main changes for industry •Publish Q&A for table GMP • APVMA • Adoption strategy notification 12m Transition Period • Deficiency reporting Assess & establish Implement Full Compliance TGA Guidance Updates TGA Manufacturing Principles Update 8
Updates to TGA Guidance Documents Currently Working to Update TGA Guidance Documents Title Technical guidance on the interpretation of manufacturing standards: Supplier qualification Product quality review for listed Complementary Medicines On-going stability testing for listed complementary medicines Sampling and testing of Complementary Medicines Process validation for listed Complementary Medicines Guide to Interpretation of the PICS Guide to GMP - 2013 applicable to medicinal gases Guide to interpretation of the Code of GMP for the manufacture of 18FDG injections - version 2 Guidance on release for supply Manufacture of medicinal cannabis for supply under 'approved access' provisions TGA Manufacturing Principles Update 9
Future Revisions of PE009 Future 1 July 2018 • 1 Jan 2017 revisions PE009- PE009- PE009- Chapters 3, 5 •Chapter 1, Chapter 4 13 14 & 8 ?? 2, 6 & 7 (Part Annexes 1, 2, I) Annex 17 11, 13, 16, 21 10 TGA Manufacturing Principles Update
PE009-14 Chapter 3 – Premises and Equipment • Additional guidance on Cross-contamination • Quality Risk Management principles should be used to assess and control the risks. • Dedicated facilities are required when: – the risk cannot be adequately controlled by operational and/ or technical measures – scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta- lactams) or – relevant residue limits , derived from the toxicological evaluation , cannot be satisfactorily determined by a validated analytical method. TGA Manuf acturing Principles Update 11
PE009-14 Chapter 5 – Production – Cross Contamination (1) • Quality Risk Management processes… should be used to assess and control the cross-contamination risks presented by the products manufactured. • Technical Measures: – Dedicated processes, equipment and facilities; – Use of closed systems, barrier, isolator, single-use technologies; – Dust extraction, air-locks, pressure cascades; – Clean-in-place, ease of cleaning considered in process/equipment design • Organisational Measures: – Campaign operation, campaign washing, cleaning verification; – Gown management, waste management, spill management; – Detailed cleaning records and instructions, continued oversight of compliance. TGA Manufacturing Principles Update 12
PE009-14 Chapter 5 – Production – Starting Materials • Selection, qualification, approval and maintenance of suppliers of starting materials, together with their purchase and acceptance , should be documented as part of the pharmaceutical quality system. • Active Substances – Supply chain traceability established and associated risks formally assessed and periodically verified. – Audits should be carried out at the manufacturers and distributors of active substances…audits should be of an appropriate duration and scope to ensure that a full and clear assessment of GMP is made. – The holder of the manufacturing authorisation shall verify such compliance either by himself/herself or through an entity acting on his/her behalf under a contract. • Excipients – formalised quality risk assessment (PI 045-1) TGA Manufacturing Principles Update 13
PE009-14 Chapter 8 – Complaints & Product Recall • Defined requirements for Personnel and Organisation within the PQS • Procedures for handling and investigating complaints including possible quality defects • Investigation and decision making • Root cause analysis and CAPA • Product Recalls and risk-reducing actions • Reflects URPTG requirements TGA Manufacturing Principles Update 14
PE009-14 Annex 17– RTRT & Parametric Release • Real Time Release Testing (RTRT) (ICH Q8 Q&A) • Control of critical parameters and relevant material attributes are authorised as an alternative to routine end-product testing of active substances and/or finished products. • RTRT may apply to any stage in the manufacturing process and to any type of finished products or active substances, including their intermediates. • Real time measurement of CPP(s) as a predictor of compliance with CQA . • Thorough understanding of critical material attributes . • Well defined control strategy: QRM, validation, change control, training, etc TGA Manufacturing Principles Update 15
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