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

Establish internal project

team

Develop gap analysis

TGA consults with TIWGG on

draft Gap Analysis

document

Comments considered and

final Gap Analysis

endorsed

Regulatory Impact

Statement (OBPR)

External communications

strategy developed

Adoption of new

Manufacturing Principles

TGA Manufacturing Principles Update 3

Gap Analysis PE 009-13 PE 009-08 Nature of

impact Estimated significance of impact

1. ORGANISING AND PLANNING FORQUALIFICATION AND VALIDATION

1.1 All qualification and validation activities should be planned and take the life cycle of facilities, equipment, utilities, process and product into consideration.

New clause, but equivalent requirements provided in PE009-8 Annex 15§2.

PLANNING FOR VALIDATION

2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and 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

Clarification of existing requirements, no change to interpretation.

Nil

TGA Manufacturing Principles Update 4

Gap Analysis PE 009-13 PE 009-08 Nature of

impact Estimated significance of impact

5.21 A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge.

New clause, but equivalent requirements provided in PE009-8 Annex 15§6.

This clause introduces the terms CPP and CQA in line with ICH Q11 terminology. While the terminology may be more prescriptive, the process of identifying critical steps (that directly influence the critical attributes of the product) and acceptance 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.

Introduction of new terminology (CPP and CQA) into validation systems.

Nil for some manufacturers; minor for some.

TGA Manufacturing Principles Update 5

Adoption Plan – Examples PIC/S GMP Requirement Between 1 January and

30 June 2018 Between 1 July 2018 and 31 December 2018

From 1 January 2019

Part I, Chapter 1

Clause 1.6 Management Reviews

Approved policy

Documented assessment of which data will be collated and reported.

Commenced amending and drafting procedures

Commenced training staff in Management Reviews

Initial management review meetings held.

Mechanisms for resolving issues formalised and implemented

Schedule for management reviews finalised.

Full implementation

• Refer TGA website for guidance for deficiency reporting during the Transition period 6 TGA Manufacturing Principles Update

Adoption Plan – Examples PIC/S GMP Requirement Between 1 January and

30 June 2018 Between 1 July 2018 and 31 December 2018

From 1 January 2019

Part I, Chapter 7

Outsourced activities

Medium Risk Item

Approved policy

Commenced drafting procedures

Risk assess/Determine list of all service providers implicated.

Develop priority list for evaluation and approval of providers.

Approved procedures

Commenced amending/drafting new contracts

Full implementation

All outsourced activities approved and covered by an appropriate contract.

• Refer TGA website for guidance for deficiency reporting during the Transition period 7 TGA Manufacturing Principles Update

TGA Adoption Timeline for PE009-13

September 2017

• 1st notification for industry

• APVMA notification

November 2017 • 2nd notification

for industry • Main changes

table • Adoption strategy • Deficiency

reporting

1 January 2018 •Adopt New GMP Guide

•Publish Q&A for GMP

31 June 2018 1 January 2019 Ongoing

12m Transition Period

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

• 1 Jan 2017 •Chapter 1, 2, 6 & 7 (Part I)

PE009-13

1 July 2018 Chapters 3, 5

& 8 Annex 17

PE009-14

Future revisions Chapter 4

Annexes 1, 2, 11, 13, 16, 21

PE009-??

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

PE009-14 Annex 17– RTRT & Parametric Release • Parametric Release – terminally sterilised products • Updates to text providing clarification of existing requirements. • Detailed guidance regarding the scope of the sterility assurance

program. • Additional emphasis on Quality Risk Management. • Guidance for pre-sterilisation bioburden testing and controls, and

consideration of heat-resistant organisms. • Well defined control strategy: QRM, validation, change control,

training, etc

TGA Manufacturing Principles Update 16

Summary • PE009-13 live from 1 January 2018

– Refer to TGA website for all updates (Ax 2, 3, 6, 7, 11, 13) – 12 month transition plan on TGA website – We encourage feedback and discussion (use Audit feedback form -

interpretation of requirements) – Refer queries to gmp@tga.gov.au

• TGA has commenced reviews of PE009-14 and will continue to work with industry

on adoption of future changes

Get involved! EMA/EC/TGA/TIWGG Feedback

17 TGA Manufacturing Principles Update