TGA is adopting updates to the PIC/S Guide to GMP including PE009-13 and future revisions such as PE009-14. Key points include: - PE009-13 was adopted on January 1, 2018 with a 12 month transition period for industry to comply. - Future revisions will address additional chapters and annexes to further clarify requirements. - TGA plays an active role in updating PIC/S GMP guidance to ensure risks are addressed and GMP keeps pace with innovation. - Adopting international standards supports TGA's mutual recognition agreements and provides assurance in international markets.

1. 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

2. Overview
• Why adopt updates to GMP?
• Update Processes:
– EMA process
– PIC/S process
– TGA process
• Future Revisions
– PE009-14
– PE009-??

3. 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.

4. 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

5. Gap Analysis
PE 009-13 PE 009-08 Nature of
impact
Estimated
significance
of impact
1. ORGANISING AND PLANNING FOR
QUALIFICATION 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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-
??

12. 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.

13. 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.

14. 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)

15. 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

16. 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

17. 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

18. 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