This presentation provides an overview of GMP clearance application process, the TGA compliance risk framework, major deficiencies and manufacturing quality challenges.

1. Good Manufacturing Practices for
Complementary Medicines
Doreene Kohalmi
Senior Inspector
Manufacturing Quality Branch
Monitoring and Compliance Division, TGA
Complementary Medicines Australia - 2015 Quality Learning Seminar
3 June 2015

2. Overview
• GMP clearance application process
• TGA compliance risk framework
• Major deficiencies commonly identified
• Manufacturing quality challenges
• TGA industry working group
Good Manufacturing Practices for Complementary Medicines 1

3. Manufacturing Quality Branch
GMP clearance application process
2Good Manufacturing Practices for Complementary Medicines
Quality
manufacturing
On-site inspections of
manufacturers and
compliance verifications
(paper-based
assessments)
Australian and overseas
manufacturers are
assessed prior to supply
of goods and are then
regularly reviewed Inspections against the
PIC/S Guide To Good
Manufacturing Practice
For Medicinal Products 15
January 2009
& other relevant
requirements

4. 3
Inspections
scheduling
Arrange inspection
dates with:
- Manufacturer
- Sponsor
Plan inspection
Conduct
inspection
Close out
inspection and
assign A1, A2, A3
or U rating
Issue licence or
certificate &
clearance
Is evidence from
recognised
regulator
available?
Australian
sponsor supplies
evidence
Yes No
High level TGA manufacturer assessment process
Good Manufacturing Practices for Complementary Medicines
If evidence is
acceptable GMP
clearance issued

5. TGA compliance risk framework
Good Manufacturing Practices for Complementary Medicines 4
Low compliance risk High compliance risk
TGA’s approach to compliance
Help and support
• Make ongoing
compliance easy
Inform and advise
• Help to become
and stay compliant
Correct behaviour
• Deter by detection
Enforce

6. TGA compliance risk framework
Good Manufacturing Practices for Complementary Medicines 5
Low compliance risk High compliance risk
Committed to doing the right thing / Trying to do the right thing but don’t always succeed / Don’t want to comply but will if made to
Regulated entity – attitude to compliance
Voluntary
compliance
• Effective compliance
systems
• Management is
compliance orientated
Accidental non-
compliance
• Ineffective and/or
developing compliance
systems
• Management
compliance orientated
but lacks capability
Opportunistic non-
compliance
• Resistance to
compliance
• Limited poor
compliance systems
• Management not
compliance orientated
Intentional non-
compliance
• Deliberate non-
compliance
• No compliance systems
• Criminal intent

7. Current MQB reinspection frequency based on risk
6
Inspection frequency matrix - medicines
Re-inspection period in months
Risk category Compliance rating
Acceptable Unacceptable
A1 A2 A3
High 24 18 12 Determined by Review Panel
Medium 30 20 12
Low 36 24 12
Good Manufacturing Practices for Complementary Medicines

8. Current MQB reinspection frequency based on risk
Compliance levels
A1 = Good Few deficiencies of a
relatively minor nature
A2 =
Satisfactory
Few major deficiencies (x<6)
and /or a large number of
minor deficiencies and no
critical.
A3 = Basic A large number of major
(5<x<11) and/or a large
number of minor
deficiencies and no critical.
Not rated =
unacceptable
One or more critical and/or a
large number of major
deficiencies.
7
Inspection frequency matrix -
medicines
Re-inspection period in
months
Risk category Compliance rating
Acceptable Unacceptable
A1 A2 A3
High 24 18 12 Determined
by Review
Panel
Medium 30 20 12
Low 36 24 12
Good Manufacturing Practices for Complementary Medicines

9. Current MQB reinspection frequency based on risk
Product/process risk
classifications
Medium risk • Non-sterile medicines,
including herbal, unless
specified as high risk
Low risk • Minerals, vitamins, fish
oils and other
supplements
• Sunscreens
• Single step –
labelling/packaging;
analysis/testing; release
for supply and storage
8
Inspection frequency matrix -
medicines
Re-inspection period in
months
Risk category Compliance rating
Acceptable Unacceptable
A1 A2 A3
High 24 18 12 Determined
by Review
Panel
Medium 30 20 12
Low 36 24 12
Good Manufacturing Practices for Complementary Medicines

10. MQB reinspection frequency under consideration
Product/process risk
classifications
Medium risk • Registered non-sterile
medicines, including
registered herbal
Low risk • All listed medicines,
including listed herbal
• Sunscreens
• Single step –
labelling/packaging;
analysis/testing; release
for supply and storage
9
Inspection frequency matrix -
medicines
Re-inspection period in
months
Risk category Compliance rating
Acceptable Unacceptable
A1 A2 A3
High 36 24 12 Determined
by Review
Panel
Medium 42 30 18
Low 48 36 24
Good Manufacturing Practices for Complementary Medicines

11. Major deficiencies commonly identified by TGA
• Quality management system (QMS)
• Personnel
• Premises and equipment
• Documentation
• Production
• Quality Control
• Storage
Good Manufacturing Practices for Complementary Medicines 10

12. Major deficiencies commonly identified by TGA
• Quality management system (QMS)
– Unsatisfactory deviation management , such as inadequate investigation and
record keeping
– Inadequate resourcing of quality management functions including product
release
– All product quality reviews not conducted and/or not all elements covered
Good Manufacturing Practices for Complementary Medicines 11

13. Major deficiencies commonly identified by TGA
• Personnel
– Inadequate training and skills assessment
– Practices do not reflect documented procedures
Good Manufacturing Practices for Complementary Medicines 12

14. Major deficiencies commonly identified by TGA
• Documentation
– Inadequate manufacturing instructions
– Inadequate records keeping – including batch records
Good Manufacturing Practices for Complementary Medicines 13

15. Major deficiencies commonly identified by TGA
• Production
– Processes not validated or inadequately validated
– Revalidation not conducted routinely
– Inadequate change control management
– Inadequate design of facilities, equipment and procedural measures for the
prevention of contamination and cross-contamination
– Reprocessing/rework inadequately controlled
Good Manufacturing Practices for Complementary Medicines 14

16. Major deficiencies commonly identified by TGA
• Quality Control
– Test methods not validated or verified and/or validation incomplete
– Testing inadequate
– Records of testing incomplete and/or ineffective review arrangements
Good Manufacturing Practices for Complementary Medicines 15

17. Major deficiencies commonly identified by TGA
• Storage
– Inadequate controls and monitoring of storage conditions
– Storage conditions not always as per label requirements
Good Manufacturing Practices for Complementary Medicines 16

18. Manufacturing quality challenges
• Control of the supply chain
• Complex formulations
• Complex manufacturing chains
Good Manufacturing Practices for Complementary Medicines 17

19. Manufacturing quality challenges
Good Manufacturing Practices for Complementary Medicines 18
GMP
Deviations
Supply chain

20. TGA – Industry Working Group on GMP
• Membership:
– Accord
– Active Pharmaceutical Ingredient Manufacturer’s Association of Australia
– Australia New Zealand Industrial Gas Association
– Australian Self Medication Industry
– Complementary Medicines Australia
– Generic Medicines Industry Australia
– Medicines Australia
• To prioritise and discuss issues of a regulatory and technical nature arising from current regulation and
propose solutions
• Establish and oversight Technical Working Groups to develop:
– new, or review existing, guidelines
– comments on draft PIC/S guidelines for tabling by TGA at PIC/S meetings
– guidance documents
19Good Manufacturing Practices for Complementary Medicines

21. TGA – Industry Working Group on GMP
• Technical guidance documents
• Guidance on release for supply
– Part 1 published TGA website version 2.0 January 2015
 Clarifies general requirements and responsibilities for undertaking release for supply (RFS)
and release for further processing (RFFP)
– Part 2 close to publication
 Includes specific examples of the manufacturing process chain and how RFS and RFFP work
in the specific examples cited
20Good Manufacturing Practices for Complementary Medicines

22. TGA – Industry Working Group on GMP
• Guidance on release for supply – Part 2
– The specific examples included to-date include the following:
• Release for supply from a secondary packaging site
• Re-release of a product after minor further steps of manufacture
• Stability conducted by a separate licensed manufacturer
• Full product manufacture at one site followed by secondary packaging at another site and
returned to the original manufacturer for release for supply
• Bulk packaging from 2 manufacturing sites
– Part 2 will be a live document that can have more relevant useful examples added as needed
21Good Manufacturing Practices for Complementary Medicines

23. References
• Latest Trends In Manufacturing Quality – Enhancing the TGA Inspection Process
– Harry Rothenfluh PhD – Assistant Secretary Manufacturing Quality Branch
– Presentation at ARCS Scientific Congress 5 May 2015
– http://www.tga.gov.au/presentation-latest-trends-manufacturing-quality
• Regulatory Compliance Framework – 27 June 2013
– http://www.tga.gov.au/regulatory-compliance-framework
• Inspection Frequency Matrix – Medicines and Blood , Tissue and Cellular Therapies
– http://www.tga.gov.au/manufacturer-inspections-risk-based-approach-frequency
• Manufacturer Compliance History
– http://www.tga.gov.au/manufacturer-compliance-history
• Manufacturer Inspections – Product/Process Risk Classifications
– http://www.tga.gov.au/manufacturer-inspections-productprocess-risk-classifications
Good Manufacturing Practices for Complementary Medicines 22

24. References
• Guidance on Release for Supply – Part 1
– 23 January 2015
– http://www.tga.gov.au/publication/guidance-release-supply
• Technical Guidance on the Interpretation of Manufacturing Standards
– http://www.tga.gov.au/publication/technical-guidance-interpretation-manufacturing-standards
• Australian Regulatory Guidelines Good Manufacturing Practice (GMP) Clearance for Overseas
Manufacturers
– 17th Edition - May 2011
– http://www.tga.gov.au/publication/gmp-clearance-overseas-manufacturers
Good Manufacturing Practices for Complementary Medicines 23