Presentation on Legislative requirements, specific risks for IMP manufacturing, manufacturing authorisations, PIC/S Guide to GMP PE009-13 and common issues

1. Manufacturing Investigational Medicinal Products
Legislative and GMP requirements
Matt Davis
Senior Inspector
Manufacturing Quality Branch
Therapeutic Goods Administration
August 2019

2. Overview
Legislative Requirements
Specific risks for IMP manufacturing
Manufacturing Authorisations
PIC/S Guide to GMP PE009-13
Common Issues
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3. Legislative Requirements
• Therapeutic Goods Act 1989
– Sections 18 & 19: Provide the basis for exemption from
Part 3-2 of the Act for IMPs
• Therapeutic Goods Regulations 1990
– Schedule 5A, item 3: “Therapeutic goods used solely for experimental purposes in humans”
– Schedule 7, item 1: “goods prepared for the initial experimental studies in human volunteers”
– Schedule 8: “Persons exempt from the operation of Part 3-3 of the Act”
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4. Manufacturing risk profile - IMPs
Dynamic
manufacturing
• Regular process developments & changes
• Specification changes
• Labelling requirements
• Stability data/updates
Risk of mix-ups
• Packaging multiple products
• Blinding processes
• Randomisation processes
The unknown
• Cross contamination risks
• Vendor qualification
• Reduced process validation
• Product use
Information from trial sponsor is critical! 3

5. Manufacturing Authorisation
Manufacturing Principles
• Medicines
• PIC/S PE009
• Blood, tissues, cellular
therapies
• Australian Code of GMP
Pharmacopoeia
(Default Standard)
• British
• European
• United States
Therapeutic Goods
Orders
• TGO 100 (microbiological
Standards)
• TGO 101 (Tablets,
Capsules and Pills)
• TGO 102 (Blood &
components)
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6. Manufacturing Principles – PE009-13
– Part I Chapter 1 Quality Control, Product Quality Review, QRM
– Part I Chapter 2 Training
– Part I Chapter 3 Premises & Equipment
– Part I Chapter 4 Documentation
– Part I Chapter 5 Production (Sampling & Contamination Control)
– Part I Chapter 6 Quality Control
– Part I Chapter 7 Outsourced Activities
– Part II Manufacturing of active pharmaceutical ingredients
– Annexes 1, 2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17 & 19.

7. Annex 13 – Product Specification File
Forms the basis for assessment of the suitability for
certification and release of a particular batch by the
Authorised Person
• Specifications and analytical methods for starting materials, packaging
materials, intermediate, bulk and finished product;
• Manufacturing methods;
• In-process testing and methods;
• Approved label copy;
• Relevant clinical trial protocols and randomisation codes, as appropriate;
• Relevant technical agreements with contract givers, as appropriate;
• Stability data;
• Storage and shipment conditions.
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8. Annex 13 – Validation
Production processes for investigational medicinal products
are not expected to be validated to the extent necessary for
routine production; however,
• PV should be commensurate with process understanding
• Premises and equipment must be fully qualified
• For sterile products:
• sterilisation processes must be fully validated
• Media fills must be conducted as per Annex 1
• Virus inactivation/removal or similar treatment other impurities of biological
origin must be demonstrated
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9. Annex 13 - Labelling
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10. Annex 13 – Blinding & Randomisation
Blinding and randomisation are risky activities
• Clear processes and controls to ensure products are
effectively blinded, whilst avoiding any mix-up.
• Effective controls for allocation and control of
randomisation codes and label generation controls.
• System validation expected
• Method of un-blinding or code-breaking in case of
emergency
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11. Annex 13 – Sampling & Testing
Increased emphasis on sampling and QC testing
• Increased sampling plans and test plans for in-process and
finished goods
• Full method validation expected
• Laboratory controls for data integrity required – particularly
when data annotation tools are needed
• Product specification file outlines agreed testing
specification
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12. Common issues…
• The requirements of Clause 1.1 vii that medicinal products are not sold or supplied
before an authorised person has certified that each production batch has been
produced and controlled in accordance with the requirements of the marketing
authorisation and any other regulations relevant to the production, control and release
of medicinal products, were not met. For example:
• The company did not maintain product specification files for clinical trial products
handled by the site. E.g. for IMP XXX for which “Manufacturer” performed release for
supply. (Also Annex 13§9, 40).
• Specifications for finished products were not generated and held by the company.
(Also Clause 4.13)
Product Specification Files
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13. Common issues…
• The requirements of Annex 13§26 regarding the labelling requirements for
immediate containers of clinical trial materials was not fully met when redressing
stock labelled with “Country” labels.
• The manufacturer’s current redressing process required the addition of a clinical
trial label onto the secondary container only, and not of the immediate
container.
• The “Country” label on the immediate container did not include all labelling
requirements as specified by clause 26 and table 1 of Annex 13, e.g. address
and telephone number of the sponsor, CRO or investigator, “for clinical trial use”
or similar wording, storage conditions.
Labels – incorrect placement or text
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14. Common issues…
• The requirements Annex 15 §11.1 & 11.4 that control of change is an important part of
knowledge management and should be handled within the pharmaceutical quality system...were
not fulfilled. For example:
• The introduction of new IMP production equipment in the wet mix and dry mix areas were
not managed under the Change Control system to assess potential risks to GMP operations
or manage the activities required to support the change.
• The cleaning validation requirements for equipment shared across different products/clinical
trial materials were not available (Also refer to Annex 13 §5).
• There was no procedure or system in place for the introduction of new products/clinical
trial material. The actions required for ensuring the safe introduction and control of new
materials was not covered by the pharmaceutical quality system.
• There were no process validation requirements in the Validation Master Plan for IMPs.
Controlled introduction of clinical trial materials
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15. Common issues…
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ARCS – August 2019
• The company’s arrangements for the introduction and management of clinical trial products did
not ensure that processes were appropriately reviewed, validated and controlled to minimise the
potential for cross contamination. Specifically:
• The risk assessment (RA) and validation master plan (VMP) for the cross contamination for
the clinical trial products (class A potent actives) did not include a detailed assessment of the
potential cross contamination issues associated with the use of non dedicated HVAC systems
for impact and any mitigating circumstances;
• There was no inclusion of the sterile clinical trial products in any cleaning validation or
routine monitoring program. ;
• In relation to “IMP XXX” sterile eye drop manufacture;
• The sterilising filter was not fully validated in relation to chemical compatibility and
microbial retention capacity;
• For batch sizes less than 60 litres, a sterilising filter pre-integrity check was not performed.
Furthermore, a bubble point for the solvent used was not determined.
Controlled introduction of clinical trial materials

16. Common issues…
• Stability studies for product IMPXXX had not been performed
since initial validation in 2011.
• The current agreements with O/S Sponsor/AU Sponsor were
ambiguous as to who was responsible for release for supply.
Furthermore, the agreements indicated that AU Sponsor was
responsible for release to market. (Also Clause 7.11).
Absence of critical information
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17. Summary
• Be aware of legislative provisions for the manufacture of IMPs
– Act and Regulations
– Specific GMP requirements
• Knowledge management is critical
– Relationship between sponsor and manufacturer
– Sharing data and information
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18. Thank you for your attention
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