TGA OMQ Medicines Release For Supply

Release of Therapeutic Goods for Supply
in Australia
Doug Fenwick
Medicines Audit Manager (Sydney)
Office of Manufacturing Quality
Therapeutic Goods Administration
May 2011
Overview
• Code requirements
• Sale or supply
• Fully or partially finished products
• Key responsibilities
• Assessment for release
• Evidence used for Release
• Personnel
• Impact of PE 009-8
• Q&A
Office of Manufacturing Quality - Release for Supply - RACI Seminar 26th May 2011 2
The principle
“The holder of the manufacturing authorisation must manufacture

medicinal products so as to ensure that they are fit for their intended use,
comply with the requirements of the marketing authorisation and do not
place the patients at risk due to inadequate safety or efficacy”
(PE 009-8 Chapter 1 Principle)
Release – Code requirements
Quality Assurance
“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”
(Clause 1.1 vii.)
Quality Control
“No batch of product is released for sale or supply prior to certification by
an authorised person that it is in accordance with the requirements of
relevant authorisations”
(Clause 1.3 vii.)
Release – Code requirements cont’d
Investigational Medicines
“Release of investigational products should not occur until after the
Authorised person has certified that the relevant requirements have been
met.....”
(Annex 13 Clause 38)
“Investigational products should remain under the control of the Sponsor

until after completion of a two-step release procedure: certification by the
Authorised Person; and release following fulfilment of the relevant
requirements”... “Both releases should be recorded and retained in the
relevant trial files held by or on behalf of the sponsor.”
(Annex 13 Clause 44)
Sale or supply
• Both terms are used within the code
• Sale – commercial product
• Supply – non-commercial product (eg clinical trial)
• TGA uses “release for supply” to identify the step of final release from the
manufacturing process for distribution to the user.
• “Release” may occur at various steps in the manufacturing chain
– API
– Bulk manufacture
– Packaging and labelling
• The release to be undertaken needs to be clearly documented,
particularly when release for supply is outsourced by the sponsor.
Fully/partially finished product
• Fully finished product is product in its final market pack at the
completion of all manufacturing processes.
• Partially finished product is at an intermediate stage in the
manufacturing process eg bulk tablets, bulk liquids, primary packaged
product.
• Partially finished product must be released at each stage of manufacture
but must remain under GMP control until fully finished and released for
supply.
• Fully finished product must be released for supply before it can leave
GMP control and be distributed in the marketplace.
• Sometimes there is lack of clarity as to what release is performed on
contract manufactured fully finished product.
Key responsibilities
• The market authorisation holder has entered into an agreement with the
regulatory authority to supply product in compliance with the marketing
authorisation as evaluated
• The Authorised Person is responsible to assess the manufactured
product against the market authorisation and relevant regulations to
ensure that the batch complies with these and will not cause unintended
consequences
• There are responsibilities for the holder of the manufacturing
authorisation, and for the Authorised Person in release
• The responsibilities relevant to the release process should be
documented in a technical agreement
Assessment
• To achieve the quality objectives there must be a comprehensively
designed and correctly implemented system of quality assurance,
incorporating GMP quality control and quality risk management. Any
assessment must take recognition of these factors and its impact on the
product to be released.
• This is a shared responsibility when more than one party is involved in
the manufacturing process.
• The responsibilities at each level need to be clearly defined in technical
agreements.
Assessment
• Is GMP being followed?
• Are all controls appropriate and have they been clearly followed?
• Are the production processes consistent with the approved processes
and compliant with GMP?
• Are all the correct materials used and have they been used in the correct
manner ?
• There should be appropriate calibrated equipment
• All validations should be carried out and approved
• The finished product is correctly processed, verified and any
investigation is completed
Assessment
• A clear procedure should be available to the Authorised Person detailing
the process and documentation of the assessment and the certification
of the release for supply of the relevant batch.
• Commonly a checklist is performed to verify the evidence used to
support the release decision.
• Records of the evidence used to support the release decision and
release documentation should be maintained as a GMP record.
Evidence required by Authorised Person
Includes:
• Marketing authorisation details (including conditions)
• Finished product specifications (reliant on above)
• Relevant batch documents (in-house) or Certificates of Analysis (contract)
– Batch records, Test records, Deviations/oos investigation records
• Stability data (initial and ongoing) to support expiry date (PE-009-8)
• Product quality reviews (PE-009-8)
• Relevant GMP Agreements outlining responsibilities of parties in the
manufacturing process, PQR, stability, reference/retention samples and
particularly how the Authorised person ensures that each batch is
manufactured and checked for compliance to the marketing authorisation
• Assessment of finished product samples and access to retention/reference
samples
Market authorisation
What can be used to verify marketing authorisation ?
– ARTG details
– Certificate of Registration/Listing – conditions
– Specifications
– Stability data
– GMP Agreements
– TGOs (particularly TGO 69, TGO 77 – micro, TGO 78 Stds for Caps/Tabs)
– Compendia (BP, USP, EP)
The role of Product Quality Reviews
• Give confidence in the consistency of the manufacturing process(es).
• Summarise key elements in the manufacturing of the product and
identify any issues requiring attention.
– Suitability of starting materials
– Suitability of equipment
– Suitability of processes
– Incidents, investigations and resolving actions
– Changes that may affect the product – MA, manufacturing, testing
– Stability programs verifying product quality over its life
– Currency of contractual arrangements.
Personnel – MA Holder (Sponsor)
The Marketing Authorisation holder:
• Must supply relevant information to the Authorised Person for
undertaking release for supply.
• Ensure marketing authorisation details are kept current and
communicated to manufacturer(s) and regulators as relevant.
• Review PQRs with relevant manufacturers.
• Ensure that appropriate technical arrangements are in place throughout
the manufacturing chain and with the Authorised Person.
• Ensure stability data to support expiry dating of products is available.
Personnel – Authorised Person
The Authorised Person should:
• Understand the manufacturing process and inherent issues
• Understand regulatory requirements relevant to the manufacture
• Understand the arrangements for manufacture and the responsibilities of parties.
• Be able to assess analytical results and their implications
• Be able to assess information on manufacture and the implications:
- Suitability of starting materials
- Complaints and their implications
- Validation recommendations
- Changes to stability data
- Changes in starting and packaging materials
- Deviations/oos
• Be able to determine compliance to approved patient information and labels.
Personnel – Manufacturers
The manufacturers should:
• Manufacture in accordance with specifications and information provided
by the Sponsor
• Communicate to the sponsor any changes relevant to the manufacture
of products that may influence marketing authorisation
• Contribute to preparation of PQRs relevant to the step of manufacture
• Perform release relevant to the step of manufacture in accordance with
Marketing Authorisation requirements
Impact of PE-009-8 on Release for Supply
• Largely centres around the information required by the Authorised
Person for release:
– Product Quality Reviews
– Stability data
• Impacted by multiple manufacturers in the process.
• Recognised by OMQ that guidance is required.
• Proposed group to develop guidance to apply across various
manufacturing types. Chaired by OMQ Technical and Quality Manager.
• Industry and TGA to be represented based on TWG model.
• Guidance proposed to be general section plus specific/examples for
different manufacturing types.
Conclusion
• Products released from manufacture need to comply with appropriate
quality attributes and regulatory requirements
• There are specific responsibilities relevant to the various parties that
need to be defined and documented to ensure product compliance
• Release for supply is the verification that all manufacturing activities
have been performed appropriately, in accordance with requirements,
and a product batch can leave GMP control for use
• The Authorised Person must satisfy themselves by an assessment of
evidence that the product conforms with requirements including the
marketing authorisation and other regulatory requirements
• Current Manufacturing Principles have introduced additional elements to
improve the confidence of both the Authorised Person and Sponsor in
the manufacturing process to ensure appropriate release
Questions and Answers
Questions
Q 1. Is it required to perform chemical testing prior to the release of
finished product when the bulk product (tablets, capsules, solutions) are
shipped in from overseas then packed and released for sale locally. Or
is physical identification sufficient ?
A 1.Normally, a Certificate of Analysis for chemical testing of the bulk

undertaken for release from bulk manufacture is acceptable if the
manufacturer releases the bulk under a valid TGA Clearance/GMP
Certificate. However, in some circumstances eg transport incidents, local
testing may be required to verify the batch. The Authorised Person should
ensure that validated or compendial methods are used and testing is
consistent with the MA.
Questions
Q 2. Is it mandatory for an additional release for sale (sic) step to be
performed in Australia for imported fully finished goods that have been
released overseas, by a registered site that has GMP clearance?
A 2.There needs to be clear evidence that the overseas manufacture has

conducted the step of release for supply to the market and not just
release from the last step of manufacture. There should be a clear
statement of this on the release documentation from the manufacturer
and clear responsibilities detailed in a technical agreement and marketing
authorisation.
Questions
Q 3. Qualifications for persons performing the release for supply functions ?
A 3. There are no prescribed qualifications for the Authorised Person

performing release for supply. When a quality nominee is proposed by a
company for inclusion on its Manufacturer Licence, details of the
qualifications and work experience of the person are to be provided to the
TGA for review.
Generally, there is an expectation that the person will hold appropriate
experience for the area of manufacture that the company undertakes.
While the quality nominee is usually the person performing release for
supply, this responsibility may be delegated to another company employee.
In all cases, it is the responsibility of the company to ensure the suitability of
the person.
Questions
Q 4.How are manufacturers expected to verify the conditions of the MA
during batch release ?
A 4. As discussed in this presentation, evidence such as the documents

below can be used to verify the MA. Normally, all these would not be used at
the time of release but a process to ensure that these have been considered
is required.
ARTG details
Certificate of Registration – conditions
Specifications
Stability data
GMP Agreements
TGOs (particularly TGO 77 – micro. TGO 78 Stds for Caps/Tabs)
Compendia (BP, USP, EP)
Questions
Q 5. Requirements for stability data and PQR data for the entity performing
the release for supply ?
A 5. The Authorised Person must hold stability data and PQR information for
use in release for supply.
The level of information required will be discussed during formulation of a

guidance document on release for supply.
Questions
Q 6.Differences between release for further processing, release for sale and
release for supply? (I think TGA recognise release for supply only as a step
in manufacture).
A 6. As mentioned in the presentation, release for further processing is

release from a particular manufacturing step eg premix, bulk tabletting,
primary packaging and the product is still within the manufacturing process.
Release for sale and release for supply are synonomous in that the fully
finished product is released to the market and outside GMP control. For sale
implies commercial product and for supply, other products eg clinical trial.
These are both considered as the manufacturing step of “release for supply”
by the TGA.
Questions
Q 7. Conditions for shipment of materials under quarantine to vendors
awaiting the release notification ?
A 7. Fully finished product cannot leave GMP control until it has been
released for supply. Generally, the only instance where shipment under
quarantine occurs is for transport from one site of a manufacturer to another
site pending final results for release.
In such cases both sites are licensed/certified to hold unreleased product

and the product does not leave the manufacturer’s control until release.
Questions
Q 8. Australian RFS vs QP release in EU recognition under the MRA ?
A 8. The requirements for release for supply are identical in terms of

compliance to MA and regulatory requirements. The QP appears on the
product licence and is legally liable for the release process. Additionally,
there are specific qualification requirements for a QP and process
requirements are different eg. Products produced in third countries require a
full quantitative analysis in the EU prior to release.
For further details see

http://www.qp-association.eu/qualified_person_qp_regulation.html
Questions
Q 9. Access to method validation data for person performing RFS ?
A 9. Sufficient confidence should be obtained by the Authorised Persons that

finished product testing has been performed using validated/compendial
methods. Review of documents such as technical agreements related to
testing arrangements, test methods/validation reports, Product Quality
Reviews may be used.
Questions
Q 10. Whether laboratories should state if methods are validated on their C
of A when supplied to a contractor performing release for supply?
A 10. Testing laboratories are not compelled to validate all test methods
unless required by the contract giver. Relevant GMP contracts should define
the roles and responsibilities of the parties including analytical method
validation and the intended purpose of the use of the results.
Certificates of analysis need not specify whether the method is validated. It
is expected that this is covered in contractual arrangements.
The onus on the party conducting release for supply step to base the batch
release decision only upon analytical results in which confidence is held –
being results derived from methodology supported by appropriate validation
evidence.

TGA OMQ Medicines Release For Supply

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Release of Therapeutic Goods for Supply

“The holder of the manufacturing authorisation must manufacture

“Investigational products should remain under the control of the Sponsor

A 1.Normally, a Certificate of Analysis for chemical testing of the bulk

A 2.There needs to be clear evidence that the overseas manufacture has

A 3. There are no prescribed qualifications for the Authorised Person

A 4. As discussed in this presentation, evidence such as the documents

The level of information required will be discussed during formulation of a

A 6. As mentioned in the presentation, release for further processing is

In such cases both sites are licensed/certified to hold unreleased product

A 8. The requirements for release for supply are identical in terms of

For further details see

A 9. Sufficient confidence should be obtained by the Authorised Persons that

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