TGA OMQ Medicines Release for Supply

8/6/2019 TGA OMQ Medicines Release for Supply

1/30

Release of Therapeutic Goods for Supplyin Australia

Doug FenwickMedicines Audit Manager (Sydney)Office of Manufacturing QualityTherapeutic Goods Administration

May 2011


2/30

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


3/30

The principle

The holder of the manufacturing authorisation must manufacturemedicinal products so as to ensure that they are fit for their intended use,comply with the requirements of the marketing authorisation and do notplace the patients at risk due to inadequate safety or efficacy

(PE 009-8 Chapter 1 Principle)

3Office of Manufacturing Quality - Release for Supply - RACI Seminar 26th May 2011


4/30

Release Code requirementsQuality Assurance

Medicinal products are not sold or supplied before an authorised personhas certified that each production batch has been produced and controlledin accordance with the requirements of the marketing authorisation and any

other regulations relevant to the production, control and release ofmedicinal 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 ofrelevant authorisations

(Clause 1.3 vii.)



5/30

Release Code requirements contd


Investigational Medicines

Release of investigational products should not occur until after theAuthorised person has certified that the relevant requirements have been

met.....(Annex 13 Clause 38)

Investigational products should remain under the control of the Sponsoruntil after completion of a two-step release procedure: certification by the

Authorised Person; and release following fulfilment of the relevantrequirements... Both releases should be recorded and retained in therelevant trial files held by or on behalf of the sponsor.

(Annex 13 Clause 44)


6/30

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 themanufacturing 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.



7/30

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 packagedproduct.

Partially finished product must be released at each stage of manufacturebut must remain under GMP control until fully finished and released forsupply.

Fully finished product must be released for supply before it can leaveGMP control and be distributed in the marketplace.

Sometimes there is lack of clarity as to what release is performed oncontract manufactured fully finished product.



8/30

Key responsibilities The market authorisation holder has entered into an agreement with the

regulatory authority to supply product in compliance with the marketingauthorisation as evaluated

The Authorised Person is responsible to assess the manufacturedproduct against the market authorisation and relevant regulations toensure that the batch complies with these and will not cause unintendedconsequences

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 bedocumented in a technical agreement



9/30

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 theproduct to be released.

This is a shared responsibility when more than one party is involved inthe manufacturing process.

The responsibilities at each level need to be clearly defined in technical

agreements.



10/30

Assessment Is GMP being followed?

Are all controls appropriate and have they been clearly followed?

Are the production processes consistent with the approved processesand compliant with GMP?

Are all the correct materials used and have they been used in the correctmanner ?

There should be appropriate calibrated equipment

All validations should be carried out and approved

The finished product is correctly processed, verified and anyinvestigation is completed



11/30

Assessment A clear procedure should be available to the Authorised Person detailing

the process and documentation of the assessment and the certificationof the release for supply of the relevant batch.

Commonly a checklist is performed to verify the evidence used tosupport the release decision.

Records of the evidence used to support the release decision andrelease documentation should be maintained as a GMP record.



12/30

Evidence required by Authorised PersonIncludes:

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 themanufacturing process, PQR, stability, reference/retention samples and

particularly how the Authorised person ensures that each batch ismanufactured and checked for compliance to the marketing authorisation

Assessment of finished product samples and access to retention/referencesamples



13/30

Market authorisationWhat 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)



14/30

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 andidentify 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.



15/30

Personnel MA Holder (Sponsor)The Marketing Authorisation holder:

Must supply relevant information to the Authorised Person forundertaking release for supply.

Ensure marketing authorisation details are kept current andcommunicated to manufacturer(s) and regulators as relevant.

Review PQRs with relevant manufacturers.

Ensure that appropriate technical arrangements are in place throughoutthe manufacturing chain and with the Authorised Person.

Ensure stability data to support expiry dating of products is available.



16/30

Personnel Authorised PersonThe 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.



17/30

Personnel ManufacturersThe manufacturers should:

Manufacture in accordance with specifications and information providedby the Sponsor

Communicate to the sponsor any changes relevant to the manufactureof 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 withMarketing Authorisation requirements



18/30

Impact of PE-009-8 on Release for Supply

Largely centres around the information required by the AuthorisedPerson 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 fordifferent manufacturing types.



19/30

Conclusion Products released from manufacture need to comply with appropriate

quality attributes and regulatory requirements

There are specific responsibilities relevant to the various parties thatneed to be defined and documented to ensure product compliance

Release for supply is the verification that all manufacturing activitieshave 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 ofevidence 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 inthe manufacturing process to ensure appropriate release



20/30

Questions and Answers



21/30

QuestionsQ 1. Is it required to perform chemical testing prior to the release offinished product when the bulk product (tablets, capsules, solutions) areshipped 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 bulkundertaken for release from bulk manufacture is acceptable if themanufacturer releases the bulk under a valid TGA Clearance/GMPCertificate. However, in some circumstances eg transport incidents, localtesting may be required to verify the batch. The Authorised Person shouldensure that validated or compendial methods are used and testing isconsistent with the MA.



22/30

QuestionsQ 2. Is it mandatory for an additional release for sale (sic) step to beperformed in Australia for imported fully finished goods that have beenreleased overseas, by a registered site that has GMP clearance?

A 2.There needs to be clear evidence that the overseas manufacture hasconducted the step of release for supply to the market and not justrelease from the last step of manufacture. There should be a clearstatement of this on the release documentation from the manufacturerand clear responsibilities detailed in a technical agreement and marketingauthorisation.



23/30

QuestionsQ 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 acompany for inclusion on its Manufacturer Licence, details of thequalifications and work experience of the person are to be provided to theTGA for review.Generally, there is an expectation that the person will hold appropriateexperience for the area of manufacture that the company undertakes.

While the quality nominee is usually the person performing release forsupply, this responsibility may be delegated to another company employee.In all cases, it is the responsibility of the company to ensure the suitability ofthe person.



24/30

QuestionsQ 4.How are manufacturers expected to verify the conditions of the MAduring batch release ?

A 4. As discussed in this presentation, evidence such as the documentsbelow can be used to verify the MA. Normally, all these would not be used atthe time of release but a process to ensure that these have been consideredis required.

ARTG detailsCertificate of Registration conditions

SpecificationsStability dataGMP AgreementsTGOs (particularly TGO 77 micro. TGO 78 Stds for Caps/Tabs)Compendia (BP, USP, EP)



25/30


26/30

QuestionsQ 6.Differences between release for further processing, release for sale andrelease for supply? (I think TGA recognise release for supply only as a stepin manufacture).

A 6. As mentioned in the presentation, release for further processing isrelease 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 fullyfinished product is released to the market and outside GMP control. For saleimplies commercial product and for supply, other products eg clinical trial.These are both considered as the manufacturing step of release for supplyby the TGA.



27/30

QuestionsQ 7. Conditions for shipment of materials under quarantine to vendorsawaiting the release notification ?

A 7. Fully finished product cannot leave GMP control until it has beenreleased for supply. Generally, the only instance where shipment underquarantine occurs is for transport from one site of a manufacturer to anothersite pending final results for release.

In such cases both sites are licensed/certified to hold unreleased productand the product does not leave the manufacturers control until release.



28/30

QuestionsQ 8. Australian RFS vs QP release in EU recognition under the MRA ?

A 8. The requirements for release for supply are identical in terms ofcompliance to MA and regulatory requirements. The QP appears on theproduct licence and is legally liable for the release process. Additionally,there are specific qualification requirements for a QP and processrequirements are different eg. Products produced in third countries require afull quantitative analysis in the EU prior to release.

For further details see

http://www.qp-association.eu/qualified_person_qp_regulation.html



29/30

QuestionsQ 9. Access to method validation data for person performing RFS ?

A 9. Sufficient confidence should be obtained by the Authorised Persons thatfinished product testing has been performed using validated/compendialmethods. Review of documents such as technical agreements related totesting arrangements, test methods/validation reports, Product QualityReviews may be used.



30/30

QuestionsQ 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 methodsunless required by the contract giver. Relevant GMP contracts should definethe roles and responsibilities of the parties including analytical methodvalidation and the intended purpose of the use of the results.

Certificates of analysis need not specify whether the method is validated. Itis expected that this is covered in contractual arrangements.

The onus on the party conducting release for supply step to base the batchrelease decision only upon analytical results in which confidence is held being results derived from methodology supported by appropriate validationevidence.


Documents

TGA OMQ Medicines Release for Supply