The TGA have announced that version 16 of the PIC/S Guide to GMP will be adopted in Australia from June 2024 – see (PIC/S Guide to GMP for medicinal products – version 16 | Therapeutic Goods Administration (TGA)).

This change will impact Annex 13 for investigational product manufacture, as well as Annex 16 for batch release and authorised person – see our take on the Annex 16 changes at TGA Adopt PIC/S Guide to GMP Version 16 Impact of Annex 16 Authorised Person and Release for Supply (qualitysystemsnow.com.au). There are no changes to Part I and II of the PIC/S Guide to GMP.

Overview of the Changes to Annex 13

Annex 13 has been significant reworked. However, the changes provide more clarity for investigational medicinal product sponsors and manufacturers, particularly when to apply full GMP and responsibilities between parties.

The changes also ensure:

• The Pharmaceutical Quality System (PQS) meets requirements of GMP

• Quality Risk Management (QRM) is used to ensure patient safety and prevent cross-contamination and mix-ups

• Full GMP documentation expectations are in place

• All facility and equipment qualifications are complete and according to Annex 15

• Cleaning validation is in place

• Sterility assurance of aseptic products meet Annex 1

• All outsourced activities must meet GMP

• Complaints must be handled and investigated according to GMP

• Release for supply must meet Annex 16

• Electronic records must meet Annex 11.

The layout of the annex has also been streamlined, removing numbered clauses, reordering some sections, and adopting a clear paragraph style as per Parts I and II. ‘Clunky’ notes and footnotes have been woven into the general text and mid-annex definitions have been sensibly moved to the end of the annex.

Taking Action

We would strongly recommend that sponsors and manufacturers of investigational medicinal products create a checklist from the key changes below to confirm your ongoing compliance.

Details of the Changes

You can review the changes in detail below, including changes to section headings and the key clause changes.

Section

Key Changes or Clarification

Introduction

• Significantly updated – includes 5 new paragraphs.

• Emphasis is on procedures needing to be flexible at this stage in the investigational product development, however the rigor of GMP must still be applied to limit risk and ensure consistency between batches.

• Includes definitions of an investigational product and manufacturing.

• Investigational products have increased complexity (randomisation, blinding, re-packaging or re-labelling etc.), which requires thorough understanding and training in GMP.

• Increased complexity in manufacturing operations requires a highly effective quality system.

• To apply GMP, there needs to be cooperation between manufacturers and sponsors of clinical trials, which must be described in a technical agreement.

1.      Scope

• New section

• Clarification of the old Notes section concerning reconstitution.

• Three new paragraphs on potential national law requirements abutting GMP completed in hospitals, health clinicals or by pharmacists with respect to:

• re-labelling or re-packaging

• preparation of radiopharmaceuticals

• preparation of medicinal products

2.      Pharmaceutical Quality System

• Renamed from ‘Quality System’

• Clarification that the PQS must be described in written procedures and that it must take into account Ch 1 of Part I with respect to investigational products. For example, the principles of GMP with engagement of senior leadership, appropriate resourcing, facility and equipment etc, as well as quality control, QRM, the PQS.

• Deviations from specifications or instructions must be registered, investigated and corrective and preventive action measures initiated as appropriate.

• Supplier assurance – selection, qualification, approval and maintenance – must be documented and maintained within the PQS to ensure product quality and integrity within the supply chain. The level of risk should be proportionate to the risks posed by the individual materials, taking into consideration their source, manufacturing process, supply chain complexity and final use.

2.1 Product Specification File

• The product specification file must contain all reference documents to ensure investigational products are manufactured according to GMP for investigation products and the clinical trial authorisation.

• The product specification file is one of the essential elements of the PQS.

• Applicable sections of the product specification file must be available at the start of manufacturing of the first batch.

• The product specification file should be continually updated as development proceeds. New requirements for the file include:

• Relevant clinical trial authorisations and their amendments

• Stability plan and reports (was previously referred to as ‘data’)

• Details of plans and arrangement for reference and retention samples

• Details of the supply chain including manufacturing, packaging, labelling and testing sites, preferably in the format of a comprehensive diagram.

• Clarification of release for supply/release for further processing expectations, including access and transparency of information – follows same intent as new Annex 16.

3.      Personnel

• Requirements of Ch 2 of Part I on Personnel should be taken into account as appropriate, in relation to investigational products. Ch 2 of Part I includes general principles, key personnel, training, personnel hygiene, and consultants.

• Specifies that personnel requirements apply to manufacture, import, storage or handling of investigational products.

• Where number of staff involved in manufacture or import, are small, then there should be separate people responsible for production and QC for each batch.

• The Authorised Person (AP) completing RFS must meet the intent of Annex 16.

4.      Premise and Equipment

• As investigational products are not well understood, then risk from cross-contamination must be minimised. Design of equipment and premises, inspection or test methods, and acceptance limits after cleaning must take into account these higher risks according to Ch 3 and Ch 5 of Part I.

• QRM must be used to assess and control cross-contamination risks, including potency and toxicological evaluation. A list of risk factors to be assessed are now mandated.

• Premises and equipment are expected to be qualified to full GMP expectations according to Annex 15.

5.      Documentation

• All documentation must meet full GMP expectations according to Ch 4 Part I.

• Retention periods should comply with national law and GMP.

• Documentation must be consistent with the Product Specification File and those documents forming part of file be retained for at least 5 years.

• The sponsor must retain the clinical trial master file for at least 25 years from the end of the trial. When the sponsor and manufacturer are not the same, the sponsor is responsible for ensuring that the manufacturer retains the relevant documentation as part of the clinical trial master file. This should be included within an agreement.

5.1 Specification and instructions

• The approval process for instructions and changes to specifications (starting materials, immediate packaging materials, intermediate products, bulk products and finished products) must include the relevant responsible personnel at the manufacturing site.

5.2 Order

• The manufacturer must retain the order for the investigational product as part of the batch documentation.

• The order should be formally authorised by the sponsor or their representative and refer to the product specification file and relevant clinical trial protocol as appropriate.

5.3 Manufacturing formulae and processing instructions

• For every manufacturing operation or supply, there must be clear and adequate written records which are prepared using the specific clinical study information detailed in the product specification file.

• Removed from the section - “It may not be necessary to have master formulae and processing instructions”.

5.4 Packaging instructions

• Procedures should describe the specification, generation, testing, security, distribution, handling and retention of any randomised code used for packaging investigational products, as well as code-break mechanism. Appropriate records must be maintained.

5.5 Batch records

• Batch records must also document deviations from predefined requirements.

• Batch manufacturing records must be retained by the manufacturer for at least 5 years after the completion or formal discontinuation of the last clinical trial in which the batch was used, or according to national law.

6.      Production

No change

6.1 Packaging materials

No change

6.2 Manufacturing operations

• Clarification and scope widened – “The manufacturing process is not required to be validated to the extent necessary for routine production but shall be validated in its entirety, as far as appropriate, taking into account the stage of product development. The validation should be documented according to Annex 15. The manufacturer must identify the process steps that safeguard the safety of the subject and reliability and robustness of clinical trial data”.

• Cleaning procedures and analytical test methods to verify the cleaning process must be available.

• Sterile product controls and processes must be validated related to sterility assurance to the same standard as for authorised medicinal products according to Annex 1.

• Likewise, for virus inactivation/removal or removal of other impurities of biological origin must be demonstrated.

6.3 Modification of comparator products

Minor changes

6.4 Blinding operations

• Where the manufacturer is delegated the responsibility of generating randomised codes, they must ensure the blinding information is available to the investigator site before investigational products are supplied.

• Blinded products must be assigned the expiry date of the shortest dated product so that blinding is maintained.

6.5 Packaging

• Packaging documentation must demonstrate appropriate segregation has been maintained during any packaging operation (even if on the same line at the same time).

• Re-packaging operations may be performed by authorised personnel at hospitals, health centres or clinics that meet the requirements of relevant national laws.

6.6 Labelling

• There are multiple clauses on labelling removed as these are address by ‘national law’ requirements.

• If the expiry date needs to change, an additional label should be affixed to the product, stating the new expiry and repeat the batch number and the clinical trial number.

• Re-labelling must be according to GMP and specific SOPs and checked by a second person. Batch records must document the re-labelling. Re-labelling must be segregated from other activities. A line clearance from start to end, including a label reconciliation, must be completed. And discrepancies must be investigated and account for before release.

• Re-labelling may be performed by authorised personnel at hospitals, health centres or clinics that meet the requirements for national law.

7.      Quality Control

• The manufacturer must establish and maintain a quality control system placed under the authority of a person with the requisite qualifications and is independent of production.

• As processes may not be standardised or fully validated, testing takes on more importance in ensuring that each batch meets the approved specification at the time of testing.

• QC testing should also include the comparator product and be completed according to the application for the clinical trial.

• Retention periods for samples must comply with national laws.

• Retention sample information related to final packaging may be stored in written, photographic or electronic records so long as they provide sufficient information. Electronic records must comply with Annex 11.

• Samples are not required for unblinded comparator products in original packaging and sourced from the authorised supply chain or one that holds a marketing authorisation.

• Reference samples of finished product must be stored under defined conditions according to GMP.

8.      Release of batches

• Multiple new requirements according to Annex 16.

• The scope of certification can be limited to assuring that the products are according to the authorisation of the clinical trial and any subsequent processing for the purpose of blinding, trial-specific packaging and labelling.

• The product specification file forms the basis of assessment for certification and release by an AP.

• Cleaning records and verification of the supply chain must be included during the batch checking by the AP.

• The AP must ensure that the investigation product has been stored and transported under conditions that maintain product quality and supply chain security.

• The AP is not required to certify re-packaging or re-labelling performed by authorised personnel at a hospital, health centre or clinic.

9.      Outsourced operations

• Must meet GMP requirements in Ch 7 of Part I.

10.  Complaints

• A complaints procedure must be in place that describes the actions to be taken when a complaint is received at the manufacturing, storage or importation site. All complaints must be documented and assessed to determine if they represent a product defect. The procedure must ensure that the sponsor is able to assess the complaints to determine if they justify the reporting of a serious breach to the relevant regulator.

• A product defect must be investigated according to GMP and Ch 8 of Part I.

11.  Recalls and Returns

• No change

11.1 Recalls

• A detailed inventory of shipments by the manufacturer must be maintained.

11.2 Returns

• ·Minor amendments.

11.3 Destruction

• Product destruction requirements must be documented in a protocol. Arrangements between sponsor and manufacturer must be in an agreement.

• Records of destruction operations must be retained, including certificate of destruction or receipt for destruction to the sponsor. These records must identify and allow traceability to the batches and/or patient numbers involved and the actual quantities destroyed.

Glossary to Annex 13

New definitions for:

• Campaign manufacturing

• Expiry date

• Manufacture

• Retest date

• Regulatory release

Need help?

Quality Systems Now  can help you get ready for these regulatory changes. You can contact us or book a free 15 min consulting call to talk about your requirements at Contact Us - Quality Systems Now.