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PE009-13, the PIC/S guide to GMP for medicinal products

TGA interpretation and expectations for demonstrating compliance

2 January 2018

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Qualification and validation (Annex 15)

For qualification and validation guidance, TGA encourage the use of PIC/S recommendation publications, as expand on various clauses within Annexes 1 and 15 of the PIC/S Guide to GMP (PE009-13). However, these are for guidance only and may not fully reflect the current requirements of PIC/S PE009-13. For example:

  • PI-006-3 Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation (recommendations)
  • PI-007-6 Validation of Aseptic Processes (recommendations)

All equipment used in the manufacture of medicinal products must be appropriately qualified following the principles outlined in Annex15 section 3. Acceptability of the approach taken will be assessed during inspections on a case-by-case basis.

The nature and extent of qualification should be determined based on risk management principles. Depending on the use, stage in the equipment lifecycle and nature of the equipment, some of the stages outlined in Annex 15 section 3 may be omitted where appropriately justified, based on risk. It is generally expected that all stages would be addressed in the qualification of new and/or complex equipment.

Retrospective process validation no longer permitted

Process validation is a critical step in assuring the quality of medicinal products. When Annex 15 was originally published in 2001 the provision for retrospective validation was given to provide a means by which existing products could be validated. As the process validation requirements of Annex 15 have been in place for over 15 years, it is now expected that all products currently manufactured are validated, and that new products undergo validation prior to release to the market.

Unfortunately the previous provisions for retrospective validation could be incorrectly interpreted by manufacturers to suggest that products may be released to market prior to process validation being completed. The changes to Annex 15 rectify this issue. There should be no existing medicines supplied for which appropriate and documented validation is not currently in place. The manufacturing process should be validated before the product is placed on the market.

Any existing validations based on retrospective validation will be accepted; however, any new products, processes, updates or changes to existing processes should undergo full prospective process validation.

Application of concurrent process validation

For registered therapeutic goods or equivalent, concurrent process validation may only be conducted where there is a strong benefit-risk ratio for the patient, i.e. to permit timely access to a critical medicine.

For listed therapeutic goods, concurrent process validation is permitted.

Concurrent process validations should be approved under the sites PQS and where used, the results and conclusion of any supporting data should be made available to the Authorised Person performing release for supply of the product.

Number of batches used in process validation

The number of batches used for process validation should be determined and justified by the manufacturer based on risk management principles. Our general expectations are that:

  • For a new process or product, a minimum of 3 batches are to be conducted for validation purposes
  • For a process subject to technology transfer from one site to another, an extensive evaluation and risk assessment (with supporting data) are to be conducted regarding the similarities and differences in manufacturing processes, equipment, methods and materials should be in place to justify performing less than three batches
  • For changes to existing (validated) processes (e.g. batch size increase), an extensive evaluation and risk assessment (with supporting data) are to be conducted regarding the similarities and differences in manufacturing processes, equipment, methods and materials should be in place to justify the number of batches selected

Any variations from this approach should be clearly documented and justified by the manufacturer using sound QRM principles.

Batch sizes for process validation

The process must be validated for the smallest and the largest batch sizes intended to be manufactured at industrial scale. Process validation may not be required for intermediate batch sizes if it can be demonstrated, based on risk assessment, that process consistency can be achieved for any intermediate batch size.

Scope and extent of validation and risk

The scope and extent of validation should be based on risk according to the manufacturer's quality risk management procedures. Qualification and validation work is required to control the critical aspects of the particular operation and a common sense approach should be applied.

Performance qualification (PQ) and process validation

For significant changes to equipment (e.g. for new or modified items of equipment), the performance qualification is separate from and precedes process validation.

For minor changes not impacting on already qualified equipment (e.g. to processing parameters only):

  • performance qualification may be performed in conjunction with operational qualification and process validation
  • separate installation qualification and operational qualification are not necessary

Complementary medicines and process validation

A separate guidance document is available for process validation for listed complementary medicines.

The technical GMP guidance for listed complementary medicines are baseline documents, elements of which can also be applied to other listed medicines if justified.

Although the principles in this guidance are still applicable, it will be revised where necessary, in consultation with industry, to clarify requirements in the PE009-13 version of the PIC/S Guide to GMP.

Critical Quality Attributes (CQA) and Critical Control Parameters (CPP)

A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are used to guide process development and control strategies. The list of potential CQAs can be modified as product knowledge and process understanding increase.

A CPP is a process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

CQAs and CPPs are important elements of product and process knowledge and should be utilised in the design, validation and control of manufacturing processes.

Ongoing process verification (Annex 15 clauses 5.28-5.32)

Ongoing process verification is used periodically to evaluate process parameters and trends and ensure that processes are consistent, and remain in a validated state. The outcomes from the OPV exercise should be used to look at any correlation between process capability and trends identified in the PQR. The frequency of the verification should be based on risk management principles.

Ongoing process verification should normally occur for all therapeutic goods (or equivalent), irrespective of the method used for process validation.

Use of materials from approved suppliers for validation

When conducting validation exercises, it would be expected that raw materials from approved suppliers are used. However, in exceptional circumstances, materials from unqualified suppliers may be used where supported by a comprehensive risk assessment. It is expected that this would only apply when concurrent vendor approval is underway, such that the material under evaluation is part of the validation exercise. There must however be an appropriate justification to use the unapproved material based on all of the following:

  • The risk to the following manufacturing process, plant and other products
  • Assurance that the vendor has met the specifications required
  • Suitable controls regarding approval, analysis and release of the material
  • Adequate control regarding the starting material issuance and reconciliation
  • Relevant systems in place to prevent release of the validation batches prior to full qualification of the material

Validation of legacy products

Legacy products are normally older products that may have been manufactured for a long period of time using well established processes and technologies. Where these products are transferred from one site to another, it is expected that the product is re-validated in accordance with the MA and that, where identified, manufacturing processes should be updated to meet current standards and the necessary modifications to the MA made.

The validation requirements for legacy products must meet the current marketing authorisation standards and if required should result in incorporating current validation requirements.

Clear processes should be in place to facilitate the transfer of process knowledge from the originating site. Manufacturers of transferred products should be in possession of appropriate validation and quality documentation from the original site of manufacture, in support of current validated processing parameters.

Transport verification

The basic expectation is that all products (including bulk products, finished products, samples and IMP's) are transported in full accordance with their labelled, authorised and appropriate storage conditions, and that the supply chain has been formally evaluated and confirmed as effective. This assessment should be conducted using sound QRM principles. It is not acceptable to store or transport medicines outside their labelled and approved storage conditions.

Consideration should be given to the supply chain used for each medicinal product, and the inherent hazards to product quality, e.g. temperature excursions, potential security breaches, and their respective risks.

Appropriate arrangements should be in place to monitor storage conditions in order to demonstrate continued compliance. The responsibilities for the transportation (including validation), monitoring and storage of medicinal products should be clearly specified within Quality or Technical Agreements.

TGA does not currently inspect the wholesale distribution of therapeutic goods that have been released for supply.

  • The responsibility for oversight of wholesale of medicines in schedules 2, 3, 4 & 8 of the Poisons Standard currently sits with the states and territories, who may issue relevant permits and licences for wholesalers
  • For medicines that are not in schedules 2, 3, 4 & 8 of the Poisons Standard and relevant biologicals, sponsors and manufacturers hold shared responsibility for ensuring that they are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life. These responsibilities should be clearly identified within Quality or Technical Agreements between the manufacturing site and Australian Sponsor

TGA inspections do include an evaluation of the transport conditions for starting materials, bulk and packed medicines between sites of manufacture and clause 1.8 (ix) would apply in these circumstances.

Validation of cleaning processes

Limits for the carryover of product residues

Limits for residue carryover should be based on a toxicological evaluation of the active materials. These evaluations should be verified by a toxicologist (or equivalent) and performed in accordance with current guidance. (Guidance may be found in EMA/CHMP/ CVMP/ SWP/169430/2012 Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (pdf,169kb)).

How to access a pdf document

Cleaning validation for listed complementary medicines

TGA generally expects cleaning processes for listed complementary medicines to be validated and appropriately documented. However, due to the low toxicity of permissible ingredients used in the manufacture of listed complementary medicines cleaning validations can be grouped looking at worse case situations. The acceptance criteria of 'visibly clean' will normally be accepted for most listed complementary medicines.

In addition to the acceptance criteria of 'visibly clean', cleaning validation studies should give consideration to:

  • The microbiological bioburden of processed materials and cleaned equipment and their acceptable limits
  • Residue limits for chemical cleaning agents where used. In these cases, additional testing e.g. pH or total organic carbon (TOC) may be used where justified to demonstrate adequate cleanliness

Additional consideration of more stringent acceptance criteria should be given to products containing potentially allergenic materials, such as:

  • milk
  • eggs
  • fish
  • crustacean shellfish
  • tree nuts
  • peanuts
  • wheat
  • soybeans
  • bee products, e.g. propolis, royal jelly and honey

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