Qualification and validation (Annex 15)

For qualification and validation guidance, TGA encourage the use of PIC/S recommendation publications such as:

• 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)

However, these are for guidance only and may not fully reflect the current requirements of PIC/S Guide to GMP.

All equipment used in the manufacture of medicinal products must be appropriately qualified following the principles outlined in Annex 15, 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.

On this page: Retrospective process validation no longer permitted | Application of concurrent process validation | Number of batches used in process validation | Batch sizes for process validation | Scope and extent of validation and risk | Performance qualification (PQ) and process validation | Critical Quality Attributes (CQA) and Critical Control Parameters (CPP) | Ongoing process verification (Annex 15 clauses 5.28 - 5.32) | Use of materials from approved suppliers for validation | Validation of legacy products | Transport verification | Validation of cleaning processes

Retrospective process validation no longer permitted

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.

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.

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, 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 medicinal cannabis product dosage forms made available under the Authorised Prescriber scheme, Special Access Scheme (SAS), or clinical trials pathways, concurrent process validation is permitted.

Concurrent process validations should be approved under the site's 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 for commercial use. 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

TGA guidance developed for the application of quality risk management in the manufacture of listed and complementary medicines (including registered complementary medicines) may assist you with Process validation activities related to manufacture of medicinal cannabis products.

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

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

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 increases.

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.

Ongoing process verification (Annex 15 clauses 5.28 - 5.32)

Ongoing process verification is required for all therapeutic goods, irrespective of the method used for process validation.

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.

Use of materials from approved suppliers for validation

When conducting validation exercises, it is 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 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 marketing authorisation and that, where identified, manufacturing processes should be updated to meet current standards and the necessary modifications to the marketing authorisation 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.

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).

Qualified toxicologist

Toxicological limit determinations should be determined by a person with reasonable knowledge/experience of the application of toxicological concerns in determining Health Based Exposure Limits (HBEL) but this person does not have to be a qualified toxicologist.

HBEL should be determined by a person who has adequate expertise and experience in toxicology/pharmacology and pharmaceuticals, as well as experience in the determination of HBEL such as Occupational Exposure Levels (OEL) or Permitted Daily Exposure (PDE). Where experts are contracted to provide the HBEL, contractual agreements in compliance with Chapter 7 requirements should be in place prior to work being conducted.

It is not considered acceptable for manufacturers to 'purchase' HBEL assessments without recording an assessment of the suitability of the provider (including the specific technical expert) as a qualified contractor.

Cleaning validation

Using a dedicated facility and equipment would minimise the risk of contamination with other APIs, this is especially significant in the case of Schedule 8 substances. However, where effective cleaning methods are used and verified through cleaning validation, a non-dedicated facility and equipment may be justified.

There are a number of cleaning validation methods used to verify cleaning effectiveness. Other than visual inspection of the cleaned surface, methods such as water/solvent rinse and swab techniques could be used. Chemical analysis of the rinse and swab extraction would determine the chemical residue level, and swab microbiology testing would determine any microbial residue.

Where cleaning validation studies are conducted using a worst case product or product grouping, there should be a scientific justification that would support such strategies.