Qualification and validation (Annex 15)

For qualification and validation guidance, TGA encourage the use of PIC/S recommendation publications, as these expand on various clauses within Annex 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)

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

All products currently manufactured are expected to be validated. New products should undergo prospective or concurrent validation. 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, the provision for retrospective validation is no longer applied.

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

Application of concurrent process validation

For sunscreen products 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. TGA's general expectations are that:

• for a new process or product, 2 batches are to be conducted for process validation purposes
• for a process subject to technology transfer from one site to another a minimum of 2 batches are to be conducted for validation purposes
• for changes to existing (validated) processes (e.g. batch size increase), an evaluation should 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

Batch sizes for process validation

The process must be validated for all batch sizes intended to be manufactured at industrial scale.

Process validation may not be required for all discrete batch sizes if it can be demonstrated, based on risk assessment, that equipment operational qualification demonstrates that mixing vessels operate consistently over a range of mixing volumes, and identifies the smallest and largest batch sizes. Process validation should demonstrate that process consistency can be achieved for the representative batch size.

Performance qualification and process validation

Performance qualification may be performed in conjunction with operational qualification and/or process validation.

A separate guidance document is available: Process validation for listed and complementary medicines, which can also be applied to sunscreens.

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

A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge (Annex 15 clause 5.21).

• A CQA is a physical, chemical or microbiological property or characteristic of the final product that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs for sunscreens products would include assay, microbial limits, pH of formulation, viscosity, blend uniformity/homogeneity, etc.
• 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. CPPs for sunscreens manufacture could include processing temperature, heating and cooling rates, mixing methods and speeds, mixing times, etc.

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 (OPV)

Ongoing Process Verification (OPV) is used periodically to evaluate process parameters and trends and ensure that processes are consistent and remain in a validated state (clauses 5.28-5.32).

Manufacturers should develop a process to monitor product quality attributes such as in-process control points across production and packaging, and finished product test results; however, OPV need not be conducted under a formal protocol. Consideration should be given to recording CQA and CPP for each batch using control charts with upper and lower limits.

Manufacturers should investigate any adverse trends concerning product quality attributes to determine if processes are consistent and remain in a validated state.

OPV should be used to support the validated status of the product and documented in the Product Quality Review.

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 some circumstances, materials from unqualified suppliers may be used where supported by a 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

Transport verification

The basic expectation is that all products (including bulk products, finished products and samples) 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 quality risk management principles. It is not acceptable to store or transport medicines outside their labelled and approved storage conditions.

The responsibilities for the transportation, 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, intermediates, bulk and packed medicines (prior to release for supply) between sites of manufacture and clause 1.8 (ix) would apply in these circumstances.

Validation of cleaning processes

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

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

• microbiological bioburden of processed materials and cleaned equipment and their acceptable limits
• potential residues for chemical cleaning agents where used. In these cases, additional testing, for example pH, may be used where justified to demonstrate adequate cleanliness