VAL-085 Process Validation Guideline

5.1 Process Validation Overview

As per the local and international GMP requirements, “When any new manufacturing formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing.  The defined process, using the materials and equipment specified, should be shown to yield a product consistently of the required quality”.

Process validation refers to the performance of the product under predetermined process conditions that demonstrates that the process yields a product consistently of the required quality.

Process validation is not limited to final testing of finished dosage form, but is used to establish a high level of confidence that the samples routinely taken for release for sale testing are an accurate representation of the process.  An essential part of process validation therefore is characterisation of pre-determined critical variables as defined in the validation protocol.  The aim of process validation within Site is to establish and validate quality product that can be determined by final product testing, i.e. to build quality into the product.

5.2 General Process Validation Requirements

All process validation activities will be performed following a pre-approved protocol as per the requirements of SOP VAL-115 Process Validation for Liquids and Solid Dose Manufacturing.  The protocol shall specify critical steps, critical process parameters, sampling requirements, and acceptance criteria.

All process validation activities will be documented in an a final validation report that will summaries all batches manufactured as part of the protocol execution as per the requirements of SOP VAL-115Process Validation for Liquids and Solid Dose Manufacturing.

For multiple product introductions, modifications, transfers or retrospective validation a validation project plan may be written detailing validation requirements for the products.  Validation project plans will be written according to SOP VAL-125Guideline for the development of a Validation Project Plan.

5.3 Process Validation Prerequisites

The ability of the manufacturing process and supporting systems (including analytical methods) to consistently achieve and maintaining process parameters must be demonstrated prior to process validation.  Process validation prerequisites are documents in SOP VAL-115Process Validation for Liquids and Solid Dose Manufacturing.

If there is more than one item of equipment, which is of the same type, process validation can be performed on any item, provided that the equipment qualification has demonstrated that the equipment is of similar design and operation.

Bracketing of a validation exercise may be used where variants such as multiple strengths, batch size, process parameters or equivalent formulas are used.  A worst-case approach should be used when bracketing.  Justification for bracketing must be document and approved in the validation protocol.

Prior to validation, the process may require trial / qualification batches which may be performed on full scale or scaled down batches.  These batches will be documented in trial protocols / Performance Qualification protocols prior to process validation.  The requirement for trial / Performance Qualification batches will be based on risk.

5.4 Approaches to Process Validation

There are 3 acceptable approaches to process validation as detailed in sections 5.4.1, 5.4.2 and 5.4.3 below.  The approach used will depend on risk and will be documented in the process validation protocol.  At minimum Validation and Quality Assurance must approve the selected approach through protocol approval.

5.4.1 Prospective Validation

Prospective validation shall be used in validating a new or substantially modified process.

Prospective validation requires three consecutive successful product batches to meet all acceptance criteria for in-process and finished product testing as defined in the protocol.  Specific justification and approval from Quality Assurance is required if three batches are not used to validate the process.

5.4.2 Concurrent Validation

Concurrent validation is defined as validation carried out during routine production of products intended for sale.  Concurrent validation may be used for a well-understood process.   The decision to carry out concurrent validation shall be justified and documented and approved by the validation committee.

Concurrent validation requires three consecutive successful product batches to meet all acceptance criteria for in process and finished product testing as defined in the protocol.  Batches may be released prior to completion of the validation study based on an interim report.  Specific justification and approval from Quality Assurance is required if three batches are not used to validate the process.

5.4.3 Retrospective Validation

Retrospective validation is defined as validation of a legacy product based upon accumulated manufacturing, testing and control batch date.  Retrospective validation is not to be used on any new products. The decision to carry out retrospective validation shall be justified and documented and approved by the validation committee.

Retrospective approaches can be used for legacy process provided that:

a. Sufficient reliable historic data is available

b. Critical process parameters and critical quality attributes are identified and used

c. In process acceptance criteria and controls are established

d. Levels of significant process/product failures attributable to causes other than operator error or equipment failure are not excessive.

Data from a minimum of ten batches will be analysed for compliance to the validation requirements.  If less than ten batches are used, it must be justified, documented and approved by Quality Assurance.

Batches selected for retrospective review must be representative of all batches made during the review period including any batches that failed to meet specifications.

5.5 Process Validation Execution Guideline

5.5.1 Validation Test Conditions

Process validation shall be conducted using standard production conditions as defined in the approved manufacturing instructions and applicable SOPs as listed in the validation protocol.  Any evaluation of challenge conditions that pose the greatest chance of process or product failure compared to ideal operating conditions shall be documented during process development studies.

5.5.2 Validation Batch Size

Validation batch sizes shall be the same size as the intended standard commercial batch size.  Any normal allowed variations in batch size should be specified with justification.

When batch size ranges are proposed for the commercial process that are outside the normal allowed variation there must be documentation justifying or demonstrating that the planned variation will not adversely affect the characteristics of the finished product.  Bracketing may be used for validation of different batch sizes.

A concurrent validation approach may be used for batch size changes from the validated batch size.

5.5.3 Critical Parameters

Critical process parameters (including ranges) and critical quality attributes of the process being validated must be identified and justified.  The validation committee is responsible for ensuring that the ranges proposed in the validation protocol for critical process parameters are correct and have supporting documentation included or referenced in the protocol.

Where a change is required to a critical process parameter during the validation study, the effect of the change should be assessed for its impact on the validation study. The change may require restarting the validation study using the new critical process parameter value(s).  The previous validation batches shall be evaluated and their disposition documented in the report.  The assessment of the impact of the change on the validation study shall be documented in the validation report.

Changes in non-critical process parameters may prove necessary during process validation to improve the performance of the process while ensuring that the process produces products that meet acceptance criteria.  Such changes shall be documented and justified in the validation report and evaluated for their impact (individual and cumulative) on the validation exercise.

5.5.4 Homogeneity

Homogeneity, including blend uniformity, shall be included or referenced in the validation protocol.

Homogeneity shall be demonstrated for a modified process when assessment of a planned change indicates a potential impact on batch homogeneity.  If homogeneity is not performed as part of the validation study, a documented rational shall be provided in the validation protocol.

5.5.5 Validation Sampling

Sampling is an essential component of process validation. Process validation sampling will be performed as per SOP VAL-100 Process Validation Sampling.  In general when sampling it is necessary to consider:

a. Release for sale requirements  / product specification

b. The design and configuration of the equipment

c. Statistical requirements.

A practical and relevant sampling pattern, defining number, frequency, technique and pattern will be established on a case-by-case basis in individual protocols.  Where sampling is performed, the specific sampling site must be identified in the protocol.

5.5.6 Validation Testing

All validation samples must meet the acceptance criteria specified in the validation protocol.  Testing should be performed using validated or compendial methods.

QC reductive testing or alternative testing using Process Analytical Technology (PAT) may be used where PAT methods are used to replace traditional test methods on validation samples only.  If used the PAT activity should be integrated into the validation approach to provide information that will assist in the conclusion of the validation exercise.  Any PAT testing must be performed using fit for use-qualified methods.

PAT testing in parallel with traditional QC testing may also be used to provide process knowledge.  Parallel PAT testing does not require fit for use-qualified methods.

5.5.7 Validation Deviation Management

Each batch shall meet all acceptance criteria defined in the validation protocol.  Failure of any batch to meet the requirements of the validation protocol shall be investigated.

The conclusion of the investigation shall include a determination of the effect of the batch failure on the process validation and further actions to be taken, if any, including possible replacement of the failed validation batch.  Any deviations encountered during the validation study must be documented in the validation protocol/report and must be approved as per the requirements of SOP VAL-075 Validation Deviation Management.

A validation batch may be excluded from the validation sequence of consecutive batches if failure to meet acceptance criteria has been investigated and documented to be the result of a non-process related cause, such as equipment failure or operator error.

Replacing a batch excluded from a non-process related cause does not require that the validation sequence be restarted.  The decision to exclude a batch must be documented, justified and approved in the validation report.

5.5.8 Statistical Analysis

Statistical analysis may be performed on all process validations for information purposes only.  The type of analysis to be performed will be determined on a case-by-case basis and will be documented in the process validation report. Statistical analysis may be used to determine the capability of critical quality attributes against release for sale specification.

5.5.9 Process Validation Acceptance Criteria

A successful validation batch shall meet the product specifications relevant to the process validation and satisfy the acceptance criteria established in the validation protocol.

5.5.10 Release of Validation Batches

Before a validation batch can be released for commercial use or distribution, the validation committee shall ensure that:

a. For prospective validation, the final validation report is approved

b.  For concurrent validation, at minimum a interim report is approved. Pending approval of the validation report, validation batches may be shipped to another GMP site of contract vendor under quarantine, providing systems are in place to prevent commercialisation of the product.

5.5.11 Stability Requirements for Validation

For new or reformulated products, or where it is believed that the change may affect stability, a minimum of one validation lot must be placed on stability whether or not it is a lot designated for commercial distribution and whether or not stability information is required for a regulatory filing.  The first three commercial lots must be placed on stability.  Stability requirements for modified existing products will be determined based on risk by the Validation Committee.

5.6 Product Transfers

All product transfers must meet the process validation requirements as detailed in this guideline.  Generally product transfers require prospective validation.

5.7 Raw Material Change

To change the supplier of a drug substance or raw material, validation work must be conducted using a pre approved protocol or risk assessment that demonstrates the change will have no adverse impact on finished drug products or processes.  Chemical and physical evaluations must be performed on three separate lots of the new drug substance/raw material and the results compared to multiple lots (minimum of three) of the current/old drug substance/raw material. Refer to SOPVAL-105Raw Material Evaluation Process.  Raw materials used for validation batches should be stored as per site procedure on material storage.

5.8 Holding Studies

If a specific in-process Bulk Hold time is critical to product quality, evaluation of the limit for the in-process hold time shall be conducted in a manner such as that used for critical process parameters.  Bulk Holding times will be performed as per the requirements of holding study plan.

5.9 Process Revalidation

Revalidation of the process may be required if any of the following occur:

a. The process equipment is substantially changed.

b. The process scale or methodology is significantly changed.

c. Product quality issues indicate revalidation is necessary.

Where there is a change to the process or equipment, change control will be used to determine if revalidation is required.

5.10 Periodic Evaluation

Each process will be reviewed on a yearly basis or in the case of a failure of a critical parameter to assure the procedure remains in a validated state.  Annual product reviews will be used to assess the validation status.  If the review shows the process has remained in a validated state no further activities are necessary.

5.11 Rework Process

Rework process if used will be validated.  An approved protocol is required to define the validation of the rework procedure, how validation will be executed, the expected result, the acceptance criteria and the requirement for stability testing if required.  A concurrent validation approach may be used.  Relevant approvals shall be obtained for rework process outside the current regulatory filing.

5.12 Reprocessing

Reprocessing that is not part of the standard manufacturing process shall be documented and evaluated as a planned deviation. The investigation shall determine the impact on the process, product, validation status, and stability testing.  The need for and extent of any validation activities resulting from the investigation shall be determined and approved by the validation committee.  Reprocessing that is applied to the majority of batches shall be included as part of the standard manufacturing process and shall be included in the validation of that process.

5.13 Change Control

All changes that may affect product quality or reproducibility of the process shall be evaluated for likely impact on the process or product.  The validation committee shall determine the impact on the validation status and/or stability testing.

If the evaluation of a process involves a regulatory change, a PCP, and a PCR are required.

Major changes to raw materials, components, equipment, utilities, facility, procedures or process require validation.  Minor changes may require a documented, expanded test program or other evaluation using the site change management system.