Introduction
This guidance provides recommendations and examples for evaluating the process validation impact of changes to manufacturing processes used for manufacture of Active Pharmaceutical Ingredients (API), Drug Products (DPs), drug substances made by biopharmaceutical processes and DP packaging processes.
This guidance applies to validated processes and identifies examples of changes for which examining the validation impact of a change should be considered. It does not apply to cleaning processes or laboratory test methods. In general, all changes that may affect product quality, patient safety, or reproducibility of the process shall be evaluated by using an established change management system. This evaluation should include assessment of the validation impact of the change. Major changes require validation, while documented evaluation of minor changes are typically documented using the site change management system.
Recommendations and Rationale
Evaluating proposed changes to a process shall include a documented assessment of the validation impact of proposed changes. Where appropriate, use of a risk assessment in evaluation of proposed changes is recommended.
Examples of major changes are provided in Table 1.
A validation protocol is typically used to describe the validation for major changes. Assessment of the validation impact of minor changes is typically documented using the site’s change management work process.
Examples of minor changes are provided in Table 2.
The level of knowledge of the proposed change (e.g., support of the change by lab or pilot studies) may help justify that the risk is lower than might otherwise have been assumed, allowing some proposed changes to be treated as minor changes.
Examples provided in the two tables are generalizations. Every proposed change should be assessed to determine the potential impact of the change and to consider the potential impact to product quality from the adopted change. This assessment must be documented. Sampling and testing, as needed, should be carefully considered to provide meaningful measurements of the impact of the change. In some cases evaluation of the adopted change might include extended monitoring or statistical trending of the performance of the process that has adopted the change to provide additional assurance that the modified process continues to perform in a validated state.
Evaluation of the validation impact of the proposed change(s) should include assessment against pre-established acceptance criteria, including (where applicable):
Impact on product acceptability: Documentation of the nature of the change and its expected impact(s) on Critical Quality Attributes (CQAs) of the final API or drug product;
Impact on product equivalence 5: Does the quality of material produced by the changed process compare favourably to acceptable material prepared previously?
Consider all CQAs that may be affected by the change.
Impact on control of critical process parameters (CPP): It is recommended that the CPP risk assessment be re-evaluated to determine if the proposed change alters the risk associated with control of process parameters that impact product quality.
Impact on product uniformity (e.g. homogeneity of API or blend uniformity of DP); and
Impact on ability of process to consistently provide product that meets all quality expectations.
Evaluation of the quality impact of the change should take place as close as practical to the step in the process where the change was made. The system owner or Technical Services may typically propose the change and should participate in assessing the impact of the change. The Quality organization must be included in approval of the assessment of impact of the change to a validated process.
When assessing and evaluating the impact of a change, in some circumstances it may be preferable and appropriate to address only that part or step of the process including the change, rather than assessing validation of the entire process. The approach chosen for evaluating the process incorporating the change should include determining expectations for commercial release of the product made using the changed process (e.g., prospective, concurrent, or Continuous Quality Verification [CQV] approaches) . In some cases CQV and statistical analysis may be very appropriate for continued monitoring of the impact of a change that has been implemented rather than performing a more traditional validation of the changes.
The number of lots needed to evaluate the impact of a change should be justified. Justification of fewer lots might be based on demonstrated understanding of the impact of the change, a risk assessment that establishes low risk to quality from the change, or bracketing of the conditions of the change by other conditions that have already been validated.
Regulatory authorities in some jurisdictions may be reluctant to accept certain types of justifications such as bracketing. Continued monitoring of the performance of a well-understood process after completing the scheduled evaluation of the change may also be considered in determining the number of lots to be evaluated.
Table 1. Types of Major Changes and Points to Consider with this Change
Examples of major changes to an established process include, but are not limited to, the following examples. Type of change applies to all (API, DP and packaging) except where noted otherwise.
Table 2. Types of Minor Changes and Points to Consider with this Change
This table provides some examples of minor changes to an established process. Type of change applies to all (API, DP and packaging) except where noted otherwise.
Example 1:
It is proposed that the proven acceptable range (PAR) for a process parameter that impacts a CQA should be tightened. The risk assessment for the CPP should be reevaluated to determine if there is increased risk that a deviation from the normal operating range (NOR) could adversely impact product quality. This change can potentially alter the decision of whether the process parameter is a CPP. Evaluation should consider ability to provide the expected degree of control for the modified parameter.
Example 2:
A new source for the API starting material is being evaluated. Qualification studies may be needed to show that the new supplier’s material meets specifications and that the final API made from it meets specifications. Availability of a supplier assessment and use test results will influence the decision of what validation, if any, is needed for this type of change. Validation may not be necessary if the impurity profile of the final API is unchanged. However if it is necessary to show that the process can adequately control product quality for a different impurity profile, validation is needed.
Example 3:
A significant process change to the API manufacturing process typically prompts activities to qualify the API made by the modified process in the DP manufacturing process. The impact of changes made in the API process may not be revealed in the routine quality testing performed on the API so examination of the DP may be performed. It is a good practice for API manufacturing to notify DP manufacturing when a process change is adopted, even when there is no apparent impact on API quality from the change.
Example 4.
A change made to an API process that is shown to not impact product quality could be regarded as a minor change (with respect to its validation impact) independent of the regulatory impact of this change. For instance, addition of salt to the aqueous phase might be recommended to improve separation of the aqueous and organic phases during an extraction, where the use of salt in this step was not previously included in the regulatory filing. In this instance a Product Change Proposal (at a minimum) would be needed 4but a validation assessment might conclude that it is a minor change with respect to validation impact.
Regardless of how the assessment of the expected validation impact of a proposed change is documented, it is important that documentation provides a description of the change, the impact assessment and acceptance criteria, if any, for evaluation of the change. When validation is executed to demonstrate acceptability and consistency of the process with the adopted change, the acceptance criteria should be determined on a case by case basis.
Acceptance criteria for evaluating the change should focus on elements that may be impacted by the change; some criteria and/or validation sampling used for the original validation may not be necessary for revalidation.
An additional consideration is the trail of documentation that accounts for all the changes in the process since it was last validated. At some point, it may be desirable to update the validation documentation for the process into a comprehensive summary rather than continuing to add individual documents to a collection through which it may be difficult to trace the impact assessments of all the changes since the last validation.