Typically, it is anticipated that process validation should be finalized before the distribution of a finished product intended for sale (prospective validation). In cases where this is not feasible, it may be essential to validate processes during regular production (concurrent validation). Additionally, processes that have been operational for a considerable duration without any major modifications may also undergo validation in accordance with an approved protocol (retrospective validation).
Prospective Validation:
In prospective validation, the validation protocol is implemented prior to the commercial utilization of the process. Throughout the product development stage, the production process ought to be divided into distinct steps. Each step must be assessed based on empirical evidence or theoretical insights to identify the critical parameters that could influence the quality of the final product. A sequence of experiments should be devised to ascertain the significance of these factors. Each experiment needs to be meticulously planned and thoroughly documented in an approved protocol.
All equipment, the production environment, and the analytical testing methods intended for use must have undergone complete validation. Master batch documents may only be created once the critical parameters of the process have been identified, and the machine settings, component specifications, and environmental conditions have been established.
Utilizing this defined process, a series of batches should be manufactured. Theoretically, the number of process runs conducted and observations recorded should be adequate to determine the normal range of variation and trends, thereby providing sufficient data for evaluation. It is generally accepted that three consecutive batches or runs within the finally agreed parameters, yielding a product of the desired quality, would constitute proper validation of the process. In practice, accumulating this data may require a significant amount of time.
Certain considerations should be taken into account when selecting the process validation strategy. These include the use of different lots of active raw materials and major excipients, batches produced during different shifts, the utilization of various equipment and facilities designated for commercial production, the operating range of critical processes, and a comprehensive analysis of the process data in the event of requalification and revalidation.
During the processing of the validation batches, extensive sampling and testing must be conducted on the product at various stages, and this should be thoroughly documented. Detailed testing should also be performed on the final product within its packaging.
Upon completion of the review, recommendations should be made regarding the extent of monitoring and the in-process controls required for routine production. These recommendations should be integrated into the batch manufacturing and packaging record or into relevant standard operating procedures. Specific limits, frequencies, and actions to be taken in the event of exceeding these limits should be clearly defined.
Matrix approaches to prospective process validation:
In certain situations, it may be feasible and permissible for a manufacturer employing the same process across multiple related products to create a scientifically robust validation plan for that process, instead of formulating separate plans for each product produced by that process.
The matrix approach typically refers to a strategy for executing process validation on various strengths of the same product. Nevertheless, distinct manufacturing steps, such as compression and coating, which utilize different tools, equipment, and process conditions for the various dosage strengths, cannot generally be validated through the matrix approach. It is important to acknowledge that the matrix approach has its limitations, particularly when there are issues regarding physical characteristics like flow properties, particle size distribution, and homogeneity.
The term “Matrix” approach signifies a strategy for conducting process validation on different products produced with identical processes and utilizing the same equipment.
The validation process employing these methodologies must encompass batches of varying strengths or products, which should be chosen to reflect the worst-case conditions or scenarios, thereby demonstrating that the process remains consistent across all strengths or products involved.
Concurrent Validation:
The Inspectorate does not advocate for the unconditional application of this method, and it is not deemed acceptable as the standard practice. Employing this method always carries the risk of necessitating adjustments to process parameters or specifications over time. This scenario frequently raises concerns about the disposition of batches that have already been approved for sale, which are later found to possess undesirable quality attributes.
Concurrent validation may serve as a viable strategy in specific situations. Instances of such circumstances include:
- When a previously validated process is being transitioned to a third-party contract manufacturer or to a different manufacturing location.
- when the product represents a different strength of a previously validated product that maintains the same ratio of active to inactive ingredients.
- When the quantity of lots assessed during retrospective validation was inadequate to provide a high level of confidence that the process is entirely under control, particularly when the number of batches produced is limited (for example, orphan drugs).
In such instances, it is crucial that the systems and equipment intended for use have undergone complete validation beforehand. The rationale for performing concurrent validation must be documented, and the validation team must approve the protocol. A report should be generated and sanctioned prior to the sale of each batch, and a final report should be compiled and authorized following the completion of all concurrent batches. Typically, it is deemed acceptable that a minimum of three consecutive batches, produced within the agreed parameters and achieving the desired product quality, would represent an adequate validation of the process.
Retrospective Validation:
In numerous organizations, processes that are stable and routinely employed have not gone through a formally documented validation procedure. Historical data may be leveraged to furnish the necessary documentary evidence that these processes are validated.
The steps involved in this type of validation still necessitate the preparation of a protocol, the reporting of the results from the data review, culminating in a conclusion and recommendation.
Retrospective validation is only deemed acceptable for well-established, detailed processes that encompass operational limits for each critical step of the process and is inappropriate where there have been recent modifications in the product formulation, operating procedures, equipment, and facilities. The data sources for retrospective validation should include, among others, batch documents, process control charts, annual product quality review reports, maintenance logbooks, process capability studies, finished product test results, including trend analyses, and stability results.
For the purposes of retrospective validation studies, it is considered acceptable to utilize data from a minimum of ten consecutive batches produced. When fewer than ten batches are available, it is regarded that the data are insufficient to retrospectively demonstrate that the process is fully under control. In such instances, the study should be augmented with data generated from concurrent or prospective validation.
Some of the key components necessary for retrospective validation include:
- Batches produced over a specified timeframe (at least the last 10 consecutive batches)
- Annual number of lots released
- Batch size/strength/manufacturer/year/timeframe
- Master documents for manufacturing/packaging
- Existing specifications for active ingredients/finished goods
- Record of process deviations, corrective measures, and modifications to manufacturing documents
- Stability testing data for multiple batches
- Trend analyses, including those related to quality complaints
Process Re-Validation:
Re-validation serves as proof that any modifications made to a process and/or its environment do not negatively impact the characteristics of the process or the quality of the product.
Documentation requirements will remain consistent with those established during the initial validation of the process.
Periodic reviews and trend analyses should be conducted at predetermined intervals. Re-validation is essential in specific circumstances.
Below are examples of both planned and unplanned changes that may necessitate re-validation:
- Modifications in raw materials (including physical characteristics such as density, viscosity, particle size distribution, and moisture content, among others, that could influence the process or the final product).
- Alterations in the source of the active raw material manufacturer.
- Adjustments in packaging materials (primary container and closure system).
- Modifications in the process (for instance, mixing duration, drying temperatures, and batch size).
- Changes in equipment (for example, the addition of an automatic detection system). Equipment changes that involve replacing equipment on a “like for like” basis typically do not necessitate re-validation, provided that the new equipment is qualified.
- Alterations in the plant or facility.
- Variations identified through trend analysis (such as process drifts).
A decision against conducting re-validation studies must be thoroughly justified and documented.