Introduction
This guidance addresses considerations for commercial release of batches of product manufactured prior to completion of process validation (PV) activities, and considerations for release of batches associated with performance qualification (PQ) and PV activities.
Batches of product manufactured prior to completion of PV activities may be released for commercial use following verification of acceptable results for all tests, verification that the acceptance criteria have been satisfied, the critical process parameters, ranges and materials used are the same as the proposed commercial manufacturing process and fulfilment of other site requirements for product release as necessary. Release for commercial use will require satisfactory completion of the validation study for that process, ensuring that the recommendations described in this bulletin are met for these pre-validation batches.
Recommendations & Rationale for Recommendations
Release to Market of Batches Manufactured Prior to PV
Product batches manufactured prior to completion of PV activities may include Demonstration (demo) batches, sometimes called ‘proof of concept’ batches, pre-validation batches, or engineering batches. These are typically manufactured for the purpose of examining a new process or a process with a significant planned change that requires revalidation, to insure that the process operations are understood and work as planned before beginning production of validation batches.
Demo/engineering batches may also include material produced for clinical/formulation studies, or API batches prepared to enable validation of the Drug Product manufacturing process (prior to preparation of the API validation batches).
Each manufactured batch or campaign of batches must be reviewed individually when determining the suitability of product for commercial use. It is preferable to pre-plan manufacturing of these batches using normal site change control procedures.
PQ and pre-validation batches (e.g. demo/engineering batches) may be considered for commercial release once validation report(s) for manufacturing processes are approved. In some instances, for example, orphan drug or low volume products, an interim PV report may be acceptable. The following list summarizes conditions that should be satisfied or reviewed for suitability, prior to release of such batches for commercial use:
- If a Prospective Validation approach is used, the manufacturing process validation is complete and a summary validation report has been approved. For Concurrent validation, an interim report should be approved.
- The process used must be within processing conditions allowed by the approved product registration, unless the validation activities include, or are as a direct result of changes to registered processing conditions. The requirements for Product Change Management system should be followed. Once registration approval has been received, the recommendations of this guidance can apply to the new manufacturing process.
- Processing of the batches must have met all site GMP requirements.
- The qualification status of supporting systems (utilities, facilities, etc.) used to manufacture the pre-validation batches has been assessed in terms of their suitability. Qualification of Systems used to manufacture the pre-validation batches should be completed prior to the release of pre-validation batches for commercial use. Exceptions to this must be approved.
- The batches were prepared according to pre-approved, documented work instructions by trained personnel. For Drug Product, pre-validation batch manufacturing is typically conducted using a pre-approved protocol, detailing the purpose of the activity. For APIs, an approved Master Record is sufficient.
- The batches were manufactured according to a process that is supported by the PV. Any changes in process, supporting systems (e.g. equipment, facilities, utilities), or scale between the pre-validation batch (es) and the subsequent validation batches should be minor. A discussion of any such changes and their impact should be documented when considering a demo batch for commercial release.
- There were no significant deviations during the preparation of the pre-validation batches that affect product quality and that were related to the process. Deviations that occur during the manufacturing of pre-validation batches shall be evaluated for their impact on the validation exercise.
- All critical parameters identified and monitored during PV were also monitored during the manufacture of these pre-validation batches and were within approved limits.
- Analytical test methods used for the PV batches were the same as those used for demo batches and the same specifications established for PV were also met for the demo batches. The analytical test methods used to release the material must be validated prior to the release of pre-validation batches for commercial use and must span the expected range of results.
- The batches have been stored in a controlled manner consistent with approved conditions for this material and identification and traceability is assured.
- Each batch has passed through the normal site change control and QA review and meets site requirements for release, including those for retest or expiry dates.
- The integrity of the documentation supporting the above points is acceptable to the Site Quality Team.
Further Processing of Batches Included in Process Validation
The scope of a validation project can vary in many ways. The decision to approve and release product batches prepared for the validation study should be made only after review of relevant data and verification that the required acceptance criteria have been met. Depending on organization of validation protocol(s) prepared for a process, there may be different points in the production process where evaluation of data and verification of meeting acceptance criteria are needed.
The manufacturing process for preparation of an API or DP typically contains multiple distinct steps defined for the process. Validation may be performed under the guidance of one or more individual protocols, each of which may apply to one or more manufacturing steps. Commercial release of the batches also awaits (in part) approval of process validation reports. While there is limited risk in moving forward with subsequent processing steps while awaiting the outcome of validation studies, performing subsequent processing steps cumulatively adds to the value of material in the supply chain.
The manufacturing site should be willing to accept the risk of having to discard or reprocess material in the event of a validation failure. In any event, an adequate method of quarantine should be in place to prevent inadvertent release of product to market prior to completion of validation activities.
Release of Validation Batches and Approval to Commence Routine Manufacturing
Process validation batches must meet the requirements established in the validation protocol, in addition to established site GMP and release requirements, before they can be released for commercial use. Several of the items included in the list above also apply to validation batches.
The decision to initiate manufacture of routine production batches immediately following completion of the final validation batch should take into account potential risks if a problem is discovered with any of the validation batches. Conversely, if validation activities have progressed without problems and no difficulties with further production is expected, the risk to proceed with routine manufacturing may be regarded as acceptable. It is recommended that all test results critical to the validation have been obtained and verified by QA before making the decision of whether or not to proceed with routine manufacture.
For Drug Product, an approved report, batch record and personnel training should be completed before proceeding with the DP manufacture. If there is a requirement to proceed with the production of commercial lots, without the report and batch record; this should be an exception, not the practice. A planned deviation should be completed and the pre-validation batches are released after the deviation report is approved.
There are two main points of concern with moving from validation to routine manufacturing.
First, the validation protocol may contain work instructions or controls and verification practices that have not yet been introduced into the routine manufacturing process. Consequently, there may be a need to update the batch record, SOPs or monitoring systems and complete any associated training of the Operations and Quality staff to reflect the outcome of the validation.
Also, should an out-of-specification result or other critical failure be determined during final review of the report, additional batches of product may have now been placed at risk.