What are the three stages of process validation?

1What process validation is.

FDA defines process validation as “the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product”. Its guidance, issued in January 2011 as Revision 1, is non-binding, but process validation itself is “a legally enforceable requirement” under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.¹

The regulations behind it are in 21 CFR Part 211. Section 211.100(a) requires written procedures for production and process control “designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess”,² and 211.110(a) requires control procedures “to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability”.³ FDA notes that process validation procedures must be established and followed before a batch can be distributed.¹

2The three stages.

FDA describes process validation as activities over the life cycle of the product and process, in three stages.¹

The stages are not watertight: FDA says “some activities might occur in multiple stages”.¹

3Stage 1: process design.

Process design builds and captures process knowledge and sets a strategy for process control. Design of experiment studies, laboratory and pilot work, and models help establish how process inputs relate to outputs, but “FDA does not generally expect manufacturers to develop and test the process until it fails.” Controls address variability, and “FDA expects controls to include both examination of material quality and equipment monitoring.” The planned commercial production and control records, with their operational limits and control strategy, carry forward to Stage 2 for confirmation.¹

4Stage 2: process qualification.

Stage 2 has two elements: design of the facility and qualification of the equipment and utilities, and process performance qualification (PPQ). Qualification work is planned, documented and reported, and the quality control unit must review and approve the qualification plan and report under 211.22.¹ EU GMP Annex 15 sets out equipment qualification as design, installation, operational and performance qualification;⁴ see IQ, OQ and PQ.

PPQ combines the qualified facility, utilities and equipment, and trained personnel, with the commercial process, control procedures and components “to produce commercial batches”. The protocol sets the tests, acceptance criteria and sampling plan, with enough samples “to provide sufficient statistical confidence of quality both within a batch and between batches”, and sampling more extensive than in routine production. Data should not be excluded “without a documented, science-based justification”.¹

“A manufacturer must successfully complete PPQ before commencing commercial distribution of the drug product”, and that decision should be supported by data from commercial-scale batches. The guidance sets no number of PPQ batches: the approach “should be based on sound science and the manufacturer’s overall level of product and process understanding and demonstrable control”; see how many PPQ batches. Releasing a PPQ batch before the protocol is complete, concurrent release, is possible in special situations, but FDA “expects that concurrent release will be used rarely”.¹

5Stage 3: continued process verification.

The goal is “continual assurance that the process remains in a state of control (the validated state) during commercial manufacture”. FDA says an ongoing programme to collect and analyse product and process data must be established under 211.180(e), with the data statistically trended and reviewed by trained personnel. It recommends that a statistician or someone trained in statistical process control design the data collection plan, and that monitoring and sampling continue at the level set during PPQ until there are enough data for significant variability estimates.¹ The regulation itself requires records to be kept so their data can be evaluated “at least annually”.⁵

For legacy products already on the market, FDA expects implementation “would likely begin with the activities described in Stage 3”.¹ Continued process verification covers monitoring plans and signals in more detail.

6How EU GMP Annex 15 compares.

EU GMP Annex 15, dated 30 March 2015 and in operation since 1 October 2015, sets the EU requirements in section 5. It does not use FDA’s three stages, but the content overlaps.¹⁴

7How it runs in Seal.

In Seal, the process validation blueprint keeps the validation basis, PPQ protocol, execution records, reviewed results and exceptions as connected records, so each requirement is reviewed against the full evidence set, including missed steps and unsuccessful outcomes. In its example, exception EX-014, a missed planned sampling time, still has no completed impact assessment, and review starts from open exceptions like that one rather than from a batch count. Reviewed controls and residual risks carry into continued process verification.

Before PPQ, process characterisation runs each study condition against a versioned protocol, so proposed operating ranges trace to the runs that support them. After it, continued process verification keeps trends connected to the batches, process versions, methods and materials behind them, with pending and non-comparable results kept visible outside the analysis.