What Drug Manufacturers Should Know About Process Validation and Continued Process Verification
Lakshmi, Editorial Team, Pharma Focus Europe
Process validation has moved from a pre-launch exercise to a lifelong obligation, and Europe's GMP rules on the subject are being rewritten. This article explains what continued process verification demands of pharmaceutical leaders, why terminology still causes costly confusion, and what one manufacturer's published experience reveals about automating the work and about its limits.
Process Validation Is No Longer a Finish Line
For many years, a signed process validation report felt like an ending. The batches had passed, the protocol was closed and the plant moved on to routine supply. Regulators abandoned that view some time ago. Europe's process validation guideline states plainly that validation should not be viewed as a one-off event, while the US framework treats commercial manufacturing as a stage of validation in its own right.
That shift carries consequences well beyond the quality department. A validated process is now a claim that must stay true for as long as a product is sold, through new suppliers, equipment ageing, site transfers and changing demand. For drug manufacturers, the question has moved from whether a process once worked to whether the company can show, at any moment, that it still does.
Three Batches, Then What? The Process Validation Lifecycle Explained
The US Food and Drug Administration set out the modern model in its 2011 guidance, organising process validation into three stages: process design, process qualification and continued process verification. The first builds understanding of how materials and parameters affect quality. The second demonstrates that the design performs at commercial scale. The third gathers evidence during routine production that the process remains in a state of control.
Europe arrives at a similar destination by a different route. Its finished product guideline covers development and validation data for the dossier, while EU GMP Annex 15 governs what follows in the factory. Traditional validation there usually means at least three consecutive production-scale batches. Annex 15 then expects manufacturers to monitor quality across the product lifecycle, evaluate process trends and use statistical tools where appropriate, with the findings supporting the product quality review.
The familiar three-batch exercise therefore proves less than many organisations assume. It offers a snapshot taken under close attention. It says little about the variation a process will meet over ten years of supply. Continued process verification exists to fill that gap.
Continued, Ongoing or Continuous? The Verification Vocabulary That Divides Teams
Few topics in validation generate as much avoidable confusion as three near-identical terms. The FDA speaks of continued process verification, the routine monitoring stage after qualification. Annex 15 calls the equivalent activity ongoing process verification. Continuous process verification, however, means something else in Europe: an alternative to traditional validation in which performance is assessed in real time on every batch, using in-line, on-line or at-line controls and process analytical technology.
The difference matters commercially. Continuous verification is a validation strategy that must be declared in the dossier and needs substantial prior process knowledge. A hybrid approach can apply it to some manufacturing steps and traditional validation to others. Ongoing verification, by contrast, applies however the process was first validated. When a survey of 116 practitioners explored this during the 2014 Annex 15 revision, 52.2% of those answering said they did not understand the difference between continuous and ongoing verification. A global company that uses these terms loosely risks building its filings and its inspection narrative on different assumptions.
The Annex 15 Clock: How Process Validation Rules Are Changing in Europe
European leaders have a further reason to look at this now. The EMA's GMP/GDP Inspectors Working Group and the Pharmaceutical Inspection Co-operation Scheme have begun revising Annex 15, the first major update since 2015. Their concept paper schedules consultation on a draft guideline to start in December 2026, with publication and adoption targeted for April 2028.
The headline change concerns active substances. Annex 15 would become formally mandatory for manufacturers of chemical and biological active substances, where it currently serves as optional supplementary guidance. The paper also proposes more emphasis on robust process development and periodic review, clearer expectations on concurrent validation, validation of material and solvent recovery, stronger control over third-party validation work, and the integration of quality risk management under ICH Q9(R1). It promises guidance on the continuous and hybrid approaches too, although the detail will not be known until the draft appears.
Since these are proposals, they should not be treated as settled requirements. Even so, an active substance supplier that has never run a formal lifecycle programme may need several years to build one, and finished product makers relying on such suppliers share that exposure.
Case Study: How Continued Process Verification Turned 40 Hours Into 10 Minutes
Published examples of continued process verification with real numbers remain scarce, which makes two technical reports from one global biopharmaceutical manufacturer worth studying. Both applied multivariate analysis to routine quality data.
The first, published in 2021, addressed the final manufacturing stage of a lyophilised therapeutic protein, from bulking and sterile filtration through vial filling, freeze-drying and capping. The team trained a principal component analysis model on 45 accepted batches, spanning multiple fill volumes, and judged new batches against 95% statistical limits. Two good batches held back for testing stayed within the limits, while two batches with known excursions breached them. For one, the model pointed to abnormal variability in fill weight. Follow-up review traced this to out-of-tolerance measurements, and the filling equipment was recalibrated. Automating the data pipeline cut report generation from about 40 hours to 10 minutes, according to the authors.
The second report, from 2023, moved upstream to raw materials. Using 43 lots of glycine powder and 12 quality variables pulled from separate laboratory and enterprise systems, the team built an interactive dashboard that flagged statistically unusual lots and showed which variables drove each signal. Users estimated that collecting and evaluating the data fell from 30–40 hours to 10–15 minutes.
The caveats are as instructive as the gains. These results come from the developers themselves, and the first model faced only two excursion batches, far too few to establish its detection performance. In the raw material work, the two-component model explained only about half the variance in the data. The flagged lots had no established root cause, and the authors stressed that subject-matter experts still had to investigate. The statistical limits described what was unusual against history, not what was unacceptable for patients.
The lesson for leadership is that automation changed where skilled people spent their time. Hours once lost to assembling data became available for judgement.
Beyond the Control Chart: What Effective Continued Process Verification Requires
Three weaknesses tend to separate a programme that informs decisions from one that merely produces reports. The first is statistical. Trending methods carry assumptions, and applying standard control charts to non-normal data, or setting limits from too few batches, can generate false comfort or constant false alarms. The rationale for each choice should be documented.
The second is scope. Monitoring every available parameter dilutes attention, whereas monitoring only release results reveals problems late. A sound plan flows from the control strategy, linking the critical quality attributes to the parameters and material properties most likely to move them. As the glycine example shows, the signal may sit outside the plant's own data entirely, which makes supplier information part of the design.
The third is data architecture. When batch records, laboratory results and supplier certificates live in unconnected systems, review becomes a periodic manual project, and a trend can run for months before anyone sees it. Any automation or cloud platform used for this work also needs validation appropriate to its GMP use, so digital ambition has to be paired with data integrity discipline.
The Boardroom View: Treating Process Knowledge as a Strategic Asset
Continued process verification is easily budgeted as a compliance cost. A stronger case rests on what the evidence makes possible. A well-characterised process gives a company firmer ground for discussing post-approval changes, faster answers during investigations and better information when choosing where to transfer a product or which supplier to qualify. These decisions carry growing weight as European policy pushes manufacturers towards more resilient supply.
Ownership is the harder issue. If process performance data belongs solely to quality, signals may reach manufacturing, supply and technical teams only after they have become deviations. Executives can test the health of their programme with a simple request: show how the last meaningful trend was detected, who acted on it and what changed as a result. The answer usually says more than any validation master plan.
Conclusion: From Proving a Process to Knowing It
Process validation still begins with sound development and disciplined qualification, but its credibility now rests on what happens afterwards. Regulators on both sides of the Atlantic expect evidence of control across the lifecycle, and the Annex 15 revision signals that Europe intends to extend that thinking deeper into the supply chain. Manufacturers that act before the new text is final, by clarifying terminology, connecting their data and investing in statistical judgement, will meet those expectations with less disruption. They will also gain a genuine understanding of why their processes behave as they do.
FAQ: Process Validation and Continued Process Verification
What is the difference between process validation and continued process verification?
Process validation is the full lifecycle of evidence that a process consistently delivers quality. In the FDA's model, continued process verification is its third stage, covering monitoring during routine commercial production.
Is continued process verification required in the EU?
Yes, in substance. EU GMP Annex 15 uses the term ongoing process verification and expects manufacturers to maintain a state of control throughout the product lifecycle.
Are three validation batches still enough?
Three consecutive production-scale batches remain the usual minimum for traditional validation in Europe, but they only open the lifecycle. They do not replace routine monitoring, and a different number may be justified.
Does continuous process verification replace traditional validation?
It can, wholly or for selected steps through a hybrid approach, if the dossier declares it and sufficient process knowledge supports it.
Will the Annex 15 revision affect active substance manufacturers?
Under the current proposal, yes. Annex 15 would become formally mandatory for them, with publication targeted for April 2028, subject to the outcome of consultation.
Lakshmi is a science writer with a foundation in the laboratory. She earned her master's in biotechnology and trained through research internships at ICGEB (JNU) and DIPAS, DRDO, with her work appearing in the Egyptian Journal of Veterinary Sciences. Now APCRM-certified and part of the editorial team at Pharma Focus America and Pharma Focus Europe, she reports on pharmaceutical technology, research, and innovation — giving complex science a clear and confident voice for industry leaders.
