Revised Draft Process Validation Guidance Emphasizes Process Understanding and Ongoing Monitoring

The US Food and Drug Administration has issued a new draft guidance document on process validation. This much-awaited revision of the 1987 guidance of the same name has been in the works for at least three years, and is being welcomed by industry experts.

The new document emphasizes that a lifecycle approach is required, as process validation should continue after approval through ongoing process monitoring of commercial manufacturing. The document describes three stages to process validation:

Stage 1 – Process design; which covers process development and scale up work;
Stage 2 – Process qualification, in which the process design is confirmed; and
Stage 3 – Continued process verification, or ongoing process monitoring during commercial manufacturing.

The document also stresses the importance of statistical data and analysis, and recommends that companies seek the expertise of statisticians. Brian Hasselbach, team leader for CGMP guidance and policy in the Office of Compliance in the FDA’s Center for Drug Evaluation and Research, agreed that the document addresses statistics in more detail than ever before in agency guidance.

“The message of this guidance is that manufacturers should be statistically confident that their operations produce acceptable quality drugs in two ways: confident that the process is in a state of control, and confident that samples tested represent the batch,” he said.

Industry experts are not surprised by the contents of the guidance, and are pleased with it. In particular, the document’s emphasis on process understanding got high marks.

“This is a big change, and a change for the better,” said Alex Kanarek, PhD, a senior consultant at BioProcess Technology Consultants (Acton, MA). “I have been saying for years that you cannot possibly validate any method, whether a process step or an analytical technique, that you don’t understand.”

Kanarek also liked the emphasis on routine monitoring. “Perhaps one day, instead of filing annual reviews, we will rely on something like a trend analysis on a quarterly basis, depending on how many batches one makes per year,” he speculated.

Peter Watler, PhD, principal consultant and chief technology officer at Hyde Engineering and Consulting (South San Francisco, CA) was also impressed by the focus on process monitoring.

“The level of process monitoring described here is not universally practiced in the industry,” he said. “It’s somewhat spotty; a lot of firms do monitor their manufacturing processes to some extent but many have informal, somewhat vague monitoring programs. This guidance makes it clear that the FDA will be asking what you are monitoring, and why.”

Although the document does not use the term Quality by Design (QbD), Kanarek, Watler, and others agree that the concepts explained in the process validation guidance are completely consistent with the ideas behind QbD, such as developing a design space that allows for continuous improvement to take place without additional regulatory filings.

“Validation is based on understanding, and so is continuous improvement” said Kanarek. “And a design space is nothing more than a figure that shows we understand our process, and how various parameters interact to affect the process.”

Watler noted that the document even makes specific reference to continuous improvement, as it says that, “information and data about product performance and manufacturing experience [must] be periodically reviewed to determine whether any changes to the established process are warranted.”

“This is quite a milestone,” said Watler.

Some experts also feel that the absence of terms like QbD was probably intentional, as some members of industry have become frustrated with what they perceive as an excessive use of buzzwords and a constantly shifting emphasis from one new concept to another, whether it be process analytical technology or QbD.

“Some people have gotten a bad taste in their mouths from a ‘flavor-of-the-month’ approach,” said Ron Branning, vice-president of corporate quality assurance at Gilead Sciences (Foster City, CA) and the outgoing chair of the ISPE’s Product Quality Lifecycle Initiative. “This document makes it easier to talk about the substance and tools for process control, rather than worrying about the terms or the banner they fall under.”

Once finalized, the guidance will replace the 1987 guideline on the same topic. Comments on the draft my be submitted to the FDA until January 19, 2009.