The International Conference on Harmonization (ICH) Q8–10 guidelines and the US Food and Drug Administration's out-of-specification
(OOS) guidance document provide approaches that allow for regulatory flexibility in process development and manufacturing
with the intention of bringing certain quality standards of the biotech industry closer to those of more established industries
such as the automobile sector. These quality guidelines have bridged many of the gaps between established regulations and
the need for flexibility in quality systems to drive innovation. The foundation has been laid, therefore, to encourage the
use of innovative processes in development and manufacturing that are based on a common understanding of risks and good science.
Stephan Krause, PhD
Following these guidelines in an ideal world, a drug would progress from early development through commercial production within
processes that are well designed and controlled. In reality, however, because of the lack of detailed process design plans
and complete understanding of any given drug's molecular form and function, there will be imperfections that currently can
be corrected only at certain lifecycle stages.
Thus, despite the progress shown in these guidance documents, the Q9 guideline on risk management and the OOS guidance still
fail to properly address two important supporting quality elements for validation. First, these guidance documents do not
set clear expectations for how to set risk-based acceptance criteria in validation protocols. If validation protocols don't
contain appropriately set limits, future risks to patients or firms may not be controlled. Second, and even more important,
these documents do not include any instructions on how to deal with validation failures. It is as if validation failures simply
do not exist or are "not allowed."
Current industry practice often demands that risks be managed by the extent of validation studies executed but not so much
by actually using risk-based acceptance criteria. The lack of a quality system that allows a firm to openly deal with validation
failures, similar to the way OOS test results are handled, has several consequences, none of which is good for the patient
or the firm. In contrast, openly accepting validation failures and having a pre-set plan to address them would encourage firms
to set risk-based acceptance criteria.
The OOS guidance document provides excellent instructions on how to deal with OOS results and how these results should trigger
process improvements. A similar system for dealing with validation failures would add great value to the validation process.
Let us first start by accepting the fact that validation failures—like OOS results—do occur. Then, we can talk about how to
set challenging validation acceptance criteria. Establishing an open system to address validation failures will allow the
important concepts contained in the ICH Q8–10 guidelines to be used more fully. And that would benefit the industry, and more
Stephan Krause, PhD, is the director of quality control at Favrille, Inc., San Diego, CA, 858.526.8026, firstname.lastname@example.org
1. Krause SO. Validation of analytical methods for biopharmaceuticals—A guide to risk-based validation and implementation
strategies. Bethesda, MD: PDA/DHI Publishing; 2007 Apr.