While never recommended, ranges that have not been challenged or assessed prior to process validation must be challenged during
the process validation effort. This "dry run" approach during process validation has a significant cost factor if a "failure"
occurs during execution of the runs. This is true even if the process is well-characterized and well-established. Without
some sort of documentation supporting the range specified (e.g., a development report), a processing failure associated with
a specified process parameter can only be assigned a defendable corrective and preventive action (CAPA) if it involves a thorough
retrospective analysis of a statistically significant number of historical batches for which the specified process parameter
data is obtainable. Of course, this would lead a savvy auditor to question the development of other parameters for other products
as well. As you can see, this can be very costly on many fronts. The only way to avoid this situation prior to digging up
the proverbial can of worms is to verify and document the origin of each specified process parameter present in the MBR prior
to the execution of the process validation runs.
Product quality attributes verification.
The purpose of this final process validation prerequisite is to verify and document that the in-process and finished product
quality attributes match those in product development reports or are the most currently approved specifications reported in
the product regulatory submission.
When a product has been approved in both the United States and countries outside the US this verification becomes even more
important because product specifications for the same product can differ from country to country. For example, a solid dosage
form manufacturer was undergoing a process (re)validation effort after making some process improvements. The product was approved
for distribution in both the US and Canada. Prior to commencing the process validation runs, this prerequisite verification
of the product quality attributes was conducted, at which time it was recognized that the impurity specification differed
between the two countries for the same product. The Canadian specifications were tighter than the US specifications. However,
only the U.S. values were listed in the validation protocol. If this prerequisite had not been verified prior to performing
the production runs, the process validation effort may have resulted in problems meeting the more strict Canadian requirements.
In order to compete in the Boston Marathon, runners must demonstrate to the race organizers that they are ready to compete,
so the unqualified entrants are weeded out of this prestigious event. In addition, the qualified runners check their own gear
before the event as they want to maximize their chances to succeed.
The same concept applies to process validation. By using the process validation prerequisite approach, many of the potential
pitfalls and hazards along the process validation route can be avoided before the costly production runs and laboratory testing.
Not only does this approach make good economical sense, but using this approach can also demonstrate, during government and
customer audits, that quality is built into the process, and the quality systems approach to regulated product manufacturing
is alive and well in your facility.
Nancy Cafmeyer, a consultant at Advanced Biomedical Consulting (ABC), LLC, with over 28 years industry experience has consulted at numerous
pharmaceutical, nutritional supplement, and medical device manufacturers and prior to working for ABC has held both hand-on
and management positions at companies such as King Pharmaceutical, Geopharma, and Daniels Pharmaceuticals.
Jonathan M. Lewis, a principal at Advanced Biomedical Consulting (ABC), LLC, has consulted at over 50 different biopharmaceutical, pharmaceutical,
and medical device manufacturers and prior to starting ABC has held both hand-on and management positions at companies such
as Cardinal Health, KMI, and PAREXEL International.
Advanced Biomedical Consulting (ABC), LLC, PO Box 76405, St. Petersburg, FL 33734, tel. 888.671.4292, fax 727.897.9522, firstname.lastname@example.org
1. I.R. Gerry and R.A. Nash, Eds. Pharmaceutical Process Validation, (Marcel Decker, Inc., New York, 2nd ed., 1993), pp. xiii-24.
2. Code of Federal Regulations, Title 21, Food and Drugs, Part 211, (FDA, Department of Health and Human Services, Rockville,
MD, April 1, 2006).
3. Guideline on General Principles of Process Validation, (FDA, Rockville, MD, May 1987).
4. Compliance Policy Guide Manual, Chapter 4, Process Validation Requirements for Drug Products and Active Pharmaceutical
Ingredients Subject to Pre-Market Approval, Document 7132c.08, (FDA, Rockville, MD, 2006).
5. Guidance for Industry, Q7A, Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, (FDA, Rockville,
MD, August 2001).
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