Risk-Based Thinking in Process Validation - Pharmaceutical Technology

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Risk-Based Thinking in Process Validation
The author describes why statistical significance would impose an unreasonable burden on manufacturers.

Pharmaceutical Technology
Volume 35, Issue 2, pp. 68-76


Validation is an essential and extremely useful activity within our industry (9). Its benefits may have been understood poorly, and thus understated for years. Nevertheless, interpreting or applying the guidance too restrictively can certainly result in a new wave of complaints regarding its proper role in pharmaceutical operations. One could easily assert that properly performed validation with good attention to scientific and engineering detail has always embodied the concepts of risk assessment and QbD since its inception. The FDA draft suggests that the "rule of three" will no longer suffice for future validation demonstrations at commercial scale, but the number of studies required should not be excessive.

Statistics certainly will play a large role in future validation studies. They should not define the number of studies required, however, lest they cause interminable delays and excessive cost. Validation, as redefined in the guidance, offers a means towards optimization and process economy, thus justifying the greater developmental effort required to achieve the desired state. Imposing excessive validation requirements on industry to attain that state on a commercial scale may not always serve a useful purpose. Given the renewed emphasis FDA is placing on process validation, it is essential that programs designed to meet it be fully compliant, and yet realistic with respect to the extent of the effort required. The adoption of a risk-based approach, as described in this article, affords perhaps a unique opportunity to accomplish both objectives at the same time.


This paper was profoundly influenced by Phil DeSantis, Sr., director of engineering compliance at Merck Global Engineering Services; James Akers, president of Akers, Kennedy, and Associates; and Russell Madsen, president of the Williamsburg Group, each of whom played a substantial role in refining the author's opinions and developing this article.

James Agalloco is the president of Agalloco and Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558,
. He also is a member of Pharmaceutical Technology's editorial advisory board.


1. FDA, Guideline on General Principles of Process Validation (Rockville, MD, May 1987).

2. FDA, Draft Guideline on General Principles of Process Validation (Rockville, MD, Nov. 2008).

3. FDA, Risk Based Compliance (Rockville, MD, Sept. 2004).

4. J. Agalloco, PDA J. Pharm. Sci. Technol. 49 (4), 175–179 (1995).

5. J. Agalloco, Pharm. Technol. 32 (7), 70–78 (2008).

6. A. Hussain, DIA Annual Meeting (Washington, DC, 2004).

7. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), part 211.180 (e)

8. J. Agalloco, Pharm. Technol. 33 (5) supp., s22–s27 (2009).

9. J. Agalloco, J. Parenter. Sci. Technol. 40 (6), 251–252 (1986).


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