Compliance Risk Management Using a Top-Down Validation Approach - Pharmaceutical Technology

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Compliance Risk Management Using a Top-Down Validation Approach
Patient safety must be the primary concern of any validation effort. The author explains how a risk-based approach to validation and compliance follows naturally from this premise.

Pharmaceutical Technology

Validation doesn't replace any of the required CGMP activities, it merely confirms their appropriateness. There is no substitute for sound process design and development, and of course CGMP compliance in all activities. Validation failures are not a consequence of the validation, but rather of poor designs, inadequate development, or CGMP problems in operations. In essence, validation only serves to keep score.

The inability to validate a process or product is usually associated with one or more of the following causes:

  • Inadequate development (poor science)
  • Poor process control (inferior equipment or poor maintenance)
  • Inadequate instructions (poor documents or sloppy development)
  • Lack of knowledge (poor science or engineering)
  • Poor validation practice (inadequate know-how).

Examples of top-down application

The following examples are drawn from real-life situations where the validation and quality focus was misdirected because the firm had lost sight of the objectives they were striving for. In each case, end-product quality was placed at risk because of inappropriate priorities in the validation or control of other processes

Environmental worries trump sterilization. One firm was experiencing a significant failure rate in its bioreactors (close to 20%), which was greatly reducing its ability to support product sales. Investigation into the problem revealed that steaming-in-place of the system was being hampered by faulty steam traps and back pressure in the condensate line. When pressed to allow the traps to discharge into the surrounding ISO-8 room, the firm's environmental-quality unit objected that the condensate would degrade the environmental conditions in the room. The ability to sterilize the bioreactors and produce contamination-free products was compromised to protect an environment without product contact.

Pursuit of sterilization effectiveness risks microbial contamination. Parts for aseptic compounding and filling were sterilized as individual components to ensure maximum exposure during the steam-sterilization process. After sterilization, the individual parts were assembled aseptically into the final fluid-handling system. The risk of contamination during the assembly was ignored in pursuit of better sterilization. The firm relied on media fills to support the efficacy of this process.

The effect of the top-down approach

The top-down approach focuses the validation on the key quality attributes of the product rather than on less critical concerns. The products manufactured in this industry are intended to serve the patient, whose needs must be paramount in the development of any validation effort. Validation began as a means to ensure sterility and protect patient welfare. It is essential that as the industry maintain a connection between what it is endeavoring to do and whom it is doing it for. The patients deserve the safest and most efficacious products possible, and the cost to provide them should be realistic as well. Misplaced efforts that fail to support patient needs are anathema.

The approach described in this article is inherently risk-based because the validation activities that directly affect critical product-quality attributes are given the greatest emphasis and priority over potentially conflicting, but certainly less important indirect concerns. Validation efforts must focus on patient needs. Risk-based validation is a significant step in the right direction. Remember, "If a thousand people do a foolish thing, it is still a foolish thing."

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

Submitted: Feb. 6, 2008. Accepted: Feb. 12, 2008.

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1. FDA, "Proposed Current Good Manufacturing Practices in the Manufacture, Processing, Packing or Holding of Large Volume Parenterals," Fed. Regist. 41 (106), 22202–22219 (June 1, 1976; Rescinded-Dec. 31, 1993).

2. FDA, "Preapproval Inspections/Investigations" CPGM 7346.832,, accessed June 9, 2008.

3. ISPE, Commissioning and Qualification, Baseline Guide, (Tampa, FL, 2001).

4. American Society for Testing and Materials, E2500-07—Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment (West Conshohocken, PA, 2007).

5. FDA, "Guideline on Sterile Drug Products Produced by Aseptic Processing," 2004,, accessed June 9, 2008.

6. FDA, "21 CFR 210.1 (a)," Fed. Regist. 43 (45076), (Rockville, MD, 1978).

7. ASTM, E2500-07—Standard Guide for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment (West Conshohocken, PA, 2007).

8. K. Chapman, "The PAR Approach to Process Validation," Pharm. Technol. 8 (12), 22–36, 1984.

9. FDA, "Guidance for Industry, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance" (Rockville, MD, 2004).

10. B. Spiller, "Process Validation of Solid Dosage Forms," in proceedings of Manufacturing Controls Seminar (The Proprietary Association, Cherry Hill, NJ, 1979), pp. 17–31.


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