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
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."
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2. FDA, "Preapproval Inspections/Investigations" CPGM 7346.832, http://www.fda.gov/cder/dmpq/CPGM7346832.htm, 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, http://www.fda.gov/cder/guidance/5882fnl.htm, 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.