A Literature Review of Pharmaceutical Process Validation 3

Disagreements R.A. Nash, associate professor of St John's University, Jamaica, did not agree with Sharp. Nash had been working in the field of validation since the early 1980s(23,31) and found Sharp's opinions to be personal attacks; he consequently wrote a heated response.26 However, in 1996,3 Nash also asked for process validation to be streamlined and simplified.
Although Gene K. Estes et al.32 had established that process validation emerged primarily from the actions of the pharmaceutical industry, Agalloco suggested the idea first came from a regulatory body,(29,30) and was adopted as a regulatory burden rather than benefit. Agalloco found that validation could be defined as an application of total quality management (TQM), stating that it was the quality of the validation that is important and not the quantity.
In 1995, Sharp criticized FDA-type validations and went as far as to suggest the term "validation" be abandoned altogether.(33,34) All that inspectors would then need to ask, he said, would be: "Prove to me that this process works, in that it achieves what it is intended to achieve."
During the 1990s, Robert G. Kieffer, a consultant at RGK Consulting (Yonkers, New York, USA), challenged the need for risk-benefit analysis and the need for remembering to take into account the human element when planning process validations,(35,36) suggesting that the steps in a process involving human intervention would present the highest risks. Additionally, the sophisticated technology being used made more demands on people's knowledge and skills. Kieffer also anticipated new trends in pharmaceutical manufacturing - the pressure to do more with less, improve quality with lower costs, the globalization of the pharmaceutical industry and an increase in contract manufacturing. These trends are currently guiding the work of industry and also the work of regulators.(37) Kieffer also suggested that the basic ideas of GMP should be based not on quality control but on total quality, which meant the empowerment of all staff. Another consultant, Keith Powell-Evans, stressed the need to educate individuals involved in the validation process.(38) European perspective In Europe, the preparation of the new guidelines on process validation began in the late 1990s. The European authorities explained the new proposals,(18,39,40) consultants and pharmaceutical schools introduced their theories about how to best survive the validation effort41-43 and positive experiences from the field were presented by the industry.(44,45)
S. Roman44 (Laboratoire Glaxo Wellcome, France) found validation to be one of the main tools for quality assurance, resulting in reduced production and control costs. M.J. Girault45 (Marion Merrell Bourgoin SA, France) presented calculations showing that the cost of validation compared with the total costs of the plant was approximately 1.2%, and compared with the total costs of the quality department was 7.8%.
D. Caubel from the French Agency for Medicines evaluated the meaning of the guidelines and stated that they should serve mainly as a framework for process validation.39 They should give guidance for reasonable documentation practice but they should only give detailed instructions in particularly sensitive cases, such as cross-contamination prevention and aseptic preparations.
Many recent comments go into specific details of validation and/or overall quality assurance, warning regulators of giving too precise instructions in their guidelines.(46,47)
A more open approach from the regulatory side is required and a need to aim ultimately for parametric release for all dosage forms is emphasized.(37,48) Interesting additions to the discussion are comments from the less-developed countries where the concept of validation is new.(49)
Discussion The debate regarding pharmaceutical process validation began in the US during the late 1970s and the first definitions of process validation were introduced at the beginning of the 1980s.(11-15, 21, 31) The discussion continued throughout the 1980s and during the preparation of US guidelines.(12-14, 22) However, the most critical comments were only published after the guidelines had come into operation.(23-28)
Comments on process validation emerged in European literature later than in the US and most of them were positive and accepting in their nature, apart from those by Sharp. This remained the case between 1997-2001 during the preparation of European guidelines on process validation.(38-45)
The authorities, the pharmaceutical industry, consultants and pharmaceutical schools have all contributed to the discussion. Many of them have been critical of some aspects of process validation but none have been totally against it. In fact, many constructive and economic ideas regarding process validation have been suggested.(29,30,33-38)
A clear evolution of the discussion can be recognized. The first comments were from US authorities who tried to explain the demands from a regulatory point of view,(11-13,15,21) referring to comments that they had received from the industry.11-13,15 It is important to note that in these early regulatory speeches, the regulators often stressed that they would not like to write too precise instructions about process validation, because they found that the practice varies so much from case to case.12,13,15 But, according to their references, it was the industry that wanted to have these detailed instructions and then started pointing out defects in them.
FDA had gone into too much detail in its guidelines and that encouraged misunderstandings, negative attitudes and a substantial amount of unnecessary work in the industry. The European guidelines, although often one step behind, were better accepted.
Since the early 1990s, there has been a greater concentration on the risk-benefit analysis, statistical analysis and prioritizing work of process validation.(28,35-37) It appears that the pharmaceutical industry has now accepted that process validation is here to stay and that it is not simply a tool for quality assurance.(50,51)
Process validation has become part of strategic quality management and performance improvement;(52) all its benefits (to patients as well as manufacturers) have been recognized and from now on, the challenge is to find the right level of cost-effective validation without any risks to consumers.
Conclusion According to literature published during the last 30 years, pharmaceutical process validation has evolved. For most people in the industry, it originally appeared as a regulatory requirement and, hence, was often regarded as a burden.
Despite originally being criticized, process validation is well accepted and regarded as part of total quality and process management. The US has been more critical of process validation; however, the lack of European literature on the subject does not reveal the true European attitude to process validation. 
1. “Note for Guidance on Process Validation. CPMP/QWP/848/96; EMEA/CVMP/598/99” (EMEA, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK, 2001).
2. “Annex 15 to the EU Guide to Good Manufacturing Practice — Qualification and Validation” (European Commission, Rue de la Loi, Wetstraat 200, B-1049 Brussels, Belgium, 2001).
3. R.A. Nash, Drug Dev. Ind. Pharm. 22(1), 25–34 (1996).4. “Guideline on General Principles of Process Validation” (US Food and Drug Administration, 5600 Fishers Lane, Rockville, Maryland 20857, USA, 1987).
5. “Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation, Document PH 1/96” (Pharmaceutical Inspection Convention, PIC/S Secretariat, 9–11, rue de Varembe, CH-1211 Geneva, Switzerland, 1996).
6. H.L. Avallone, Pharm. Eng. 10(4), 38–41 (1990).
7. C. DeSain and C.V. Sutton, Pharm. Technol. 19(10), 131–136 (1995).
8. J. Agalloco, J. Parenter. Sci. Tech. 47(May/June 1993).
9. D.C. Montgomery, Design and Analysis of Experiments (John Wiley & Sons Inc., Hoboken, New Jersey, USA, 1997) pp 315–322.
10. B.T. Loftus in I.R. Berry et al., Eds., Pharmaceutical Process Validation, 2nd Edition (Marcel Dekker Inc., New York, New York, USA, 1993) pp 1–8.
11. G.W. Melliger, Pharm. Ind. 42(Nr.11a), 1199–1202 (1980).
12. E.M. Fry, Pharm. Ind. 46(6), 601–605 (1984).
13. E.M. Fry, Drug Cosm. Ind. 133(7), 46–51 (1985).
14. J.R. Sharp, Pharm. J. 236(1), 43–45 (1986).
15. B.T. Loftus, Pharm. Ind. 42(Nr. 11a), 1202–1205 (1980).
16. W. Gibson et al., Validation Fundamentals: How to, What to, When to Validate (Interpharm Press, Inc., Buffalo Grove, Illinois, USA, 1998) pp 46–47.
17. “Current Good Manufacturing Practice; Proposed Amendment of Certain Requirements for Finished Pharmaceuticals, 21 CFR Parts 210 and 211” (US Food and Drug Administration, 5600 Fishers Lane, Rockville, Maryland 20857, USA, 1996).
18. J.M. Morris, S.T.P. Pharma Pratiques 7(5), 383–388 (1997).
19. “Annex 17 to the EU Guide to Good Manufacturing Practice — Parametric Release” (European Commission, Rue de la Loi, Wetstraat 200, B-1049 Brussels, Belgium, 2001).
20. “Note for Guidance on Parametric Release,” CPMP/QWP/3015/99 (EMEA, 7 Westferry Circus, Canary Wharf, London E14 4HB, UK, 2001).
21. T.E. Byers, Drug Cosm. Ind. 130(6), 43–44, 82, 86 (1982).
22. J.P. Agalloco, J. Parenter. Sci. Technol. 40(6), 251–252 (1986).
23. R.A. Nash, Clin. Res. Reg. Affairs 10(4), 253–264 (1993).
24. Editor’s page, J. Parenter. Sci. Technol. 46(Sep/Oct), 141 (1992).
25. J. Sharp, J. Parenter. Sci. Technol. 47(Jan/Feb), 2–3 (1993).
26. R.A. Nash, J. Parenter. Sci. Technol. 47(Jul/Aug), 150–151 (1993).
27. M.H. Anisfeld, PDA J. Pharm. Sci. Technol. 48(1), 45–48 (1994).
28. J. Akers, J. Parenter. Sci. Technol. 47, 281–284 (1993).
29. J.P. Agalloco, “Validation — Yesterday, Today and Tomorrow,” in Proceedings of the PDA International Congress (Basel, Switzerland, 22–24 February 1993).
30. J.P. Agalloco, PDA J. Pharm. Sci. Technol. 49(4), 175–179 (1995).
31. R.A. Nash, Pharm. Technol. 3(6), 105–107 (1979).
32. G.K. Estes and G.H. Luttrell, Pharm. Technol. 7(4), 74, 76–78, 80, 84 (1983).
33. J. Sharp, PDA J. Pharm. Sci. Technol. 49(3), 111–118 (1995).
34. J. Sharp, PDA J. Pharm. Sci. Technol. 51(3), 104–110 (1997).
35. R.G. Kieffer, PDA J. Pharm. Sci. Technol., 49(5), 249–252 (1995).
36. R.G. Kieffer, PDA J. Pharm. Sci. Technol. 52(2), 52–54 (1998).
37. R.G. Kieffer, PDA J. Pharm. Sci. Technol. 52(4), 151–153 (1998).
38. K. Powell-Evans, Pharm. Technol. Eur. 10(1), 29–30 (1998).
39. D. Caubel, S.T.P. Pharma Pratiques 7(5), 378–382 (1997).
40. P. Piccerelle et al., S.T.P. Pharma Pratiques 10(2), 75–78 (2000).
41. R. Acquier, S.T.P. Pharma Pratiques 7(5), 327–331 (1997).
42. H. Leroux and C. Tanu, S.T.P. Pharma Pratiques 7(5), 368–371 (1997).
43. R.G. Dusel, S.T.P. Pharma Pratiques 7(5), 392–397 (1997).
44. S. Roman, S.T.P. Pharma Pratiques 7(5), 332–338 (1997).
45. M.J. Girault, S.T.P. Pharma Pratiques 7(5), 346–348 (1997).
46. PDA Solid Dosage Process Validation Committee, “Technical Report No. 25 — Blend Uniformity Analysis: Validation and In-Process Testing,” PDA J. Pharm. Sci. Technol. 51(Nov/Dec suppl. 3), S1–S99 (1997).
47. J. Agalloco, PDA J. Pharm. Sci. Technol. 52(4), 149–150 (1998).
48. J.E. Moldenhauer and R. Madsen, PDA J. Pharm. Sci. Technol. 54, 32 (2000).
49. K. Ruckmani et al., Eastern Pharmacist 42(Aug), 27–29 (1999).
50. R.G. Kieffer, “Why Validation,” in F.J. Carleton and J.P.Agalloco, Eds., Validation of Aseptic Pharmaceutical Processes (Marcel Dekker, Inc., New York, New York, USA, 1986) pp 1–6.
51. J. Nally and R. Kieffer, Pharm. Technol. 17(10), 106–116 (1993).
52. K.L. Stoddart, Eur. J. Parenter. Sci. 5(4), 87–92 (2000).

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