A Literature Review of Pharmaceutical Process Validation 2

European regulations. At the same time, a similar process was taking place in Europe (Table I), particularly in the UK. In 1968, new guidelines were introduced in the UK governing the sale and distribution of medicinal products, and in 1971 the first edition of Orange Guide, a guide to GMP, was published by the Pharmaceutical Inspection Convention (PIC). This guide already mentioned validation as being beneficial, but it was only in the 1977 and 1983 editions that validation practices in sterilization, aseptic processing and non-sterile processes were included.
In 1989, the first edition of the European Guide to GMP superseded all national guidelines within the European Union (EU).(16) This guide from the European Commission, together with the EMEA guidelines, has served as a model for all European countries regardless of whether or not they belong to the EU. As in the US, European process validation for sterile and aseptic processes was accepted and put into practice soon after the first regulatory guidelines demanded it. Yet, up until recently, process validation for other non-sterile processes has been introduced much more slowly and in limited amounts. More precise guidelines and definitions were also demanded for the European medicinal industry before the systematic validation of all pharmaceutical manufacturing processes was regarded as necessary.
The preparation of more detailed instructions went on between 1997-2001,18 and in September 2001, Annex 15 to the EU Guide to GMP came into operation titled Qualification and Validation2 and the Note for Guidance on Process Validation for marketing authorization applicants was introduced.1 It is worth mentioning that these instructions were issued at the same time as the GMP Annex and Note for Guidance on Parametric Release.(19,20) Parametric release is important because it adds more value to process validation.
FDA interpretations At the beginning of the 1980s, US authorities published several guidance speeches relating to process validation.(12,13,15,21) Additionally, Loftus defined process validation as nothing more than proving that a process works; that is, common sense. He also underlined that FDA emphasized "what to do" and left the "how to do it" to the manufacturer.(15) He stated that the regulatory body should insist on documented validation and was preventing initiatives and progress with meaningless regulatory controls.
Ted E. Byers, a consultant and former FDA inspector, explained how to best organize validations and how to maximize their benefits.(21) He introduced the team approach as a model for process validation organization and asked for better co-operation between FDA and the industry when planning individual validation cases. In conjunction with the preparation of the US Guideline on General Principles of Process Validation, Edmund M. Fry, director of the Parenteral Drug Association (PDA), attempted to clarify some points of the draft guideline that had raised questions from the industry.(12,13) His main message was that guidelines are not mandatory, but simply explain one approach to accomplishing the objective of the law. However, FDA comments suggested that it never wanted to define too many details of process validation, but that the industry itself asked for them.
FDA criticized In both the US and Europe, the authorities underlined how beneficial it would be if the industry made an effort to provide constructive comments on the guidelines before they were published.(12,18) As Loftus from FDA stated: "There is clearly a public policy need that we regulate the industry, but not that we manage it."(15)
James P. Agalloco was more positive about process validation, highlighting the business aspects and listing the numerous benefits to the manufacturer.(22) However, there was one person who attacked FDA's principles of process validation - John Sharp. He initiated a discussion on process validation just before the US guideline came into operation,(14) although the majority of the discussion took place between 1993-1995.(23-29) Sharp believed that validation in the US was in danger of becoming a cult-like activity where the original purpose had already been forgotten by spiralling onwards and upwards on a stairway of increasingly demanding standards. Not only did he blame FDA for this, but also found the pharmaceutical industry guilty. Sharp claimed that the need for validation should be inversely proportional to the adequacy of product design, raw material control and other quality control aspects, and directly proportional to the hazard to the consumer that a process failure might present.
Representing European authorities, Sharp found the European method of validating more reasonable than the US approach. He also emphasized the need for an improved level of interpretive consistency among US authorities. According to Sharp, this consistency was an area where the British Medicines Inspectorate had invested a lot of time.
Michael H. Anisfeld,(27) who worked at Interpharm Consulting (Buffalo Grove, Illinois, USA), agreed with Sharp and emphasized the importance of the patient perspective. He asked: "How much validation can the patient and the world afford?" and made comparisons of the expenditures on validations and their influence on prices of medicinal products with annual incomes of people in developing countries in need of those medicines. He also highlighted the exaggeration of US regulations and their consequences; some companies were not manufacturing products aimed at the US market in accordance with regulations because they did not want to go through costly FDA validation programmes for new facilities.
James Akers28 (Akers, Kennedy & Associates, Cary, North Carolina, USA) agreed with both Sharp and Anisfeld. According to Akers, validation was becoming a negative force within the pharmaceutical industry and the time had come for some fundamental change in the way the industry approached the subject. He wanted to go back to the basics of validation and forget all the bureaucratic exercises with irrelevant definitions and terms. Furthermore, Akers observed that process validation served as an excuse to do nothing new and, therefore, hindered the creativity of scientists and engineers.