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The renewal of European regulations regarding pharmaceutical process validation in autumn 2001 has been the subject of much discussion. The purpose of this article is to summarize and review the development of pharmaceutical process validation, and demonstrate how industry opinion regarding the concept has shifted from that of a regulatory burden to something driving total quality management and cost benefits.
Process validation has been widely discussed and criticized by the pharmaceutical industry during the past 20-30 years. Regulatory guidelines in the US and Europe have slowly been modernized, and revisions will certainly continue; in autumn 2001 for example, new guidelines for process validation came into force in Europe.(1,2) The unofficial debate regarding process validation has always been quite lively, although ostensibly negative. The advantages and disadvantages of process validation have never been systematically evaluated, and validation is frequently performed without a real understanding of the work involved. The challenge for the pharmaceutical industry is to streamline and/or simplify validation without sacrificing product quality.(3)
To successfully fulfil the challenge, those practising validation need to be aware of the best way to perform validations and the real aim of these procedures. This review examines how pharmaceutical process validation has evolved, the attitudes towards it and how it has been accepted by the industry.
The three most often referred to definitions of pharmaceutical process validation are those presented by the European Agency for the Evaluation of Medicinal Products (EMEA), the US Food and Drug Administration (FDA) and the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The latest versions of their definitions are described in the sidebar "Current definitions of pharmaceutical process validation."
Current definitions of pharmaceutical process validation
The three definitions are very similar; the only difference is that FDA expresses a minor uncertainty of the concept, despite the efforts of validation, by stating that process validation only provides a high degree of (not absolute) assurance that the process will produce the intended product.
This amendment by FDA is, however, essential. Even when approaching process validation as scientifically as possible, by incorporating elements of validation during each stage of product development(6–8) and evaluating the influence of different process parameters on the final product with statistical principles,(3,9) the possibility of erroneous results still remains.
The definition and meaning of pharmaceutical process validation has never really been clear. The expression "pharmaceutical process validation" is said to have first been used approximately 30 years ago by the US authorities,(10) and since then, people have demanded more precise and understandable definitions. But the more the authorities have tried to explain their meanings and provide guidelines, the greater the ensuing confusion and misunderstanding.11-14 John R. Sharp,(14) who at the time was the principal medicines inspector at the Department of Health in the UK, said that such definitions only confused those who already had an idea of what pharmaceutical process validation is and would not enlighten those who did not. He said that process validation is nothing more than common sense - it is simply proving that a process does what it is designed to do.(14,15)
There is also much confusion as to what constitutes process validation and what does not. Pharmaceutical process validation has always been understood in one of two ways - either as the total validation activity in a pharmaceutical manufacturing site from development qualification of the equipment to the final validation of three consequent batches of the final product; or as the final production-scale validation of a pharmaceutical preparation only. This discrepancy is not surprising because interpretations vary between the authorities(1,4) and the textbooks.(10,16)
Concept. The idea of process validation is not new and is common in many different fields of life; one can find the need for process validation in almost any kind of process, for example, building a spaceship or treating illnesses. It is important to be sure that these processes do what they are expected to do, otherwise the consequences could be serious.
Sharp also interpreted pharmaceutical process validation simply as a step in developing the maintenance of the quality of manufactured medicines.14 Process validation has been included in the first interpretations of good manufacturing practice (GMP) to ensure that medicines are safe and have the identity and strength they are supposed to have.
Table I: Regulatory history of process validation in the US and Europe.
US regulations. Bernard T. Loftus,(10) a former director of FDA, previously described how the principles of process validation evolved in the US from the first current good manufacturing practice (cGMP) in 1963 to the first Guideline on General Principles of Process Validation in 1987.4 Prior to 1963, the only way for FDA to prove that a process had not done what it was designed to do was to take samples from the final product, analyse them and show deviations from the specifications.
From 1963, the law stated that a pharmaceutical manufacturer had to follow cGMP regulations whilst FDA received authorization to inspect manufacturing facilities. This was a direct consequence of a series of accidents in which people were injured and even killed.
These incidents led to the evaluation of manufacturing processes, but it still took a long time before the authorities could point out clear and serious production faults and demand better procedures and processes.
Things began to change during the late 1960s and early 1970s when new types of incidents, such as poorly mixed, highly potent tablets and insufficient sterilization procedures for large volume parenterals caused serious patient disorders.(10,15) Many speeches pointing out the need for process validation were made by US authorities and the expression "validated manufacturing process" was finally defined in the Drug Process Inspections Compliance Program in 1978. The more precise definition and adjustment of the concept for process validation was published in the Guideline on General Principles of Process Validation in 1987 and, since then, exhaustive process inspections have been routinely performed by FDA. It took a long time before process validation was directly named in US cGMP regulations. To this day, process validation is not clearly defined, although a new version of the US cGMP rules, including more precise definitions of process validation, has been in preparation for a couple of years.(17)
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.
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.
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.
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)
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)
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.
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.
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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).
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