Jukka-Pekka Mannermaa

Many doubts regarding the value of process validation (PV) have been raised during the past 30 years. For many, validation is still associated with bureaucracy and excessive paperwork, which only serves to hinder progress. However, a systematic evaluation of its real value has long been overdue.	

The value of PV is difficult to estimate because it cannot be evaluated using solid empirical measurements. Therefore, a method capable of both evaluating the subject by informed judgement and structuring the information for which there is some evidence, but not quantitatively measurable knowledge, was needed. Therefore, the synthesis method of technology assessment (TA) was applied.1	

For the first part of the assessment, a literature search was performed,2 but a lack of European opinion was evident. To address this, an Internet Delphi survey was performed in autumn 2001 involving 36 experts from the pharmaceutical fields of industry, regulation and academia.	

to explore the value of pharmaceutical PV and to ascertain the best tools to perform it

to explore the advantages and disadvantages of PV using the experiences of the pharmaceutical industry and regulators

to search for differences in approach between the three parties or between countries.

Once collected, the information and knowledge was used to provide support for the further development of pharmaceutical PV.	

The Delphi method. The survey was performed using the Delphi technique - a series of questionnaires based on a structured process with controlled feedback. The results of one round of questions were summarized and used to construct the next questionnaire. 				

The method attempts to mimic discussion through controlled feedback allowing respondents to change their minds on the basis of the opinions from the previous round. This reiterative process is continued until the participants reach consensus or clear disagreement. To accelerate the process, the Internet and e-mail were used. Furthermore, the Internet offered additional tools during the survey.3	

Questionnaires and analysis. Only two rounds of questionnaires were required for adequate consensus. Both questionnaires mostly consisted of multiple-choice questions under the following subheadings:	

How can we get the most out of PV and how can we make it easier and more effective?

What are the main barriers to positive thinking of PV?

For quantitative measurement regarding PV, the multiple-choice answers were categorized using a 1–5 Likert scale, which was used to summarize the results.4 A "no opinion" option was added and these were omitted from the mean calculation.	

Attitudes were also tested by asking the participants how far they agreed/disagreed with a number of  statements concerning PV in general and its usefulness in specific areas. The overall attitude was also estimated through one control question, which was the first question in the first round (Q1) and repeated as the last question in the second round (Q2). The estimation of the application possibilities of PV was based on the responses to statements presenting applications of PV and statements under the heading of "Benefits of Process Validation."	

The sections of the questionnaire trying to ascertain the reasons for the overall attitude were evaluated question by question, calculating percentages for different choices. To determine whether there had been any evolution of the opinions between Q1 and Q2, the quantitative values of Q1 for certain questions were compared with the Q2 values for the same questions. The decision to continue the survey with further rounds rested on this comparison. Because the size of the expert group was relatively small, no further statistical analysis could be performed on the results.	

Figure 1:  Q1 participants' attitudes towards process validation (using a scale of 1-5, where 55highly positive and 15highly negative) and Figure 2:  Overall attitude to process validation (using a scale of 1-5, where 55highly positive and 15highly negative).			

In total, 36 experts from the three pharmaceutical parties participated in Q1, 28 of whom continued to Q2. There were participants from 10 European countries - Belgium, Denmark, Finland, France, Germany, Iceland, Norway, Sweden, Switzerland and the UK.3								

Overall attitude and application possibilities. The overall attitude to PV appeared to be very positive, but some stated that its applications were not practicable and others believed that PV should be reserved for its original purpose: to ensure patient security. Therefore, the mean value for application possibilities was less than that for overall attitude (Figure 1).	

No one had the opinion that PV was just a regulatory requirement without real benefits for the manufacturer. There were no differences in this opinion between the three parties and the opinion was not dependent on the participants' age, gender, education, primary business or function. Q1 answers did not differ statistically from the Q2 results and results for the overall attitude are presented in Figure 2.	

The proposed application areas of PV were:	

as an opportunity to learn about the process

The lowest reported value related to the usefulness of PV as a marketing tool. The participants agreed that PV increases patient security, and provides cost savings through better performing manufacturing processes and less rejectable material, reprocessing and retesting. Further benefits of PV included cost savings through the early detection of failures and less troubleshooting. However, half of the participants had doubts concerning whether PV could provide cost savings by reducing control requirements for the final product. It was also unclear whether PV would ensure better conformance with regulatory requirements and thus shorten delays in obtaining marketing authorization. No clear differences regarding these attitudes were apparent between Q1 and Q2 - all application areas received positive mean values (Figure 3).		

Figure 3:  Q1 and Q2 participants' attitude towards PV application (using a scale of 1-5, where 55highly positive and 15highly negative) and Figure 4:  Opinions of different pharmaceutical groups regarding the statement: "Process validation can be used as a marketing tool" (using a scale of 1-5, where 55 totally agree and 15 strongly disagree).			

Two questions in Q1 highlighted major differences in opinion. Little agreement could be found on whether PV simply constitutes a bureaucratic exercise or whether validation provides an enormous opportunity for consulting companies to earn money at the cost of the pharmaceutical manufacturers.	

Some differences between the attitudes of the pharmaceutical parties could be seen regarding the application possibilities of PV. The regulators were most critical of PV as a useful marketing tool (Figure 4); however, they found the application possibilities quite extensive. Of the three pharmaceutical parties surveyed, academia most strongly agreed with the survey statement that PV is a hindrance to flexible product development and a destroyer of innovation (Figure 5); however, they had the least positive attitude to the application possibilities of PV, unlike the industry participants who found merit in all suggested applications. 			

Figure 5:  Opinions of different pharmaceutical groups regarding the statement: "Process validation as it is currently practised is a hindrance to flexible product development and a destroyer of good ideas" (using a scale of 1-5, where 55 totally agree and 15 strongly disagree).			

Cost of validation. In Q1 there were seven questions regarding validation costs. The results showed that the costs are difficult to estimate.	

Half of the participants, particularly the regulators, considered that validation costs are not one of the main reasons for the high prices of medicinal products. Most were of the opinion that negative attitudes regarding PV could be blamed 	

on the general assumption that validation is expensive. In Q2, a new question was added, asking participants whether they had ever seen reports clearly showing that validation had increased total quality costs - 92% had not.	

The participants were also asked to estimate the cost-effectiveness level of PV if the minimum effort to meet the requirements of the European regulators was made. Sixty eight per cent of Q1 participants found that that level would represent the optimum economic level of PV; this attitude was further strengthened in Q2 (81%).		

Figure 6:  The traditional quality cost model and Figure 7:  The continuous improvement model for quality costs.			

In Q2, participants had to choose between two suggested models for pharmaceutical quality costs - the traditional quality cost model (Figure 6) and the continuous improvement model (Figure 7). Eighty five per cent favoured the continuous improvement model.	

Optimizing process validation work. The best organizational model. In Q1, the participants were asked to choose the best organizational model for PV. The most popular (86%) was a validation group composed of production, quality assurance (QA) and product development personnel because they felt that as a cross-functional discipline, PV would benefit from experience from all of these departments. Some people even added engineering experts to the group. 	

Those who opted for a separate validation department did so because they believed that this provided a company with separate resources with validation knowledge. Having a validation group as part of the product development department was supported by some people because they believed it would offer the perfect combination for process improvements. Other participants felt that having a validation group as part of QA department would offer the most benefits.	

In Q2, the question was modified, asking participants to name the model that is currently employed by their company or was used by previous employers. Again, the most popular model (55%) was a validation group composed of production, QA and product development staff. It was discovered that in some companies, validation activities had been divided between several departments, each performing different parts of the PV, but this model never worked perfectly, because communication between the departments was ineffective. Other named models are listed in the sidebar "Other named models for optimizing PV."	

Prioritizing process validation. Results showed that the most popular (63%) method for choosing which processes to validate was the use of common sense. Failure Mode Effect Analysis (FMEA),5–7 was unknown by 43% of the experts and the process capability method,8 was only slightly better known.		

Articles

European expert opinions regarding pharmaceutical process validation were collected and studied by performing an Internet Delphi survey. In total, 36 experts from 10 countries representing the pharmaceutical fields of industry, regulation and academia participated in the survey. The overall attitude to process validation appeared to be positive; however, a number of concerns were raised. More education, better use of prioritizing tools and increased evidence of cost-effectiveness is needed to further develop and facilitate process validation.

Using a Delphi Survey to Assess the Value of Pharmaceutical Process Validation Part II: Expert Opinions

Despite the long history of pharmaceutical validation, process validation in pharmaceutical manufacturing continues to be topical. European regulations regarding process validation were renewed in autumn 2001, which again brought the subject under the spotlight. Many people working in pharmaceutical production are now reviewing the state of their compliance practices and posing the question: "How will we benefit from process validation?"	

To estimate the value of process validation, a systematic evaluation of the collected opinions and experiences of it was performed using technology assessment (TA). TA is an evaluation process that aims to protect people/society from the consequences of rapid technological developments and attempts to identify all the possible impacts of a technology, not just the intended ones.1 Today, technology in this context refers not only to the logical products of science, but also to the attitudes, processes, apparatus and consequences associated with it, and in that wider meaning, the principles of TA are well suited to the evaluation of process validation as a tool for pharmaceutical manufacturing.	

There are a number of different methods of TA; this study used the synthesis (the compilation and evaluation of all available knowledge1) method. Initially, a literature search was performed,2 which revealed a lack of European experts' comments. Therefore, during autumn 2001, an experimental survey was conducted amongst European experts in pharmaceutical fields of manufacturing, regulation and academia to unearth their opinions.	

The main objectives of the study were to explore the value of process validation and to ascertain the best tools to perform it. Additionally, the study provided an opportunity to test how the principles and methods of TA could be used in the field of pharmaceutical quality assurance.				

Given that there is no single solution to process validation and that the value of process validation cannot be evaluated by using solid empirical measurement, but rather by informed judgement, 3 a discussion group was found to be an effective method for collecting information. For this reason, the Delphi method was chosen.				

Delphi method. The procedure used in the Delphi method aims at structuring and distilling the mass of information from a selected group of experts by means of a series of questionnaires based on a structured process with controlled feedback.4 Moreover, this method was chosen for the following benefits:	

it enables participants from various countries and different fields (industry, authorities, schools) to take part

it allows anonymous participation; a benefit that was of special value because the survey intended to facilitate discussion between the industry and its authorities, and to obtain comments from different organizational levels

participants can take part asynchronously; that is, one may choose when to participate

participants can choose to contribute to areas in which they are best qualified.

For development in the Delphi survey, see sidebar "Changes in the Delphi survey."

The Internet and e-mail. To accelerate communication, the Internet and e-mail were used. Using the Internet was also beneficial because it offered supporting tools for group communication, such as the potential for online discussion.6 Furthermore, the Internet provides a better and more illustrative means of informing the participants of the survey's key elements.		

Although TA synthesis methods are frequently used to predict future scenarios, they can also be employed to critically examine the state-of-the-art of a given field.1,7 One of the most popular tools of synthesis is the Delphi technique. The aim of most Delphi techniques is the reliable and creative exploration of ideas or the production of suitable information for decision-making.				

The replies to one round of questions are summarized and used to construct the next questionnaire. This reiterative process is continued until consensus or clear disagreement is reached among the participants.	

One disadvantage of the Delphi method is the definition and selection of experts; that is, whom to regard as an expert and how to create a representative group. 				

For this survey, experts were defined as those people working on process validation in:	

Representatives of the pharmaceutical industry were chosen from quality assurance, production and product development positions; representatives of the authorities had to either evaluate pharmaceutical and chemical aspects of the marketing authorization applications or work in inspection; and the representatives of pharmaceutical education had to teach process validation. Further details were unspecified; educational background was disregarded and the objective was to obtain the widest possible representation of different organizational levels. The level of experience of pharmaceutical process validation would have been of interest, but because of the limited number of experts in the field, this issue was not used as an exclusion criterion. 

Given the pharmaceutical industry's sensitivity concerning knowledge sharing and to get both the regulating authorities and the regulated industry involved in the survey, anonymity was regarded as essential.	

The search for participants took 5 months and was the most challenging part of the survey, particularly contacting industry experts because their e-mail addresses could not be located. To find suitable people from the pharmaceutical industry, a snowball method was used.23 Additionally, addresses for quality assurance, product development and production experts were requested from the representatives of appropriate foreign companies in Finland and from the qualified persons of appropriate domestic companies. However, only a few participants from the foreign companies participated because the representatives did not know who the right people were to ask, or the company refused to participate because of time constraints. The only effective way of obtaining willing participants was finally found to be direct telephone contact; this method also worked well for all three pharmaceutical fields.		

The size of the expert group is also important to the outcome of a Delphi study, but it depends on the homogeneity of the expert population and whether the study searches for qualitative or quantitative results.23 Other Delphi surveys have varied in size from 10–15 up to 2000–3000.23,24 For this survey, the number of experts was limited and the study mainly searched for qualitative results. Thus, a group of approximately 30–50 participants was considered apposite.	

An extremely important part of the Delphi method is the questionnaires, particularly the first round questionnaire (Q1). Q1 needs to be easy and clear, to motivate and encourage the respondents; otherwise they may lose interest.				

The design of the questionnaires was carefully discussed by the advisory group before the start. The objective was to form easy-to-use and fast-to-complete questionnaires. It was agreed to keep the number of questions to a minimum and to limit the use of open-ended questions. Not only would these measures avoid making the survey too time consuming, but they would deter those who would use these factors as reasons for abandoning the survey. The use of open-ended questions is, though, often found necessary to eliminate the possible external bias linked to the guiding role of the investigator.7 Instead of open-ended questions, the external bias was eliminated using a mixture of negatively and positively influenced arguments. The questionnaires were also pre-tested with a pilot study among the advisory group and external experts.	

Although the aim was to identify the attitude on the usefulness of pharmaceutical process validation, a further aim was to establish whether there are differences in attitudes between European countries or the different parties.	

Operationalization of the subject was done under five headings:	

How do you feel about process validation?

What are the benefits of process validation?

What are the negative aspects of process validation?

How can we make process validation easier and more effective to get the most from it?

What hinders positive thinking on process validation?

The first three questions were designed to measure the overall attitude towards process validation and the final two were mostly determined the reasons underlying the attitudes, and also attempted to find out if some specific tools of process validation were known among the participants.

The initial round started with a background information questionnaire, which also included one final question estimating the overall opinion on process validation. This questionnaire was to be completed before commencing Q1, and thus, the last question served as a control, measuring the attitude at the beginning of the study. The same question was repeated at the end of the second round questionnaire (Q2).	

Q1 consisted of 31 questions, most of which were multiple-choice. Only three of the questions were open-ended to increase the inclination and quality of personal expression. Q2 included some new or modified questions, but most were repeated in their original form together with a summary of the answers from Q1. 		

Figure 5:  Pharmaceutical participant demography: gender, education and age.	

In Q2, the opportunity to add comments was provided after every question and was encouraged by offering participants the option to answer in their native language. Also in this round, the questions were posed in a slightly different order, with the addition of one new heading - "Cost of validation." In Q1, questions concerning the cost of validation had been spread under other headings.	

The Internet as an environment for the survey 

The WebCT (WebCT, Inc., Lynnefield, Massachusetts, USA) learning environment26 was chosen as the platform for the survey because it was already being used in Helsinki University and offered the required tools. Extranet homepages were constructed and the questionnaires, together with supporting communication tools and information pages, were available from the Internet public page. The participants were e-mailed the passwords required to access these pages.				

Guidance and other information, including definitions of the critical terms, were offered on the homepages and an online forum was available for anonymous discussion. The discussion area was continuously available and an online forum was organized twice during the survey - before and after Q2. The surveys' Internet public homepage can still be viewed.	

Response rate and expert demography. Of the total 73 used e-mail addresses, 36 experts' responses to Q1 were received, 28 of whom continued to Q2. Thus, the response rates were 49% and 38% respectively, for Q1 and Q2.				

Some of the experts' demography can be seen in Figures 1–5, which show a comprehensive variation in their background. There were participants from Finland, Denmark, France, Germany, the UK, Norway, Sweden, Belgium, Iceland and Switzerland; however, the number of participants from each country was not equal.		

During autumn 2001, a Delphi survey was conducted using the Internet to discover the opinions of European experts from the pharmaceutical fields of industry, regulation and academia regarding pharmaceutical process validation. The Internet Delphi method was found to be an appropriate tool for exploring the opinions and experiences of pharmaceutical manufacturing because it allowed anonymous participation and discussion between geographically dispersed parties. However, to obtain reliable results, many factors were taken into account, as this article examines.

Using a Delphi Survey to Assess the Value of Pharmaceutical Process Validation Part 1: Survey Methodology

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.	

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).

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.