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.		

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Features

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

During 1999, DMV International (Veghel, The Netherlands) began an ambitious programme to implement current good manufacturing practice (cGMP) for the production of active pharmaceutical ingredients (APIs) conforming with International Conference on Harmonization (ICH) Q7A guidelines. Three years later, DMV received official notification from the US Food and Drug Administration (FDA) that its Veghel facility, which manufactures pharmaceutical lactose, had passed inspection.	

As a global supplier of pharmaceutical excipients, DMV has been aware of the increasing demands of the pharmaceutical industry during recent years. Although no regulations exist with respect to GMP for excipients, DMV had already implemented a quality system based on the US Guidance on Good Manufacturing Practice for Bulk Pharmaceutical Excipients, (United States Pharmacopeia <1078>). 				

However, moving into the 21st century, it became obvious that this level of quality would no longer fulfil the needs of customers. Pharmaceutical companies began requiring increased quality levels from raw material suppliers. This was highlighted during audits that focussed increasingly on areas such as process validation, cleaning and computer systems, and more detailed documentation, reflecting the expectations of US and European companies.	

In addition to pharmaceutical lactose for wet granulation, DMV's strategy focussed on developing and marketing lactose for direct compression and dry powder inhalation. Specifically, given its application, the latter is treated as though it were an API. Consequently, in 2000, DMV decided to upgrade its existing quality system to API standard in compliance with ICH Q7A guidelines.							

To realize this ambitious plan, DMV implemented Pharma 2000 - a project backed by the company's board, which assembled a multidisciplinary team of 40 people. Based on an analysis of current standards versus ICH standards, a detailed action plan was drawn up that would allow stepwise improvements to attain the required quality level. Major areas of attention included the quality assurance/quality control (QA/QC) structure; training; documentation system; procedures and working instructions; and the validation programme. Project progress was continually monitored by internal audits and the company's customers were actively involved in the process, providing useful advice and information. 	

After 2 years of hard work, an external consultant was asked to conduct a mock FDA audit of the facility to API standards. The report concluded that the GMP system had been successfully installed and that DMV could move to the next phase of further implementation and increasing understanding within the company. In June 2002, the consultant returned to the facility and reported that DMV had sufficiently implemented cGMP and increased awareness to a level that would pass an FDA inspection.	

Only 2 months later, DMV was officially informed that FDA planned to inspect the Veghel manufacturing plant. The inspection was triggered by a DMV customer who registered an inhalation product in the US that used pharmaceutical lactose as the carrier. The inspection was scheduled for October 2002 and was to be conducted by an investigator and a microbiologist. 				

Full preparations were made with the management of the operations and QA divisions heading the process, including training of all personnel involved. The company's commitment, previous experience and appreciation that there is only one chance to succeed meant that DMV was fully prepared for the inspection.	

The inspection took place in October. Originally meant as a preapproval inspection in relation to the inhalation product mentioned previously, the investigator extended the audit to a general cGMP systems audit, covering the complete range of pharmaceutical lactose and using the ICH Q7A for APIs as a reference. During the exit meeting, DMV was complimented for its solid quality system and implementation. A Form 483 was issued with only one minor observation. The efforts of all involved DMV employees had paid off, leading to this major success.	

In December 2002, FDA notified DMV International that its pharmaceutical lactose manufacturing facility in The Netherlands had passed inspection. It was only 3 years earlier that DMV had started an ambitious programme to implement cGMP for API production conforming with ICH Q7A guidelines.

Inspection Success for DMV

In the Brussels Report of the April issue of Pharmaceutical Technology Europe,1 Albedo stated that despite of the European Union's (EU's) wish to keep pharmaceutical and biotechnology development moving in the right direction, things are not going according to plan. This is hardly surprising given that the EU's answer to most problems in the industry is to write another piece of legislation. However, this only achieves the opposite effect and forces EU companies to relocate - mainly to the US.	

Indications during the last 5 years suggest that many of the big pharmaceutical companies have moved their research and development (R&D) units to the US, leaving Europe with mainly small-sized companies.2 No reasons have been provided for the moves, but the US must offer something that Europe does not. This article briefly considers the possible reasons why large pharmaceutical companies are relocating from Europe to the US.	

Europe is not short of highly qualified scientists and salaries are not significantly different compared with the US.3 The market size of both is similar, although Europe will perhaps has a slight advantage after enlagement in 2004. Prices paid by health servers and insurance companies in Europe are lower than in the US, making Europe less profitable to big pharmaceutical companies. Perhaps relocation is being caused by regulations.	

Every year, European pharmaceutical companies are burdened with as many as 3000 pieces of non-pharmaceutical legislation in addition to hidden and overt tax increases such as business rates; national insurance and/or health insurance increases; environmental levies; inheritance law changes; and compliance with national fiscal policies. Over-rigorous application of EU laws by some countries, such as the UK, has resulted in large additional costs including compliance with health and safety regulations and environmental pollution laws. This means that the authorities spend a significant amount of time inspecting compliance in addition to normal good manufacturing practice (GMP) inspections.				

In many EU countries, corporation and personal taxes are much higher compared with the US and in some EU countries, unions are so strong that management can no longer run the business profitably. Although pharmaceutical regulations such as GMP are similar in both the US and the EU, they do differ in the way regulations are implemented. In addition to the EU regulatory body, the European Agency for the Evaluation of Medicinal Products (EMEA), each member state has its own regulatory body. If a company wants to market a product outside its home country, up to 14 other regulatory bodies must be consulted because a centralized EU registration system has not yet been widely adopted. 	

This means that companies have to employ an army of regulatory professionals and each product registration means multiple fees. In comparison, the US has only one body, the US Food and Drug Administration (FDA), and so companies only pay one fee. Translation fees can also be very expensive when they are required for registration in a member state that requires a different language.	

In the UK, another regulatory body, the National Institute for Clinical Excellence (NICE), deters product marketing because it evaluates if a drug is good value for money. NICE was established to end 'postcode prescribing' in the UK, where treatments are available from one health authority but not another. This, however, discourages pharmaceutical companies to bring new drugs to market in case they fail NICE's evaluation. Many other EU countries are now looking with interest at this new barrier to registration, which could save them money.				

Another reason why big pharmaceutical companies move their R&D operations to the US is because in the EU, there are too many changes too often, many of which are often unnecessary. For example, each country has its own laws regarding the registration, manufacture and marketing of dietary supplements and herbal medicines, which work very well for each country; the EU, however, has decided that these processes must be harmonized. This will mean additional costs and more uncertainty to an industry already overburdened by legislation and worried about its future, and some small manufacturers will go out of business. 				

Every country in the EU has a well proven system of clinical practice to evaluate new products, but this will no longer be allowed when  GCP is harmonized across the EU by directive EU.2001/10/EC, which will require further inspections and additional staff. As a result, many small companies and biotech start ups will no longer be able to afford to undertake clinical research. 				

Harmonization will bring with it criminal offences for breeching any of its regulations and directors of pharmaceutical companies could face prison sentences. These new penalties could also increase insurance premiums to the point where companies will be forced to stop R&D.	

A further barrier to research are patent fees. It has taken the EU more than 30 years to agree provisions for an EU-wide patent, although this is not yet in force. Therefore, individual country patents are required, which can cost up to e50000 to file in just eight member states; in the US and Japan, the cost is approximately e10000. This is extremely expensive for smaller companies, particularly biotech start-ups that need the patents.				

It is said that Europe subsidizes pharmaceutical R&D with grants. However, with the exception of the UK Department of Trade and Industry SMART Awards, this is not strictly true. The EU's Framework Programme Six grants are so limited and difficult to obtain they are only suitable for academia. 								

The application process is very complicated, and UK small and medium-sized enterprises (SMEs) are advised to apply for a preparatory research award (PRA) of E14000, which is paid to a consultant to examine the application on a company's behalf. The grant itself is structured in such a way that any resulting intellectual property rights (IPR) must be shared with other companies in other member states. 	

In comparison, the US offers funding for research via its National Institute for Health for cancer research and other diseases and the various states can provide funding to keep jobs in the state.2 Lenders in Europe generally do not take risks until a project is reaching maturity and even then rarely lend to small manufacturers.	

If the EU pharmaceutical industry does not want to fall too far behind its US counterpart, it must quickly understand that the decrease in pharmaceutic companies in Europe is directly proportional to the rise in European regulation. The additional legislation is causing increasing costs, which detrimentally affect SMEs. 				

The EU must realize that large pharmaceutical companies grow from smaller companies. During the last 10 years, there have been large numbers of redundancies in the industry caused by pharmaceutical mergers and acquisitions, but a reduction in the number of start-ups has meant that people have had to relocate to the US to find work. This vicious circle is causing the EU pharmaceutical industry to shrink.	

1.	Albedo, "More Trouble at the EU Pharmaceutical Mill," Pharm. Technol. Eur. 15(4), 13-16 (2003). 				

2.	Scrip Magazine No. 2840 11 April, 18 (2003).	

3.	M. Rios "Fifth International Employment Survey," Pharm. Technol. Eur. 15(1), 23-29 (2003).	

During the last few years, it has become increasingly apparent that many large pharmaceutical companies are moving their research and development operations to the US, leaving Europe with increasing numbers of smaller companies. This article briefly examines the possible motives for relocation, including the impact of regulation differences between the US and Europe.

Pharmaceutical Technology Europe-08-01-2003

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

Inspection Success for DMV

Why EU Pharmaceutical Companies are Being Forced to Relocate