Jyrki Heinamaki

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.