A Literature Review of Pharmaceutical Process Validation 1

By: Marjo-Riitta Helle, Jouko Yliruusi, Jukka-Pekka Mannermaa
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.

Current definitions of pharmaceutical process validation

Current definitions 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." 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.
Confusion 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)
Historical background 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.

Table I: Regulatory history of process validation in the US and Europe.

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. 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)