Pharmaceutical Technology - May 2018

Pharmaceutical Technology eBook - Biologics and Sterile Drug Manufacturing

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Page 50 of 61

Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 51 A brief history The need for formal process validation became evi- dent following a series of incidents beginning in the early 1960s. Thalidomide, a widely prescribed drug for morning sickness in pregnancy, was de- termined to have caused birth defects, leading to the 1962 Kefauver-Harris Amendment to the US Federal Food, Drug, and Cosmetic Act, which, among other provisions, authorized FDA to issue good manufacturing practice (GMP) regulations for "manufacturing, packaging, or holding of fin- ished pharmaceuticals." Those regulations were fi- nalized in 1963 as 21 Code of Federal Regulations (CFR) 133 "Drugs; Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding" (1). During the period 1966–1972, a series of inci- dents at Evans Medical Ltd., Liverpool, England, led to the deaths of five people due to microbially contaminated infusion f luids. The contamination was found to be due to problems with the auto- claves used to process terminally sterilized paren- terals (2). From 1970–1973, a series of septicemia events in hospitals throughout the United States due to contaminated IV f luids were linked to inadequate container-closure systems and terminal steril- ization conditions for large-volume parenterals (LVPs) produced by several manufacturers. Fol- lowing a series of inspections, FDA questioned the manufacturers' ability to ensure sterility of these products, leading to the promulgation of GMP regulations for LVPs in 1976 (3). Although the LVP GMP regulations were never finalized and were ultimately withdrawn, they established formalized requirements for the validation and monitoring of critical processes such as sterilization. When the US GMP regulations underwent a major revision in 1978, validation requirements for sterilization processes were included (4). Subse- quent revisions to US and international regulations and guidance documents stressed the need for pro- cess validation and quality management systems to ensure pharmaceuticals and biopharmaceuticals are safe and effective. In May 1987, FDA issued a draft process vali- dation guidance document for comment (5). That draft guidance was followed by two more, one in 2008 (6) and one in 2011 (7). Each of these guid- ance documents was intended to clarify FDA's ex- pectations regarding process validation. The International Council for Harmonization (ICH), an organization composed of regulatory authorities from the US, Europe, Japan, Canada, Switzerland, Brazil, China, and the Republic of Korea, and representatives of pharmaceutical in- dustry organizations, has published a series of documents that, among other things, relate to process validation: Q6B for setting specifications for biotechnological and biological products (8), Q7A for active pharmaceutical ingredients (9), Q8 for pharmaceutical process development (10), Q9 for quality risk management (11), Q10 for phar- maceutical quality systems (12), and Q11 for drug substance development and manufacture (13). In 2007, ASTM International published E2500, Standard Guide for Specification, Design, and Verifica- tion of Pharmaceutical and Biopharmaceutical Manu- facturing Systems and Equipment, which describes an alternative to conventional process validation (14). The literature is full of references to process vali- dation, and many of them seem to be contradictory. What is process validation, really? To understand this, we need to define "process" and "validation."

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