Charting Process Improvement in Sterile Product Manufacturing

Sterile product manufacturing and related testing have evolved significantly during the last 30 years. From requirements for acceptance criteria for media-fill tests, to developing validated approaches for moist-heat sterilization, to the introduction of formalized sterility-testing practices, the pharmaceutical industry has made significant advances in testing and in key technology such as isolators, prefilled syringes, automation, and robotics. The author outlines the key regulatory and technical..
Jul 02, 2007
Volume 31, Issue 7

I am honored to have been asked to contribute an essay on the occasion of Pharmaceutical Technology's 30th anniversary. I became a regular reader of this fine publication in 1981, only four years after PharmTech's beginning. So, I can honestly say that I've grown up in this industry alongside Pharmaceutical Technology. It has been a distinct pleasure to read the magazine and to make the occasional contribution to its contents over the years.

An evolution in testing

Milestone. 30 years of Pharmaceutical Technology
My primary field of interest has been well-covered in this periodical during its 30 years of service to the industry and has developed in ways that neither I nor, I suspect, those responsible for the technical content of Pharmaceutical Technology could have envisioned fully back in 1977. Incredible as it may seem, media-fill tests were not a universal requirement. In fact, these process-simulation tests were not extended to all types of aseptically produced dosage forms until several years later. The first international standard that mentioned an acceptance criterion for media-fill tests, to the best of my knowledge, is the WHO Technical Bulletin No. 28 that suggested a 0.3% contamination rate (1). When I started in this business, many firms considered 9 positives out of 3000 units filled to be a successful media-fill test. Just writing the previous sentence today leaves me shaking my head in amazement at how far capability and expectations have evolved in the past 30 years.

Process validation emerges

Not only was the media-fill test only starting on the pathway to becoming a mandatory requirement, in 1977 the word validation was only starting to enter our lexicon. At that point, firms were validating autoclaves, and that was by and large the full extent of process validation. The appropriate approach for validation of moist-heat sterilization processes would have been a topic of considerable debate in 1977, although Irving Pflug, PhD, Carl Bruch, PhD, and other sterilization scientists were hard at work attempting to educate what was already an audience eager for knowledge. The seminal industry document about moist-heat sterilization, PDA Technical Monograph No. 1 (2) had not yet been issued at the time Pharmaceutical Technology began publication. It is with some disappointment that I must report that in some ways the art and science of sterilization validation has actually regressed over these three long decades. The clear thinking and analytical approach of Dr. Pflug has been replaced by a mishmash of requirements, some of which seem to have been borne out of worst-case thinking run amok or by efforts to force parochial approaches on industry, ironically enough in the alleged interest of harmonization. What has not changed is that sterilization, in 2007 as in 1977, is still a process best measured by microbiological analysis. The statement that will forever be associated with Dr. Pflug still rings true today: "The bugs don't lie." It is important to remind ourselves that those spores are just as honest and reliable evaluators of sterilization now as they were in 1977. None of the foregoing is intended to diminish the importance of thermometric and pressure data; it is to remind the reader that the purpose of sterilization is to destroy microbial contamination. Thankfully, there are ample data on the destruction of microorganisms by moist heat, heat, radiation of various types, and chemicals, so let us not reinvent the wheel.

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