Issue link: https://www.e-digitaleditions.com/i/1118782
6 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m as required. Parametric release, the most evolved state of validation, can assure what testing can- not: that the product meets its required quality attributes without analysis. Validation may not be able to provide absolute proof of the absence of a substance, but it comes closest to confirming absence and is substantially better than results de- rived from sampling and testing. Patient safety concerns A primary concern is patient safety when adminis- tering injectable products. The sterility test (7) was introduced in the 1930s, when injectable product manufacturing used primitive process equipment in minimally controlled environments and per- sonnel often interacted directly with sterilized materials. While the test's statistical limitations have long been understood, it remains a regula- tory requirement despite the many improvements that have been made to manufacturing processes since the 1930s (8). In commercial-scale opera- tions, passing the sterility test is minimally useful and can reliably detect microbial contamination resulting from failure of the sterilizing cycle or aseptic processing system, typically in the range of 15–20% of the units processed. There are also technical constraints to the ste- rility test: the test media supports a limited range of detectable microorganisms; the limit of detec- tion is non-zero, unknown; etc. (9). Recent efforts to develop rapid sterility tests have been similarly f lawed (10). Rapid sterility tests suffer many of the same limitations as the conventional test, includ- ing sampling, detectability, and sensitivity, albeit providing results more quickly. The presence of particles in parenterals has been associated with pain and other adverse effects and patient risks (11–12), the extent and importance of which are being debated. The complete absence of particles is, like the complete absence of microbes, or sterility, a laudable but unreachable goal that cannot be demonstrated by testing. Knapp estab- lished a level of "uncertainty of outcomes" from any inspection method (13) and the US Pharma- copeial Convention (USP) acknowledged this real- ity in the phrase "essentially free of particles"(14). This phrase implies the goal of no particles, but acknowledges that there will be some. Unfortu- nately, FDA's expectations do not align with the technical realities that Knapp elucidated so clearly, and numerous recalls of entire product lots have occurred after one single particle was detected in a single vial of product (15). Environmental monitoring Another technical issue concerns environmental monitoring, a practice that FDA has been sup- porting since the agency issued its first guidance on aseptic processing in 1986 (16). Expectations went off the scale when the 2004 version of the FDA guidance was released, which included the statement, "Samples from Class 100 (ISO 5) envi- ronments should normally yield no microbiologi- Aseptic Manufacturing An instrument may record zero, but that only means that whatever is being measured is 'not detected,' which is different from saying that it is 'not present.' All tests have a limit of detection below which they cannot be used.