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8 Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 P h a r mTe c h . c o m Aseptic Manufacturing cal contaminants"(17). This requirement creates a regulatory environment in which the only accept- able outcome, at least from a compliance perspec- tive, is absence. This ignores scientific realities, and limitations in sampling, microbial recovery, as well as the potential for both false negatives and false positives. It also ignores the fact that microbiology is a logarithmic science, and reliable quantification below 1 log is simply not possible (11). Non-sterile products Absence of specified organisms. Some microorgan- isms induce adverse reactions in patients, and their presence in non-sterile drug products is considered unacceptable. Zero-microbial limits may be well intended, but the reality is simple. Products manufactured from non-sterile ma- terials under non-aseptic conditions without a terminal sterilization process can never be com- pletely free of microbial content (18). Thus, the globally harmonized pharmacopeial desire for absence of microbes is based upon a false prem- ise. Simple testing cannot confirm the absence of anything. Blend and content uniformity. Similarly, one cannot prove that each and every unit of a solid dosage- form batch has the strength and potency that it is purported to possess. This is especially true where the percentage of active ingredient(s) in the formulation is low. Blend uniformity and content uniformity testing, combined with dissolution testing, can provide some assurance in this regard; however, the level of confidence is predicated on the robustness of the manufacturing process and conditions along the supply chain. Sampling, including sample size and location, also affects the validity of the evaluation. To be meaningful, such testing must be based on the presumption of adequate process control. Studies have shown that, in addition to sampling location, sample size is critical in establishing the validity of the analytical result (19). Two extreme examples serve to illustrate the point. Assuming the correct amounts of material have been added to a blender, if the sample con- sists of the entire blender load, the content of the active ingredient(s) will be 100% of the theoretical formulation amount. At the other extreme, if the sample from the blender consists of a single grain, the measured concentration of the active could range from zero to far in excess of the formula- tion amount (20). It is only through process control, process vali- dation, and rigorous sampling protocols that the results of content uniformity testing will be a meaningful measure of what the patient receives in each dosage unit (21). The old advertisement, "The one you took wasn't tested," is always true. Trace impurities. Where materials are present in trace amounts, the assay limit of detection and sensitivity are important factors. Sometimes, specifications do not correspond with the limit of detection, resulting in uncertainty regarding the concentration of the impurity, or even its presence or absence. The globally harmonized phar- macopeial desire for absence of microbes is based upon a false premise. Simple testing cannot confirm the absence of any- thing.