Pharmaceutical Technology - May 2019

Pharmaceutical Technology - eBook

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Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2019 5 All test methods, however, are limited when they are required to confirm the absence of some- thing. 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. When combined with the vagaries of sampling, the act of report- ing "zero," "none," or "absent" as a test result is irresponsible. Thus, "absence of evidence is not evidence for absence"(3). Detection limits These issues are confronted directly in the follow- ing situations, when: • One attempts to measure things when the limit of detection is below the sensitivity of the mea- surement method. • The sample is not representative of the material from which it is taken. • The measurement method is not suitable for the attribute to be measured. • Sampling inf luences the final measurement. Examples include sterility testing of aseptically- manufactured sterile products; microbial envi- ronmental monitoring; container-closure integ- rity; visual inspection of parenteral products; trace impurity levels in APIs and excipients; blend uni- formity of wet and dry granulations; and content uniformity of dosage forms, especially those with low levels of active ingredients. When it is impossible to determine a quality at- tribute by testing, the correct approach is to rely on a system of measurements that yields accurate, reproducible, and definitive results for the param- eters being evaluated. These results can then be used to estimate the levels of an attribute that can't be directly measured. This approach is used, for example, in the parametric release of terminally sterilized parenteral products. It demonstrates a state of control, in which every action produces the intended result every time. The importance of validation To produce drug products that routinely and con- sistently have the identity, strength, quality, and purity they are said to have, the measurement sys- tem for production and quality control must be in a state of control. Quality cannot be verified through testing, especially at the limit of detection. This is where validation comes in. In the mid 1970s, validation requirements for sterilized products were set after some patients died after being treated with terminally sterilized parenteral drugs made in the United States and the United Kingdom (4,5). These drugs had all been tested and had passed the sterility testing require- ments of the time. To prevent any future problems, processes now had to be validated, and manufac- turers had to provide regulators with "documented evidence which provides a high degree of assur- ance that a specific process will consistently pro- duce a product meeting its predetermined specifi- cations and quality attributes"(6). Validation is based on independent verifica- tion that the operational controls (e.g., equipment, procedures, and materials) collectively provide confirmation that the system or process performs Any measurement comes with questions, not only of accuracy and precision, but of relevance.

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