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22 BioPharm International eBook September 2019 www.biopharminternational.com Regulatory Sourcebook Pharmacopoeia Compliance Series Table II. Examples of compendial compliance observations from FDA 483s. USP is United States Pharmacopeia. Year Observation 2018 The firm has not established that your purified water system is adequately designed, controlled, maintained, and monitored to ensure it consistently produces water that meets Purified Water USP monograph specifications and appropriate microbial limits. 2017 The firm has not established or implemented all appropriate specifications for the active pharmaceutical ingredient in accordance with the accepted USP standards and consistent with the manufacturing process. Specifically, the firm has not included a control of all process impurities such as residual solvents. 2017 The firm does not always follow of ficial USP monographs when testing drug products for release and distribution to the United States. 2016 Grow th promotion test is not per formed in accordance with standard pharmacopeia. 2016 The USP test method for Loss on Dr ying, which is used for the release of finished product to market has not been verified. 2016 The firm could not provide documentation to show that you did not use an expired batch of USP reference standard. The laborator y staf f does not document and record the expiration dates for of ficial USP standards. 2013 USP-grade active pharmaceutical ingredients are not always fully tested against USP monographs (e.g., Identification, Acidit y, Alkalinit y, Chloride, Sulfate, Residue on Ignition). 2012 Compendial methods for active pharmaceutical ingredients are not verified under actual conditions of use (e.g., Water Determination, Loss on Dr ying, Reside on Ignition). 2010 The firm does not per form current USP monograph testing (e.g., Assay, Identification, Distillation Range) on the final active pharmaceutical ingredients prior to distribution for use in human and veterinar y drug products. 2009 USP active pharmaceutical ingredients have been released for distribution by the firm prior to testing and/or which did not meet USP specifications (e.g., Assay, Loss on Dr ying). 2009 The firm's procedure for stabilit y testing is insuf ficient. The firm does not test the stabilit y samples of USP-grade material to ensure compliance with the USP method and limit for moisture content. drug substances and excipients, and additional information related to packaging, labeling, storage, etc. All this information must be taken together to determine the specific quality requirements for bio/phar- maceutical products. Within each phar macopoeia, there is a section referred to as general notices, which is critical to the full understanding of the scope and technical approaches in that pharmacopoeia. As stated in the USP–NF, the general notices section presents the basic assump- tions, definitions, and default con- ditions for the interpretation and application of the USP–NF, and the requirements apply to all articles recognized in the compendia and to all general chapters, unless spe- cifically stated otherwise. Similarly, the general notices in Ph. Eur. and other pharmaco- poeias apply to all monographs and other texts in the pharmaco- poeia. The general notices provide a wide range of important infor- mation, from a statement of what conformance to compendial stan- dards means, to a description of specific monograph components, considerations for the use of alter- native methods, rules for round- ing, and a definition of "about". They have been described anecdot- ally as the most important pages of the pharmacopoeia that most users have never read. Thus, read- ing and understanding the general notices is critical to ongoing phar- macopoeia compliance. There are more than 350 gen- eral chapters in USP–NF, and more than 370 general texts in Ph. Eur., i nclud i ng genera l monog raphs and chapters. Many of the general chapters in the pharmacopoeias are mandatory and enforceable by regulatory authorities, containing information on specific chemical, biolog ical, and microbiolog ical test methods and assays, as well as specific requirements for particu- late contamination and packaging components, for example. O t her genera l c hapter s may instead be informational and not necessarily enforceable, intended to provide background knowledge and practical considerations that are useful to bio/pharmaceutical manufacturers' understanding of the production, testing, and over- all quality of their products. In the USP–NF, these informational chap- ters are numbered above <1000> and include <1079> "Good Storage and Distribution Practices for Drug Products," <1121> "Nomenclature" a n d <1 2 2 6 > " Ve r i f i c at i o n o f Compendial Procedures." The Ph. Eur., JP, and other pharmacopoeias similarly contain general chapters that are mandatory and enforce- able, as well as chapters that are stated as being for information and non-mandatory. It is worth noting that Ph. Eur. Chapter 5.4 "Residual Solvents" represents the information contained separately in the International Council for Harmonization (ICH) Q3C guide- line, a reminder of the important connection that may exist between reg ulator y g u ida nce a nd pha r- macopoeia requirements. This is