Tablets & Capsules

© Copyright Tablets & Capsules 2020 usp.org Highlights of USP's analysis of the 2017 –2018 FDA warning letters include the following: Failure to test component samples or validate supplier COA. Thirty-eight companies were cited between January 2017 and November 2018 for failing to conduct at least one identity test of incoming components of the drug product prior to release to production and/or failing to test for conformity to appropriate specifications for pu- rity, strength, and quality of each component (or in lieu of such testing, failing to establish the reliability of their supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals). Warning letter recipients were instructed to provide the FDA with the procedures they would use in the future to test incoming components, including excipients, for conformity with all appropriate written specifications for identity, purity, strength, and quality. If the recipients accept their suppliers' COAs in lieu of testing the components for purity, strength, and quality, the warning letters direct the recipients to spec- ify how they plan to establish the reliability of their suppliers' test results through periodic validation. Import alerts. Twenty-eight of the 38 companies that re- ceived FDA warning letters in 2017 and 2018 citing excipient testing deficiencies were located outside the US, including facilities in Australia, Austria, Canada, China, France, Hong Kong, India, Ireland, Mexico, South Korea, Spain, Taiwan, and the United Kingdom. The warning letters cited all of these facilities for multiple cGMP violations, and the FDA placed all but three of them on import alert. According to the FDA's website, placing a facility on im- port alert means that the agency has enough evidence to allow for the detention without physical examina- tion (DWPE) of products from that facility that appear to be in violation of FDA laws and regulations. Further- more, the FDA warning letters notified these companies that the FDA may withhold approval of any new appli- cations or supplements listing their firm as a drug man- ufacturer and may continue to refuse admission of the companies' products until all violations are corrected and the FDA has confirmed their compliance with cGMP. Testing for diethylene glycol (DEG) in glycerin. FDA warning letters to six companies in 2017–2018 citied their failure to analyze lots of glycerin raw material from their suppliers for the presence of DEG and ethylene glycol. DEG contamination in glycerin-containing pharmaceuti- cals was first recognized as a problem in 1937 and has resulted in numerous lethal poisoning incidents in humans worldwide. Both the FDA and industry have tried to ed- ucate manufacturers to help ensure that they are using quality materials. USP has updated the glycerin mono- graph to include this adulterant as part of the required identification test, and the FDA issued a guidance on the testing of glycerin for DEG [2]. Five firms cited in 2017–2018 warning letters that failed to follow USP's established testing procedure for DEG con- tamination in glycerin raw material from their suppliers were instructed to provide a detailed risk assessment for their drug products containing glycerin that were within expiry in the US market. If the firms found that they had released any batch for which results were out of speci- fication, they were instructed to indicate the corrective actions they would take, such as customer notifications and product recalls. One additional firm had already initi- ated a recall of all their drug products from the US market because of cGMP violations, including failure to test for DEG contamination in glycerin, prior to being issued an FDA warning letter. Contract manufacturers. Several of the warning letters in 2017–2018 notified drug manufacturers that, as contract facilities, they are responsible for the quality of the drug products they produce regardless of the quality agree- ments they may have with their suppliers or product own- ers. In other words, they are required to ensure that drug products are made in accordance with the cGMP require- ments for safety, identity, strength, quality, and purity. The FDA has issued a guidance on contract manufacturing and quality agreements [3]. cGMP consultants. In 36 of the 38 excipient-related warning letters from 2017–2018 that USP analyzed, the FDA strong- ly recommended that companies engage a qualified con- sultant to assist their firm in meeting cGMP requirements. In one of the remaining cases, the FDA acknowledged that the company had already hired a cGMP consultant. USP standards and resources USP's science-based public standards and resources can help with drug component testing and supplier COA val- idation. For example, USP monographs and quality stan- dards for excipients provide the appropriate, validated test procedures to establish the identity, purity, and lim- its of contaminants in an excipient. Currently the United States Pharmacopeia and the Natural Formulary (USP- NF) includes more than 530 excipient monographs. In addition, USP is continually developing new monographs and public standards for materials that are not currently contained in USP-NF. USP also maintains extensively characterized physical ref- erence standards that help pharmaceutical manufacturers verify the quality of their excipient supply. These specimens have well-defined physical and chemical properties and when used in conjunction with the monograph help ensure the identity, strength, quality, and purity of materials. USP encourages manufacturers to provide information for the development of new monographs or to donate reference standard candidate materials. 7

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