Issue link: https://www.e-digitaleditions.com/i/1173734
Tablets & Capsules October 2019 11 for purity, 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 pro- vide 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 compo- nents for purity, strength, and quality, the warning letters direct the recipients to specify how they plan to establish the reliability of their suppliers' test results through peri- odic validation. Import alerts. Twenty-eight of the 38 companies that received FDA warning letters in 2017 and 2018 cit- ing excipient testing deficiencies were located outside the US, including facilities in Australia, Austria, Can- ada, China, France, Hong Kong, India, Ireland, Mexico, South Korea, Spain, Taiwan, and the United Kingdom. The warning letters cited all of these facilities for multi- ple cGMP violations, and the FDA placed all but three of them on import alert. According to the FDA's website, placing a facility on import alert means that the agency has enough evidence to allow for the detention without physical examination (DWPE) of products from that facility that appear to be in violation of FDA laws and regulations. Furthermore, the FDA warning letters notified these companies that the FDA may withhold approval of any new applications or supplements listing their firm as a drug manufacturer 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 cited 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 pharma- ceuticals was first recognized as a problem in 1937 and has resulted in numerous lethal poisoning incidents in issued between 2013 and 2018. This increase represents a significant uptick in warning letters that expressly iden- tify excipients or inactive ingredients in current good manufacturing practice (cGMP) violations. We note that a majority of the 38 warning letters issued in 2017 and 2018 were sent to firms that manu- facture over-the-counter (OTC) medicines. FDA has stated that in the past several years it has been work- ing to inspect all facilities that had not been previously inspected [1]. The agency also noted that this work has contributed to an increase in basic cGMP problems iden- tified in facilities making lower-risk OTC medicines. According to the FDA's Regulatory Procedures Manual, the agency issues warning letters for violations of regu- latory significance. The FDA warning letters analyzed by USP are written notifications that the FDA has found manufacturers to have violated cGMP regulations such that their drug products are adulterated within the mean- ing of the Federal Food, Drug, and Cosmetic (FD&C) Act. The letters also inform the companies that they are responsible for correcting the problems cited and inform- ing the FDA of their plans for correction. Warning letters give firms an opportunity to take voluntary and prompt corrective action before the agency initiates an enforce- ment action, if warranted. According to the warning letters: • Pharmaceutical manufacturers must perform at least one test to verify the identity of each drug component; and • If relying on COAs from suppliers for confor- mity with other appropriate written specifications, manufacturers must validate and establish the reli- ability of the suppliers' test analyses at appropriate intervals. Analysis of excipient-related FDA warning letters USP staff reviewed the FDA warning letters posted on fda.gov for cGMP violations issued by CDER's Office of Manufacturing Quality and the Office of Regulatory Affairs (ORA) district offices from 2013 through 2018 to pharmaceutical manufacturers that marketed drugs in the US. USP staff searched the letters for keywords that indicated excipient testing issues, such as excipient (or a specific excipient), inactive ingredient, drug components, or raw materials, separate from active pharmaceutical ingredients and noted the specific Code of Federal Reg- ulations (CFR) violations cited in the warning letters. Table 1 shows the number of FDA warning letters issued to drug product manufacturers each year that mention excipients or inactive ingredients for the years analyzed. Highlights of USP's analysis of the 2017–2018 FDA warning letters include the following: Failure to test component samples or validate sup- plier 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 fail- ing to test for conformity to appropriate specifications Table 1 Excipient-related FDA warning letters issued to drug product manufacturers by year (2013–2018) Year Excipient-related warning letters 2018 21 2017 17 2016 0 2015 1 2014 0 2013 2