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4 BioPharm International eBook December 2019 • Poorly maintained equipment and facilities • Inadequate maintenance and monitoring of water systems • Insufficient cleaning validation processes • Inadequate—or the lack of— written procedures for stabil- ity testing, release testing, and other quality testing steps • Inadequate controls over data and computer systems • Failure to explain discrepancies in drug batches • Failure to have an adequate quality control unit. A recent warning letter illustrates how an inadequate response to vio- lations can create additional prob- lems for a drug company. Mylan Laboratories received a warning letter for failing to have adequate written procedures for the receipt, identification, testing, and han- dling of raw materials. Specifically, the citation addressed the compa- ny's failure to identify nitrosamine impurities in solvents used to manu- facture valsartan API. The company also was cited for inadequate pro- cesses for testing and handling of these solvents and the subsequent steps the company took to remedy the problem. In addition, FDA noted that Mylan's cleaning methods for non-dedicated equipment were not adequate to prevent contamination or carry-over to other drugs manu- factured on that equipment (3). Another letter, to Greenbrier International—the Dollar Tree dis- count stores—illustrates two points: quality issues by contractors can result in warning letters to the drug license holder, and drug license holders must pay close attention to regulatory enforcement activity. In a January 2019 inspection, FDA noted that Greenbriar "used contract manufacturers and suppli- ers with histories of significant drug CGMP [current good manufactur- ing practice] violations." Some sup- pliers were placed on import alert, and Greenbriar was sent copies of the warning letters when issued. In addition, FDA noted that Greenbriar required suppliers to use a testing laboratory, Bureau Veritas (BVS), to test products it distributes. BVS representatives told FDA that BVS's test methods "were not suit- able for drug CGMP purposes and that its test results were not suitable to make release decisions of drug products for distribution into the US supply chain." FDA reminded Greenbrier that the company was "responsible for ensuring that the drugs you distrib- ute are not adulterated, including ensuring that all drug manufactur- ers supplying Greenbrier with drugs have had release testing conducted in accordance with CGMP require- ments" (4). IN THIS ISSUE T he latest insta llments of t he Pharmacopoeia Compliance Series emphasize the need for drug com- panies to establish formal processes to monitor global and national pharmacopoeia changes to stay i n for med, a nd potent ia l ly get involved with defining changes in compendial guidelines. Likewise, the quality teams at drug compa- nies and contract service providers should closely monitor regulatory enforcement activity. FDA's online compliance information and Data Dashboard are useful references. Links to other regulatory sources can be found in this ebook on pages 38–43. REFERENCES 1. FDA, Novel Drug Approvals for 2019,, accessed Dec. 11, 2019. 2. FDA, FDA Data Dashboard, accessed Dec. 11, 2019. 3. FDA, Mylan Laboratories Limited - Unit 8, Warning Letter, Nov. 5, 2019. 4. FDA, Greenbrier International, Inc dba Dollar Tree, Warning Letter, Nov. 6, 2019. BP Regulatory Sourcebook Enforcement Update Draft Guidance Proposes Approval Pathway for Insulin Biosimilars FDA is seeking comment on a draft guidance, Clinical Immunogenicit y C onsiderations for Biosimilar and Interchangeable Insulin Products, that is designed to clarify what data and information may–or may not–be needed to support a demonstration of biosimilarity or interchangeability for a proposed insulin product (1). In the draft guidance, the agency recommends that, under certain circumstances where the agency expects the risk of clinical impact from immunogenicity to be minimal, a comparative clinical immunogenicity study would not be necessary for approval of certain proposed biosimilar and interchangeable insulin products. However, for some products, a comparative clinical immunogenicity study may be needed to address uncertainty regarding immunogenicity, such as were there are differences in certain impurities or novel excipients the agency noted. Applications for the proposed products must include data and information sufficient to demonstrate biosimilarity or interchangeability. Public comments on the draft guidance will be accepted via this link until Jan. 28, 2020. Reference 1. FDA, "Statement on Efforts to Help Make Development of Biosimilar and Interchangeable Insulin Products More Efficient," Press Release, Nov. 25, 2019.

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