致读者
允咨培训中心特邀请资深GMP顾问，每天为您解说几例具有代表性缺陷项问题背后的前因后果，'道不在于深而在于实用'，本系列文章只为让您的GMP执行不仅合规更要合理。
问题1. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
你们公司没有设置恰当的具有批准和拒绝所有原辅料、药品容器、密封系统、中间体、包装材料、标签及成品的职责与权力的质量管理部门。(21 CFR 211.22(a))
Your Quality Unit (QU) was responsible for releasing ophthalmic drug product manufactured under contract but failed to assure its sterility.
你们的质量部门（QU）负责放行委托生产的眼用药品，但却没能保证其无菌性。
You contract with (b)(4) to manufacture a multi-dose, preservative-free, homeopathic ophthalmic drug product for your customer, (b)(4). According to your quality agreement with (b)(4), you bore responsibility for approving or rejecting the product or results of its manufacturing operations among other CGMP responsibilities.
你们委托(b)(4)生产一种多剂量、不含防腐剂的顺势疗法眼用药品。根据你们与(b)(4)的质量协议，你们的主要职责是批准或拒绝所生产的产品或他们生产操作的结果以及其他CGMP职责。
However, you sent your contract manufacturer ophthalmic dropper bottles, tips, and caps to use in the manufacture of the ophthalmic drug product without ensuring that your contract manufacturer was capable of sterilizing containers and closures before use in manufacturing.
然而，你们在没有确保合同生产商能在使用前对容器和盖进行灭菌的情况下将眼用滴管瓶，吸头和瓶盖发送给合同生产商去生产眼用药品。
Furthermore, you did not ensure that your contract manufacturer had adequate facilities and controls to manufacture sterile drugs. Without adherence to CGMP requirements, you risk that your drugs may not meet requirements of strength, quality, purity, and safety. For example, microbiological contamination of an ophthalmic drug poses an unacceptable risk to patients including infection and potential for vision loss.
而且，你们不能保证你们委托生产商有足够的设施和控制措施来生产无菌药品。没有遵守CGMP的要求，你们的药品可能存在不符合规格、质量、纯度和安全性要求的风险。例如，眼用药物的微生物污染对患者来说是一个不可接受的风险，包括感染和潜在的视力丧失。
In addition, it is essential that multi-dose ophthalmic drug products contain one or more suitable substances that will preserve a product and minimize the hazard of injury resulting from incidental contamination during use. Without an adequate QU, you are unable to ensure that drug products meet required specifications and manufacturing standards for identity, strength, quality, and purity.
此外，多剂量眼用药品含有一种或多种物质来保护产品，并最大限度地降低因使用过程中偶然污染而导致伤害的风险。没有能胜任的QU，你们不能确保药品在性状、规格、质量和纯度方面符合所要求的质量标准和生产标准。
See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at url.
请参见FDA指南文件Quality Systems Approach to Pharmaceutical CGMP Regulations，url，有助于实施质量体系和风险管理方法以符合CGMP法规（21 CFR 210 和 211）的要求。
FDA Sample Results & Drug Recall FDA FDA取样结果＆FDA药品召回
FDA laboratory analysis of multiple lots of collected ophthalmic drug product confirmed they were contaminated with Bacillus spp., high levels of particulate matter, or both.
FDA实验室对所采集的多批眼用药品进行分析表明这些眼用药品已被芽孢杆菌、大量颗粒物质或两者兼有污染。
Your customer, (b)(4) recalled all lots of (b)(4) after being contacted by the FDA regarding the contaminated ophthalmic drug product.
你们的委托生产商被FDA就被污染的眼用药品联系后召回了所有批次产品。
Cessation of Drug Manufacturing暂停药品生产
In your November 7, 2018, response, you said “[f]rom this point forward, we have decided not to participate in any part of the process relating to drug products. Moreover, we will not be seeking an FDA registration at this point, unless our plans change in the future.” You did not propose any specific corrective actions or preventative actions for the CGMP violations observed at your facility and your contractor’s facility.
你们在2018年11月7日的回复中说：“从现在开始 , 我们决定不再参与药品相关的任何生产。而且 , 我们不会在这方面申请FDA注册 , 除非我们今后的计划有变”。你们没有针对你们公司和你们委托生产商的违反CGMP的行为采取任何专门的纠正措施或预防措施。
If you decide to pursue the manufacture of sterile drugs, notify the FDA of your plans in writing. A meeting can then be scheduled between you and the FDA to discuss the CGMP requirements for the manufacture of sterile drugs.
如果你们决定继续生产无菌药品 , 请以书面形式通知FDA你们的生产计划。FDA可以为你们安排一次会议来讨论关于无菌药品生产的CGMP要求。
Responsibilities as a Contractor 合同生产商的职责
Drugs must be manufactured in conformance with CGMP. FDA is aware that many drug manufacturers use independent contractors such as production facilities, testing laboratories, packagers, and labelers. FDA regards contractors as extensions of the manufacturer.
药品必须在符合CGMP条件下生产。FDA注意到很多药品生产商使用独立的合同商 , 例如生产公司、检验实验室、包装生产商和标签生产商。FDA认为合同商被视为生产商的延伸。
You and your customer (b)(4) have a quality agreement regarding the manufacture of drug products. You are responsible for the quality of drugs you produce as a contract facility regardless of agreements in place with product owners. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act for safety, identity, strength, quality, and purity. See FDA’s guidance document Contract Manufacturing Arrangements for Drugs: Quality Agreements at url.
你们与你们的客户应签订一个关于药品生产的质量协议。无论是否与产品持有人签订质量协议，你们都有义务为产品的质量负责。你们必须保证药品是按照FD&C法案501(a)(2)(B)节关于安全、性状、规格、质量和纯度的要求来生产的。参见FDA指南文件Contract Manufacturing Arrangements for Drugs: Quality Agreements, url。
Conclusion 结论
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
此信中所引述的违规行为并未涵盖全部。你们有责任调查这些违规行为，确定原因，防止其再次发生，防止其它违规行为的发生。
Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.
请立即纠正本信件中所述的违规行为。如果不能立即纠正这些违规行为将导致不经通知的法律行动 , 包括但不限于：没收和强制禁止令。本警告信中未解决的违规行为也可能妨碍其它联邦机构的已签订合约的执行。
Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.
在这些违规行为被整改完成之前，FDA可能暂停批准该企业登记的未决药品申请。FDA可能会再次确认你们已经完成的纠正措施。我们也可能拒绝你们出口要求。
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
在你们收到此函后 , 在15个工作日内回复至本办公室。在回复中说明自从我们检查后你们做了哪些工作来纠正违规行为和防止其再次发生。如果你们不能在15个工作日内完成纠正措施，要说明延迟的原因以及完成计划。
——摘自FDA对美国某药企开出的警告信。
GMP咨询顾问观点：
这家药企的主要问题是未确保委托生产加工的眼用药品的无菌保证。在签订委托加工合同时未对该公司的无菌保证方面进行有效处理。明知存在风险仍然贸然签订委托生产合同让其进行生产。
委托生产商的生产也必须在符合CGMP的条件下进行生产，所有生产的产品必须要既定的标准。
作为药品持有人，必须对所委托的公司进行有效管理，比如定期审计、抽测样品，审核批记录、偏差、变更、OOS、年度质量回顾等文件，了解产品的质量和生产过程，以确定其符合CGMP的要求和药品的质量标准要求。
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