近日，FDA对意大利Corden公司发布了警告信，警告缺陷内容主要涉及厂房设施、清洁程序和微生物检查等方面。
1、厂房设施建造不恰当，不利于清洁、维护和操作。如无菌区地面为瓷砖。无菌区地面有地漏等。
2、无菌区清洁程序不恰当。无菌灌装机下面有积水。
3、未能建立实验室控制。
4、微生物取样碟失效。
原文如下：
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Corden Pharma Latina S.p.A., Via del Murillo Km 2800, 04013 Sermoneta, Italy, from May 21–29, 2015.
FDA于2015年5月21-29日对你们意大利工厂进行了审计。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, 21 CFR parts 210 and 211, and significant deviations from CGMP for active pharmaceutical ingredients (API).
此警告信中列出了原料药重大CGMP缺陷。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
由于你们生产、加工、包装或保存的方法、设施或控制不符合CGMP要求，你们的原料药被认为是掺假。
We reviewed your firm’s June 19, 2015 response in detail and acknowledge receipt of your subsequent responses.
我们已详细审核了你公司于2015年6月19日发来的回复，也收到了之后的回复。
Our investigators observed specific violations and deviations including, but not limited to, the following.
我们的调查人员在检查期间发现了一些特定的缺陷，包括但不仅限于以下：
Finished product violations
制剂违规
1. Your firm failed to have facilities used in the manufacture, process, packaging and holding of drug products of appropriate construction to facilitate cleaning, maintenance, and proper operations. (21 CFR 211.42(a))
你们公司用于药品生产、加工、包装和保存的设施建造不恰当，不利于清洁、维护和适当操作。(21 CFR 211.42(a))
We observed (b)(4) floor tiles (approximately (b)(4) by (b)(4)) in your sterile (b)(4) manufacturing area. Black grime and filth were visible in the tile (b)(4) throughout the aseptic area, including in the direct vicinity of the manufacturing equipment. Furthermore, cracked and inadequately repaired floor tiles created more gaps to hold filth.
我们查看了你们某无菌产品生产区域的地面瓷砖（大约有几乘几面积）。在整个无菌区域都肉眼可以看到瓷砖上有黑色污垢，包括紧邻生产设备的地方。另外，地面瓷砖上有许多裂纹，没有好好修复，这使得污垢存留有更大空间。
In your response, you stated that you repaired cracked floor tiles and damaged seals in the (b)(4) room and under the(b)(4), and replaced the flooring in the area of the aseptic filling machine.
在你们的回复中，你们说你们修复了裂开的地面瓷砖和某房间里和XX下面的损坏的密封，替换了无菌灌装机区域的地面。
Your response is inadequate. Floors should be (b)(4) where sterile products are manufactured. Smooth, hard surfaces that are easy to clean prevent accumulation of filth and discourage microbiological growth. There is no assurance that the repairs you made to the floors and the new tiles installed are adequate and appropriate for an aseptic processing facility. Specifically, there is no assurance that the repaired/replaced tile floors can ever be sufficiently cleaned and disinfected.
你们的回复是不充分的。无菌药品生产的地面应该是XX。光滑的硬地面易于清洁，防止污垢累积，减少微生物滋长。你们无法确保对地面的修复和新装的瓷砖对于无菌加工设施来说是足够的，恰当的。特别是，不能确保修复/替换后的磁砖可以进行足够的清洁和消毒。
In your response to this letter, provide:
在你们对此函的回复中，请提交
A plan and timeline to replace the floors, including underneath heavy equipment, with a (b)(4) floor that is easy to clean and sanitize, without cracks and crevices. Send your plan and timeline before you install the new floors. Include your remediation actions for contaminants found under the tile floor. The remediation plan should include details regarding use of cleaners, sporicidal agents, and moisture removal.
替换地面的计划和时间表，包括在重型设备下面的地面，使用XX地面更易于清洁和消毒，不会裂开和产生缝隙。在你们安装新地面之前，将你们的计划和时间表发给我们。包括你们对于在磁砖地面下发现的污染物的补救措施。补救措施应包括使用清洁剂、杀孢子剂和除湿的详细内容。
Your plan to requalify the facility after construction, including environmental qualification and media fill strategy.
你们在改造之后重新确认设施的计划，包括环境确认和培养基灌装策略。
Photographic evidence after you complete the floor replacement to demonstrate that your facility meets CGMP requirements.
你们完成地面替换之后的图片证据，证明你们的设施符合CGMP要求。
2. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. (21 CFR 211.67(a))
你们公司未能在适当的时间间隔清洁、维护，在适用于药品特性时，消毒和/或灭菌设备和工器具，防止误用或污染，导致改变药品的安全、鉴别、剂量、质量或纯度，使其超出官方或其它既定的要求。(21 CFR 211.67(a))
Your cleaning procedure includes spraying (b)(4) of water throughout the aseptic area. As a result, stagnant water collects underneath the aseptic filling machine. Stagnant water is a potential source of microbiological contamination, including biofilms and other filth.
你们的清洁程序包括在无菌区域喷洒XX水。在无菌灌装机下面的积水，积水是微生物污染的潜在来源，包括生物膜和其它污垢。
According to your response, you are using a “(b)(4)-Mop” after cleaning to remove pools of water under the filling machine, and evaluating alternative disinfecting agents that will not require removal with water as a (b)(4) step. You did not demonstrate that the “(b)(4)-Mop” and new disinfectants are adequate for cleaning and sanitizing the floor.
根据你的回复，你们在清洁之后使用XX抹布来除去灌装机下的积水，评估了交替使用消毒剂就不需要将除水作为XX步骤。你们未能证明XX抹布和新的消毒剂足以清洁和消毒地面。
After you have remediated your facility in line with the items above, update your cleaning procedures to ensure no stagnant water remains, and review all your cleaning practices to ensure they do not increase the risk to the product for microbial or particulate contamination.
在你们根据上面要求修复你们设施之后，更新你们的清洁程序以确保没有积水存留，审核你们所有的清洁操作以确保他们不会增加产品微生物或颗粒污染的风险。
3. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. (21 CFR 211.160(b))
你们公司未能建立实验室控制，包括科学合理和适当的规格、标准、取样计划、检测方法，以确保药品成分、药品容器、密闭器、中控物料、标签和药品符合适当的鉴别、剂量、质量和纯度标准。(21 CFR 211.160(b))
You do not take samples for (b)(4) analysis from the (b)(4) bulk solution during routine commercial production. Instead you rely on sampling (b)(4) which does not provide meaningful results of (b)(4).
你们在常规的商业生产中，没有从XX散装溶液中取样用于YY分析，而是依赖于ZZ的取样，但它并不能提供XX有意义的结果。
According to your response, during process validation you sampled the (b)(4) bulk solution for (b)(4) to verify (b)(4) of the (b)(4). However, you did not test the bulk drug solution (b)(4) to detect (b)(4) contamination.
根据你们的回复，在工艺验证过程中，你们从XX散装溶液取样，对YY进行了确认。但是，你们没有检测散装药品溶液ZZ来发现MM污染。
(b)(4) test samples for aseptically-filled products should be taken (b)(4) steps to ensure that the (b)(4) da
无菌灌装产品的XX测试样品应该从XX步骤取样，以确保XX数据反映真实的中控YY水平。超出中控YY可能会导致MM，或者其它副产物，可能会NN和污染制剂产品。
In your response to this letter, provide evidence that your (b)(4) testing regimen can detect (b)(4) contamination in (b)(4) bulk, and provide an updated procedure that stipulates that (b)(4) bulk drug solution (b)(4) analysis is required for each lot you produce.
在你们对此函的回复中，请提交证据证明你们的XX检测计划可以发现ZZ散装品的YY污染，提交更新后的程序，规定需要对对于你们生产的每个批次XX散装药品溶液都进行YY分析。
API deviations
原料药缺陷
4. Your test procedures are not scientifically sound and appropriate to ensure that your API conform to established standards of quality and/or purity.
你们的分析方法不科学合理，不适当于确保你们的原料药符合既定的质量和/或纯度标准。
Your environmental monitoring da
你们的环境监测数据是不可靠的。在2015年5月27日，我们的调查人员发现碟读数时有61个损害的XX碟。损害的例子包括脱色XX，干燥XX从微生物碟边缘收缩，完全分离的YY，以及在XX培养过程中掉进YY。
(b)(4) that is desiccated, cracked, or damaged fundamentally compromises microbial growth promotion and accurate enumeration, and may result in the underestimation of microbiological counts and false negatives.
XX已经干了、裂开或损坏，从根本上无法保证微生物促生长和准确计数，可能会导致对微生物计数的低估，假阴性。
In your response, you evaluated each type of plate damage and concluded that the effects of plate damage are negligible, because microbiological growth on such (b)(4) is possible. This response is inadequate; use of deficient media fundamentally compromises the validity of your microbiological test results. Furthermore, you did not commit to stop using damaged plates for microbiological tests.
在你们的回复中，你们评估了每种碟损坏情形，并得出结论说碟损坏的影响是可以忽略的，因为微生物是可能在此XX上生产的。此回复是不充分的，使用有问题的培养基从根本上来说会对你们微生物测试结果产生影响。另外，你们没有承诺不再使用损坏的碟来做微生物检测。
In your response to this letter, provide:
在你们对此函的回复中，请提交
An accelerated timeline for completing retroactive microbiological testing of all potentially-compromised batches via an independent laboratory, and a commitment to respond promptly with all OOS results.
快速通过独立化验室对所有可能有问题的批次进行回顾性微生物测试的完成计划，承诺会对所有OOS结果进行快速反应。
Your review of all microbiological test methods to ensure that they are suitable for their intended use.
你们对所有微生物检测方法的审核，以确保他们适用你们既定用途。
5. The buildings and facilities used in the manufacture of your API are not designed and constructed to limit exposure to objectionable microbiological contaminants.
你们用于原料药生产的建筑和设施设计和建行不能限制暴露于致病菌污染。
The floor of the sterile API aseptic processing area has multiple drains. In International Standards Organization Class 5 (ISO 5/Grade A) areas for aseptic filling, drains should not be used because of microbiological contamination risks.
无菌原料药无菌工艺区域的地面有多个地漏。在ISO5级（ISO 5/A级）标准中，无菌灌装的区域，不应该使用地漏，因为有微生物污染风险。
In your response, there is insufficient scientific rationale for drains in the floor of your sterile API filling suite.
在你们回复中，对于你们无菌原料药灌装间里地面上设地漏没有给出充分的科学理由。
In response to this letter, provide your plan for removing drains from sterile API manufacturing areas.
在回复此函时，请提供你们从无菌原料药生产区域将下水口除去的计划。
CGMP Guidance
CGMP指南
FDA’s Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice guidance document may help you ensure that all aseptically-filled drug products meet standards for drugs purported to be sterile. Download from:
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070342.pdf
FDA无菌工艺生产的无菌药品---CGMP指南文件可能有助于你确保所有无菌灌装药品符合所需的无菌标准。可以从上述网址下载。
Conclusion
Violations and deviations cited in this letter are not intended to as an all-inclusive list. You are responsible for investigating these violations and deviations, for determining the causes, for preventing their recurrence, and for preventing other violations and deviations.
If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of drugs produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Staff immediately at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drugs under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products. In appropriate cases, you may be able to take corrective act
After you receive this letter, you have 15 working days to respond to this office in writing. Specify what you have done since our inspection to correct your violations and deviations and to prevent their recurrence.
If you cannot complete corrective actions within 15 working days, state your completion date and reasons for delay.
Until you completely correct all violations and deviations and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer. Failure to correct these violations and deviations may also result in FDA refusing admission of articles manufactured at Corden Pharma Latina S.p.A, Via del Murillo Km 2800, 04013 Sermoneta, Italy into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to within the meaning of section 501 (a)(2)(B) of the FD&C Act, 21 U.S.C. 351 (a)(2)(B).
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