美国当地时间11月17日，FDA官网更新了一封对Family Pharmacy of Statesville, Inc.
原文链接：FDA警告信-Family Pharmacy of Statesville, Inc.（
FDA警告信-Family Pharmacy of Statesville, Inc.）
FDA警告信-Family Pharmacy of Statesville, Inc.）
Mr. Eudy:
From February 3, 2020, to February 12, 2020, a U.S. Food and Drug Administration (FDA) investigator inspected your facility, Family Pharmacy of Statesville, Inc., located at 208 Old Mocksville Road, Statesville, North Carolina 28625. During the inspection, the investigator noted that drug products you produced failed to meet the conditions of section 503A of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353a] for exemption from certain provisions of the FDCA. In addition, the investigator noted serious deficiencies in your practices for producing sterile drug products, which put patients at risk.
在2020年2月3日到2020年2月12日，FDA检查员检查了您的工厂。在检查期间，检查员注意到您生产的药品不符合《联邦食品，药品和化妆品法》（FDCA）503A节的规定[21 U.S.C. §353a]豁免的某些规定。此外，研究人员指出，您生产无菌药物产品的做法存在严重缺陷，这使患者处于危险之中。
FDA issued a Form FDA 483 to your firm on February 12, 2020. FDA acknowledges receipt of your facility’s response, dated February 25, 2020. Based on this inspection, it appears that you produced drug products that violate the FDCA.
FDA于2020年2月12日向您的公司签发了FDA 483表
A. Compounded Drug Products Under the FDCA
A. FDCA规定的复合药品
Section 503A of the FDCA describes the conditions under which human drug products compounded by a licensed pharmacist in a State licensed pharmacy or a Federal facility, or a licensed physician, qualify for exemptions from three sections of the FDCA: compliance with current good manufacturing practice (CGMP) (section 501(a)(2)(B)); labeling with adequate directions for use (section 502(f)(1)); and FDA approval prior to marketing (section 505) [21 U.S.C. §§ 351(a)(2)(B), 352(f)(1), and 355(a)].Receipt of valid prescriptions for individually-identified patients is one of the conditions for the exemptions under section 503A.
FDCA第503A节描述了由州特许药房或联邦机构的持牌药剂师或持照医生配制的人类药品符合FDCA三个部分的豁免条件：符合现行良好生产规范（CGMP）（第501（a）（2）（B）节）；贴上适当的使用说明（第502（f）（1）节）；上市前食品和药品管理局批准（第505节）[21 U.S.C.§§351（a）（2）（B）、352（f）（1）和355（a）]。根据第503A节的规定，收到针对个体识别患者的有效处方是豁免的条件之一。
B. Failure to Meet the Conditions of Section 503A
B.不符合第503A条的条件
During the inspection, the FDA investigator noted that drug products produced by your firm failed to meet the conditions of section 503A. For example, the investigator noted your firm did not receive valid prescriptions for individually-identified patients for a portion of the drug products you produced, including(b)(4)
在检查过程中，FDA调查员注意到贵公司生产的药品不符合第503A节的条件。例如，调查员指出贵公司生产的部分药品没有收到针对个别患者的有效处方
Therefore, you compounded drug products that do not meet the conditions of section 503A and are not eligible for the exemptions in that section, including the FDA approval requirement of section 505 of the FDCA, the requirement under section 502(f)(1) of the FDCA that labeling bear adequate directions for use, and the requirement of compliance with CGMP under section 501(a)(2)(B) of the FDCA. In the remainder of this letter, we refer to your drug products that do not qualify for exemptions under section 503A as the “ineligible drug products.”
因此，您的合成药品不符合第503A节的条件，并且不符合该节中的豁免条件，包括FDA批准FDCA第505节的要求，以及FDCA第502（f）（1）节的要求，即标签上有足够的使用说明，以及FDCA第501（a）（2）（B）节规定的遵守CGMP的要求。在本函的其余部分，我们将不符合第503A节规定豁免条件的药品称为“不合格药品”
Specific violations are described below.
具体违规情况如下所述。
C. Violations of the FDCA
C. 违反FDCA
Adulterated Drug Products
掺假药品
The FDA investigator noted that drug products were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA. For example, the investigator observed:
FDA调查人员指出，药品是在不卫生的条件下制备，包装或保存的，因此可能已被污物污染或危害健康，从而导致您的药品根据第501（a）（2）（A）的规定被掺假。 ）。例如，研究者观察到：
1. Your firm did not use a sporicidal agent in the ISO 5 areas.
1.您的公司未在ISO 5区域使用杀孢子剂。
2. Your firm re-used bottles containing(b)(4)
2.您的公司重复使用了包含（b）（4）的瓶子，以便在ISO 5区域使用，但不能保证瓶子在多次使用后仍保持无菌状态。另外，以ISO 5区域使用的商业方式购买的无菌擦拭布，其存储方式会增加被引入擦拭布中的污染可能性。
3. Your firm handled hazardous drugs products without providing adequate cleaning of work surfaces to prevent cross-contamination.
3.您的公司在处理危险药物产品时未对工作表面进行足够的清洁以防止交叉污染。
4. Your facility is designed and operated in a way that may permit the influx of lesser quality air into a higher quality air area. Specifically, material flows directly from an unclassified area into a room in which sterile production occurs via a pass-through window. In addition, the investigator observed dust on the inner door levers of the pass-through, which represent difficult to clean equipment. Furthermore, the anteroom, where gowning occurs prior to aseptic production, did not have HEPA filtration.
4.您设施的设计和运行方式应允许将质量较差的空气流入质量较高的空气区域。没有进行HEPA过滤。
5. Your media fills were not performed under the most challenging or stressful conditions. Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility.
5.您的培养基灌装试验不是在最具挑战性或压力最大的条件下进行的。
6. Your firm produced drug products with materials that had not been verified to assure that they did not contribute to endotoxin contamination that may be objectionable given the product’s intended use.
6.贵公司生产的药品原料未经验证
7. Your firm failed to confirm that the quality of water was suitable for its intended use in the production of non-sterile drug products.
您的公司未能确认水的质量是否适合其在非无菌药品生产中的预期用途。
Furthermore, the manufacture of the ineligible drug products is subject to FDA’s CGMP regulations, Title 21, Code of Federal Regulations (CFR), parts 210 and 211. The FDA investigator observed significant CGMP violations at your facility, causing the ineligible drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.
此外，不合格药品的生产还需遵守FDA的CGMP法规，联邦法规（CFR）第21章，第210和211部分。FDA调查人员在您的工厂发现严重违反CGMP的行为，导致不合格药品根据FDCA第501（a）（2）（B）条的规定掺假。
The violations included, for example:
违规包括，例如：
1. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
1.您的公司未建立足够的系统来清洁和消毒房间和设备以产生无菌条件
2. Your firm failed to adequately design the facility with adequate separation or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(b)).
2.您的公司未能对设施进行充分的设计，以确保其没有足够的间隔或定义的区域或其他防止污染或混淆的控制系统
3. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
3.您的公司未建立并遵循适当的书面程序，旨在防止声称是无菌的药品受到微生物污染，包括对所有无菌和灭菌过程进行验证
4. Your firm failed to use appropriate air filtration systems for production areas (21 CFR 211.46(c)).
4.您的公司未在生产区域使用适当的空气过滤系统
It is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being adulterated.
根据《联邦食品法典》第301（k）节的规定，【21 U.S.C.§331（k）】禁止对药品采取任何行为，前提是该行为是在药品在州际贸易中装运后进行销售，并导致药品掺假。
Misbranded Drug Products
贴错商标的药品
The ineligible drug products you compounded are intended for conditions not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses.2
您所配制的不合格药品旨在用于非医生无法自我诊断和治疗的疾病； 因此，不能写出足够的使用说明，以使外行可以安全地将这些产品用于预期用途。 因此，它们的标签不能为预期用途提供足够的指导。因此，根据FDCA第502（f）（1）条，这些不合格的药品被贴错了标签。 根据FDCA第301（k）条，禁止对药品采取任何行为，前提是该行为是在药品在州际贸易中装运后进行销售，并导致该药品被贴上错误的标签。
D. Corrective Actions
D.纠正措施
We have reviewed your firm’s response to the Form FDA 483.
我们已经审查了贵公司对FDA 483表格的答复。
Regarding your responses related to the insanitary conditions, some of your corrective actions appear adequate; however, we cannot fully evaluate the adequacy of the following corrective actions described in your response because you did not include sufficient information or supporting documentation:
关于您对不卫生条件的回应，您的一些纠正措施似乎足够充分；但是，由于您没有提供足够的信息或支持文档，因此我们无法完全评估您的回复中所述以下纠正措施的充分性：
1. Regarding the use of a sporicidal agent in the ISO 5 areas:
1. 关于在ISO 5区域使用杀孢子剂：You state that you have amended your cleaning procedures to include the use of(b)(4)您声明已经修改了清洁程序，以在ISO 5区域中使用（b）（4）；但是，您没有提供支持文档，例如发票，采购订单或完整的清洁日志。Your cleaning procedure documents a contact time of(b)(4)(b)(4)(b)(4)您的清洁程序记录了（b）（4）与（b）（4）的接触时间，“以获得最大的消毒效果”；但是，（b）（4）不足以产生杀菌作用。Your cleaning procedure did not address how cleaning will be conducted in response to adverse environmental monitoring sample results (excursions), and your procedure documents the use of a non-sterile and non-cleanroom compliant disinfectant to be used in the “cleanroom facility” ((b)(4)您的清洁程序未解决如何应对不良的环境监测样品结果（偏移）进行清洁，并且您的程序记录了在“无尘室设施”中使用的非无菌和无尘室兼容消毒剂的使用（ （b）（4））。You did not provide evidence of re-training on cleaning procedures such as training materials and training records.您没有提供有关清洁程序（例如培训材料和培训记录）的再培训证据。
2. You state that you have updated your cleaning procedures to include use of(b)(4)(b)(4)(b)(4)(b)(4)
2.您声明已更新清洁程序，以包括在ISO 5区域中使用（b）（4）和（b）（4）。但是，您未在未分类的传递框中解决（b）（4）的问题，并且不清楚新购买的（b）（4）在打开且不使用时将存储在何处。此外，您没有提供再培训的证据，例如培训材料和培训记录。
3. You state that you have updated your procedure for hazardous drug cleaning and will(b)(4)
3.您声明已经更新了危险药物清洁程序，并将（b）（4）清洁层流工作台的内部。但是，您没有提供再培训的证据，例如培训材料和培训记录。
4. Regarding the pass-through box:
4.关于传递窗：You state that you have updated your cleaning procedure to include cleaning of the pass-through box. However, we remain concerned with this set up as unclassified air may be introduced directly into the cleanroom in which sterile production occurs. In addition, you have not adequately addressed the difficult to clean levers within the pass-through box.您声明已经更新了清洁程序，以包括对传递窗的清洁。但是，我们仍会担心这种设置，因为未分类的空气可能会直接引入发生无菌生产的洁净室。此外，您还没有充分解决传递窗内难以清洁的杠杆问题。You have not provided evidence (e.g., photographs) of the cleaning to remove dust that was accumulated in the ceiling vent above the pass-through box.您尚未提供清洁措施的证据（例如照片）以清除堆积在传递窗上方的天花板通风孔中的灰尘。You did not provide evidence of re-training such as training materials and training records.您没有提供再培训的证据，例如培训材料和培训记录。
5. Regarding the anteroom HEPA filtration, you state that you have contacted a vendor to add a HEPA filter to your anteroom. However, you have not provided an update or a completion date of when the HEPA filter was or will be added to the anteroom. If the HEPA filter has been installed, a cleanroom re-certification has not been submitted post-construction.
5.关于前厅的HEPA过滤，您声明已与供应商联系，将HEPA过滤器添加到前厅。但是，您尚未提供将HEPA过滤器添加到前厅的更新或完成日期。如果已安装HEPA过滤器，则施工后尚未提交无尘室重新认证。
6. You state that you now have(b)(4)(b)(4)
6.您说您现在有（b）（4）来模拟你公司日常执行的“最复杂的操作”。但是，您没有提供完成（b）（4）的时间表，如果完成，您也没有提供结果供我们审查。
7. You state that you discontinued the use of(b)(4)
7.您声明您已在非无菌药品中停止使用（b）（4）。但是，您没有提供支持文档，例如经过修订的程序，也没有提供重新培训的证据，例如培训材料和培训记录。
Please be aware that section 501(a)(2)(A) of the FDCA concerning insanitary conditions applies regardless of whether drug products you compound meet the conditions of section 503A, including the condition on receipt of a prescription for an identified individual patient prior to compounding.
请注意，无论您配制的药品是否符合第503A节的条件，包括在配制前收到已确认的个人患者处方的条件，FDCA关于不健康条件的第501（a）（2）（a）条均适用。
In addition, you did not address issues related to the conditions of section 503A of the FDCA. Specifically, you have not addressed the compounding of drug products without receipt of valid prescriptions for individually-identified patients.
此外，您没有解决与FDCA第503A节的条件有关的问题。具体来说，如果您未收到针对个别患者的有效处方，就没有解决药物的配制问题。
Should you continue to compound and distribute drug products that do not meet the conditions of section 503A, the compounding and distribution of such drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the drug CGMP regulations. Before doing so, you must comply with the requirements of section 505 and 502(f)(1) and fully implement corrections that meet the minimum requirements of the CGMP regulations.
如果您继续配制和分销不符合第503A节条件的药品，则此类药品的配制和分销应符合新药批准要求、药品标签上有适当使用说明的要求以及药品CGMP法规。在此之前，您必须遵守第505节和第502（f）（1）节的要求，并完全实施符合CGMP法规最低要求的纠正措施。
In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products. See section 501 of the FDCA. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you produce are neither adulterated nor misbranded. [See 21 CFR 210.1(b), 21 CFR 200.10(b)].
除了上面讨论的问题外，您还应该注意，CGMP要求对药品生产实施质量监督和控制，包括原料安全，药品生产中使用的材料以及成品药品的安全性。参见FDCA的501部分。如果您选择与实验室签约以执行CGMP所需的某些功能，则必须选择合格的承包商，并对承包商的运营进行充分的监督，以确保其完全符合CGMP要求。无论您是否依赖合同工具，您都有责任确保所生产的药物不会掺假或贴错标签。 [参见21 CFR 210.1（b），21 CFR 200.10（b）]。
FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems. In particular, this review should assess your aseptic processing operations. A third-party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.
FDA强烈建议您的管理层对运营进行全面评估，包括设施设计，程序，人员，过程，维护，材料和系统。特别是，此审查应评估您的无菌处理操作。具有相关无菌药物生产专业知识的第三方顾问应协助您进行这项全面的评估。
E. Conclusion
E.结论
The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including FDA regulations.
这封信中提到的违规行为并非旨在构成您机构中所有违规的陈述。您有责任调查和确定上述违规的原因，并防止其再次发生或发生其他违规情况。您有责任确保您的公司符合联邦法律的所有要求，包括FDA法规。
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure and injunction.
您应立即采取措施纠正此信中提到的违规行为。不及时纠正这些违法行为可能会导致采取法律行动，恕不另行通知，包括但不限于扣押和强制令。
Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If you cannot complete corrective action within fifteen (15) working days, state the reason for the delay and the time within which you will complete the correction.
在收到这封信后的十五（15）个工作日内，请将您为纠正违规行为所采取的具体步骤书面通知本办公室。请说明为防止再次发生违规所采取的每个步骤，以及相关文档的副本。如果您不认为上述产品违反了FDCA，请提供您的理由和任何支持信息，以供我们考虑。如果您不能在十五（15）个工作日内完成纠正措施，请说明延迟的原因以及完成纠正的时间。
In addition, based on our review of photographic evidence obtained by the FDA investigator during the inspection of your facility, the Agency is concerned with the suitability of the work surfaces within your ISO 5 production area. Specifically, the work surface inside your vertical laminar flow hood appears to have multiple unsealed holes in the critical area, which may be difficult to clean and may allow the influx of lesser quality air. Furthermore, there appears to be multiple ledges inside the ISO 5 area. These ledges appear to have signs of wear, are located in front of the direct compounding area, appear difficult to clean, may increase the likelihood of microbial contamination, and may impact and compromise unidirectional airflow in the ISO 5 area. This is concerning because aseptic manipulations are conducted near the holes and directly in front of these ledges. As part of your response, provide supporting documentation to demonstrate that this hood is suitable for use and that the holes and ledges within the ISO 5 classified area do block or disrupt first pass air.
此外，根据我们对FDA调查人员在检查您的设施期间获得的照相证据的审查，该机构担心ISO 5生产区域内工作表面的适用性。具体来说，您的垂直层流通风橱内部的工作表面在关键区域似乎有多个未密封的孔，这些孔可能难以清洁，并且可能会流入质量较差的空气。此外，在ISO 5区域内似乎有多个壁架。这些壁架似乎有磨损痕迹，位于直接复合区域的前面，似乎难以清洁，可能会增加微生物污染的可能性，并可能影响并损害ISO 5区域中的单向气流。这是令人担忧的，因为无菌操作是在孔附近和这些壁架的正前方进行的。作为回应的一部分，请提供支持文档，以证明该引擎盖适合使用，并且ISO 5分类区域中的孔和壁架确实会阻塞或破坏首次通过的空气。
Your written notification should refer to the Warning Letter Number above (Case # 611664). Please electronically submit your signed reply on your firm’s letterhead to CDR John W. Diehl, M.S., Director, Compliance Branch, at john.diehl@fda.hhs.gov and orapharm2_responses@fda.hhs.gov.
If you have questions regarding the contents of this letter, you may contact Mr. Thao Ta, Compliance Officer, via phone at214-253-5217or e-mail at thao.ta@fda.hhs.gov.
