无菌生产不符合cGMP，FDA发出警告信。
WARNING LETTER
Age Management Institute Santa Barbara
MARCS-CMS 625261 — APRIL 18, 2022
April 18, 2022
Dear Dr. Repik:
From March 22, 2021, to April 12, 2021, a U.S. Food and Drug Administration investigator inspected your facility, Age Management Institute Santa Barbara, located at 533 East Micheltorena Street, Suite 203, Santa Barbara, California 93103. During the inspection, the investigator noted serious deficiencies in your practices for producing products intended or expected to be sterile, which put patients at risk.
从2021年3月22日到2021年4月12日，美国食品和药物管理局检查了企业位于加利福尼亚州圣巴巴拉市东Micheltorena街533号附203号的Age Management Institute Santa Barbara。在检查中，检查员注意到企业生产无菌产品的做法存在严重缺陷，这将患者置于危险之中。
The FDA issued a Form FDA 483 to your firm on April 12, 2021. The FDA acknowledges receipt of your facility’s response, dated April 16, 2021. Additionally, the FDA acknowledges that your firm voluntarily ceased production of drug products for IV therapy as of the date of our inspection. Based on this inspection, it appears that you produced drug products that violate the Federal Food, Drug, and Cosmetic Act (FDCA).
FDA于2021年4月12日向贵公司出具了FDA 483表格。FDA确认收到工厂2021年4月16日的回复。此外，FDA承认，自检查之日起，贵公司自愿停止生产用于静脉治疗的药品。根据这次检查，企业生产的药品违反了联邦食品、药品和化妆品法案(FDCA)。
A. Compounded Drug Products Under the FDCA
A. FDCA下的复合药品
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)].
FDCA第503A条描述了由州授权药房或联邦机构的授权药剂师或授权医生配制的人用药品符合FDCA的三个部分豁免条件:符合当前的gmp (CGMP)(第501(a)(2)(B));标签有足够的使用说明(第502(f)(1)条);和FDA上市前批准(第505条)[21 U.S.C.§§351(a)(2)(B)， 352(f)(1)和355(a)]。
B. Violations of the FDCA
B.违反FDCA
Adulterated Drug Products
掺假的药物产品
The FDA investigator noted that drug products intended or expected to be sterile 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 that:
FDA检查员注意到，预期或预期无菌的药品是在不卫生的条件下生产、包装或保存的，因此它们可能被污染或对健康造成损害，导致企业的药品根据FDCA第501(a)(2)(a)条规定为掺假药品。例如，检查员观察到:
1. Your facility lacked a certified ISO 5 classified area for sterile compounding.
1. 工厂缺乏验证的ISO 5无菌合成区域。
2. Your aseptic processing areas had difficult to clean and visibly dirty equipment and surfaces. For example:
2. 企业的无菌加工区域难以清洁，设备和表面脏。例如:
a. A (b)(4) hood, used to produce drug products purporting to be sterile, had a visibly dirty filter installed. Also, there was staining and peeling paint on the (b)(4) hood surfaces and supporting table.
a.用于生产无菌药品的(b)(4)罩，安装了一个明显不干净的过滤器。此外，发动机罩表面和支撑台上有油污和表皮脱落。
b. An air vent in the “IV storage and mixing room” was visibly dirty and part of the floor was covered with carpet.
b.“IV储存和混合室”的一个通风口明显很脏，部分地板被地毯覆盖。
c. A refrigerator with dripping and standing water on the inside shelf was used to store sterile drug products used to produce IV therapy products. The containers/closures were in direct contact with the condensate water.
c.在内部货架上放置有滴水和静置水的冰箱，用于储存用于生产IV治疗产品的无菌药品。容器/封盖与冷凝水直接接触。
3. Your firm distributed drug products that were prepared using expired components.
3.贵公司销售使用过期原料生产的药品。
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FDCA (21 U.S.C.§331(k))第301(k)条的规定，禁止对药品采取任何行动，前提是在该药品在州际商业运输后被持有待售期间进行的，并导致该药品被掺假。
C. Corrective Actions
C .纠正措施
We have reviewed your firm’s response to the Form FDA 483. We acknowledge that your firm voluntarily ceased production of drug products for IV therapy as of the date of our inspection.
FDA已经审阅了贵公司对FDA 483表格的回复。我们知道贵公司自检查之日起自愿停止生产用于静脉治疗的药品。
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.
请注意，无论企业生产的药品是否符合第503A节的条件，FDCA中关于不卫生条件的第501(a)(2)(a)节均适用。
The FDA strongly recommends that if you decide to resume production of sterile drug products, your management first 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 processing expertise should assist you in conducting this comprehensive evaluation.
FDA强烈建议，如果企业决定恢复无菌药品生产，企业的管理层首先要对操作进行全面评估，包括设施设计、程序、人员、工艺、维护、原材料和系统。特别是，该审查应评估企业的无菌工艺操作。具有相关无菌药品加工专业知识的第三方顾问应协助企业进行此综合评估。
D. Conclusion
D、 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 any violations 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.
在这封信中提到的违规行为并不是工厂违规行为的全面描述。企业有责任调查和确定任何违规行为的原因，并防止其再次发生或其他违规行为的发生。企业有责任确保公司遵守联邦法律的所有要求，包括FDA法规。
If you decide to resume operations to produce drugs intended or expected to be sterile, you should take action to correct any violations and ensure such drugs meet the conditions of section 503A, including that the drug products are compounded by a licensed pharmacist in a state-licensed pharmacy or a federal facility or by a licensed physician, before resuming. Failure to adequately address any violations may result in legal action without further notice, including, without limitation, seizure and injunction.
如果企业决定恢复生产预期或预期为无菌的药物，应采取行动纠正任何违规行为，并确保此类药物符合第503A条的条件，包括在恢复生产之前，该药物产品是由州授权药房或联邦机构的授权药剂师或授权医生配制的。如果未能充分解决任何违规行为，可能会在不另行通知的情况下导致法律行动，包括但不限于扣押和禁令。
Within fifteen (15) working days of receipt of this letter, please notify this office in writing if you have taken any specific steps to address any violations, or you may inform us that you do not intend to resume production of drugs intended or expected to be sterile. If you intend to resume production of these drugs in the future, please include an explanation of each step being taken to prevent the recurrence of any violations, as well as copies of related documentation. If you believe your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration. In addition to taking appropriate actions to address this matter, you should notify this office fifteen (15) working days prior to resuming production of any drugs intended or expected to be sterile in the future.
在收到本函后的十五(15)个工作日内，如果企业采取了具体步骤来解决任何违规问题，请以书面形式通知本办公室，或者企业可以通知FDA，企业不打算恢复生产预期或预期为无菌的药物。如果企业打算在未来恢复这些药物的生产，请说明为防止任何违规事件再次发生而采取措施，以及相关文件的副本。如果企业认为产品没有违反FDCA，请提供理由和任何支持信息，以供FDA考虑。除了采取适当的措施来解决这个问题外，企业还应该在未来打算恢复任何或预期无菌药品的生产前十五(15)个工作日通知本办公室。
Send your electronic reply to ORAPHARM4_Responses@FDA.HHS.GOV or mail your reply to:
将电子回复发送至ORAPHARM4_Responses@FDA.HHS.GOV或邮寄至:
CDR Steven E. Porter, Jr.
Director, Division of Pharmaceutical Quality Operations IV
U.S. Food & Drug Administration
19701 Fairchild Road
Irvine, California 92612-2506
Please identify your response with unique identifier 625261.
If you have any further questions, please contact Nayan Patel, Compliance Officer, by email at Nayan.Patel1@fda.hhs.gov or by phone at (303) 236-3010.
Sincerely,
/S/
Steven E. Porter, Jr.
Program Division Director
Division of Pharmaceutical Quality Operations IV
