New England District Office
One Montvale Avenue
Stoneham, MA 02180
WARNING LETTER
CMS # 489281
UNITED PARCEL SERVICE
OVERNIGHT DELIVERY
December 15, 2016
Mr. Andrea F. Sama
Plant Manager
Aplicare, Inc.
550 Research Parkway
Meriden, CT 06450-7172
Dear Mr. Sama:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Aplicare, Inc., 550 Research Parkway, Meriden, Connecticut, from December 14, 2015 to January 15, 2016.
美国FDA于2015年12月14日至2016年1月15日检查了你们位于康涅狄格州的工厂。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) for finished pharmaceuticals. See 21 CFR, parts 210 and 211.
本警告信总结了制剂产品严重违背CGMP的情况。参见21CFR第210和211部分。
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products 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、包装和存贮药品的方法、设施和控制不符合CGMP，根据FDAC501(a)(2)(B)和21 U.S.C. 351(a)(2)(B) ，你们的药品被认为是掺假药。
We reviewed your firm’s February 8, 2016, response in detail, and acknowledge receipt of your subsequent correspondence.
我们详细审核了你们公司于2016年2月8日及之后发送的回复。
Our investigators observed specific violations including, but not limited to, the following.
我们的调查人员发现的违规情况包括但不仅限于以下：
CGMP Violations CGMP违规
1. Your firm failed to 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)).
你们公司未能遵守适当的书面程序，这些程序是设计来防止理应无菌的药品免受微生物污染的，其中包括所有无菌和灭菌工艺的验证(21 CFR 211.113(b))。
Your firm failed to implement adequate microbial controls for your povidone-iodine drug products, which purport to be sterile. These products are intended for significant indications, including the “disinfection of wounds or burns,” as well as “preparation of skin and mucous membranes prior to surgery or injections.”
你们公司未能对你们的理应无菌的聚维酮碘药品进行充分的微生物控制。这些药品是用于重大病症的，包括“外伤和烧伤感染”以及“外科手术和注射之前皮肤和粘膜消毒”。
Inadequate “sterilization” process “灭菌”工艺不充分
You failed to adequately validate your process and the claim that it achieves “sterilization.” Your process relies (b)(4). You used a biological indicator organism (b)(4) that your studies found is less resistant than organisms routinely found in your manufacturing environment, such as Bacillus licheniformis.
你们未能充分验证你们的工艺，声明其达成“灭菌”目标。你们的工艺依赖于XX。你们使用了一种微生物指示剂YY，而你们的研究发现其抗性低于你们生产环境中常规发现的微生物，例如地衣形芽孢杆菌。
Further, since at least 2012, spore-forming microorganisms have been repeatedly isolated using your surrogate sterility test. You failed to adequately investigate and implement corrective actions to prevent recurrence of these contamination incidents. Examples of contamination found using your surrogate sterility test include:
还有，至少是从2012年开始，使用你们的替代无菌测试已反复分离出孢子形态微生物。你们未能进行充分调查，实施有效措施以防止这些污染事故的反复发生。使用你们的替代无菌检测所发现的污染例子包括：
? ? Fluid Ounce Povidone-Iodine Solution (Lot 2K040, November 14, 2012). Paenibacillus polymyxa andPaenibacillus pasadenensis were isolated.
? ?液体盎司聚维酮碘溶液（批号2K040，2012年11月14日），分离出多粘类芽胞杆菌和Paenibacillus pasadenensis
? ? Fluid Ounce Povidone-Iodine Solution (Lot 2K052, November 14, 2012). Paenibacillus barengoltzii was isolated.
? ?液体盎司聚维酮碘溶液（批号2K052，2012年11月14日），分离出巴伦葛兹类芽孢杆菌
? One Povidone-Iodine Gel Swabstick (Lot 54751, October 09, 2013). Brevundimonas vesicularis was isolated.
? 一种聚维酮碘胶擦拭棒（批号54571，2013年10月09日），分离出泡囊短波单胞菌
? Large Winged Sponges with PVP-I Scrub (Lot 57448, June 11, 2014). Bacillus licheniformis was isolated.
? 大翅海绵与PVP-I清洗液（批号57448，2014年6月11日），分离出地衣形芽孢杆菌
? Povidone-Iodine Ointment (Lot 59858, February 23, 2015). Bacillus subtilis was isolated.
? 聚维酮碘膏剂（批号57448，2015年2月23日），分离出枯草芽胞杆菌
? One Povidone-Iodine Gel (Lot 61995, November 12, 2015). Nigrospora orzyae was isolated.
? 一种聚维酮碘胶（批号61995，2015年11月12日），分离出稻黑孢菌
In your response, you said that you would revalidate your “sterilization” process for povidone-iodine products. Specifically, you proposed to characterize the anti-microbial effects (b)(4), assess biological indicator organism suitability, and requalify the process. You anticipated completion of this revalidation plan within 14 to 18 months.
在你们的回复中，你们说你们会重新验证你们的聚维酮碘“灭菌”工艺。你们提出会对抗菌效果进行鉴定，评估生物指示剂生物种类的适用性，重新确认工艺。你们预期会在14-18个月内完成此再验证计划。
Your response is inadequate because you have unsuccessfully attempted these actions as corrections in the past. While your firm provided references that indicate that your disinfection process is capable of substantial bioburden reduction, your references and other available literature also indicate that some microbes (e.g., certain species of spore-formers, Pseudomonas, or Burkholderia) can persist in povidone-iodine.
你们的回复是不充分的，因为你们在过去已经尝试过将此措施用作纠正措施，但没有成功。在你们公司提交的证明你们的消毒工艺能够大大降低生物负载的参考文献中，这些文献和其它一些能够找到的文献也显示出有一些微生物（例如，特定的孢子形态微生物、绿脓杆菌或伯克氏菌）可能会耐受聚维酮碘。
We also note that your firm failed to test numerous product lots for sterility using USP <71> or an equivalent method. You instead used a surrogate sterility test that lacks a representative sample of the batch and is insufficiently sensitive. We acknowledge that your firm commits to testing sterility of finished products using USP <71> in the future. It should be noted, however, that a passing sterility test alone is insufficient to support release of products unless the manufacturing operation is designed to robustly and reproducibly assure batch sterility.
我们还注意到你们公司没有使用USP<71>或等同方法来检测大量批次药品。你们使用的是替代无菌测试方法，该方法缺乏具有代表性的批次样品，并且灵敏度不够。我们知晓你们公司承诺要在将来使用USP<71>来检测成品的无菌性。要提醒注意的是，仅是无菌检测合格并不足以支持对产品的放行，除非生产操作设计的稳定性和可重复性能确保批产品的无菌性。
You lack scientific justification that your process is capable of robustly rendering products sterile. In your response to this letter, describe improvements to your manufacturing operation that will establish a high level of sterility assurance. If you intend to implement a terminal sterilization process, provide us with a rigorous sterilization validation protocol and study results demonstrating that the new process can achieve a sterility assurance level of 10-6 or more, and using a biological indicator that represents the resistant spore-forming organisms found in your environment. If you plan to continue to use the(b)(4) bioburden reduction step at the conclusion of processing, describe the facility and process improvements that will ensure that units subjected to that step are first produced under aseptic processing conditions.
你们对于你们的工艺是否足够稳定保证药品无菌性没有科学论证。在你们对此函的回复中，请描述对你们生产操作的改进，以建立高度无菌保证。如果你们有意实施终端灭菌工艺，请向我们提交一份严谨的灭菌验证方案，并提交能够证明新的工艺可以达到10-6或更高的无菌保证水平，在其中使用一种能代表你们环境中发现的具有抗药性的孢子形态微生物的生物指示剂。如果你们工厂在工艺结论部分持续使用XX生物负载降低步骤，则请描述设施和工艺方面的改进，说明这些改进能够确保经过该步骤的药品首先在无菌加工条件下生产的。
In your response, also include the microbiological testing procedures that you will be using in your process validation studies.
在你们的回复中，还请包括你们将在工艺验证研究中使用的微生物检测方法。
2. Your firm failed to use appropriate air filtration systems for production areas (21 CFR 211.46(c)).
你们公司的生产区域未能使用适当的空气过滤系统。(21 CFR 211.46(c))
You do not manufacture your povidone-iodine drug products in production areas of appropriate air cleanliness. Your firm manufactures povidone-iodine drug products that purport to be sterile in unclassified areas. These are inadequate conditions to protect the drug and its packaging components during production.
你们生产聚维酮碘产品的生产区域没有适当的空气洁净度。你们公司在洁净度不符合要求的区域生产理应无菌的聚维酮碘药品，在生产中没有足够的条件来保护药品和其包装组件。
Your firm’s povidone-iodine products should be produced in cleanrooms that are designed and controlled to meet appropriate cleanliness standards and supplied with air from high-efficiency particulate air (HEPA) filters.
你们公司的聚维酮碘药品所生产的区域的设计和控制应符合适当的洁净度标准，并从高效过滤器送风。
Your response acknowledges the need to establish cleanrooms. However, it lacks a detailed corrective action and preventive action (CAPA) that describes all actions to be taken relating to facilities, equipment, manufacturing methods, controls, and raw materials to assure sterility.
你们的回复说明了需要重建洁净间。但是，并没有提供详细的纠正和预防措施（CAPA），在其中描述要采取的与设施、设备、生产方法、控制和原料相关的所有措施，以确保无菌性。
3. Your firm failed to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups (21 CFR 211.42(c)).
你们公司没有单独的或指定的区域，或其它必要的控制系统来防止污染和混淆(21 CFR 211.42(c))。
Your environmental monitoring of production areas where you manufacture povidone-iodine products is performed (b)(4). This level of monitoring is insufficient to evaluate whether the manufacturing environment is in control. During your limited environmental monitoring, you have isolated Bacillus species in numerous instances and in various locations in your facility. For instance, approximately (b)(4) of (b)(4) samples collected in March 2015 were identified as Bacillus species, which are spore-forming bacteria.
你们生产聚维酮碘的区域环境监测频次为XX。此水平的监测不足以评估生产环境是否受控。在你们有限的环境监测中，你们在大量物体以及设施的不同位置中分离出了芽孢杆菌类。例如，2015年3月采集的大约XX个样品中约有YY个经鉴别为芽孢杆菌类，这是一种孢子形态的细菌。
In your response, you provided a revised environmental monitoring procedure. Your revised procedure is inadequate for the following reasons.
在你们的回复中，你们提交了一份修订过的环境监测程序。你们修订后的程序是不充分的，理由如下：
? You did not provide sufficient scientific rationale for establishing microbial alert/action limits. The limits appear to be based solely on historical average and standard deviation, without adequately considering other factors.
? 你们没有提交建立微生物警戒/行动限的充分的科学合理性。该限度看起来仅仅基于历史平均水平和标准念头，没有充分考虑其它因素。
? The settle plate microbial action limits (b)(4) to be used in the newly established cleanrooms (b)(4) appear to permit unnecessarily high levels of air contamination.
? 在新订立的洁净间XX沉降菌微生物行动限XX貌似会允许空气污染达到不必要的高水平。
? You did not provide an adequate program for identifying organisms in the environment. You currently selectively identify certain microbes (e.g., gram-positive spore-formers, filamentous fungi) and only when they reach microbial action limits.
? 你们没有提交鉴别环境中微生物的充分计划。你们目前有选择性地鉴别某些微生物（例如，革兰氏阳性菌孢子形态、丝状真菌），并且只有在达到微生物运行限时才会做此鉴别。
Your firm should establish a comprehensive environmental monitoring program to assist in assuring control of the pre-sterilization bioburden of your products. The program should set appropriate alert and action limits in order to detect adverse environmental conditions and trigger prompt corrective actions that prevent contamination.
你们公司应订立全面的环境监测计划，帮助确保你们产品在灭菌之前的生物负载控制。计划中应设计适当的警戒限和行动限，以检出不良环境条件，并快速启动纠正措施以防止污染。
In response to this letter, please provide revised environmental monitoring procedures. These procedures should include appropriate:
在回复此函时，请提交修订过的环境监测程序。这些程序应包括适当的：
? action and alert limits for each ISO classified area you intend to implement.
? 你们将要实施的每个ISO洁净级别区域的行动限和警戒限。
? instructions regarding investigations of out-of-limit (OOL) environmental monitoring results.
? 关于OOL环境监测结果的指令。
? plans for routinely identifying organisms. For example, microorganisms recovered from the filling and sealing room should be routinely identified.
? 常规微生物鉴别计划。例如，日常应鉴别从灌装间和密封间收到的微生物。
In a previous inspection (October 16 through November 17, 2014) FDA cited similar environmental monitoring deficiencies and sterility positive findings.
在之前的检查中（2014年10月16日至11月17日），FDA签发了类似的环境监测缺陷和无菌阳性缺陷。
4. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products (21 CFR 211.166(a)).
你们公司未能建立和遵守设计用以评估药品的稳定性特性的充分书面检测程序(21 CFR 211.166(a))。
During your stability studies of povidone-iodine drug products, which purport to be sterile, you failed to test sterility. Therefore, there is no assurance that your povidone-iodine drug products can meet their specifications for sterility through their 36-month expiration period.
在你们理应无菌的聚维酮碘药品的稳定性研究中，你们未检测无菌性。因此，无法保证你们的聚维酮碘药品能够在36个月有效期内符合其无菌质量标准。
Products manufactured as sterile must maintain their container-closure integrity and sterility throughout the labeled expiration period.
无菌生产的药品必须在标示的有效期内维持其容器密闭完整性和无菌性。
For all povidone-iodine products labeled as sterile, provide us with data to demonstrate that each product is sterile at the end of the expiration period, that the integrity of the container-closure system is maintained throughout the shelf life, and that each product passes USP <51> “Antimicrobial Effectiveness Testing.”
针对标示为无菌的所有聚维酮碘药品，请向我们提交数据证明每种产品在有效期结束时仍为无菌，在整个生命周期中都能维护容器密闭系统的完整性，并且每个产品均能通过USP<51>“抗菌有效性测试”。
Unapproved new drug charges for the following Aplicare products
? Aplicare 3/4 Fluid Ounce Povidone-Iodine Solution
? Aplicare One Povidone-Iodine Gel Swabsticks
? Aplicare One Povidone-Iodine Scrub Swabsticks
? Aplicare Three Povidone-Iodine Swabsticks
The product labels and websites (
www.aplicare.com and
https://www.cloroxprofessional.com/ industry/health/overview/
1) for Aplicare 3/4 Fluid Ounce Povidone-Iodine Solution, Aplicare One Povidone-Iodine Gel Swabsticks, Aplicare One Povidone-Iodine Scrub Swabsticks and Aplicare Three Povidone-Iodine Swabsticks (collectively, the Aplicare Povidone-Iodine products) include the following labeling claims that demonstrate the intended uses of the products. This list is not inclusive of all claims demonstrating the products’ intended use.
All four product labels include the following claims:
? “Use…antiseptic skin preparation”
? “ANTISEPTIC STERILE Solution”
Aplicare 3/4 Fluid Ounce Povidone-Iodine Solution
“Proven Efficacy…Broad-spectrum efficacy shown against skin pathogens, including gram-negative bacteria, gram-positive bacteria and yeasts”
Aplicare One Povidone-Iodine Gel Swabsticks
“Broad-spectrum against skin pathogens, including Gram-negative and Gram-positive bacteria, fungi, viruses, protozoa and yeasts”
Aplicare One Povidone-Iodine Scrub Swabsticks
“Proven Efficacy…Broad-spectrum efficacy shown against skin pathogens, including gram-negative bacteria, gram-positive bacteria and yeasts”
“Broad-spectrum against skin pathogens, including Gram-negative and Gram-positive bacteria, fungi, viruses, protozoa and yeasts”
Aplicare Three Povidone-Iodine Swabsticks
“Proven Efficacy…Broad-spectrum efficacy shown against skin pathogens, including gram-negative bacteria, gram-positive bacteria and yeasts”
“Broad-spectrum against skin pathogens, including Gram-negative and Gram-positive bacteria, fungi, viruses, protozoa and yeasts”
Based on their labeling, the Aplicare Povidone-Iodine products are “drugs” as defined under section 201(g)(1)(B) of the FD&C Act (21 U.S.C. 321(g)(1)(B)), because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act (21 U.S.C. 321(g)(1)(C)) because they are intended to affect the structure or any function of the body of man. Specifically, these products are intended as topical antiseptics and antifungals.
The antifungal claims, “Broad-spectrum against skin pathogens, including…fungi,” and “Broad-spectrum efficacy shown against skin pathogens, including…yeasts” subject the Aplicare Povidone-Iodine products to the requirements of the OTC Final Monograph for Topical Antifungal Drug Products (21 CFR 333.201). These products are neither formulated nor labeled in conformance with this final monograph. Specifically, these products do not contain the permitted antifungal active ingredients listed under 21 CFR 333.210. In addition, the products’ labeling does not include any of the required labeling for antifungal products under 21 CFR 333.250.
In addition, drug products intended for topical antiseptic general use to reduce bacteria and microorganisms on the skin such as the labeled purpose of the Aplicare Povidone-Iodine products are being evaluated under the ongoing rulemaking for OTC Topical Antimicrobial Drug Products within FDA’s OTC Drug Review. OTC Topical Antimicrobial Drug Products include OTC healthcare antiseptics and OTC consumer antiseptics such as these products. Tentative final monographs (TFM) for these products were first published in the Federal Register in 43 FR 1210 (January 6, 1978) and amended at 56 FR 33644 (July 22, 1991), 59 FR 31402 (June 17, 1994), 78 FR 76446 (December 17, 2013), and 80 FR 25166 (May, 1, 2015). These documents are available on FDA’s website:
http://www.fda.gov/Drugs/Develop ... ings/ucm070821.htm.
Pending a final monograph,2 FDA does not object to marketing OTC drugs that meet the formulation and labeling requirements described in the relevant TFM or that are otherwise eligible for inclusion in the OTC Drug Review (see 68 FR 75585 at 75590-91, Dec. 31, 2003). However, the Aplicare Povidone-Iodine products are not labeled in accordance with the Antimicrobial TFM. Specifically, the claims to the public referenced above regarding effectiveness against pathogens such protozoa and viruses go beyond merely describing the general intended use of a topical antiseptic as described in the relevant rulemaking. Moreover, such claims are not described in any OTC final monograph, tentative monograph, or any rulemaking being considered under the OTC Drug Review. Also, we are unaware of any evidence that a product formulated and labeled for such uses was marketed in the United States on or before the inception of the OTC Drug Review.
Therefore, the Aplicare Povidone-Iodine products are “new drugs” under section 201(p) of the FD&C Act (21 U.S.C. 321 (p)) because they are not generally recognized among scientific experts as safe and effective for the drug uses described in their labeling. “New drugs” may not be legally marketed in the United States without an approved application under section 505(a) of the FD&C Act (21 U.S.C. 355(a)). The Aplicare Povidone-Iodine products are not subjects of approved new drug applications; therefore, marketing these products in the United States is prohibited under section 301(d) of the FD&C Act (21 U.S.C. 331(d)), and violates section 505 the FD&C Act (21 U.S.C. 355).
Aplicare Benzalkonium Chloride Swabsticks
The label for Aplicare Benzalkonium Chloride Swabsticks includes a statement that the product is a “skin cleanser.” However, the website for Aplicare Benzalkonium Chloride Swabsticks includes a link to Safety Data Sheet for Aplicare Benzalkonium Chloride Swabsticks that states: “Recommended Use Topical skin antiseptic.” You also prominently declare the ingredient benzalkonium chloride on the immediate label and in the product name implying, in the context of your product’s labeling, that the ingredient has pharmacological activity. In fact, benzalkonium chloride is a well-known topical antimicrobial. Aplicare Benzalkonium Chloride Swabsticks is a drug as defined by section 201(g)(1)(B) of the FD&C Act (21 U.S.C. 321(g)(1)(B)) because it is intended to diagnose, cure, mitigate, treat, or prevent disease, and/or under section 201(g)(1)(C) of the FD&C Act (21 U.S.C. 321(g)(1)(C)) because they are intended to affect the structure or any function of the body of man.
Drug products intended for topical antiseptic general use are being evaluated under the ongoing rulemaking for OTC Topical Antimicrobial Drug Products within the OTC Drug Review. As mentioned above, pending a final monograph, the agency does not object to marketing OTC drugs that meet the formulation and labeling conditions described in the relevant TFM or that are otherwise eligible for inclusion in the OTC Drug Review. However, your product does not follow the formulation and labeling conditions described in the TFM. Products that are not marketed according to the conditions of the TFM and are not generally recognized as safe and effective by qualified experts would require an approved new drug application.
CGMP consultant recommended
We acknowledge that your firm has engaged a consultant to assist your firm in meeting CGMP requirements. Based upon the nature of the violations we identified at your firm, and your failure to correct repeat violations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all violations and ensuring ongoing CGMP compliance.
Evaluating OOS results
Your program for handling OOS result is among the areas that should be reviewed by your consultant. For example, Aplicare General Procedure 7.9M, Packaging Machine Fill Pump Cleaning Validation, appears to permit averaging of discrete cleaning validation sample test results if the initial results are not within the specified criteria
Your laboratory should report each individual chemical test result, not averaged results, for your quality control unit to evaluate and consider. For guidance on evaluating out-of-specification test results, see FDA’s guidance document, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production, at
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdf.
In response to this letter, conduct a global assessment of your standard operating procedures to ensure that discrete sample results are considered separately. Provide us with a summary of the results of this assessment. In addition, provide the revised AGP 7.9M with evidence that you have trained your staff on the revised procedure.
Conclusion
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.
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at
drugshortages@fda.hhs.gov, so that FDA 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 or interruptions in your drug manufacture under 21 U.S.C. 356C(b) 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.
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.
Until you completely correct all violations and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer.
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.
Send your reply to:
Maya M. Davis, Compliance Officer
U.S. Food and Drug Administration
New England District Office
One Montvale Avenue
Stoneham, MA 02180
Please identify your response with CMS 489281.
Sincerely,
/S/
Joseph Matrisciano, Jr.
District Director
New England District Office
Cc:
Mr. Benno Dorer, CEO
The Clorox Company
1221 Broadway
Oakland, CA 94612
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2 Once a final monograph becomes effective, it may be necessary to reformulate and/or relabel such products to conform to its requirements, or, in the alternative, to seek FDA approval of a new drug application (NDA) under section 505 of the FD&C Act. (21 U.S.C. 355)
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