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发表于 2014-8-14 08:46:54
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这是一个青霉素类产品的警告信
这东西说不好就误导了，还是去找一些警告信之类的，或许能得到一些信息
WARNING LETTER
FLA-10-18
May 12, 2010
Terry E. Yon, President and CEO
Terry Yon & Associates, Inc
dba TYA Pharmaceuticals
2930 Crescent Drive
Tallahassee, FL 32301
Dear Mr. Yon:
During our November 16-18, 2009 inspectionof your pharmaceutical manufacturing facility, Terry Yon & Associates, Inc.,dba TYA Pharmaceuticals, located at 2930 Crescent Drive, Tallahassee, FL 32301, investigators from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug products to be adulterated within the meaning of section501 (a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351 (a)(2)(B)) in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing,or holding do not conform to, or are not operated or administered in conformity with, CGMP.
在2009年11月16-18日对贵公司Terry Yon& Associates, Inc., dba TYA Pharmaceuticals, 位于2930 Crescent Drive, Tallahassee, FL 32301（弗罗里达州塔拉哈西）的药品生产设施进行检查期间，FDA检查官在制剂生产中发现严重不符合CGMP CFR 210&211的缺陷。根据联邦食品药品化妆品法案[21 U.S.C. § 351 (a)(2)(B))501 (a)(2)(B) ，由于贵公司在药品生产、加工、包装或存放过程中使用的设施或控制不符合CGMP或未按照CGMP进行操作和管理，这些缺陷导致贵公司药品被认定为假药。
We have reviewed your firm's response of December 7, 2009, and note that it lacks sufficient corrective actions.
我们已收到贵公司2009年12月7日的回复，注意到其中整改措施不充分。
Specific violations observed duringthe inspection include, but are not limited to, the following:
检查期间发现的不符合情况包括，但不限于下列
1. Your firm has failed to establish separate or defined areas or such other control systems for your firm's manufacturing and processing operations [21 C.F.R. § 211.42(c)(5)]. Your firm has also failed to perform operations related to the manufacture, processing, and packing of penicillin in facilities separate from those used for other drug products for human use [21 C.F.R. §211.42(d)).
1. 贵公司未能建立独立的或指定区域或类似的控制体系用于公司生产和工艺操作[21 C.F.R. § 211.42(c)(5)]，贵公司未能在独立于其它人用药品的设施内进行青霉素的生产、加工和包装相关的操作。[21 C.F.R. § 211.42(d))
For example, your firm does not have facilities for repackaging penicillin drug products (e.g., amoxicillin capsules) that are separate from those used for repackaging non-penicillin betalactam products(e.g., cephalexin capsules, a type of cephalosporin drug). Amoxicillin capsules and cephalexin capsules are both repackaged into unit-dose "bingo cards"inside a single hooded cabinet (b)(4) within a single "laminar air-flow room."
例如，贵公司没有独立于其它非青霉素BETA内酰胺产品（如头孢氨苄胶囊，一种头孢类药品）的青霉素重新包装用的设施（如阿莫西林胶囊），阿莫西林胶囊和头孢氨苄胶囊进行单剂量宾果卡重新包装均在一个仅有的层流间的仅有的一个层流罩下。
In your December 7, 2009 response, you state that you have discontinued repackaging all penicillin products and will only market such products in unopened, original containers in the future. Further, you state that the laminar air-flow room will only be used to repackage cephalosporindrug products. We find your response to be inadequate because your firm has previously made similar assurances, but resumed repackaging penicillin and cephalosporin drug products in December 2008 without having full segregation in place to prevent cross contamination.
在贵公司2009年12月7日的回复中，你们申明已停止青霉素产品的重新包装，并会仅销售原封装形式的产品。另外，你们申明层流间仅用于头孢菌素药品。我们发现你们的回复是不充分的，因为贵公司在之前已作过类似的保证，但在2008年12月，在没有充分的隔离以防止交叉污染的情况下又恢复了青霉素和头孢菌素产品的重新包装。
This is a repeat observation from the February 2007 inspection.
这个缺陷实际上2007年2月检查中已发现。
2. Your firm has failed to test non-penicillindrug products for the presence of penicillin when a reasonable possibility exists that a non-penicillin drug product has been exposed to cross contamination with penicillin [21 C.F.R. § 211.176].
2. 在非青霉素产品可能与青霉素产品产生交叉污染时，贵公司没有对非青霉素药品检测青霉素残留。[21 C.F.R. §211.176]
For example, your Firm repackages penicillind rug products (e.g., amoxicillin) with non-penicillin beta-lactam drug products(e.g., cephalexin) within a single laminar air-flow room without testing or providing assurances that the non-penicillin beta-lactam drug products are free from penicillin contamination. Between December 18, 2008 and November 13, 2009, your firm has repacked(b)(4) batches of cephalexin drug products and (b)(4) batches of penicillin drug products in the same laminar air-flow room.
例如，贵公司非青霉素药品与青霉素药品在同一层流间进行重新包装，且并未提供保证措施及检测以防止青霉素对非青霉素产品的污染。从2008年12月18日 至2009年11月13日，贵公司在同一层流间对头孢氨苄和青霉素产品某些批次进行了重新包装。
Under regulation 21 C.F.R. § 211.176, you are required to test non-penicillin drug products for the presence of penicillin where a reasonable possibility of exposure to penicillin cross-contamination exists. Your non-penicillin drug products should not be marketed if detectable levels of penicillin are found. Since you repackage penicillin drug products in the same laminar air-flow room as non-penicillin beta-lactam drug products, there is a reasonable possibility of penicillin cross-contamination at your facility. Therefore, all non-penicillin beta-lactam drug products you repackage at your facility must be tested for the presence of penicillin.
根据21 C.F.R. § 211.176，如果有交叉污染可能性存在时，贵公司应该检测非青霉素药品中青霉素残留量。如果产品中有青霉素检出，贵公司非青霉素产品不应上市销售。由于贵公司青霉素产品与非青霉素产品在同一层流间进行重新包装，因此贵公司的设施有产生交叉污染的可能性，所以，所有在贵公司设施中重新包装的非青霉素BETA内酰胺产品均必须检测青霉素。
In your December 7, 2009 response, you state that you will secure swab samples from the laminar-airflow room and from various other areas in your packaging facility to test for the presence of penicillin. Your response is inadequate in that the referenced environmental testing does not address the issue of testing non-penicillin beta-lactam products for the presence of penicillin.
在贵公司2009年12月7日的回复中，你们申明会对层流间及包装设施中其它不同区域取擦拭样进行青霉素检测。你们的回复是不充分的，因为其中未说明关于非青霉素BETA内酰胺产品中青霉素检测。
3. Your firm has not cleaned and maintained equipment at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 C.F.R. § 211.67(a)].
3. 贵公司未按照适当的间隔时间对设备进行清洁和维护以防止污染，这有可能会改变药品的安全性、鉴别、剂量、质量或纯度。[21 C.F.R. § 211.67(a)]
For example, your firm has failed to validate its cleaning procedures for all equipment used in its repacking operations to ensure that drug residues from repackaged drug products are not transferred to other drug products repackaged using the same equipment. Your firm's Standard Operating Procedure (SOP) requires annual testing using either a Glo-Germ Kit test (test for residues of a UV florescent powder) or a swab test (test for Total Organic Carbon (TOC)) on the surfaces of repackaging machines after cleaning to ensure that the cleaning process is adequate. Your SOP also states that all repackaging equipmentis to be scrubbed with disinfectant and steam-cleaned annually. However, your cleaning procedures have not been shown to adequately clean multi-product equipment to prevent cross-contamination of drug products. The cleaning process itself must first be validated to ensure that your cleaning procedures (or "cleaning SOP") are adequate to prevent equipment contamination of drug products.
例如，贵公司未验证重新包装操作的所有设备的清洁程序，以保证药品残留未转移到其它使用同套设备进行重新包装的产品上。贵公司的SOP要求每年在重新包装设备清洁后，对表面取样进行Glo-Germ Kit（紫外荧光粉末残留检测）检测，或擦拭样（总有机碳TOC）检测，以保证清洁程序是充分的。贵公司SOP也申明所有重新包装设备每年会用消毒液擦洗和蒸汽清洁，但是清洁程序显示清洁并不足以防止交叉污染。清洁工艺本身必须验证以保证清洁程序（或清洁SOP）是足以防止药品因设备产生污染的。
In your December 7, 2009 response, you stated that you have previously validated the cleaning procedure by conducting a swab test, after cleaning, in three different repackaging machines repacking three different drug products. Since the swab tests were found negative, you considered the cleaning procedure to be validated. However, you provided the results of two swab tests (conducted April 2007) during our inspection that had been performed on an Auto-Med strip filling machine and an (b)(4) machine to detect residues ofa single drug product. We find your response referencing your April 2007 results to be inadequate because you failed to test other filling equipment or test for other drug product residues that would fully represent the operations at your firm. As such, we find that you have not validated cleaning procedures.
贵公司2009年12月7日回复中，你们申明在三个不同的重新包装设备各重新包括三个不同产品，并进行清洁后已验证清洁程序，取样方式为擦拭取样。由于擦拭样品显示为未检出，你们认为清洁程序已得到验证，但是你们在检查期间提供的两个擦拭样品检测结果（2007年4月实施）是对Auto-Medstrip充填机和某个设备单个产品残留检测。我们发现你们回复引用2007年4月结果是不充分的，因为你们未检测其它充填设备或其它药品残留，而这可能全面代表贵公司的操作。因此，我们认为贵公司并未对清洁程序进行验证。
This is a repeat observation from the February 2007 inspection.
该缺陷在2007年2月检查中已发现。
4. Your firm has failed to establish an expiration date determined by appropriate stability testing, described in 21C.F.R. § 211.166, for your repackaged drug products to assure that they meet applicable standards of identity, strength, quality, and purity at the time of use [21 C.F.R. § 211.137(a)].
4. 贵公司未根据适当的稳定性检测，为重新包装产品建立有效期，以确保其鉴别、剂量、质量和纯度在其被使用 时符合应用标准。[21 C.F.R. § 211.137(a)]
For example, your firm is repackaging solid oral dosage products into unit-dose Class A packaging strips and Class A bottles, and declaring a one year expiration date without supporting stability data. Examples of repackaged products using this one year expiration date include lithium carbonateextended-release (ER) 300 mg tablets and trihexyphenidyl 5 mg tablets.
例如，贵公司将固体口服制剂产品重新包装为单一剂量A类包装袋和A类瓶，在没有稳定性数据情况下给定有效期为1年。其中包括碳酸锂缓释剂（ER）300mg片剂和苯海索5mg片剂。
In your December 7, 2009 response, you support the use of a one-year expiration date by referencing the draft revisionof the FDA Compliance Policy Guide Section 480.200 "Expiration Dating of Unit Dose Repackaged Drugs - Testing/Examination under CGMPs (CPG 7132.13)," dated May 2005. This draft would revise the Current CPG 480.200 recommended maximum 6-monthexpiration to a maximum one-year expiration. However, as you also acknowledge in your response, the draft has not been made final and as such, you have now revised your SOP to observe the current FDA recommended maximum expiration dating of 6-months.We will verify this revision during our next inspection.
贵公司2009年12月7日的回复中，你们引用2005年5月FDA草案认证政策指南480.200部分“单剂量重新包装产品效期计算—CGMPs下的检测/检查(CPG 7132.13)”来支持一年的有效期给定，该草案将现行的CPG 480.200中推荐的最多给定6个月有效期修订为最多给定1年有效期。但是，正如你们回复中所被告知的，该草案尚未最终定稿，因而你现在修订SOP应给定效期为6个月。我们会在下一次的检查中查看该修订。
This is a repeat observation from the February 2007 inspection.
该缺陷在2007年2月检查中已出现。
The violations documented during this inspection demonstrate that you have not implemented a robust Quality System at your firm. Several of the CGMP deficiencies observed during this inspection were also observed during our inspection in 2007. We recommend that you implement a comprehensive Quality System at your firm to encompass all repackaging operations.
该违规情况在本次检查中被记录，说明贵公司未实施有效的质量体系。本次检查中发现的其它一些CGMP缺陷在2007年检查中也有被发现。我们建议贵公司实施综合质量体系指导所有重新包装的操作。
This Quality System should also include an effective containment control program to prevent cross-contamination of non-beta-lactamrepackaged drug products by beta-lactam drug products (such as penicillin products and cephalosporin products). In addition to full segregation of facilities, the containment control program procedures should address procedures for detecting and correcting any flaws or deviations in your containment program. Any beta-lactam contamination on surfaces alerts a firm that contamination is present in the manufacturing environment due to poor containment practices. Major elements of an effective beta-lactam containment control program include:
该质量体系应还包括有效的污染控制程序以防止非BETA内酰胺产品重新包装时由BETA内酰胺产品所交叉污染（如青霉素产品和头孢菌素产品）。除设施的隔离外，交叉污染的控制程序还应说明任何缺点或偏差的发现和整改。任何BETA内酰胺的表面污染对公司都是一种由于防止污染不足够而对生产环境产生污染的警示，一个有效的BEETA内酰胺污染控制程序应包括：
(1) a representative sampling plan to test production areas, including worst-case locations, for undesired beta-lactamresidues;
(1) 建立有代表性的取样计划，对生产区域包括最坏点取样以监测BETA内酰胺残留；
(2) containment control procedures to include SOPs that address how to determine, control and correct deficiencies, control the movement of personnel, equipment and materials between beta-lactam and non-betalactamre packaging areas, and investigate the extent and cause of any failures, with proper corrective actions;
(2) 污染控制程序包括SOP，说明如何确认、控制和纠正缺陷，BETA内酰胺和非BETA内酰胺重新包装区域间人员、设备和原料移动控制，调查偏差范围和原因，并提出适当的整改措施；
(3) analytical procedures of proper sensitivity and specificity to detect undesired residues of beta-lactam drugs in the application of surface sampling techniques to assess the effectiveness of your containment control program;
(3) 分析程序，具有适当的灵敏度和专属性以检测表面取样样品中非期望之BETA内酰胺药品残留，对贵公司的污染控制程序有效性进行评价；
(4) a provision to conduct product testing before release if there is a reasonable possibility of contamination of non-betalactam products with beta-lactam drugs. The risks presented by the cross-contamination of drug products with non-penicillin beta-lactam drugs (such as the cephalosporins) are similarly serious to those of cross-contamination with the penicillins. Thus,equal care must be given to providing containment control for the repackaging of cephalosporins as for penicillins.
(4) 非BETA内酰胺产品有被BETA内酰胺产品污染可能性时，其产品放行应包括进行产品污染残留检测。药品被非青霉素BETA内酰胺产品（如头孢菌素）交叉污染的风险与青霉素产品交叉污染的风险同等严重，因而，对头孢菌素产品的污染控制必须和青霉素污染一样给予同样重视。
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.
在本警告信中引用违规情况并不是想对贵公司现有的违规行为作概括说明，贵公司有责任调查和确认上述违规行为的原因，以防止其再次发生，以及其它违规行为的发生。贵公司有责任保证符合所有联邦法律和FDA法规所有要求。
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. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
贵公司应采取积极措施纠正本信中所述的违规情况。如否，可能会导致不再发出通知的执法行为包括，无限制的扣押和禁令。其它联邦机构在考量合同订立时可能将此警告信内容考虑在内。FDA可能撤销出口许可的批准，或贵场地在审药品申请的批准，直至上述违规行为得到整改。FDA可能进行再次检查以确认整改措施已完成。
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation.If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distributethe repackaged drug products manufactured at this facility, and provide the date(s)and reason(s) you ceased production.
在收到此信的15个工作日内，请书面通知本办公室，说明贵公司已采取的纠正措施，包括采取的预防措施的解释，及支持性文件的复印件。如果在15个工作日内不能完成整改措施，请说明延迟的原因及其完成时间。另外，如果你们不再在该设施上生产或销售重新包装的产品，在回复应说明停止生产的日期和原因。 |
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