美国FDA警告信翻译-上海沪汇日用化学品有限公司
上海沪汇日用化学品有限公司12年11月14日
卫生和人类服务部
公共卫生服务
食品和药物管理局（FDA）
马里兰州Silver Spring
MAIL&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
WL：320-13-02
华丰江先生
上海沪汇日用化学品有限公司
浦东新区新区
中国上海，201322
亲爱的蒋先生：
我们在2月6-10日2012年检查你的过度的非处方（OTC）药品生产设施，上海沪汇日用化工制品有限公司位于旅大路8号，上海，中国，六灶镇，美国食品和药物管理局（FDA）的调查员发现重大违反现行良好生产规范（CGMP）的规定，的成品药品，第21，美国联邦法规，配件210和211。&&这些违规行为造成药品掺假内这意味着第501（A）（2）（B）“联邦食品，药品和化妆品法”（该法）[&21
USC&351（A）（2）（B）]中使用的方法，或不符合的设施或控制使用，制造，加工，包装，或控股，或不符合CGMP经营或管理。
我们已收到贵公司的信件，日期为日。
在检查过程中观察到的具体侵犯包括，但不限于，下列：
1。&&&&组件相关的测试记录在您的工厂生产的批次的药物产品，没有现成的授权检验在保留期内。[21
CFR&211.180（c）〕
。&&&&公司拒绝提供测试记录（B）（4）&，用于制造药品的活性药物成分（API），&（二）（4）皮肤保护剂和（二）（4）皮肤保护。你的公司拒绝提供（二）（4）进行的测试的结果，而不是绝密的试验方法和验收标准（二）（4）原料规格表之前的研究者提供本文件的副本。
（二）&&&&公司也拒绝提供测试记录（二）（4）&，所使用的API在你的（B）（4）皮肤保护霜，通过数据之前redacting这提供了一个副本（B）（4）原材料规格表的调查。
这些文件是必须保留的组件测试记录，并在检查过程中审查和复印件。上面的例子构成不合理的拒绝允许FDA在您的工厂的生产条件进行评估。在你的回应这封信，请提供您的测试要求和结果（二），（4）及（B）（4）在药品使用的API。具体来说，包括有关的药品运到美国，并，保持在到期。
2，&&&&你公司未能建立足够的质量控制部门的职责和权限批准或者不批准的所有成分，药品容器，瓶盖，加工材料，包装材料，标签，药品，有权审查生产记录，以确保没有错误发生，如果发生了错
​​误，他们已经充分的调查。[21 CFR&211.22（a）〕
&211.22（一）违反四个例子如下：
。&&&&你的品质控制单元（QCU）没有到充分审查批生产记录你的产品（B）（4）皮肤保护霜，散批＃（二）（4）&。我们的检查记录批量的生产和清洁记录之间的差异。例如，您的批次产品记录显示，日，公司开始处理散批＃（二）（4）（B）（4）&7:20
AM，生产结束（B）
（4）&AM的同一天。但是，你的清洁记录表明，相同的（B）（4）第3
8:00&（B）（4）&日上午在同一天也打扫干净了。所收集的信息表明，两种不同的操作被执行的时间在同一期间内。
（二）&&&&你的QCU没有注意到您的批生产记录和原始数据记录表的同一批次的药物产品（B）（4）皮肤保护霜产率之间的矛盾。您的生产记录文件的大小，此批散批（二）（4）（B）（4）&。你的原始数据记录表显示共（B）（4）最终产品的包装的散批批号（二）（4）成品的批次编号（B）（4）&。贵公司的管理不能解释和辩护的起源额外的（B）（4）成品。同样，调查人员发现，生产的数量，散批＃（二）（4）（B）（4）&，而原始数据的记录显示，成品的数量（，批＃（B）（4）&）从这个散批是（B）（4）&。
（三）的&&&&QCU未能确保生产的（B）（4）皮肤保护霜在使用该批次批号的可追溯性。贵公司的QCU是无法确定的最终成品的产品很多从两散手＃（二）（4）&（批次大小：&&（B）（4）&）和第（二）（4）&（批次大小：&&（B
）（4）&）。
（四）&&&&研究者也观察到了不透明的修正液，在许多生产记录（二）（4）皮肤保护霜。例如，你的公司使用不透明修正液更改批号的两种原料在散批批号（二）（4）&，散装批号（二）（4）的签名，和很多过程中的温度和粘度读数＃（二）（4）&。在每一种情况下，有没有符号的变化或何时和为什么变化。请注意，批生产记录是准确地记录每一批生产和控制有关的活动。一个QCU不能合理地依赖于含有不明原因的更正的记录进行批量释放决定。&
上述四个例子，引起了严重的关切生成并记录在批生产记录的数据的完整性，可靠性和可追溯性。你的QCU未能充分审查和核实这些生产记录的准确性，之前发布的产品。在你的回应这封信，说明您的综合评价和修复您的公司使用的文件系统，在制造和实验室操作。提供详细的纠正行动计划，说明采取的步骤，以防止类似事件再次发生。包括在你的反应回顾性分析和评估问题的程度和潜在的风险（例如，其他的产品，系统和数据）。还提供了详细的说明您的QCU的责任。&
3，&&&&你的公司未能建立适当的书面程序，并按照设计，生产和过程控制，以确保药品制造的身份，实力，质量和纯度，他们声称或代表拥有，和你的QCU也没有审查和批准这些程序。[21
CFR&211.100（a）和（b）〕
。&&&&在检查的时候，你的公司没有进行任何验证的，或设备的资格，您的（B）（4）皮肤保护霜制造工艺。此外，您的QCU没有批准此产品的批生产记录。检查记录，您的公司依赖于进口/出口公司的批生产记录（二）（4）皮肤保护霜批量的生产无需现场验证的过程。此外，您的工作人员后，转入批生产记录。
（二）&&&&在检查的时候，你的公司没有进行验证研究药物产品的包装过程，包括容器或管帽密封，填充量，和标签。
在这封信中，提供了详细的纠正行动计划，以解决缺乏的工艺验证和设备的药物产品出口到美国市场的资格问题。请注意，每个药物产品的制造过程中必须得到充分的验证。必须知道的关键控制和处理参数，并显示在控制。您还应该证明您的生产过程是可重复的。
4，&&&&你的公司没有足够的书面测试计划，旨
​​在评估药品的稳定特性，以确定适当的贮存条件和截止日期。[21
CFR&211.166（a）〕
一个&&&&你的公司缺乏数据支持（B）（B）（4）皮肤保护霜（4）到期日成立。考察期间，FDA的调查人员获悉，加速稳定性试验数据产生。然而，这样的数据供审查。此外，调查记录，您的公司还没有建立的一个书面测试程序，并没有配备适当资格的稳定性室
​​进行必要的稳定性研究。
（二）&&&&我们的调查发现，成品（二）（4）皮肤保护霜，（B）（4）皮肤保护剂，和（B）（4）皮肤保护剂，已存放在仓库里，没有温度控制。你的公司缺乏稳定的数据来支持你的标签要求，“在室温下存储（二）（4）&-&（B）（4）&˚C。“
在这封信你的回应，包括一份声明中关于你的公司打算做什么目前市场上的产品，你有没有配套的稳定性数据。请提供详细的稳定性研究计划，其中包括，但不限于，产品测试，分析测试方法，合格的稳定性室，进行特定的测试，稳定性规格和测试地点。另外，请提供您的验证报告摘要稳定性指示分析方法的稳定性研究评估。&
5，&&&&你的公司没有隐瞒使用每批成分，药品容器和密封件，直到该地段已被取样，测试，或为例，适当的，并发布质量控制部门使用。[21
CFR&211.84（一）]具体而言，贵机构失败来进行的至少一个特定的标识测试的组件上，未能以建立供应商的分析的可靠性，通过适当的验证供应商的测试结果在适当的时间间隔，当依靠该组件供应商的分析。[21
CFR&211.84（D）（2）]
。&&&&你的公司还没有足够的合格的药物成分的制造供应商（B）（4）皮肤保护霜。您的公司（二）（4）进口/出口公司。但是，您的进口/出口公司的认证分析（COA）（B）（4）批次编号（B）（4）没有未披露的（B）（4）制造商或在实验室，进行测试的名称该批次。此外，您还没有进行特定的标识测试，也没有建立对供应商的可靠性分析。&
（二）&&&&你的公司没有适当的测试组件，（B）（4）（API），因为您的规格不符合要求的USP专着。您当前的原料规格不包含的杂质，比重测试，一致性，和（B）（4）的要求，USP专着。此外，贵公司没有提供任何理由不进行这些必要的测试。此外，贵公司的QCU仅依赖于供应商的分析，这种材料没有充分核实供应商的测试结果的准确性。
在这封信你的回应，提供一个详细的计划，符合资格的供应商的原材料和科学证据来支持你的决定依赖于供应商的测试结果。此外，描述的常规的身份测试进行接收和用于制造药品的原料每次发货。此外，澄清你的公司和你的进口/出口公司之间的关系和责任。请注意有足够的供应商的资格是至关重要的，确保您的药物产品的质量意。
6，&&&&你的公司还没有建立科学合理的，适当的规格，标准，取样计划，设计，以确保药品的身份，实力，质量符合相应的标准和测试程序，和纯洁性。[21
CFR&211.160（b）〕
。&&&&公司没有进行身份和分析测试（二）（4）（API）和身份测试（二）（4）（API）在你的成品，（二）（4）皮肤保护霜（批号＃（二）（4）&）。你的公司是无法提供任何测试结果，以支持您的产品标签上的成分要求研究者。
（二）&&&&你公司没有进行试验测试（二）（4）（API）（B）（4）在您的成品皮肤保护剂（很多第（二）（4）&）。你的公司是无法提供任何测试结果，以支持您的产品标签上的成分要求研究者。
在回信中，提供自愿纠正行动，你打算主动纠正这方面的不足和你的理由采取这些行动的信息。详细说明您的测试方法上面所描述的产品。总结相关的分析方法验证协议，这些协议的执行提供时间表。&
未经批准的和冒牌的柜台交易（OTC）药物
（B）（4）皮肤保护霜（B）（4）目前制定的皮肤保护，标记和推广，是违反规定的行为的OTC产品。在下面详细描述，这些产品未经批准的“新药”，违反第505（A）该法21
USC&355（a）所示。此外，（二）（4）皮肤保护霜和（B）（4）皮肤保护是冒牌的，根据第502（E）（1）（A）（ii）条的法[21
USC&352（E）（ 1）（A）（II）&（二）（4）皮肤保护霜是冒牌根据该法第502节（a）条[21
USC&352（A）]。
下面是一个法规状况的分析（二）（4）皮肤保护霜和（B）（4）&&皮肤保护，其中包括摘录的违规标签和具体的新药物和misbranding的费用。请注意，这不是一个包容各方的违规标签为OTC药品的说明。
（B）（4）皮肤保护霜
（二）（4）皮肤保护霜的包装标签包括声称，建立目标作为药物使用的产品。根据权利要求的具体实例如下：
&&&&&&&&&&&
“皮肤保护”
&&&&&&&&&&&
“活性成分：...&（二）（4）&％，（二）（4）&％“
&&&&&&&&&&&
“的目的：闭塞的皮肤保护霜（二）（4）&。“
&&&&&&&&&&&
用途：艾滋病的预防和治疗尿布皮炎（皮疹）。有助于保护皮肤免受潮湿和潮湿。“
上述声明表明，（二）（4）皮肤保护霜是一种“药物”的定义法“[21
USC&321（G）（1）]，因为它的目的是通过第201（g）（1）预防疾病或影响人的身体结构或功能。虽然标签清楚列表（二）（4）和（二）（4）作为活性成分，（二）（4）和（二）（4）是21岁以下的“活性成分”CFR&201.66（二）（
2）由于在产品标签上的陈述（例如，并列的“
（二）（4）&“&的标签，声称”目的：闭塞性皮肤防护剂“）的基础上，他们的目的是提供药理活性或其他直接作用缓解和治疗尿布疹。
根据FDA的的OTC专着系统（也被称为“OTC药品审查”），该机构正在评估提供用于治疗或预防尿布疹的OTC皮肤防护剂中活性成分的有效性和安全性。之前最后的规则或对这类产品的专着，FDA并不反对这样的尿布皮疹的营销产品，只要同时满足这些产品或产品在的暂定最终的专着（TFM）的配方和标签的要求，否则是有资格考虑下进行的规则制定。TFM
6月20日，1990年（55 FR
25204）在联邦纪事上发表。请参见：
然而，（二）（4）皮肤防护剂霜既不是标记也不配制按照与TFM。具体而言，在正在进行的规则制定并没有提出或以其他方式包括与（二）（4）作为活性成分的皮肤保护产品。此外，我们不知道有任何证据，制定和标记的产品在美国市场上销售或之前成立以来，OTC药品审查，因此这样的产品将不获考虑下持续检讨。因此，（B）（4）皮肤保护霜不符合资格的评估和市场营销下的OTC药品审查。此外，我们不知道任何证据证明，（B）（4）皮肤保护霜，制定和标记，通常被认为是安全和有效的。因此，它是一种“新型毒品”根据该法第201（P）[21
USC&321（P）]，且不得在美国没有合法销售的已批准的申请根据该法第505条（一） [21
USC&355（a）〕。
违反药品注册管理办法
你的公司未能履行登记义务，根据第510（I）（1）第510（1）（2）和510（J），这是根据第301（P）禁止该法的上市规定的义务。21
USC [360（ⅰ）（1）和（2），360（j）条，和331（对）]
例如，从2009年到2012年，贵公司提供进口到美国药物制造或以其他方式处理，在上面提到的建立。然而，在同一时期，贵公司没有与FDA保持当前的设立登记，完整和准确的药物产品上市。&&&&&
请注意，用于进口到美国的药物可能会被拒绝入场，根据该法第801（O），如果进口商，所有者或收货人无法提供一个建立生产登记表。另外，如果药物是根据该法第510节，包括中未列出的，如果上市的药物引用一个的制造业建立，不保持当前的设立登记，这种药物似乎是冒牌根据第502节（O）根据第801（A）（3）拒绝录取。[21
352（O）]&&&
FDA调查员（S）与你讨论过这个问题，在检查过程中。您的回应并没有解决这个问题。关于如何注册和名单可在下列互联网网址：。如果继续生产药物提供进口到美国，你必须完成必要的登记和上市。你的回应这封信你已经满足了这些要求，您应提供证据。
这封信中提到的侵犯人权行为，并不打算成为一个包容各方的名单在您的设备存在侵犯。你是负责调查和确定上述侵犯行为的原因，为防止其复发和其他违规行为的发生。&&
直到所有的修正已经完成，并FDA已确认改正的违法行为和贵公司的符合CGMP，FDA拒绝审批任何新的应用程序或补充上市公司作为药物产品的制造商。此外，你的失败来纠正这些违规行为，可能会导致在制品在上海沪惠日用化工制品有限公司，在上海，六灶镇，根据第801（A）（3）进入美国的FDA拒绝承认该法案，21
USC 381（A）（3）。文章拒绝接纳根据该法第801（A）（3）[21
USC&381（A）（3）]，方法和控制的生产过程中使用不出现，以符合CGM P在该法第501（A）（2）（B）的意义[21
USC&351（A）（2）（B）]。&
15个工作日内收到这封信，请以书面形式通知该办公室已经采取了纠正和防止发生侵权行为的具体步骤，并提供支持性文件的副本。如果你可以不完成纠正措施15个工作日内，状态的原因的延迟，并通过它你将有完成的修正的日期。&&此外，如果你不再生产或分配（B）（4）皮肤防护剂霜，（b
）（4）皮肤保护剂，或（B）（4）皮肤保护剂，提供的日期（S）和停止生产的原因（S）。请确定您的FEI＃的响应。
请发送您的回复至以下地址：
欣欣（珍妮）秦
高级政策顾问
美国食品和药物管理局
药物评价和研究中心
办公室生产和产品质量
国际药品质量处
白橡，51楼
10903新罕布什尔州大道
马里兰州Silver Spring 20993
联系电话：&&&&&
（301）796-3207
传真：&&&&
（301）847-8741
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
办公室生产和产品质量
合规办公室
药物评价和研究中心
最后更新日期：号&注：如果您需要帮助，访问不同的文件格式的信息
Shanghai Huhui Daily Use Chemical Products
Co., Ltd. 11/14/12
Department of Health and Human Services
Public Health Service
Food and Drug Administration
Silver Spring, MD&20993
Warning Letter
MAIL&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
November 14, 2012
Mr. HuaFeng Jiang
General Manager
Shanghai Huhui Daily Use Chemical Products Co., Ltd
No. 8 Luda Road
Liuzao Town
Pudong District New Area
Shanghai, China 201322
Dear Mr. Jiang:
During our February 6-10, 2012 inspection of your
over-the-counter (OTC) drug manufacturing facility, Shanghai Huhui
Daily Use Chemical Products Co., Ltd. located at No. 8 Luda Road,
Liuzao Town, Shanghai, China, an investigator 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 section
501(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.
We acknowledge receipt of your firm’s correspondence dated
March 11, 2012.
CGMP VIOLATIONS
Specific violations observed during the inspection include,
but are not limited to, the following:
Component test records specifically associated with batches of drug
product manufactured at your facility were not readily available
for an authorized inspection during their retention period.
&[21 C.F.R. & 211.180(c)]
Your firm refused to provide the test records of
(b)(4), an active pharmaceutical ingredient (API)
used to manufacture the drug products, (b)(4) Skin
Protectant and (b)(4) Skin Protectant.
&Your firm refused to provide the results of tests
performed on (b)(4) and instead redacted the test
methods and acceptance criteria in your (b)(4) raw
material specification sheet prior to providing a copy of this
document to the investigator.
Your firm also refused to provide the test records for
(b)(4), an API used in your
(b)(4) Skin Protectant Cream, by redacting this
data before providing a copy of (b)(4) raw
material specification sheet to the investigator.
These documents are component test records that must be
retained and are subject to review and photocopy during an
inspection. The above examples constitute unreasonable denials in
permitting FDA to assess the manufacturing conditions at your
facility. &In your response to this letter, please
provide your testing requirements and results for the
(b)(4) and (b)(4) APIs used in
your drug products. Specifically, include information regarding the
drug products shipped to the US and that remain within
expiration.
Your firm failed to establish an adequate quality control unit with
the responsibility and authority to approve or reject all
components, drug product containers, closures, in-process
materials, packaging material, labeling, and drug products, and the
authority to review production records to assure that no errors
have occurred or, if errors have occurred, that they have been
fully investigated. &[21 C.F.R. & 211.22(a)]
Four examples of violations of & 211.22(a) are as
Your quality control unit (QCU) failed to adequately review the
batch production record for your product (b)(4)
Skin Protectant Cream, bulk batch # (b)(4).
&Our inspection documented discrepancies between
your batch production and cleaning records. &For
example, your batch product record indicated that on August 31,
2011, your firm began processing bulk batch
#(b)(4) in (b)(4) at 7:20 A.M.,
and that the production ended at (b)(4) A.M. of
the same day.& However, your cleaning record
showed that the same (b)(4) #3 had been cleaned
between 8:00 to (b)(4) A.M. on the same day of
August 31, 2011. &The information collected
indicates that two different operations were being performed during
the same period of time.
Your QCU did not notice the contradictory yields obtained between
your batch production record and raw data record sheet for the same
batch of the drug product (b)(4) Skin Protectant
Cream. &Your production records for bulk batch
(b)(4) document the size of this batch as
(b)(4). &Your raw data record
sheets for finished product batch #(b)(4) showed
that a total of (b)(4) of final product were
packed from the bulk batch lot
#(b)(4).& Your firm’s management
could not explain and justify the origins of the extra
(b)(4) of finished product.
&Similarly, the investigator found that the
quantity of bulk batch # (b)(4) produced was
(b)(4), whereas your raw data records show that
the quantity of finished product (batch #(b)(4))
produced from this bulk batch was (b)(4).
Your QCU failed to ensure the traceability of the batch lot number
used in the production of (b)(4) Skin Protectant
Cream. &Your firm’s QCU was unable to determine
the final finished product lot produced from the two bulk lots
#(b)(4) (batch
size:&(b)(4)) and
#(b)(4) (batch
size:&(b)(4)).
The investigator also observed the presence of opaque correction
fluid in many of your production records of (b)(4)
Skin Protectant Cream. &For instance, your firm
used opaque correction fluid to change lot numbers of two raw
materials in the bulk batch lot #(b)(4),
signatures in bulk lot #(b)(4), and process
temperature and viscosity readings in lot #(b)(4).
&In each instance, there was no notation of who
made the change or when and why the change was made.
&Please note that batch records are to document
accurately the production and control activities associated with
each lot. &A QCU cannot reasonably rely on records
containing unexplained corrections to make batch release
decisions.&
The above four examples raise serious concerns regarding the
integrity, reliability and traceability of the data generated and
documented in your batch production records. Your QCU failed to
adequately review and verify the accuracy of these production
records prior to releasing the products. &In your
response to this letter, describe your comprehensive evaluation and
remediation of your firm’s documentation systems used in both
manufacturing and laboratory operations.& Provide
a detailed corrective action plan that describes the steps you have
taken to prevent recurrence of similar events.
&Include in your response a retrospective review
and assessment of the extent of the problem and potential risks
involved (e.g., other products, systems and data). Also provide a
detailed description of the responsibilities of your
Your firm failed to establish and follow adequate written
procedures for production and process control designed to assure
that the drug products you manufacture have the identity, strength,
quality, and purity they purport or are represented to possess, and
your QCU also did not review and approve those
procedures.&[21 C.F.R. &211.100(a) and (b)]
At the time of the inspection, your firm had not conducted any
process validation, or equipment qualification for your
(b)(4) Skin Protectant Cream manufacturing
process. &Additionally, your QCU had not approved
the batch production records for this product.&The
inspection documented that your firm relied on your import/export
company’s batch production record for producing the
(b)(4) Skin Protectant Cream bulk without on-site
validation of
the&process.&Moreover, your
personnel were not following the transferred batch production
At the time of the inspection, your firm had not conducted
validation studies for your drug product packaging processes,
including container cap or tube sealing, fill volumes, and
In response to this letter, provide a detailed
corrective action plan to address the lack of process validation
and equipment qualification issues for the drug products exported
to the U.S. market. &Please note that each drug
product’s manufacturing process must be adequately validated.
&The critical controls and processing parameters
must be known and shown to be in control. You should also
demonstrate that your manufacturing process is reproducible.
Your firm does not have an adequate written testing program
designed to assess the stability characteristics of drug products
in order to determine appropriate storage conditions and expiration
dates. &[21 C.F.R. & 211.166(a)]
Your firm lacked data to support the (b)(4)
expiration date established for (b)(4) Skin
Protectant Cream.& During the inspection, FDA’s
investigator was informed that accelerated stability data was
generated.&Nonetheless, such data was never made
available for review. In addition, the investigator documented that
your firm has not established a written testing program and is not
equipped with appropriately-qualified stability chambers to conduct
the necessary stability studies.
Our investigator found that your finished products,
(b)(4) Skin Protectant Cream,
(b)(4) Skin Protectant, and
(b)(4) Skin Protectant, have been stored in a
warehouse with no temperature control. &Your firm
lacks stability data to support your labeling claim, “Store at room
temperature (b)(4) & (b)(4)
˚C.”
In your response to this letter, include a statement regarding
what your firm intends to do with products currently on the market
for which you have no supporting stability data.&
Please provide details of your stability study program, including,
but not limited to, products tested, analytical test methods,
qualification of the stability chambers, specific tests performed,
stability specifications, and testing location.&In
addition, please provide your summary validation report for your
stability-indicating analytical methods used in the assessment of
your stability studies.&
Your firm failed to withhold from use each lot of components, drug
product containers, and closures until the lot had been sampled,
tested, or exampled, as appropriate, and released for use by the
quality control unit. &[21 C.F.R. & 211.84(a)]
&Specifically, your firm failed to conduct at
least one specific identity test on a component and failed to
establish the reliability of the supplier’s analyses, through
appropriate validation of the supplier’s test results at
appropriate intervals, when relying on that component supplier’s
analysis. &[21 C.F.R. & 211.84(d)(2)]
Your firm has not adequately qualified your drug component
suppliers used in the manufacture of (b)(4) Skin
Protectant Cream. &Your firm received
(b)(4) from your import/export company.
&However, your import/export company’s Certificate
of Analysis (CoA) for (b)(4) batch
#(b)(4) did not disclose the name of the
(b)(4) manufacturer or the laboratory that
conducted the testing of the batch. &Moreover, you
did not conduct a specific identity test nor did you establish the
reliability of the supplier’s analyses.&
Your firm failed to appropriately test the component,
(b)(4) (API), because your specification did not
meet the requirements of the USP monograph.&Your
current raw material specification does not include testing of
impurities, specific gravity, consistency, and
(b)(4) as required by the USP monograph.
&Also, your firm did not provide any justification
for not conducting these required tests. &In
addition, your firm’s QCU relied solely on the supplier’s analysis
without adequately verifying the accuracy of the supplier’s testing
results for this material.
In your response to this letter, provide a detailed plan to
qualify your suppliers of raw materials and the scientific
justification for your decision to rely on your suppliers test
results.&Also, describe the routine identity
testing you will conduct for each shipment of raw materials
received and used to manufacture your drug
products.&Additionally, clarify the relationship
and responsibilities between your firm and your import/export
company. &Please note that adequate qualification
of suppliers is critical in assuring that your drug products are of
the quality intended.
Your firm has not established scientifically sound and appropriate
specifications, standards, sampling plans, and test procedures
designed to assure that drug products conform to appropriate
standards of identity, strength, quality, and purity.
&[21 C.F.R. & 211.160(b)]
Your firm failed to conduct identity and assay tests of
(b)(4) (API) and identity test of
(b)(4) (API) in your finished product,
(b)(4) Skin Protectant Cream (batch
#(b)(4)).&Your firm was not able
to provide the investigator any testing results to support your
product label’s ingredient claims.
Your firm failed to conduct assay testing of
(b)(4) (API) in your finished product of
(b)(4) Skin Protectant (lot
#(b)(4)). Your firm was not able to provide the
investigator any testing results to support your product label’s
ingredient claims.
In your response, provide information regarding any voluntary
corrective actions you intend to initiate to correct this
deficiency and your rationale for taking those actions.
&Describe your testing methodology for each of the
products described above.&Summarize the relevant
analytical method validation protocols and provide timelines for
execution of these protocols.&
Unapproved and Misbranded Over-the-Counter
(OTC) Drugs
(b)(4) Skin Protectant Cream and
(b)(4) Skin Protectant as presently formulated,
labeled, and promoted, are OTC products that violate provisions of
the Act.&As described in more detail below, these
products are unapproved “new drugs” in violation of section 505(a)
of the Act [21 U.S.C. & 355(a)].&In addition,
(b)(4) Skin Protectant Cream and
(b)(4) Skin Protectant are misbranded under
section 502(e)(1)(A)(ii) of the Act [21 U.S.C. & 352 (e)(1)(A)(ii)]
and (b)(4) Skin Protectant Cream is further
misbranded under Section 502(a) of the Act [21 U.S.C: &
Below is an analysis of the regulatory status of
(b)(4) Skin Protectant Cream and
(b)(4)&Skin Protectant which
includes excerpts of the violative labeling and the specific new
drug and misbranding charges.&Note that this is
not an all-inclusive description of violative labeling for your OTC
drug products.
(b)(4) Skin Protectant Cream
The package labeling for (b)(4) Skin
Protectant Cream includes the claims that establish the intended
use of the product as a drug.&Specific examples of
claims are as follows:
&&&&&&&&&&&
“Skin Protectant”
&&&&&&&&&&&
“ACTIVE INGREDIENT:…(b)(4)% and
&&&&&&&&&&&
“PURPOSE: &Occlusive Skin Protectant Cream with
&&&&&&&&&&&
“USES: &Aids in the prevention and treatment of
diaper dermatitis (rash). Helps protect skin from moisture and
wetness.”
The above statements demonstrate that (b)(4)
Skin Protectant Cream is a “drug” as defined by section 201(g)(1)
of the Act [21 U.S.C. & 321(g)(1)] because it is intended to
prevent disease or to affect the structure or function of the body
of man.&Although the labeling clearly lists
(b)(4) and (b)(4) as active
ingredients, (b)(4) and (b)(4)
are also “active ingredients” under 21 C.F.R. & 201.66(b)(2)
because, based on representations on the product label (e.g., the
juxtaposition of “(b)(4)” to the label claims
“PURPOSE: Occlusive Skin Protectant”), they are intended to furnish
pharmacological activity or other direct effect in the mitigation
and treatment of diaper rash.
Under FDA’s OTC monograph system (also referred to as the “OTC
Drug Review”), the agency is evaluating the safety and
effectiveness of active ingredients in OTC skin protectants offered
for the treatment or prevention of diaper
rash.&Pending a final rule or monograph for such
products, FDA does not object to the marketing of such diaper rash
products as long as they meet both the formulation AND labeling
requirements described in the tentative final monograph (TFM) for
these products or the product is otherwise eligible for
consideration under the ongoing rulemaking.&The
TFM was published in the Federal Register of June 20, 1990 (55 FR
25204).&See:
However, (b)(4) Skin Protectant Cream is
neither labeled nor formulated in accordance with the
TFM.& Specifically, the ongoing rulemaking does
not propose or otherwise include a skin protectant product with
(b)(4) as an active
ingredient.&In addition, we are unaware of any
evidence that a product so formulated and labeled was marketed in
the United States on or before the inception of the OTC Drug Review
and therefore such a product would not be eligible for
consideration under the ongoing review.&Therefore,
(b)(4) Skin Protectant Cream does not qualify for
evaluation and marketing under the OTC Drug
Review.& Furthermore, we are not aware of any
evidence establishing that (b)(4) Skin Protectant
Cream, as formulated and labeled, is generally recognized as safe
and effective.&Therefore, it is a “new drug” under
section 201(p) of the Act [21 U.S.C. & 321 (p)] and may not be
legally marketed in the United States without an approved
application under section 505(a) of the Act [21 U.S.C. &
DRUG REGISTRATION VIOLATIONS
Your firm failed to fulfill its registration obligations under
Section 510(i)(1) of the Act and its listing obligations under
Sections 510(i)(2) and 510(j), which is prohibited under Section
301(p).&21 U.S.C. [360(i)(1) and (2), 360(j), and
For example, from 2009 through 2012, your firm offered for
import into the United States drugs that you manufactured or
otherwise processed at the above-referenced
establishment.&During that same time period,
however, your firm did not maintain a current establishment
registration and complete and accurate drug product listing with
Please note that a drug offered for import into the United
States may be refused admission under Section 801(o) of the Act if
the importer, owner, or consignee is not able to provide a
statement of the registration of the establishment that
manufactured it.&In addition, if a drug is not
listed in accordance with Section 510 of the Act, including if the
listing for the drug references a manufacturing establishment that
does not maintain a current establishment registration, the drug
appears to be misbranded under Section 502(o) and subject to
refusal of admission under Section 801(a)(3).&[21
352(o)]&&&
The FDA investigator(s) discussed this issue with you during
the inspection.&Your response did not address this
issue.&Information on how to register and list is
available at the following internet website: .&If
you continue to produce drugs that are offered for import into the
United States, you must complete the required registration and
listing.&& You should provide
evidence that you have fulfilled these requirements in your
response to this letter.
The violations cited in this letter are not intended to be an
all-inclusive list 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.&&
Until all corrections have been completed and FDA has
confirmed corrections of the violations and your firm’s compliance
with CGMP, FDA may withhold approval of any new applications or
supplements listing your firm as a drug product
manufacturer.&In addition, your failure to correct
these violations may result in FDA refusing admission of articles
manufactured at Shanghai Huhui Daily Use Chemical Products Co.,
Ltd, in Liuzao Town, Shanghai, into the United States under section
801(a)(3) of the Act, 21 U.S.C. 381(a)(3).&The
articles are subject to refusal of admission pursuant to section
801(a)(3) of the Act [21 U.S.C. & 381(a)(3)], in that the methods
and controls used in their manufacture do not appear to conform to
CGM P within the meaning of section 501(a)(2)(B) of the Act [21
U.S.C. & 351(a)(2)(B)].&
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 and prevent the recurrence of violations, and
provide 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 corrections.&Additionally, if
you no longer manufacture or distribute (b)(4)
Skin Protectant Cream, (b)(4) Skin Protectant, or
(b)(4) Skin Protectant, provide the date(s) and
reason(s) you ceased production.&Please identify
your response with FEI #.
Please send your reply to the following address:
Yanyan (Jenny) Qin
Senior Policy Advisor
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD&20993
(301) 796-3207
(301) 847-8741
Sincerely,
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Steven Lynn
Office of Manufacturing and Product
Office of Compliance
Center for Drug Evaluation and
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