近年来，国内外官方陆续出台了共线生产的指南，本文收集和整理了FDA警告信中的共线生产相关的缺陷，共计5条缺陷，供同行参照或学习。
根据21 CFR 211.42（C）规定，FDA对于共线生产的法规要求是：应在明确规定的，大小适中的区域操作。企业在以下操作应有独立或指定的区域，或有其他必须的控制系统用以防止污染和混淆。
缺陷1
Your firm failed to perform operations
within specifically defined areas of adequate size and to have separate or
defined areas or such other control systems necessary to prevent contamination
or mix-ups (21 CFR 211.42(c)).
Your firm manufactures over-the-counter
(OTC) antibacterial hand soap and hand sanitizer drug products. You manufacture
these drug products using the same equipment that you use to manufacture
numerous non-pharmaceutical materials in your facility, including industrial
detergents and degreasing products. It is unacceptable as a matter of CGMP to
continue manufacturing drugs using the same equipment that you use to
manufacture these non-pharmaceutical products due to the risk of
cross-contamination.
企业未明确要求在空间足够的区域内进行生产操作，也未设有隔离或指定区域或必要的类似控制系统，用以防止污染或混淆（21 CFR 211.42(c)）。
企业生产OTC抗菌洗手皂和洗手液，并相同的设备用于生产药品与多个非药用物料，包括工业清洁剂和脱脂产品。从cGMP角度，由于存在交叉污染的风险，使用相同的设备生产非药用产品和药品是不可接受的。
缺陷2
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)).
You manufacture finished drug products,
including toothpaste and mouth rinse products containing sodium fluoride,
stannous fluoride, and potassium nitrate using the same equipment you use to
manufacture numerous nonpharmaceutical materials in your facility, including
(b)(4). This product is labeled as "Caution: Keep away from children, do
not consume and avoid contact with eyes."
The ingredients in your nonpharmaceutical
products could contaminate the drug products that you manufacture on shared
equipment, such as the various drugs for oral use discussed above. It is
unacceptable as a matter of CGMP to continue manufacturing drugs using the same
equipment you use to manufacture nonpharmaceutical products.
In your response, you state each
"follow up batch" is tested for microbial analysis, pH, taste, and
other attributes prior to the filling process, and that it is not standard for
a manufacturer to have a tank for every product and every flavor. You also
state you have purchased a swab kit and a luminometer to assess the cleanliness
of surfaces.
企业没有单独的或指定的区域，或其他必要的控制系统来防止污染和混淆（21 CFR
211.42(c)）。
企业生产制剂，包括含有氟化钠、氟化亚锡和硝酸钾的牙膏和漱口水产品，使用相同的设备生产多种非药用物料，包括XX。该产品标记为“注意：请远离儿童，请勿食用，并且避免接触眼睛。”
非药用产品的成分可能会污染共线生产的药品，例如，上文讨论提及的各种口服药品。从cGMP的角度来看，使用相同的设备生产非药用产品和药品是不可接受的。
在企业的回复中，表示每个“后续批次”在灌装工艺前都取样检测了微生物、pH值、味道和其他属性，并且对于生产商来说，为每种产品和每种调味剂配备一个储罐并不是标准做法。企业还表示已购买拭子试剂盒和光度计来评估表面的清洁度。
缺陷3
Your firm failed to maintain adequate
separate defined areas necessary to prevent contamination or mix-up (21 CFR
211.42(c)).
Your firm manufactured topical human drugs
and several pesticides in the same building, using shared equipment. It is
unacceptable as a matter of CGMP to continue manufacturing drugs using the same
equipment that you use to manufacture pesticides or other non-pharmaceutical
products due to the risk of cross-contamination.
Records we reviewed during our inspection
and information you submitted in your response confirmed that two of the human
drugs you manufactured contained the pesticide (b)(4). You manufactured the
pesticide and the human drugs using shared equipment.
In your response, you committed to
improving your contamination controls and to test for the presence of other
cross-contaminating pesticides in other human drugs that you manufacture. You
also described plans for a multi-phase shutdown during which you would make
certain corrections, including discontinuing the use of shared equipment for
human drug and non-pharmaceutical products, using self-contained suites for
non-pharmaceutical manufacturing, and enhancing controls of in-process bulk
material transport throughout your facility. These corrections will be verified
on the next inspection.
If you intend to continue to manufacture
both pharmaceutical and non-pharmaceutical products at your facility, provide a
plan to show how you will maintain adequately separated and dedicated
manufacturing equipment for your pharmaceutical and pesticide manufacturing
operations. In addition, provide an analysis of your results for testing
additional human drugs for pesticides and include a risk assessment for all
drugs you have previously produced on equipment also used for pesticide
production. For each product, assess the risk of potential contamination due to
the shared equipment, and provide your plans for addressing the product quality
and patient safety risks for any product still in distribution within expiry,
including potential recalls or market withdrawals.
企业没有单独的或指定的区域，或其他必要的控制系统，用以防止污染和混淆（21 CFR
211.42(c)）。
企业生产在同一建筑内共线生产外用的人用药和多种杀虫剂。从cGMP角度，由于存在交叉污染的风险，杀虫剂或其它非药用品相同与药品共用生产设备是不可接受的。
在检查期间审查的记录以及企业在回复中提交的信息证实，企业所生产的两种人用药品含有某杀虫剂。企业使用共用设备生产杀虫剂和人用药。
在企业的整改回复中，企业承诺会改进污染控制措施，并检测所生产的其它人用药中是否存在其它交叉污染的杀虫剂。企业还提供了阶段性关闭的整改计划，在此期间会采取一些纠正措施，包括停止使用共用设备生产人用药和非药用产品，非药用产品生产使用独立套件，以及加强中间过程散装物料的运输。这些纠正措施将在下次检查时进行核实。
如果企业打算继续在工厂内生产药用和非药用产品，应提供一份整改计划，说明将如何为药品和杀虫剂的生产操作维护过程充分隔离，并采用专用的生产设备。此外，请提供一份对其它人用药中含有杀虫剂的检验分析报告，并包括一份针对之前在杀虫剂生产所用设备上生产的所有药品的风险评估报告。对于每种产品，评估共线生产可能导致的污染风险，并针对在销售且在效期内的任何产品提供解决产品质量和患者安全风险的计划，包括可能的召回或撤市。
缺陷4
Your firm failed to maintain adequate
separate defined areas necessary to prevent contamination or mix-up (21 CFR
211.42(c)).
Your firm uses the same mixing tank,
mixers, and hoses to manufacture OTC topical drug products, (b)(4), and (b)(4).
It is unacceptable as a matter of CGMP to continue manufacturing topical drugs
using the same equipment that you use to manufacture industrial-grade products,
including those that contain known skin irritants.
Our investigator observed a mixer motor,
used to mix drug products in open tanks, covered in flaking paint. The
investigator also observed a scale, used for weighing raw materials, covered in
an unknown white powder and splattered with an unknown yellow liquid. You had
no written cleaning procedures or documentation to show that this non-dedicated
manufacturing equipment was cleaned between production of industrial-grade
products and OTC drugs. You did not demonstrate that you maintained adequate
separation to prevent the substances observed on your mixed-use equipment from
contaminating your OTC topical drugs with ingredients from your
non-pharmaceutical products.
In your response, you stated you would
draft cleaning procedures for equipment and manufacturing areas. Although we
acknowledge that you cleaned the manufacturing area and equipment during the
inspection, your response is inadequate because you did not address the
potential for cross-contamination posed by the manufacture of
non-pharmaceutical products on the same equipment used to manufacture OTC drug
products.
In response to this letter, discontinue
manufacturing drugs on shared equipment in your facility. If you intend to
continue to manufacture both pharmaceutical and non-pharmaceutical products at
your facility, provide a plan to show how you will separate the areas in which
you will maintain dedicated manufacturing equipment for your pharmaceutical
manufacturing and industrial product manufacturing operations.
In addition, conduct a risk assessment for
all drugs you have previously produced on equipment shared with industrial
products. For each product, assess the risk of potential contamination due to
the shared equipment, and provide your plans for addressing the product quality
and patient safety risks for any product still in distribution, including
potential recalls or market withdrawals.
企业没有防止污染和混淆所必需的足够的单独指定区域(21 CFR 211.42(c))
企业使用相同的混合罐，搅拌机和软管来生产OTC外用药品XX和XX。从cGMP角度，使用工业级产品（包括含有已知皮肤刺激成分的产品）与外用药品混用设备是不可接受的。
FDA检查员发现，有一台在开放式储罐中混合药品的电动混合机，其表面油漆脱落。检查员还观察到一种用于称量原辅料的天平，被一种未知的白色粉末覆盖，并溅上了一种未知的黄色液体。企业没有书面清洁规程或文件记录能证明这种非专用的生产设备在工业级产品与OTC药品的生产切换之间经过了清洁。企业没有证据证明非药用产品与药品保持充分的隔离，以防止在混合用设备上观察到的物质引入非药用产品中的成分，从而污染了OTC外用药品。
在回复中，企业表示，将起草设备和生产区域的清洁规程。尽管FDA承认在检查期间企业清洁了生产区域和设备，企业的回复还是不充分的，因为没有解决在OTC药品生产所用相同设备上生产非药用产品造成的交叉污染的可能性。
作为对此函的回复，请停止在工厂共用设备上生产药品的行为。如果企业打算继续在工厂同时生产药品和非药用产品，请提供一份计划，说明如何将维护药品生产专用和工业产品生产专用设备的区域隔离。
此外，请对以前在与工业产品共用的设备上生产的所有药品进行风险评估。对于每种药品，请评估由于共用设备而可能被污染的风险，并提供解决所有仍在售药品的质量和患者安全风险问题的计划，包括可能的召回和撤市。
缺陷5
Your firm failed to maintain adequate
separate defined areas necessary to prevent contamination or mix-up (21 CFR
211.42(c)).
You manufacture several over-the-counter
(OTC) oral rinses and oral moisturizing drug products, including (b)(4), (b)(4)
Mouth Moisturizer, and (b)(4) Oral Solution, for your customer, (b)(4) Products
Inc. You manufacture these oral drug solutions using the same equipment that
you use to manufacture numerous non-pharmaceutical materials in your facility,
including an industrial car care product, (b)(4) Polish and Sealant.
This car care product is paraffin-based and
labeled as “Harmful or fatal if swallowed” and “Keep out of reach of children.” You also manufacture other toxic non-pharmaceutical industrial and
automotive care products, such as leather treatments ((b)(4) Leather Care,
(b)(4) Leather Lotion) and sealants ((b)(4) Poly Sealant), using the same
mixing tank and filling line you use for OTC oral drug products.
The ingredients in your non-pharmaceutical
products are extremely difficult to remove from manufacturing equipment, and
could contaminate the drug products that you manufacture on shared equipment,
such as the various oral solutions discussed above. It is unacceptable as a
matter of CGMP to continue manufacturing drugs using the same equipment that
you use to manufacture toxic industrial-grade car care products.
In response to this letter, discontinue
manufacturing drugs on shared equipment in your facility. If you intend to
continue to manufacture both pharmaceutical and non-pharmaceutical products at
your facility, provide a plan to show how you will separate the areas in which
you will maintain dedicated manufacturing equipment for your pharmaceutical
manufacturing and industrial product manufacturing operations.
In addition, conduct a risk assessment for
all drugs you have previously produced on equipment shared with industrial
products. For each product, assess the risk of potential contamination due to
the shared equipment, and provide your plans for addressing the product quality
and patient safety risks for any product still in distribution, including
potential recalls or market withdrawals.
没有防止污染和混淆所必要的足够的单独指定区域(21 CFR 211.42(c))
企业为其客户XX Products Inc 生产OTC口腔冲洗液和口腔保湿液，包括XX、XX口腔保湿液和XX口服溶液。这些口服溶液与多个非药用物料（包括一种工业汽车护理产品XX抛光剂和密封胶）共用生产设备。
这款汽车护理产品含有石蜡且标签声明“如果吞食会致伤或致死”和“避免儿童接触”。企业还生产其它有毒的非药用工业和汽车护理产品，例如皮革用产品（XX皮革护理剂、XX皮革乳液）和密封胶（XX聚合密封胶），与生产非处方口服药品共用混合罐和灌装线。
企业生产的非药用产品成分很难从生产设备上清除，会污染在此共用设备上生产的药品，例如，从cGMP角度，上述讨论提及的各种口服药品溶液。使用生产了有毒工业级汽车护理产品的设备来继续生产药品是不可接受的。
作为对此函的回应，请停止使用共用设备生产药品。如果工厂打算继续在设施中同时生产药品和非药用产品，需提供一份计划说明将如何为药品生产和工业产品生产分别保留专用设备并划分单独区域。
此外，需对所有曾在与工业产品共用的设备上生产的药品开展风险评估。对于每种产品，评估由共用设备造成的潜在污染风险，并给出在售产品的产品质量和患者安全风险的解决方案，包括可能的产品召回或撤市。
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