APIC 201405原料药厂清洁验证指南：10.0关于验证的问题（中英文）

2014-07-08 julia翻译 蒲公英

Juia:该指南比较有意义，或者说比较有新意的部分，译者认为当属首次提出了原料药与制剂生产中残留是否全部进入下批产品的比较。遗憾的是没有列出实际数据来证明，只是给出了理论论述。

作为原料药工作者，比较困惑的其实并不在于不懂上述道理，也不在于法规对该清洁验证的要求（大多比较宽泛），而是官方和客户在检查时往往都会从制剂的要求出发提要求（比如直接就要求10ppm），这些要求往往不实用，无法实施或无法达到。

所以，这份指南最应该的读者其实是制剂对原料的检查工作者们。

APIC清洁验证中关于验证的问题中英文如下，原文版权归属原作者，译文仅供参考。

10.0 Validation Questions 关于验证的问题

Question 1: When should a company validate/ revalidate cleaning procedures? When is validation not required?

Advice: Ref. Section 7.0 and 10.0

Companies should look at each situation individually and determine the need for validation. Section 7.0 provides a basic template, which may be used as a starting point in this evaluation. The necessity to revalidate cleaning procedures should be determined under change control parameters - See Section 10.0.

If routine verification procedures are used, these should be monitored to ensure that the procedure is in control. Companies should consider a periodic evaluation of cleaning procedures , which are subject to variation (i.e. manual procedures etc.), as an additional precaution to assure that the procedures are still valid.

问1：公司在什么情况下对清洁程序进行验证/再验证？什么时候不需要验证？

建议：参见7.0和10.0部分。

公司应检查单独检查每一种情形，决定是否需要验证。在7.0部分中提供了一个基本模板，可以用来开始此项评估。是否需要对清洁程序进行再验证应在变更控制下进行评估---参见10.0部分。

如果使用了日常确认程序，则需要进行监测以保证程序受控。公司应考虑对可能会有变化（即人工操作程序等）的清洁程序进行定期评估，作为额外的预防措施来保证清洁程序仍然有效。

Question 2: When is it appropriate to use Prospective, Concurrent or Retrospective Validation

Advice: Ref. Section 9.0

Retrospective Validation of cleaning is not condoned by regulatory Authorities

Prospective Validation is the ideal method of validation.

In situations where very few runs are manufactured in any given period and/ or a business decision has been taken to release the next material manufactured after cleaning based on a high level of testing of the equipment (i.e. Validation level,) concurrent release of material may take place.

问2：什么时候应该使用前验证、同步验证和回顾性验证？

建议：参见9.0部分。

药监当局不认可对清洁方法进行回顾性验证。

前验证是理想的验证方法。

如果在给定的时间段内只生产较少的轮次，且/或已从业务角度决定了清洁后的下一生产物料将在对设备较高水平测试（即，验证水平）后才放行，则可以在验证同时放行物料。

Question 3: What level of testing is needed after cleaning validation?

Advice: Ref. Section 5.3

The answer to this question depends on individual situations. Typically, companies perform visual inspection and take rinse samples to monitor the effectiveness of the cleaning in pre-defined intervals (time or number of batches).

If after validation company decides to perform always cleaning verification non-specific scientifically sound analytical methods may be used.

A practical approach for monitoring the effectiveness of cleaning after completion of cleaning validation in an effective, scientific sound and inexpensive way is given below:

1.)Visual inspection of the cleaned equipment. Only after this check is considered satisfactory, proceed with the next step.

2.)Take a rinse and/or swab sample (one litre of rinsing liquid is usually required)

3.)Determine the dry residue by evaporating about 500 ml to dryness in a small flask using a rotary evaporator. This unspecific test covers also inorganic salts, known or unknown organic products and will detect the total residues. (this test might be omitted for the drying equipment, in this instance we have a pure API or intermediate and typically no potential for side products, degradation, etc.)

4.)If the result meets the specification, proceed to specific (chromato-graphic) technique. Start with a TLC-limit test (inexpensive and fast to validate, broad detection range – UV and specific derivatisation – if these techniques are combined, the method is very specific for the different impurities potentially present in the sample. Apply 2 samples: the last washing liquid (to see all potential residues), the rinsing liquid (to look for the residue) and two standards: one of the suspected residual product at a concentration that is the limit accepted, and a 1:2 dilution of the standard. If the main spot in the rinsing liquid has lower intensity than the standard, the equipment is clean. The second standard is for confirmation of detection.

5.)If TLC is not the appropriate technique, revert to HPLC or GC.

问3：清洁验证后的检测要求是怎样的？

建议：参见5.3部分。

对此问题的回答取决于各不同情形。一般来说，公司先进行目视检查，然后以预定的间隔（时间或批次）取淋洗样品检查清洁的有效性。

如果公司决定在验证后一直实施清洁检查，可以采用非专属性且科学合理的方法。

以下给出了清洁验证完成后，较为实用的对清洁有效性进行监控的有效且科学合理的便宜方法：

1）对清洁后的设备进行目视检查。此检查符合要求后，方可进入下一步。

2）取一个淋洗样和/或擦拭样品（一般使用一升淋洗样）

3）使用旋转蒸发器将约500ml样品在小烧瓶中蒸干检测蒸发残留。该非专属方法包括了无机盐、已知或未知有机产品，可以检出总残留。（烘干设备不需要做此项测试，此时，设备中只有纯的原料药或中间体，一般没有潜在的副产物、降解产物等）。

4）如果结果符合标准，则可以采用特定的技术（色谱法）。从TLC限度测试开始（便宜且易于验证，具有较宽的检测范围----紫外和特定衍生产品---如果将这些技术合并，方法会对可能出现在样品中的不同杂质具有专属性），测试2个样品，一个是最后洗涤液（检查所有潜在残留物），一个是淋洗液（检查实际残留），测试2个标准品，一个是认为可能残留的产品，浓度为可接受的限度，另一个是1：2稀释的标准品。如果淋洗液中的主斑点不深于标准，则认为设备已清洁。第二个标准品是用来确认检测限的。

5）如果TLC不适用，改成HPLC或GC。

Question 4: What critical parameters need to be looked at during cleaning validation?

Advice: Ref. Section 8.2 for details

It is vital that the equipment design is evaluated in detail in conjunction with the product residues to be removed, the available cleaning agents and the cleaning techniques. Also the ruggedness and reproducibility of the cleaning procedure should be covered.

问4：在清洁验证过程中，要查看哪些关键的参数？

建议：参见8.2部分。

在设备设计中，要结合需要清除的产品残留、可以获得的清洁剂和清洁技术进行评估。还要包括清洁程序的耐用性和可重复性。

Question 5: What number of cleans should be run in order to validate a cleaning procedure?

Advice: Ref. Section 9.0

A validation program generally encompasses three consecutive successful replicates. However, companies should evaluate each situation individually.

问5：要验证一个清洁程序，需要重复几轮清洁？

建议：参见9.0部分。

一个验证程序一般是经过三次连续成功的重复。但是，公司应对各种情形进行单独评估。

Question 6: Is it acceptable for a validated cleaning procedure to be continued until the analytical results demonstrate it is clean?

Advice: Regulatory authorities do not condone this practice.

When the analytical result does not meet the acceptance criteria an investigation to determine the possible root cause should be performed. If needed re-training of the operators should be performed and/or adjustment of the cleaning procedure to solve the issue.

问6：是否可以重复一个经过验证的清洁操作直至分析结果显示其已清洁？

建议：药监当局不接受这种方法。

如果检测结果不符合可接受标准，则需要进行调查，找出可能的根本原因。必要时，应对操作人员进行再次培训，和/或对清洁程序进行调整以解决问题。

Question 7: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be dirty before cleaning?

Advice: Companies should have SOPs in place, which require cleaning to be performed immediately after production has stopped. This scenario should be validated.

However, if for some reason immediate cleaning is not always possible, companies should consider the effect of time on the material deposited on the equipment. It may be possible to ‘Group’ or ‘Bracket’ products, and validate a worst case scenario.

问：公司是否需要验证在清洁前，脏的设备可以放置的最长时间？

建议7：公司应制订SOP，其中说明生产结束后应立即对设备进行清洁。这种情况是需要验证的。

但是，如果因为某些原因，使得没法总是立即清洁，公司应考虑放置时间对设备中存留物料的影响。可以考虑对于“一组”或“一类”产品，验证其最差情形。

Question 8: Is it necessary for companies to validate a maximum time allowed for a piece of equipment to be left clean before re-use?

Advice: Companies should have SOPs in place to ensure that pieces of equipment are adequately protected from any contamination after cleaning has taken place i.e. ensure that the equipment is adequately covered, closed from dust etc.

If the company feels that there is any risk of contamination during ‘idle time’ after cleaning, validation should be considered.

问8：公司是否需要验证在清洁后，已清洁的设备在使用前可以放置的最长时间？

建议：公司应制订SOP，保证清洁后的设备受到充分的保护，不受到污染，例如保证设备被遮盖、关闭防止灰尘进入等。

如果公司觉得在清洁后的“闲置时间”内还是有被污染的风险，则需要考虑验证。

Question 9: Is it necessary to establish time limits for cleaning if equipment is not used frequently?

Advice: Please see previous advice to question 8.

问9：对于不经常使用的设备，是否需要设定清洁时间限制？

建议：请参见问8的回答。

Question 10: What is the maximum time allowed after cleaning with water as last rinse?

Advice: Equipment should not be left with water in it after cleaning. The last step of the cleaning procedure involve drying with solvent or flushing with Nitrogen, thus ensuring that there is no opportunity for microbial growth.

问10：用水最后淋洗后，可以放置的最长时间是多少？

建议：清洁后不应有水留在设备内。清洁程序的最后一步应是采用溶剂干燥或氮气吹干，这样保证微生物没有机会滋生。

Question 11: Is it possible that a deterioration of equipment may take place over time, thus invalidating the original validation results?

Advice: Materials used to manufacture equipment for the pharmaceutical / chemical industry is of a very high standard. However, equipment materials used should be evaluated to ensure their durability over time as part of the preventative maintenance programme. The possibility of surface roughness and any possible effects that it may have on cleaning should be considered.

Companies employing verification methods after validation should monitor analytical data generated as part of this process.

问11：是否有可能经过一段时间，设备情况会变差，这样原来的验证结果不再有效？

答：用于药品/化学行业生产的设备的材质一般都有很高的标准。但是，所用的设备材质应经过评估，保证其能经受一段时间的使用，这应该是预防性维保计划的一部分。要考虑表面粗糙的可能性，以及可能对清洁产生的影响。

Question 12: If a company has validated a worst case scenario (grouping or bracketing regime), should they also need to validate a ‘less’ worst case?

Advice: When grouping products and determining worst case situation scenario for validation, companies should determine whether or not the worst case being validated is one, which is appropriate for routine manufacture. For operational reasons it may be beneficial to validate a ”less” stringent cleaning procedure for some products.

问12：如果一个公司已经验证了最差情形（分组或分类），是否还需要验证“较差”情形？

答：如果将产品分组，并确定了最差情形用于验证，公司应决定所验证的最差情形适用于日常生产。由于操作原因，可能需要对某些产品的“其次”严格的清洁程序进行验证。

Question 13: In a case of a dedicated plant with no degradants, is there a need to validate?

Advice: Ref. Section 7.0

Companies should consider each situation individually and validate where there is a potential for contamination. In the above situation, there may not be a need. However, consideration should be given to the number of runs being performed prior to full cleaning.

问13：如果使用的是专用车间，且没有降解产物，是否还需要进行验证呢？

建议：参见7.0部分。

公司要单独考虑每种情形，如果有潜在污染时则需要验证。在上述情形下，可能不需要验证。但是，要考虑在进行全面清洁前可以生产的轮次。

Question 14: Should cleaning validation be part of a development programme?

Advice: While it is not a requirement of ICH that cleaning validation be performed during development phase the following should be considered:

If the equipment being cleaned after the development product in question is used to manufacture commercial product or product for human use for example clinical trials, it is essential to verify the appropriate cleanliness of the equipment prior to re-use.

Development of the Cleaning procedure for the product should take place at development phase for validation when the product becomes commercially available. The cleaning procedure validation should be performed or at least should start with the process validation campaign.

问14：清洁验证是否应该作为研发计划的一部分？

建议：ICH并没有要求在研发期间进行清洁验证，但要考虑以下内容：

如果设备在用于研发产品生产后，又用于生产商业化产品，或用于人用药品例如临床试验药品生产，则需要确认设备再次使用前已被适当清洁。

产品清洁程序应该在产品研发，可以商业化生产时建立。清洁程序验证应在工艺验证周期时进行，或至少开始。

Question 15: Is it necessary to include microbiological testing / aspects in the cleaning validation programme?

Advice: Ref. Section 8.1

Yes, if the following product needs to have a low microbiological load, also depending on the cleaning agent used, if there is any risk for microbiological contamination of the subsequent product (e.g. if water is used for final cleaning).

问15：清洁验证计划中是否要包括微生物测试？

建议：参见8.1部分。

是的，如果下一产品对微生物负载有要求，另外也取决于所用的清洁剂，以及之后的产品是否有微生物污染的风险（例如，如果最后清洁用的是水）。

Question 16: Which analytical methods should be used in cleaning validation studies (is only HPLC -testing acceptable?) and to which extend should these methods be validated?

Advice: Ref. Section8.0 of this “Guidance on Aspects Document”

Any analytical method suitable for its intended use could be used. In general limit tests are performed in cleaning validation studies which result in less stringent validation requirements. (as outlined in ICH-Q2A and Q2B).

However, if a company decides to validate analytical methods, suitable for the determination of the residue over a certain range (e.g. decay-curve, to prove the success of cleaning during proceeding of a defined cleaning procedure consisting of individual cleaning steps) also less stringent validation requirements for e.g. linearity and accuracy could be established compared with figures typically required in the validation of API release testing methods.

问16：什么样的检验方法可以用于清洁验证检测（只能用HPLC吗）？这些检验方法要验证要什么程度？

建议：参见8.0部分。

所有适用的检验方法都可以使用。清洁验证一般所用的检测方法为限度检测，方法验证要求较低（如ICH-Q2A和Q2B所列）。

但是，如果公司决定要验证一个检验方法，用于一定范围内残留量的检测（例如，清除曲线，证明某个清洁步骤是否成功），其验证要求比起原料药放行检测方法的验证来说要低，例如可以建立线性和准确度。

Question 17: Do we have to wait for swab and rinse samples to be approved prior using the equipment for production?

Advice: During cleaning validation studies it is recommended to wait for completion of all planned tests prior to release equipment for further use (to be able to perform an investigation if tests fail). In routine operations (after validation has been completed) the release of equipment pending testing results (verification, monitoring status of the tests) could be done. Responsibilities and circumstances for using equipment pending release should be defined within the company.

问17：在将设备用于生产前，是否需要等擦拭样品和淋洗样品被批准？

建议：在清洁验证研究期间，建议等所有计划的测试完成后再放行设备，用于后续使用（这样如果检测失败可以进行调查）。在日常运行中（验证完成后），可以在检测结果（核查、测试监控状态）未出来前将设备放行用于后续使用。公司应界定使用未放行设备的责任人和条件。

好东东，感谢分享，楼主辛苦