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师说 | 李鸿阳:再确认和再验证还需要吗?
发布时间:2021-12-27 点击次数:161 作者:李鸿阳


李鸿阳老师曾提出过在实施了持续工艺确认(CVP)的GMP工厂里是否还需要进行再确认(Requalification)和再验证(Revalidation)的问题。这个问题仍有被澄清的必要,故有此文。另外,本文也将梳理国内外部分有关再确认和再验证的法规。
 
注:文中【】内的数字为文末的参考文献号。


 

李鸿阳 老师

诺华技术运营本地化工厂平台制药科学与技术部(MS&T)负责人、高级制药工程师
药品制造管理课程建设委员会委员
 
李鸿阳老师曾任诺华全球技术运营固体制剂亚太区制药科学与技术部负责人、苏州诺华工厂质量总监、诺和诺德天津生产厂器械质量副总裁、礼来公司美国生产厂质量主管及礼来公司总部质量管理系统咨询员。拥有20多年丰富的医药产品生产,技术和质量管理经验,包括五年多在美国FDA监管下的跨国医药生产企业的一手工作经验。精通美国FDA cGMP政策法规、体系要求及实施细则,熟悉医药企业的生产、质量保证、实验室、合规和质量体系,领导或参与过许多质量审核。经验覆盖原料药生产、固体制剂生产、针剂灌装、产品组装、包装,包括药品、医疗器械和药械合一产品。曾参与国家药监局GMP两个附录(确认与验证和计算机验证)的定稿讨论和“药品数据管理规范”的起草。美国质量协会(ASQ)认证的“质量经理(CQM)”和“质量审核员(CQA)”,资深会员;2015-2016 ISPE中国理事会副主席;美国PDA法规和质量咨询专家委员会成员等。
 


 



 
什么是再确认和再验证?
 
笔者首次接触再验证是1996年(90后的读者朋友别不好意思啊)。当时笔者签署了一份由国外专家起草的工艺验证报告,其中一段写着:该工艺验证将于三年后再验证。签署的当时并不明白这句话的奥妙,直到1999年,记忆超强的QA经理提醒我:我们的工艺需要再验证了。我这才明白三年前签署的报告意味着什么。当时已临近总部GMP审计,故赶紧找出3年前的工艺验证方案,修改了日期,其他基本保持不变,尽快安排生产完成了再验证。这也造就了我对再验证的初始理解,且此概念延续多年。之后,更换过不同的公司,再验证做法类同,只不过再验证的期限有一年、两年、三年甚至五年。直到2011年,美国FDA发布了工艺验证工业指南【4】,再验证的概念才被更新。再确认的概念和做法类同,恕不赘述。
 
国内外欧宝app官网再确认和再验证的法规(读者可以跳过法规的原文,仅仅阅读中文解释即可)
为了澄清什么是再确认和再验证,笔者参考了国内外GMP法规文件中欧宝app官网这两个概念的应用。结果发现国内外的GMP法规文件中经常会用到再确认和再验证,但却少有其定义。例如:
 
中国2010版GMP【1】两处分别提到再确认或再验证,没有定义:
 
第一百四十四条 确认和验证不是一次性的行为。首次确认或验证后,应当根据产品质量回顾分析情况进行再确认或再验证。关键的生产工艺和操作规程应当定期进行再验证,确保其能够达到预期结果。
 
第二百六十七条 应当对回顾分析的结果进行评估,提出是否需要采取纠正和预防措施或进行再确认或再验证的评估意见及理由,并及时、有效地完成整改。

中国2010版GMP 附录《确认与验证》【2】,3处提到再确认,5处提到再验证,也没定义这两个词:
 
第三章第四条 (七)保持持续验证状态的策略,包括必要的再确认和再验证。
 
第六章第十九条 …工艺验证应当包括首次验证、影响产品质量的重大变更后的验证、必要的再验证以及在产品生命周期中的持续工艺确认,以确保工艺始终处于验证状态。
 
第九章第五十一条 关键的生产工艺和操作规程应当定期进行再验证,确保其能够达到预期效果。
 
第九章第五十二条 应当采用质量风险管理方法评估变更对产品质量、质量管理体系、文件、验证、法规符合性、校准、维护和其他系统的潜在影响,必要时,进行再确认或再验证。
 
第九章第五十三条 当验证状态未发生重大变化,可采用对设施、设备和工艺等的回顾审核,来满足再确认或再验证的要求。
 
值得指出的是“再确认和再验证”在中国GMP的附录《确认与验证》中自成一章,即第九章。如此可见其在中国GMP中的重要性。
 
国外GMP法规,先看美国。FDA药品GMP(21CFR210/211)【3】中既没提到revalidation,也没出现requalification。FDA工艺验证工业指南【4】这个权威性的工艺验证指南也没有提到revalidation。

美国FDA医疗器械GMP 21 CFR 820【5】仅出现一次revalidation,没有requalification。同样也没有定义。其原文如下:
 
CFR 820.75(c) When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate.

美国FDA的“Validation of Cleaning Processes (7/93): Guide To Inspections Validation Of Cleaning Processes”【6】也仅用到一次revalidation,没有提到requalification。其原文如下:
 
“FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required”.
 
美国FDA工业指南“Analytical Procedures and Methods Validation for Drugs and Biologics” 【7】中有一节专门欧宝app官网分析方法再验证。原文如下:
 
Principles described in the validation section (section VI) apply to revalidation. When a change is made to an analytical procedure (e.g., a change in a piece of equipment or reagent or because of a change in manufacturing process or formulation), revalidation of all or part of the analytical procedure should be considered. Analytical method revalidation may also be warranted because of manufacturing process changes, such as an alteration in the drug substance manufacturing process that could impact method performance (e.g., route of synthesis, fermentation) or introduction of a new drug product formulation.

You should revalidate to ensure that the analytical procedure maintains its critical performance characteristics (e.g., specificity, precision, accuracy). The degree of revalidation depends on the nature of the change.
 
 
再看欧盟,其药品GMP【8】中2处用到revalidation,但没有出现requalification。原文如下:

1.11 The manufacturer and, where different, marketing authorisationholder should evaluate the results of the review and an assessment made as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System. (EU GMP Chapter 1)

6.40 Deviations from the protocol should be investigated prior to closure of the technical transfer process. The technical transfer report should document the comparative outcome of the process and should identify areas requiring further test method revalidation, if applicable. (EU GMP Chapter 6)

欧盟GMP之附录15《确认与验证》【9】,另一个权威性的验证指南文件,也没有提到revalidation,仅两次提到requalification, 却也没有定义。原文如下:

egy, including requalification, where applicable.1.5 vii. The qualification and validation strat
 
11.4. Quality risk management should be used ...... to plan for any necessary process validation, verification or requalification efforts.
 
欧盟GMP附录1 《无菌药品生产》(现行2008版) 【10】两处用到revalidation,均是欧宝app官网工艺培养基灌装:
 
69. The number of containers…. The target should be zero growth and the following should apply:
 
·When filling 5,000 to 10,000 units: a) One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill; b) Two (2) contaminated units are considered cause for revalidation, following investigation.

·When filling more than 10,000 units: a) One (1) contaminated unit should result in an investigation; b) Two (2) contaminated units are considered cause for revalidation, following investigation.
 
欧盟GMP附录1 《无菌药品生产》正在被更新,其2020草案【11】中6处提到revalidation或repeated validation,原文如下:

8.35 …. Revalidation of the sterilization process should be conducted whenever significant modifications have been made to the product, product packaging, sterilization load configuration, sterilizing equipment or sterilization process parameters.

8.57 ….These critical parameters should be subject to defined limits (including appropriate tolerances) and be confirmed as part of sterilization validation and routine cycle acceptance criteria. Revalidation should be performed annually.

9.40 Process simulation tests should be performed as initial validation, generally with three consecutive satisfactory simulation tests per shift, and after any significant modification to the HVAC system, equipment, major facility shut down, process and number of shifts, etc. Normally process simulation tests (periodic revalidation) should be repeated twice a year (approximately every six months) for each aseptic process and filling line, and at least annually for each operator.

9.41 Where manual filling occurs, each product, container closure, equipment train and operator should be revalidated approximately every 6 months. The APS batch size should mimic that used in the routine aseptic manufacturing process. An aseptic process or filling should be subject to a repeat of the initial validation when: a) Revalidation of the unique process has failed and corrective actions have been taken.

欧盟GMP附录1 《无菌药品生产》2020草案【11】中5处出现requalification:
 
4.5 。。。Once disqualified, retraining and requalification is required before permitting the operator to have any further involvement in aseptic practices.
 
5.3 。。。During initial qualification and requalification air speeds may be measured either close to the terminal air filter face or at the working height, where ever the measurement is taken.
 
5.26d) “Inoperation” classification, qualification and requalification may be performed during normal operations, simulated operations or during aseptic process simulations (where worst case simulation is required).

5.29 Clean rooms should be requalified periodically and after changes to equipment, facility or processes based on the principles of QRM. For grade A and B zones, the maximum time interval for requalification is 6 months. For grades C and D, the maximum time interval for requalification is 12 months.
 
原料药GMP ICH Q7【12】中两次用到revalidation,没有提到requalification,同样也没有定义。原文如下。
 
2.51 The results of this review should be evaluated and an assessment made of whether corrective action or any revalidations hould be undertaken.
 
12.60 Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation.
 
世界卫生组织的GMP附录3验证(WHO TRS No.1019, 2019)【13】,包括其5个附件,多处用到revalidation(不包括标题共17处)和requalification(不包括标题共14次)。尽管没有requalification的定义,但有revalidation的定义,这也是笔者找到的唯一的一个定义。其定义为:
 
Revalidation再验证:Repeated validation of an approved process (or a part thereof) to ensure continued compliance with established requirements
 
为确保一个已批准工艺持续符合已建立的要求而对该工艺(或其一部分)的验证进行重复。

世界卫生组织的GMP附录3验证的正文部分包括以下revalidation内容,其中第11节专门是再验证:

 
5.9 Qualification and validation (as appropriate), should be performed:
 
·for new premises, equipment and utilities;
·for new systems, methods, processes and procedures;
·when changes are made, depending on the outcome of risk assessment;
·where necessary or indicated, based on the outcome of periodic review (and may include requalification and revalidation).
 
7.1 A manufacturer should have a validation master plan that reflects the key elements of validation. It should be concise and clear and at least contain reference to/have a short deion of the following:
 
·........
·requalification and revalidation;
·........

11.2 Revalidation should be done based on the identified need and principles of risk management.

 
11.3 Any changes made to, for example, procedures, processes and methods, should be managed through the change-control procedure. The extent of validation or revalidation as a result of such a change should be determined based on principles of risk management.
 
11.4 Where appropriate, periodic revalidation may be performed.

世界卫生组织的GMP附录3验证之附件3 清洁验证中包括:

 
3.2 The manufacturer should have a cleaning policy and an appropriate procedure for cleaning validation, covering:
 
·。。。。
·periodic evaluation and revalidation of the number of batches manufactured between cleaning validations.

 
4.3 The cleaning validation protocol should include:
 
·。。。。
·revalidation requirements.

 
世界卫生组织的GMP附录3验证之附件4 分析方法验证中包括共6条revalidation,其中第7节专门是欧宝app官网分析方法再验证(Procedure revalidation):

2.7 Changes to procedures should be managed in accordance with the authorized change-control procedure. 。。。。。。Verification or revalidation should be considered, where appropriate.
 
2.8 The need and scope of verification or degree of revalidation depend on the nature of the change(s) and the outcome of risk assessment.
 
7.1 Procedures should be maintained in a validated state over the life-cycle of the procedure (see point 2.5). Whenever there are changes made to the analytical procedure, the impact assessment should be conducted and revalidation of the procedure should be considered. For example for a high-performance liquid chromatography (HPLC) method, changes requiring revalidation may include (please refer to The International Pharmacopoeia (3) and other pharmacopoeias for the acceptance limits beyond which revalidation must be performed):。。。。
 
7.3 Periodic revalidation of analytical procedures should be considered and the interval should be scientifically justifiable.
 
7.4 It is acceptable for revalidation to include only the validation characteristics of relevance to the particular change and procedure.

世界卫生组织的GMP附录3验证之附件5 计算机化系统验证中包括

 
13.15 Computerized systems should be periodically reviewed to determine whether the system remains in a validated state or whether there is a need for revalidation. The scope and extent of the revalidation should be determined using a risk-based approach. The review should at least cover:

世界卫生组织的GMP附录3验证之附件7 工艺验证中的第7节变更管理包括:

 
Manufacturers should follow change-control procedures when。。。。。。Validation should be considered when changes to production and/or control procedures are planned. Based on risk assessment, changes that may require revalidation could include (but are not limited to):

欧宝app官网Requalification,世界卫生组织的GMP附录3 验证的正文部分包括专门的一节,共6条:

 
10.24 Utilities, systems and equipment should be maintained in a qualified state. Any changes made to these should be managed through the change- control procedure. The extent of qualification or requalification as a result of such a change should be determined based on principles of risk management.
 
10.25 Requalification should be done based on the identified need and risk management principles. Factors such as the frequency of use, breakdowns, results of operation, criticality, preventive maintenance, repairs, calibration, and verification may be considered.
 
10.26 Requalification should also be considered after cumulative/multiple changes.
 
10.27 The scope and extent of requalification should be determined when components or parts are replaced.
 
10.28 Where a system or utility or equipment has not been used for an extended period of time, requalification may have to be considered.
 
10.29 Where appropriate, periodic requalification may be performed.

世界卫生组织的GMP附录3 验证之附件6 确认指南中包括7处requalification, 其中的第11节专门是定期审核和再确认(Periodic review and requalification):

4.3 The scope and extent of qualification and requalification should be determined based on the principles of impact assessment and risk management.

 
4.15 Utilities and equipment should be maintained in a qualified state and should be periodically reviewed for the need for requalification. Requalification should be considered when changes are made.
 
11.2 Utilities and equipment should be reviewed periodically, to confirm that they remain in a qualified state or to determine the need for requalification.
 
11.3 Where the need for requalification is identified, this should be performed.
 
11.4 Principles of risk management should be applied in the review and requalification and the possible impact of small changes over a period of time should further be considered (such as, through change control).
 
11.6 The qualification status and periodic requalification due dates should be documented, for example, in a qualification matrix, schedule or plan
 
世界卫生组织的GMP的附录3验证(2019)【13】是在世界卫生组织的GMP的附录4 (WHO TRS No. 937, 2006)【14】更新来的。查看这个老的指南,其中有专门的再验证一节,包括这样的条款:
 
11.18 There should be periodic revalidation, as well as revalidation after changes. (See also points 5.2.5 above, point 11.21 below and section 12 below.).

接着,这个老指南进一步将再验证分为periodic revalidation(11.21和11.22)和Revalidation after change (11.23-11.26)两类,即:

 
Periodic revalidation定期再验证
 
11.21 Periodic revalidation should be performed to assess process changes that may occur gradually over a period of time, or because of wear of equipment.
 
11.22 The following should be considered when periodic revalidation is performed:
 
·master formulae and specifications;
·SOPs;
·records (e.g. of calibration, maintenance and cleaning); and
·analytical methods.

 
Revalidation after change 变更后再验证
 
11.23 Revalidation should be performed following a change that could have an effect on the process, procedure, quality of the product and/or the product characteristics. Revalidation should be considered as part of the change control procedure.
 
11.24 The extent of revalidation will depend on the nature and significance of the change(s).
 
11.25 Changes should not adversely affect product quality or process characteristics.
 
11.26 Changes requiring revalidation should be defined in the validation plan and may include:
 
·。。。。(共10项,此处省略)Changes of equipment which involve the replacement of equipment on a “like-for-like” basis would not normally require a revalidation. For example, installation of a new centrifugal pump to replace an older model would not necessarily require revalidation
 
因此,笔者认为老的WHO GMP的附录4 (WHO TRS No. 937, 2006)【14】对再验证的分类非常有利于工作中的对再验证的理解和应用。这也是本文有大量篇幅介绍WHO验证指南的原因。. 

 
讨  论
 
通过以上对有关再确认和再验证法规的整理,可以看出再确认和再验证有着广泛应用,但普遍没有明确的定义,仅WHO定义了再验证,即“为确保一个已批准工艺持续符合已建立的要求而对该工艺(或其一部分)的验证进行重复”。但该定义并没有完全表达上述所涉及到的法规中再验证的真正含义。
 
笔者综合上述法规分析,认为再验证有两重含义。一是定期对已完成的验证进行重复,即笔者在1999年所进行的再验证,其特点是:验证需求完全由时间驱动,不涉及工艺的任何变更;验证的基本条件和假设与前一次的验证完全一致,包括车间、公用设施、原物料、设备(线)、工艺参数、产品批量、甚至人员等均与前一次验证相同。其目的是确证已验证的工艺在经历了一定时间之后没有发生如设备磨损所造成的工艺漂移(drift),也就是WHO TRS No. 937, 2006【14】中的“定期再验证”。这也是再验证最初始的概念。至于有人在再验证时加入某些变更,此乃个例,非再验证之本意。笔者认为欧盟GMP正在更新的附录1(2020版)中的8.57,9.40和9.41中的“再验证”就属于这层含义。中国GMP 2010版【1】第一百四十四条以及其附录《确认与验证》【2】的第五十一条之“再验证”也属于这一层含义,应用于“关键的生产工艺和操作规程”。而其第十九条中的“再验证”看上去也属于这一层含义,但将“再验证”与“持续工艺确认”并列作为“确保工艺始终处于验证状态”的手段,笔者认为此为不妥之处。因为在工艺验证生命周期【3】的理念中,设施了持续工艺确认(CPV)的工艺并不需要进行所谓的定期再验证。但这并等于说定期再验证就不需要做了。很显然,有法规专门要求再验证药企必须进行,例如:中国GMP所定义的“关键的生产工艺和操作规程”【1】【2】;欧盟GMP附录1修订版(2020)【11】中欧宝app官网灭菌和培养基模拟灌装的要求,即8.57,9.40和9.41。值得注意的是:有些国家目前的GMP仍规定要进行定期再验证,如埃及、巴基斯坦等。那么在这些国家里,无论是否进行CPV,定期再验证都是必须要进行的。
 
再验证的另一层含义是由各种原因的变更(通过变更管理体系)导致需要对已验证的工艺进行重新验证。其特点是新的验证一定有区别于前一次验证的地方,如来自于车间、公用设施、原物料(包括其供应商)、设备(线)、工艺参数、产品批量等任何方面变更。这也是主要的法规文件中大多数“revalidation”的含义,包括通过产品质量回顾(APR)所产生的“再验证”需求【8】【12】。至于什么变更需要对工艺进行重新验证,不是本文所要讨论的范围,而是变更管理的范畴。

再验证的第二重含义与第一层面的“再验证”有着本质的区别。准确地说,这种验证不应被称之为再验证,笔者建议称之为“重新验证”,以区别于“再验证”。一旦某个工艺进行了重新验证,也就成为该工艺“再验证”的计时起点。例如:某个供应欧盟的产品的灭菌工艺的上一次灭菌工艺验证日期为2019年5月20日,该灭菌工艺需要在2020年5月20日之前进行再验证【11】。可是,由于该工艺在2020年1月15日变更了该灭菌设备的产品摆放架被进行了重新验证,那么,下一次定期再验证的日期则变为,2021年1月15日,而不再是2020年5月20日。重新验证源自于变更或其他方面的需求,而非源自于时间。是否需要进行重新验证与药企是否实施了持续工艺确认(CPV)没有直接关系。即便实施了CPV也必须要进行由变更引发的必要的工艺验证。. 

 
总  结
 
国内外GMP法规中均有许多再验证的要求,但大多并没有明确定义再验证。笔者根据对一些国内外GMP法规的梳理,认为再验证有两重含义。一是传统意义上的定期再验证,其需求由时间驱动,是对前一次验证的复制或重复,工艺本身没有任何的改变。对于大多数普通的生产工艺,这种定期再验证在实施了持续工艺确认(CPV)的工艺不需要进行,除非有法规的明确要求,如欧盟GMP对灭菌工艺和培养基模拟灌装的要求,中国GMP对“关键的生产工艺和操作规程”的再验证要求,以及有些国家GMP的定期再验证要求。
 
另一层含义是由于工艺变更导致的需要对工艺进行重新验证。笔者称之为“重新验证”以区别于定期再验证。这种重新验证是许多GMP法规中revalidation的含义。这种重新验证在工艺验证的生命周期中始终在进行,无论药企是否实施了持续工艺确认(CPV)。
 
总之,再验证是否需要并不是仅仅基于药企是否设施了持续工艺确认(CPV),而是要分辨“再验证”与“重新验证”。药企应基于法规的要求进行“再验证”,而“重新验证”在工艺验证生命周期中始终都是需要的。

注:尽管本文的讨论和结论仅集中在“再验证”,但是“再确认”的理念也完全相同。再确认同样可以分为“再确认”和“重新确认”。因此不再赘述。
 
 
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