USP General information 1224
TRANSFER OF ANALYTICAL PROCEDURES
分析方法转移程序
INTRODUCTION
前言
Testing to the specification of an ancillary material, intermediate, and/or ingredient and product is critical in establishing the quality of a finished dosage form. The transfer of analytical procedures (TAP), also referred to as method transfer, is the documented process that qualifies a laboratory (the receiving unit) to use an analytical test procedure that originated in another laboratory (the transferring unit, also referred to as the sending unit), thus ensuring that the receiving unit has the procedural knowledge and ability to perform the transferred analytical procedure as intended.
对辅料、中间体、和/或药物成分和产品进行检验确定是否符合质量标准对确定制剂成品的质量是非常重要的。分析方法转移程序(TAP),通常也称作方法转移,该程序就是记录一个实验室(接收方)能够使用由另一个实验室(转移方,也称作转出方)所开发检验方法的过程,并确保接收的实验室知道检验的程序并有能力按规定进行检验。
The purpose of this general informational chapter is tosummarize thetypes of transfers that may occur, including the possibility ofwaiver of anyverification, and to outline the potential components of atransfer protocol.This chapter does not provide statistical methods and doesnot encompass thetransfer of microbiological or biological procedures.
该节内容的目的是总结可能存在的分析方法转移的类型,包括可能不需要进行任何确认,概述转移方案中需包含的内容。该节不包括统计方法,也不包含对微生物和生物检验方法的转移。
TYPES OF TRANSFERS OF ANALYTICAL PROCEDURES
分析方法转移类型
TAP can be performed and demonstrated by several approaches. The most common is comparative testing performed on homogeneous lots of the target material from standard production batches or samples intentionally prepared for the test (e.g., by spiking relevant accurate amounts of known impurities into samples). Other approaches include covalidation between laboratories, the complete or partial validation of the analytical procedures by the receiving unit, and the transfer waiver, which is an appropriately justified omission of the transfer process. The tests that will be transferred, the extent of the transfer activities, and the implementation strategy should be based on a risk analysis that considers the previous experience and knowledge of the receiving unit, the complexity and specifications of the product, and the procedure.
进行分析方法转移有好几种方法。其中最常用的方法是:对从生产批次取出的同批次样品或为检验专门制备的样品(例如:将相对准确的一定量的已知杂质添加到样品中),两个实验室同时进行检验并进行对比。其他的方法包括:实验室间一起进行验证;接收方进行完整的或部分的分析方法验证;或者有充分理由证明不需进行分析方法转移。将要转移的方法,需进行的转移工作的程度以及执行的方法应根据风险分析来进行,需考虑到之前的经验,接收方得情况、产品的复杂性和规格标准以及相应的方法等内容。
ComparativeTesting
对比试验
Comparativetesting is the most common methodfor TAP and requires the analysis of apredetermined number of samples of thesame lot by both the sending andreceiving units. Other approaches may bevalid, e.g., if the receiving unitmeets a predetermined acceptance criterionfor the recovery of an impurity in aspiked product. Such analysis is based ona preapproved transfer protocol thatstipulates the details of the procedure,the samples that will be used, and thepredetermined acceptance criteria,including acceptable variability. Meeting theacceptance criteria and comparingdata generated by both parties are ways ofassuring that both sending andreceiving units are similarly qualified to runthe procedure.
进行对比试验是分析方法转移时最常用的方法,需要转出方和接收方同时对同一批次的样品进行检验(需要进行的检验批次数应预先规定)。其他的方法也可能是有效的,例如:对于一个掺了杂质的产品,接收方测定的杂质回收率符合预先规定的标准。所进行的分析应根据预先批准的转移方案来进行,方案中规定的程序的具体细节,应使用的样品,和预先规定的标准,包括可接受的变异性。检验结果符合标准规定并且将转出方和接收方的所得的结果进行比较,可以保证双方都能进行检验,能力相当。
CovalidationBetweenTwo or More Laboratories
两个实验室或多个实验室间的共同验证
The laboratory thatperforms the validation of ananalytical procedure is qualified to run theprocedure. Manufacturers caninvolve the receiving unit in an interlaboratorycovalidation, including them asa part of the validation team and therebyobtaining data for the assessment ofreproducibility. This assessment is madeusing a preapproved transfer orvalidation protocol that provides the detailsof the procedure, the samples tobe used, and the predetermined acceptancecriteria. General chapter Validationof Compendial Procedures 1225 providesuseful guidance about whichcharacteristics are appropriate for testing.
进行分析方法验证的实验室要求可以使用检验方法。生产企业可让接收方参与多个实验室的共同验证工作,包括让接收方在转移方中作为验证小组的成员,因此需进行重现性的评估并获得相关数据。该评估按照预先批准的转移或验证方案来进行,方案中规定该程序的具体细节,应使用的样品和预先规定的标准。通则1225“药典方法的验证”对哪些项目进行验证提供了非常有用的指南。
Revalidation
再验证
进行再验证或部分验证是分析方法转移中使用的另一个可行的方法。应注意1225中描述的特性预计会受转移影响。
(非本章内容:进行再验证或部份验证是分析方法转移中使用的另一个可行的方法。这种方法比仅作对比试验要耗费时间,生产商更难发现不同场地、不同操作人员和不同仪器之间的偏移。
在早期研发阶段,对分析方法的理解也是有限的,转移过程会更具挑战性,因为对方法中存在的变动因素认识不充分,尤其是否方法的耐用性。因为对本应该尽可能简单的系统增加了更多的变动因素,所以使转移过程变得更复杂。)
Transfer Waiver
转移豁免(不需要进行分析方法转移的情况)
The conventional TAP may be omitted under certain circumstances. In such instances, the receiving unit is considered to be qualified to use the analytical test procedures without comparison and generation of interlaboratory comparative data. The following examples give incidences that may justify the waiver of TAP:
在某些特定的情况下,不需要进行常规的分析方法转移。在这种情况下,不需要进行对比,也不需要获得实验室间的对比数据,就可认为接收方是有资格进行分析方法的。下面的情况不需要进行方法转移。
l The new product’s composition is comparable to that of an existing product and/or the concentration of active ingredient is similar to that of an existing product and is analyzed by procedures with which the receiving unit already has experience.
新产品的成份与已有的品种的成份类似和/或活性药物的浓度与已有产品的浓度类似,并且对于使用的分析方法,接收方有经验。
l The analytical procedure is the same or very similar to a procedure already in use.
检验方法与已使用的方法相同或非常相近。
l The personnel in charge of the development, validation, or routine analysis of the product at the sending unit are moved to the receiving unit.
负责方法开发、验证或产品日常检验的人员有转出方调到接收方。
ELEMENTS RECOMMENDED FOR THE TRANSFER OF ANAYTICAL PROCEDURES
进行分析方法转移建议需考虑的因素
Several elements, many of which are interrelated, are recommended for a successful TAP using the comparative testing approach. When appropriate and as a part of pre-transfer activities, the sending unit should provide training to the receiving unit, or the receiving unit should run the procedures and identify any issues that may need to be resolved before the transfer protocol is signed. Training should be documented.
在使用对比检验来进行成功的方法转移时,建议应考虑到一些因素(其中很多内容是相互关联的)。作为方法转移前的准备活动,转出方应对接收方进行培训或者在转移方案签字前,接收方应使用一下将转移的方法并确认存在哪些问题。进行的培训应记录。
The transferring unit, often the development unit, is responsible for providing the analytical procedure, the reference standards, the validation reports, and any necessary documents, as well as for providing the necessary training and assistance to the receiving unit as needed during the transfer. The receiving unit may be a quality control unit, another intracompany facility, another company, or a contract research organization. The receiving unit provides qualified staff or properly trains the staff before the transfer, ensures that the facilities and instrumentation are properly calibrated and qualified as needed, and verifies that the laboratory systems are in compliance with applicable regulations and in-house general
laboratory procedures. Both the transferring and receiving units should compare and discuss data as well as any deviations from the protocol. This discussion addresses any necessary corrections or updates to the final report and the analytical procedure as necessary to reproduce the procedure.
转出方,通常是研发部门,负责提供分析方法,对照品,验证报告,必要的文件,并且须提供必要的培训,在方法转移的过程中给予接收方必要的帮助。接收方可能是质量控制部门、公司内部的其他部门、其他公司或委托研发机构。在方法转移前,接收方应确保具有适当资质的人员或在方法转移前对人员进行适当的培训,确保设施也仪器都根据需要进行合适的饿校正和确认,并确定实验室的体系是符合相应法规和内部的实验室管理程序要求的。转出方和接收方都应对数据进行比较并讨论,包括与方案发生的偏差。经讨论决定对最终的报告和检验方法需要进行哪些更改或更新,这些内容对重新起草检验方法是必要的。
A single lot of the article may be used for the transfer because the aim of the transfer is not related to the manufacturing process but rather to the evaluation of the analytical procedure’s performance at the receiving site. If two or more different lots are used, the lot-to-lot variability should not be computed.
对于方法转移可能选择一个批次,因为方法转移的目的与生产工艺无关,而是为了评估检验方法在接收方是否可行。如果选择两个批次或更多的批次的话,不需计算批与批间的差异。
PREAPPROVED PROTOCOL
预先批准的方案
A well-designed protocol should be discussed, agreed upon, and documented before the implementation of TAP. The document expresses a consensus between the parties, indicating an intended execution strategy, and should include each party’s requirements and responsibilities. The protocol should describe the objective, the scope, the responsibilities of the transferring and the receiving units, and the materials and instruments that will be used, as well as the analytical procedure, the experimental design, and the acceptance criteria for all the tests and/or methods included in the transfer. Based on the validation data, and the procedural knowledge, the transfer protocol should identify the specific analytical performance characteristics (see 1225 ) that will be verified and the analysis that will be used to evaluate acceptable outcomes from the transfer exercise.
设计好的方案在执行方法转移前经过大家讨论并获得一致同意并形成文件。文件能表明对将要采取的执行策略各方已达成一致意见,其应包含各方的要求和职责。方案中应说明目的、范围、转出方和接收方的职责、使用的仪器和试剂以及分析方法、试验的设计和转移中使用的所有检验和/或方法的可接受的标准。根据验证数据和检验方法,在转移方案中规定需对哪些项目进行确认(见1225)以及对方法转移进行评估可接受结果的方法。
The transfer acceptance criteria, which are based on method performance and historical data from stability and release results, if available, should include the comparability criteria for results from all study sites. These criteria may be based on the difference between mean values and established ranges and should be accompanied by an estimation of the variability [e.g., percent relative standard deviation (%RSD) for each site], particularly for the intermediate precision %RSD of the receiving unit and/or a statistical method for the comparison of the means for assay and content uniformity tests. In instances of impurity testing, where precision may be poorer, a simple descriptive approach can be used. Dissolution can be evaluated by a comparison of the dissolution profiles using the similarity factor f
2 or by comparison of data at the specified time points. The laboratories should provide a rationale for any analytical performance characteristic not included, as well as any transfer waiver. The materials, reference standards, samples, instruments, and instrumental parameters that will be used should be described.
依据方法性能及稳定性和放行历史数据(如有的话)制定的分析方法转移可接受的标准,应包括在所有场地获得的数据之间的可比性标准。这些标准的制定可依据平均值和标准规定间的差异来制定,并应考虑变异性(例如:每个场地的相对标准偏差),尤其应包括接收方的中间精密度和/或含量和含量均匀度检验方法的对比用的统计学方法。就杂质检验而言,精密度会差些,可使用简单描述的方法。溶出可通过对比溶出曲线(使用相似因子F2)来评估,或将在规定点获得的数据来比较。实验室对于没有进行的项目和不进行方法转移的情况应说明理由。对使用的物料、对照品、样品、仪器和仪器参数应说明。
Expired or aged samples should be carefully chosen and evaluated to identify potential problems related to differences in sample preparation equipment and to evaluate the impact of potential aberrant results on marketed products. The documentation section of the transfer protocol may include report forms to ensure consistent recording of results and to improve consistency between laboratories. This section should contain the additional information that will be included with the results, such as example chromatograms and spectra, along with additional information in case of a deviation. The protocol should also explain how any deviation from the acceptance criteria will be managed. Any changes to the transfer
protocol following failure of an acceptance criterion must be approved before collection of additional data.
应慎重选择并评估过期或久置的样品,以确定与样品配制仪器间的差异相关的潜在问题,并评估异常值对已销售产品的影响。转移方案的文件部分应包括报告的格式,以确保可以持续地记录检验结果并提高不同实验室间的一致性。该部份还应包含结果及其他附带信息,例如:样品的色谱图和光谱图,如果发生偏差的话还应包含其他的信息。方案中还应说明如果与可接收的标准发生偏差的话应采取哪些措施。当不符合标准规定的情况后,对转移方案发生的任何变更,必须在获得其他额外的数据前获得批准。
THE ANALYTICAL PROCEDURE
分析方法
The procedure should be written with sufficient detail and explicit instructions so that a trained analyst can perform it without difficulty. A pre-transfer meeting between the transferring and receiving units is helpful to clarify any issues and answer any questions regarding the transfer process. If complete or partial validation data exist, they should be available to the receiving unit, along with any technical details required to perform the test in question. In some cases it may be useful for the individuals who were involved with the initial development or validation to be on site during the transfer. The number of batches, replicates, and injection sequences in the case of liquid or gas chromatography should be clearly expressed, and, in the case of dissolution testing, the number of individual dosage units should
be stipulated.
分析方法应起草成书面的文件,其中应对细节详细说明并有明确的指导说明,以便经过培训的人员可以顺利的进行检验。转出方和接收方应预先开个会议,这样便于双方就方法转移过程争议的地方可以讲清楚,并解答相关问题。如有全验证或部分验证的数据,接收方应可获得这些数据,包括检验过程中应注意的技术细节。在一些情况下,参与研发或验证的人员在方法转移的过程中应在场,这样会很有帮助的。如果使用的是液相或气相进行检验,那么需检验批次的数量,进样的数量以及进样的顺序应明确规定;如果是溶出试验,需要进行溶出试验的样品的数量也应明确规定。
TRANSFER REPORT
转移报告
When the TAP is successfully completed, the analyst should prepare a Transfer Report that describes the results obtained in relation to the acceptance criteria, along with conclusions that confirm that the receiving unit is now qualified to run the procedure. Any deviations should be thoroughly documented and justified. If the acceptance criteria are met, the TAP is successful and the receiving unit may be qualified to run the procedure. Otherwise, the procedure cannot be considered transferred until effective remedial steps are adopted in order to meet the acceptance criteria. An investigation may provide guidance about the nature and extent of the remedial steps, which may vary from further training and clarification to more complex approaches depending on the particular procedure.
当分析方法转移成功的完成后,分析人员应起草分析方法转移报告,其中应描述转移的结果,是否有符合标准规定,并应有结论确定接收方是可以是可以使用转移的分析方法的。发生的任何偏差应记录完整并说明理由。如果符合标准规定,则进行的分析方法转移是成功的,接收方是可以使用转移的方法的。否则的就不能认为分析方法已完成转移,应采取有效的补救措施使其符合标准规定。进行的调查可为将要采取的补救措施以及需要完成的程度提供指南,根据不同的情况,采取的补救措施包括进一步培训和进一步阐明复杂的检验方法等。