Real time release testing EMA 实时放行检测指南2012年十月执行

7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8416 E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2012. Reproduction is authorised provided the source is acknowledged. 29 March 2012 EMA/CHMP/QWP/811210/2009-Rev1 Committee for Medicinal Products for Human Use (CHMP) Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) Final Draft Agreed by CHMP / CVMP Quality Working Party 26 November 2009 Adopted by CHMP for release for consultation 17 December 2009 End of consultation (deadline for comments) 31 August 2010 Agreed by Quality Working Party 2 February 2012 Adopted by CHMP 15 March 2012 Date for coming into effect 1 October 2012 This guideline replaces the Note for Guidance on Parametric Release CPMP/QWP/3015/99 Keywords Parametric release, batch release, sterilisation, Process Analytical Technology, Quality by Design, real time release testing Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) EMA/CHMP/QWP/811210/2009-Rev1 Page 2/10 Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) Table of contents Executive summary ..................................................................................... 3 1. Introduction (background)...................................................................... 3 2. Scope....................................................................................................... 3 3. Legal basis .............................................................................................. 3 4. General considerations............................................................................ 4 5. Real Time Release Testing....................................................................... 4 5.1. RTRT as part of a Control Strategy ....................................................................... 4 5.2. Application of RTRT ............................................................................................ 5 5.2.1. Application of RTRT to biological/biotechnological products .................................... 5 5.2.2. RTRT examples ............................................................................................... 6 5.3. Retesting upon importation from third country ....................................................... 6 6. Submission requirements ........................................................................ 7 6.1. General requirements ......................................................................................... 7 6.2. Documentation .................................................................................................. 7 7. Parametric Release and Sterilisation ....................................................... 8 7.1. Sterilisation by moist and dry heat ....................................................................... 9 7.2. Sterilisation by radiation ..................................................................................... 9 Definitions................................................................................................. 10 References ................................................................................................ 10 Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) EMA/CHMP/QWP/811210/2009-Rev1 Page 3/10 Executive summary Medicinal products must comply with their approved specifications before they are released into the market. Compliance with release specifications can be demonstrated by performing a complete set of tests on the active substance and/or finished product, according to the approved specifications. Under certain conditions, an alternative strategy to systematic end product testing is possible. So far this concept has been mainly applied to sterility testing of terminally sterilised products and has become associated with parametric release applications. Recent guidelines adopted in the ICH context (ICH Q8, Q9 and Q10) have made it possible to apply a similar release decision process to tests other than sterility, this approach has been called Real Time Release Testing (RTRT). This guideline addresses the requirements for application of RTRT to different kinds of products e.g. chemical and biological products and its scope is to facilitate the introduction of RTR testing. The guideline is a revision of the guideline on parametric release and does not introduce new requirements. 1. Introduction (background) A medicinal product must comply with the requirements stated in the authorised specifications for release and shelf life. RTRT is a system of release that gives assurance that the product is of intended quality, based on the information collected during the manufacturing process, through product knowledge and on process understanding and control. RTRT recognises that under specific circumstances an appropriate combination of process controls (critical process parameters) together with pre-defined material attributes may provide greater assurance of product quality than end- product testing and the context as such be an integral part of the control strategy. The RTRT principle is already authorised for use as an optional alternative to routine sterility testing of products terminally sterilised in their final container i.e. parametric release1,2. Enhanced product knowledge and process understanding, the use of quality risk management principles and the application of an appropriate pharmaceutical quality system, as defined within ICH Q8,Q9 and Q103,4,5,6 provide the platform for establishing RTRT mechanisms for other applications, for new products as well as established marketed products. Release of a product can be a combination of a RTR approach for certain critical quality attributes (CQAs) and a more conventional evaluation for other CQAs (partial RTR). 2. Scope This guideline outlines the requirements for applications that propose RTR testing for active substances, intermediates and finished products. It also outlines the different requirements that have to be fulfilled in the application and the need for interaction between quality assessors and GMP inspectors in the approval process. The principle of RTRT may be applied during the stages of manufacture of chemical and biological products resulting in the elimination of all, or certain, specific tests in the specifications of the finished active substance or finished medicinal product. This guideline is not applicable to investigational medicinal products although a company may be at various stages of development aiming at RTRT of the final product. 3. Legal basis This guideline should be read in conjunction with the introduction and general principles (4) and part I of the Annex I to Directive 2001/83 as amended. Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) EMA/CHMP/QWP/811210/2009-Rev1 Page 4/10 4. General considerations The application of RTRT may offer advantages to a manufacturer and from a regulatory point of view the enhanced knowledge gained is welcomed, however it is not a mandatory requirement. Potential benefits are e.g. to enable real time control and process intervention (feed-back or feed-forward options), assessment based on a larger set of data and reduced overall operational cycle times. The introduction of RTRT requires pre-authorization by the competent authority. In general the documentation submitted for a new market authorization or a variation should address only those quality aspects that are specific for the medicinal product. Site specific quality aspects not specific to the product (i.e. quality systems and process implementation), fall within the remit of GMPs. RTRT may be introduced as a part of an application that is based on an enhanced product understanding of what is responsible/critical for product performance or may be introduced following a variation of an existing market authorization when more experience has been gained with the manufacture of the product and sufficient product and process knowledge has been demonstrated. In both cases adequate risk management should be demonstrated in line with the relevant ICH guidelines. Although the assessment of applications is primarily made by the assessors, close collaboration with inspectors is highly recommended as the input from both parties will form the basis for the approval where the assessors will focus on the product related issues and the inspectors more on the system related ones. Approval as well as withdrawal of RTR testing is at the discretion of the Competent Authority. A withdrawal may be based on the results of an inspection or on the receipt of other information. If a company after approval of RTRT wishes to return to end product testing, a variation of the marketing authorization is required. 5. Real Time Release Testing 5.1. RTRT as part of a Control Strategy Before a medicinal product is released for sale, the Qualified Person responsible for its release should take into account, among other aspects, the conformity of the product to its specification7. In the case of approved RTRT, this conformity would not routinely be supported by results of end product testing. Nevertheless a specification has to be established and each batch of a product should comply with it if tested. A specification is also necessary for stability studies, in order to establish a product shelf-life as well as for Official Medicines Control Laboratory (OMCL) controls. The application for RTRT should be supported by adequate validation of the RTR test method. The relationship between the RTR test, including acceptance criteria, and the end product test and associated specification should be well understood and, where applicable, supported by substantial comparative data at commercial scale (parallel testing). When RTRT has been approved this should be routinely used for batch release. In the event that the test results of RTRT fail or are trending toward failure, RTRT may not be substituted by end-product testing. Any failure should be investigated and trending should be followed up appropriately. Batch release decisions will need to be made based on the results of these investigations, and must comply with the content of the marketing authorization and current GMP requirements. Attributes (e.g. uniformity of content) that is indirectly controlled by approved RTRT should still appear in the Certificate of Analysis for batches. The approved method for end-product testing should be mentioned Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) EMA/CHMP/QWP/811210/2009-Rev1 Page 5/10 and the results given as ”Complies if tested” with a footnote: ”Controlled by approved Real Time Release testing”. In case of equipment failure the control strategy provided in the application should include a contingency plan specifying the use of alternative testing or monitoring approaches on a temporary basis. In this situation, the alternative approach could involve use of end-product testing or other options, while maintaining an acceptable level of quality. Testing or monitoring equipment breakdown needs to be managed in the context of a deviation under the Quality Management System and can be covered by GMP. 5.2. Application of RTRT The exact approach to RTRT will vary depending on the process requirements. The RTRT strategy may be based on control of process parameters, monitoring of product attributes or on a combination of both at appropriate steps throughout the process. Critically, the RTRT strategy should be based on a firm understanding of the process and of the relationship between process parameters, in-process material attributes and product attributes. Process monitoring may be applied to various manufacturing steps or unit operations, such as tabletting, on the basis of appropriate testing at various stages in the process. Some parameters/attributes are usually checked routinely at defined intervals regardless of the design of the manufacturing process of a tablet. Uniformity of mass, crushing strength and disintegration are such examples. The results of a comprehensive set of in- process tests and controls in these cases may constitute sufficient grounds for replacing the corresponding end product testing and may also offer greater assurance of the finished tablet meeting certain criteria in the specification, without the tests being repeated on a sample of the finished product, as the amount of data will in general be substantially larger. If testing of units is part of the RTRT a sampling strategy should be defined that provides the number of locations sampled throughout the batch as well as the number of dosage units tested at each location. RTRT will, in general, comprise a combination of process controls which may utilise process analytical technology (PAT) tools e.g. near infrared spectroscopy (NIR) and Raman spectroscopy (usually in combination with multivariate analysis), together with the control of relevant material attributes. Spectral data monitored on-line controlling content of active substance, polymorphism, water content, blending homogeneity, particle/powder properties or film thickness could thereby replace end-product testing e.g. uniformity of content, tablet strength and drug dissolution. In active substance manufacturing, RTRT can apply to continuous manufacturing processes, but also to discrete unit operations such as distillations, hydrogenations, crystallisations and all sorts of other chemical reactions or separations (e.g. diastereoisomers). When RTRT is applied, the attribute that is indirectly controlled (e.g. sterility, uniformity of content) together with a reference to the associated test procedure, should still be included in the specification as “Conforms if tested” (see 5.1). The relationship between end-product testing, material attributes, process monitoring and acceptance criteria, should be fully explained and justified. In addition, the use of any prediction models should be fully explained, justified and verified at the commercial site. 5.2.1. Application of RTRT to biological/biotechnological products Alternate approach to routine end product testing could be considered for quality attributes included in the specification of a biological/biotechnological product, provided that it can be demonstrated that acceptable level would be maintained in the final product level, if tested. Product/process understanding, in-process parametric control and/or attribute testing at an earlier step in the process Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) EMA/CHMP/QWP/811210/2009-Rev1 Page 6/10 are elements that can be used to justify the replacement of end product testing on a routine basis by RTRT. For instance, the level of process related impurities such as residual host cell DNA or host cell proteins (HCP), which are typically tested on a routine basis on the active substance, may be evaluated using a routine testing approach and/or a validation approach. A routine testing approach would be based on the monitoring, using suitable analytical tools, of the level of those impurities at appropriate step(s) of the process, in order to ensure acceptable levels in the final product. A validation approach would be based on evidence of successful validation of the manufacturing process establishing that at given steps of the purification scheme, those impurities are removed in a consistent and reproducible manner to an acceptable level. In this situation, the demonstration of high process clearance capability, based on reduction factors, may be sufficient to justify the lack of end product testing of these quality attributes on a routine basis. A justification based on a combination of routine testing and validation approaches is also possible. Such approach could be used, for instance, where the application data alone are not sufficient to completely remove routine testing (e.g. reduction factor not sufficient). In this situation, routine testing at an earlier step, before a purification step which has been demonstrated to appropriate clearance capability with regards to the given impurities, could also be used to justify the lack of end product testing of these quality attributes on a routine basis. 5.2.2. RTRT examples For illustrative purposes some examples are given, which are not intended in any way to limit the scope of the application of RTRT. A combination of in-process tablet weight, blend content uniformity measurement e.g. by NIR, drug substance purity and particle size could serve as a control strategy for drug content of a tablet if the relationship has been demonstrated. Core tablet weight, blend uniformity, drug substance purity and particle size in this example are the RTR tests. The production batches are released by the Qualified Person based on the outcome of the RTR tests, any other required tests and GMP compliance. Attributes relating to the properties of a tablet granule such as porosity, particle size, surface area, bulk/tapped density etc. if shown to have a predictive relationship with dissolution behaviour could serve as RTR testing surrogates for dissolution testing. These dependencies would have to be confirmed on a product-by-product basis. RTRT for impurities for an active substance may be achieved through control of starting materials and process parameters which directly impact impurity levels, supported by empirical and mechanistic knowledge of impurity formation and purging during processing. 5.3. Retesting upon importation from third country For products coming from third countries into the EU it is a requirement in Directive 2001/83/EC “that each production batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least the active substances and all the other tests or checks necessary to ensure the quality of medicinal products in accordance with the requirements of the marketing authorization”8. This normally means a complete reanalysis of the product according to the approved specification. When a company has approval for RTRT for one or more tests in the specification, these tests would not be considered a “necessary test or check to ensure the quality of the medicinal product in accordance with the requirements of the marketing authorization”. Therefore a relief from this testing Guideline on Real Time Release Testing (formerly Guideline on Parametric Release) EMA/CHMP/QWP/811210/2009-Rev1 Page 7/10 will be accepted. Identification upon receipt of material as part of GMP will apply even if this test subject to RTRT. 6. Submission requirements 6.1. General requirements For some substances and dosage forms, the different stages of the manufacturing process will be discrete, thus allowing sampling at critical parts of distinct stages of the process. For other substances and dosage forms, the manufacturing process may be partially or wholly continuous, necessitating a more integrated process monitoring. It is therefore not possible to specify in a guideline specific details of how RTRT can be applied. This must be assessed in each individual case verifying that the requirements of appropriate Notes for Guidance are met. The authorizatio