30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
28 April 2016 EMA/CHMP/BWP/187338/2014 Committee for Medicinal Products for Human U (CHMP) Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission
Draft Agreed by Biologics Working Party
April 2014 Adoption by CHMP for relea for consultation 25 April 2014 Start of public consultation
1 May 2014 End of consultation (deadline for comments)
31 October 2014 BWP Drafting Group review of comments November 2014 -
January 2016
Agreed by BWP
February 2016 Adoption by CHMP
28 April 2016 Date for coming into effect
长孙神经病的症状1 November 2016
Keywords active substance, biologics, process validation, process evaluation,
process verification, lifecycle
Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission
Table of contents
Table of contents (2)
1. Introduction (3)
2. Scope (4)
3. Legal basis (4)
4. Process characterisation (4)
4.1. Process development (4)
4.2. Process evaluation (5)
5. Process verification (6)
5.1. Approaches to process verification (6)
5.2. Ongoing process verification during lifecycle (7)
6. Points to consider in process characterisation and verification (8)
6.1. Upstream process (8)
6.1.1. Evaluation of upstream process (8)
6.1.2. Verification of upstream process (9)
6.1.3. General issues related to single u equipment (9)
女人的奶水6.1.4. General issues related to multiple harvests (9)
6.2. Downstream process (9)
6.2.1. Evaluation of downstream process (10)
6.2.2. Verification of downstream process (10)
6.2.3. Reprocessing (10)
6.2.4. Hold time, storage and transportation (11)
无人机英语6.3. Multifacility production (11)
Definitions (12)
References (13)
Executive summary
The guideline covers process validation which includes process characterisation and process verification of biotechnology-derived active substances in the manufacture of medicinal products. This guideline address the data requirements for process characterisation and verification for submission of a marketing authorisation application or variation.
•Process characterisation can be bad on a traditional or enhanced approach to process development. Traditional and enhanced approaches are not mutually exclusive.
•Process verification can be performed in a traditional way regardless of the approach to development taken. However, there is also the possibility to implement continuous process
verification if an enhanced approach to development has been performed or where a substantial amount of product and process knowledge and understanding has been gained through historical data and manufacturing experience.
Current experience shows that a company can u a traditional or an enhanced approach to process validation, or a combination of both. Regardless of the approach followed, the validation data to be included in the regulatory submission should cover information relating to the evaluation and the verification of the manufacturing process.
1. Introduction
Process validation is the documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an active substance or intermediate meeting its predetermined specifications and quality attributes (ICH Q7).
如何学好高中英语
Process characterisation is the activity of defining the commercial manufacturing process that will be reflected in planned master production and control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently deliver an active substance that meets its quality attributes. Process characterisation includes process development and process evaluation. For the purpo of this guideline the following definitions apply:
•Process development includes studies to reach a potential design of a future manufacturing process;
•Process evaluation includes studies performed at small and/or commercial scale, to provide evidence that the complete manufacturing process and each step/operating unit have been
appropriately designed to define the full operating ranges of the manufacturing process. The
process is controlled to obtain an active substance of the intended quality for which, when
challenging the ranges in univariate and multivariate studies, the quality will fulfil the pre-t acceptance criteria.
Process verification studies should confirm that the final manufacturing process as established bad on the process evaluation studies performs effectively in routine manufacture and is able to produce an active substance or intermediate of the desired quality on an appropriate number of concutive batches produced with the commercial process and scale.
Process validation should not be viewed as a one-time event. Process validation incorporates a lifecycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.
Process characterisation and verification studies should normally be completed and included in the marketing authorisation application or a variation application as appropriate. It is acknowledged that process validation activities do not end at the time of the marketing authorisation, but continue through the lifecycle of the product. This document address the information, which normally includes process evaluation and verification studies, expected to be prented in a regulatory submission to demonstrate that the manufacturing process, described in the Common Technical Document (CTD) ction S.2.2 Description of manufacturing process and process controls consistently performs as intended.
Subquent to successful process validation activities for regulatory submission, product quality and process performance must be maintained in a state of control throughout the commercial part of the product lifecycle.
周平凡2. Scope
This document provides guidance on the data to be included in a regulatory submission to demonstrate that the active substance manufacturing process is in a validated state. The principles adopted and explained in this document apply to recombinant proteins and recombinant polypeptides, their derivatives, and products of which they are components (e.g. conjugates).
The principles that are outlined in the document may also apply to other biological products such as vaccines or plasma-derived products, as appropriate. To determine applicability, manufacturers should consult with the appropriate regulatory authorities.
For evaluation of viral safety, plea refer to ICH Q5A.
3. Legal basis
This guideline has to be read in conjunction with the introduction and general principles (4) and Part II of Annex I to Directive 2001/83/EC, as amended.
4. Process characterisation
4.1. Process development
The goal of manufacturing process development of the active substance is to establish a commercial manufacturing process capable of consistently producing an active substance of the intended quality. Process development fulfils an esntial role in defining the criteria and conditions to be addresd in further process evaluation and verification studies. For further information, plea refer to the ICH Q11 guideline.
Manufacturing process development should identify which inputs (e.g. material attributes, process parameters) and outputs (e.g. quality attributes, performance indicators such as cell density, yield) for each process step/unit operation should be further evaluated during process evaluation and verification studies.
Documented prior knowledge and risk asssment are valuable tools to identify and justify the material attributes (e.g. of raw materials, starting materials, reagents, solvents, process aids, intermediates) and process parameters which have the potential to affect the active substance critical quality attributes (CQAs) and/or process performance.
Process development information should usually be submitted in Section 3.2.S.2.6 of the CTD.
心如火焚4.2. Process evaluation
Process evaluation studies should provide evidence that, when operating in accordance with the Description of manufacturing process and process controls (CTD ction S.2.2), the complete manufacturing process and each step/operating unit have been appropriately designed and controlled to generate a product of the intended quality. Successful process evaluation should thus demonstrate that the design of the manufacturing process, with the preliminary definition of operatio
nal ranges along with its control strategy is appropriate for commercial manufacturing.
The applicant should study lected inputs and outputs according to their potential criticality and justify their lection. For tho which are not studied further it may be necessary to explain how it is ascertained that the are kept within the range that has been shown to have a non-critical impact. The studies should include the evaluation of the ability of each step to generate an active substance or intermediate of desired quality at small and/or commercial scale as appropriate, when operating in accordance with the described process and process controls. Input data and results of outputs should be prented for each step. The data should demonstrate that when operating within the propod input ranges, the output meets relevant quality criteria (i.e. predefined acceptance criteria or internal limits) and thus supports the proven acceptable ranges (PAR) that will be claimed. The outcome of the evaluation studies rves as the main basis of defining the control strategy and also in tting the acceptance criteria for the verification studies. Elements of the control strategy may be optimid following the outcome of the verification studies.
拈花微笑Prior knowledge (for example platform data) can be ud as supportive information. The contribution of the data (e.g. to justify operating ranges, input t points) to the overall validation package will depend upon justification that the data is reprentative of the propod commercial process.
Where appropriate, evaluation of lected step(s) operating in worst ca and/or non-standard conditions (e.g. impurity spiking challenge) can be performed to support or demonstrate the robustness and the capability of the process to deliver product of the intended quality in the conditions.
Small scale models are important tools in the development and evaluation of biopharmaceutical manufacturing process. During process evaluation, small scale models enable evaluation of input material and parameter variability to an extent that may not be feasible at manufacturing scale.
A small scale model must be designed and executed, and ultimately justified, as an appropriate reprentation of the manufacturing process.
When ud, small scale models should be described and their relevance for the commercial scale should be justified, in terms of objective, design, inputs and outputs. When validation studies are highly dependent on the small scale model studies (e.g. design space claimed), it may be necessary to demonstrate that when operating under the same conditions using reprentative input materials, the outputs resulting from the commercial scale process match tho of the small scale model. Any difference in operating conditions, inputs or outputs should be appropriately justified. Depending on t
he differences obrved and their understanding, approaches to managing the differences (e.g. u of correction factors in cas where Design of Experiments is ud) could be acceptable if well documented and justified. The u of such an approach requires appropriate management of the risks linked to this uncertainty (e.g. managed through the control strategy).
