How to get acceptance of CEP revisions quickly

Transcription

1 How to get acceptance of CEP revisions quickly EDQM WEBINAR 13 November 2017 Florence SCHULIAR - Certification of Substances Department 1 How to get acceptance of CEP revisions quickly Aim of this presentation : Draw attention to best practices for submissions Highlight key points to prepare optimised submissions 2 1 1

2 How to get acceptance of CEP revisions quickly By improving the quality of the data submitted, the time taken for approval can be decreased (less time on assessment, less need for additional information or clarifications) and/or rejection of notifications avoided Interest for applicants? Get approval /significant gain of time / resources / limit costs 3 How to get acceptance of CEP revisions quickly How to achieve this? Applicants should facilitate a quick understanding of the changes made and their impact TO DO : submit clear requests and accurate documentation 4 2 2

3 Overview How to apply for revisions? Application form Comparative table Make best use of the EDQM guideline Frequent changes 5 How to apply for revisions? What to provide and where to include it? Applications need to be submitted in electronic format, refer to the webinar on «Electronic submissions for CEP applications» May 2016, available on EDQM website IMPORTANT CHANGE IN JANUARY 2018 for revisions and renewals: PDFs no more accepted! -> need to be Nees or ectd (exceptions : for TSE only PDF will continue to be accepted) 6 3 3

4 How to apply for revisions? (cont.) A submission should be composed of : o a completed application form and cover letter module 1 o a comparative table of the changes, highlighting approved and proposed content module 1 o data supporting the request for revision module 1 and module 3 o update of all impacted section(s) of the CTD dossier module 3 7 How to apply for revisions? (cont.) TO DO : when preparing the submission be familiar with, understand and refer to the EDQM Guideline on requirements for revisions and renewal PA/PH/CEP(04)2,6R. The changes must be individually classified and identified in the application form (if not, they would be considered as not declared = not assessed = not approved)

5 Application form TO DO: choose properly the type of revision you apply for, by taking into account all the changes declared Notification (may include several changes) Minor revision (may include several changes including notifications) Major revision (may include notifications and minor changes) Renewal (notifications and minor changes may be included) Grouped revision (several dossiers affected) Transfer of holdership! Always use the latest version of the application form (including declarations e.g. holder s commitments)! 9 Application form (cont.) GROUPED REVISIONS : when? When the SAME change(s) affect(s) 2 or more CEPs and there is no need for an individual assessment NOT TO DO : don t include other changes which affect only one or some of the CEPs listed -> in this case single applications for revision are needed TO DO : list all the dossiers in the common application form, AND provide the relevant update of the CTD sections for each CEP!

6 Application form (cont.) GROUPED REVISIONS : when? (cont.) The grouped revision option applies typically to administrative changes in name/address of the holder/manufacturer (notifications) -> applies rarely to changes other than administrative since for quality changes a specific assessment of the impact on each dossier is usually required (except : grouped notification to change a non-significant control parameter for a common reagent used in several dossiers). 11 Comparative table Importance of comparative table : Key element of the request for a revision /notification / renewal! TO DO : use the format of the table as proposed in annex 7 of the application form

7 Comparative table (cont.) Expectations: CTD section reference Approved text of the dossier1 Proposed text of the dossier Classification of the change(s) and brief justification Classification and justification: CTD section reference Approved and proposed contents of the dossier: changes should be easily identifiable and highlighted (e.g. in bold). - For minor and major revisions: brief description of the change and justification of the classification according to Guideline PA/PH/CEP (04)2 For notifications: brief description of the change and confirmation that all the conditions listed in the Guideline PA/PH/CEP (04) 2 are fulfilled. 13 Comparative table (cont.) TO DO : fill it in with text/content extracted from the dossier and highlight the changes ( e.g. bold, colours ) copy as much information as needed so that a reader can have an easy overview of the change summaries are very rarely appropriate

8 Comparative table (cont.) Approved/ proposed text : limited exceptions where a complete comparison of the text of the dossier is not relevant are : stability data, certificates of analysis, method validation reports, detailed description of an analytical method when the method is completely replaced -> the comparative table should however mention what kind of update has been made 15 Comparative table (cont.) TO DO : always ensure readability, for instance when flow-charts are copied in the table NOT TO DO : Editorial changes should not be reported in the table (periodical updates of the format of specifications of raw materials/ updates of the internal codes for specification are to be considered as editorial updates)

9 Comparative table (cont.) TO DO : last column of the table is where the change can be summarised, its classification justified, some context explained TO DO : last column of the table is also where it can be detailed where the corresponding supportive information is available ( for instance in module 1 page xx ) 17 Comparative table (cont.) TO DO : Example of ways to complete the table

10 Comparative table (cont.) TO DO : Example of ways to complete the table CTD section reference 3.2.S.4.2 Proposed text of the dossier Approved text of the dossier Related substances HPLC: Chromatographic conditions: Column 25 cm x 4.6 mm packed with BDS, C18, (5µm) Wavelength: 286 nm Injection volume: 20 µl Run time: 45minutes Classification of the change(s) and brief justification. Related substances HPLC: Chromatographic conditions: Column: 15 cm x 4.6 mm, C-8, (3µm) Wavelength: 286 nm Injection volume: 10 µl Run time: 35minutes Minor change: replaced in-house HPLC method with change in type of column and adapted parameters. No change is made in the specifications of the final substance. Refer to page xx of module 1/ module 3 for complete description of the method/ validation data/ cross validation data with EP method/analytical data 19 Comparative table (cont.) TO DO : for addition/deletion/changes to the materials used in the process (solvents/ reagents/catalysts) always also provide a comparative list of the materials used in approved and proposed process steps : Step 1 Step 2 Approved process Dichloromethane Cyclohexane Methanol Purified Water Sodium hydroxide Purified water Ethyl acetate Raney nickel Chloroform Ethyl acetate Proposed process Dichloromethane Methanol Purified Water Sodium hydroxide Toluene Acetic acid Purified water Ethyl acetate Raney nickel

11 Comparative table (cont.) DO NOT : don t fill columns using general comments such as update or just reporting short sequences of text without enough context CTD section reference Approved text of the dossier Existing specifications and test methods for methanol no 02 Proposed text of the dossier Classification of the change(s) and brief justification. Proposed version of specifications and test methods for methanol no 03 Update of section 3.2.S.2.3 Page 22/ sub-section 1 : NaOH 20L Page 23 : 300L Page 25 : C Page 26 : yield 12-13kg For process update 3.2.S.2.3 Page 22/ sub-section 1 : NaOH 10L 3.2.S.2.2 Page 23 : isopropanol 200L Page 25 : 20 C page26 : yield 12kg 21 Comparative table (cont.) DO NOT : CTD section reference Approved text of the dossier Proposed text of the dossier Update of the microbiological control test, see dossier p. 254 Classification of the change(s) and brief justification. Annual notification 3.2.S.4.1 Specifications for acetone New version 3.2.S.2.3 Annual update of SOP

12 How to make best use of the EDQM Guideline for Revisions GUIDELINE ON REQUIREMENTS FOR REVISION/RENEWAL OF CERTIFICATES OF SUITABILITY TO THE EUROPEAN PHARMACOPOEIA MONOGRAPHS PA/PH/CEP(04)2, current version Divided in different parts : administrative changes and quality changes. The last part of the guideline gives more details on : classification of the TSE changes, changes linked to the use of a CEP in another application, the renewal of CEP and transfer of holdership. 23 How to make best use of the EDQM Guideline for Revisions different categories of changes : Notifications follow the do and tell principle and would cover administrative changes and certain changes with no impact on the quality of the final substance. Major changes are substantial changes where an assessment is needed on the potential impact on the quality of the substance. Changes which are not a notification nor a major change are to be considered as Minor (by default)

13 How to make best use of the EDQM Guideline for Revisions 25 Notifications TO DO : confirm formally that all the conditions listed in the guideline are met TO DO : provide all the corresponding documentation listed in the guideline, either under module 1 /module 3 ( for instance declarations or batch analysis data ) example : up to 10-fold increase in the batch size of the substance: declare that the conditions 1,2,3,4,6,7 are met, and provide the following documentation: 1,2,3,

14 Minor changes TO DO : the minor change should be clearly reported in the comparative table and in supportive documentation in module 1 (module 3 update, as relevant) Some typical minor changes are already described in the guideline, refer to it for the documentation to be provided: for instance declarations, updated process description, batch analysis data, stability data 27 Major changes TO DO : classify as major change any substantial changes to process* or to specifications e.g. widening *potential impact on the quality of the final substance which needs to be assessed TO DO : discuss the impact on the quality and control strategy for the final substance, provide relevant analytical data / science-based argumentation TO DO : when a re-test period was granted before the change: discuss the need to provide stability data according to the EMA Guideline on stability testing for application for variations to a marketing authorisation -> avoid a request for additional information!

15 Important note on the definition of the synthetic route For Minor changes in the process (minor by default) a declaration that the route of synthesis is the same as approved is needed (same INCLUDING all the solvents/ reagents /catalysts used) TO DO : For changes to the process make a clear statement regarding the route of synthesis 29 Important note on the definition of the synthetic route (cont.) In case new reagents/catalysts or solvents are introduced the revision should be classified as a major change. Any differences between the approved and proposed synthetic routes have to be detailed and discussed. Changes to compounds used during synthesis may have a potential impact on the quality of the final substance and have to be assessed. NOT TO DO : avoid terms such as similar route / essentially the same further details on the differences between processes are needed > major change! Speaker name 2014 EDQM, Council of Europe. All rights reserved

16 Which supportive information? Supportive documentation depends on the classification of the change For notifications the table may be used to confirm that the conditions of the guideline are met but need to refer to further documentation requested in the revision guideline such as declarations from the holder, batch analysis data (to be included in the module 1 or module 3). For minor changes and major changes the short justification of the comparative table is not sufficient, further supportive information is needed regarding quality and control of the final substance 31 Which supportive information? (Cont.) TO DO : Ensure the supportive documentation answers the following questions : - Need for the change and associated risks : why are you making the change and what are the critical points of the change to be considered? What are the risks associated with the change? What impact has this on the quality of the final substance? - Impact on the control strategy : how does the control strategy ensure that the quality of the final substance is maintained? What science based discussions and/or supporting data is provided which helps to justify the change?

17 Typical changes Changes to the manufacturing process : A change to the process for the final substance is to be declared as: - a major revision, if there is any substantial change made to the synthetic route which may impact the qualitative and quantitative impurity profile of the final substance (e.g. any new solvent, reagents or catalysts introduced in the synthesis). The replacement of an ICH Class 2 solvent by a Class 3 solvent should be declared as a major revision. 33 Typical changes Changes to the manufacturing process : (cont.) - a notification for some minor updates to the process that do not have an impact on the quality of the final substance, e.g. adapted operating conditions, addition of a reprocessing step which is the exact repetition of an existing step, repetition of a washing within the same step. - a minor revision (by default) if the request is neither a notification nor a major revision. e.g. addition of a solvent in a synthetic step (excluding final purification) when that solvent is already used elsewhere in the approved process. Notification? Minor change?: Refer to the related FAQs available on EDQM website (topic 07/ section 02/ questions 03 and 04) What Minor Changes to the Manufacturing Process may be submitted to EDQM through a notification? And What kind of Minor Changes to the Manufacturing Process are considered as minor changes by default?

18 Typical changes Changes to specifications: A change to the specifications of starting material(s), intermediate(s) or final substance or in in-process controls is to be declared as: - a notification, provided that the conditions of the EDQM Guideline are met and that the change does not result from unexpected events during manufacturing. E.g. tightening of limits for impurities, or deletions of nonsignificant tests (a non-significant parameter obviously does not impact the quality of the final substance its change does not require assessment. e.g. a test for odour.) n.b. Related substances are not considered as nonsignificant parameters. - a major revision, if the limits of a critical specification parameter are widened, for instance when an impurity limit is widened. 35 Typical changes Changes to specifications: - if the request is neither a notification nor a major revision, it is classified as a minor revision (by default). A widening of approved limits within the limits of the Ph.Eur./ICH-VICH guidelines is a minor change,otherwise -> a major change. E.g. widening limits within the range of ICH requirements for an ICH Class 2 or Class 3 residual solvent that is limited in the final substance is a minor revision

19 Typical changes Changes to analytical procedures A change to a test procedure is to be declared as: - a notification, provided that all the conditions of the EDQM Guideline are met. The method should remain essentially the same : typically changes should be within the ranges allowed by Ph. Eur. general chapter Chromatographic separation techniques. - if not a notification -> a minor revision. -> for a method used to control the final substance a summary of validation data may be needed. Editorial changes to a method description for control of the final substance should be submitted as a notification only if appended to the CEP since the CEP would need to be revised. 37 Typical changes Other comments Changes to manufacturer of an intermediate TO DO : full update of the description of synthetic steps and controls from the starting material to the intermediate has to be made in the dossier. Include information on the starting material(s) suppliers used by proposed manufacturer(s) of intermediate. TO DO : discuss the impact on the control strategy (intermediate specification, IPC, carryover of impurities) when the route of synthesis of the intermediate is changed

20 Quinquennial Renewal TO DO : submit the request for renewal in time -> about 6 months prior to the expiry date 2 options: - either Declaration that no changes occurred since the last revision - OR Minor revisions and notifications can be submitted BUT NO MAJOR REVISION In both cases, include recent batch data Assessment will focus on compliance with: GM 2034, recent Eur. quality guidelines e.g. Q3D, solvents, etc 39 Consult EDQM website

21 Take-home messages - Facilitate a quick understanding of the changes made - Submit a consolidated comparative table! - Correctly classify the changes - In some cases explaining more on the context of the changes made can help a better understanding ( e.g. why this particular specification has been widened in a given inprocess control) 41 Take-home messages - Consider and discuss the need for the change and associated risks and impact of the change on the control strategy for the manufacturing process - for notifications confirm that all conditions are met and provide the requested documentation (see guideline )

22 Any question, doubts on classification? Consult EDQM website for supportive guidance documents The Certification Department is also providing support through the EDQM helpdesk for general questions, or on the account communicated by EDQM for specific dossiers Technical advice meetings are also possible (fees) One-to-one meetings during conferences/cphis 43 Thank you for your attention, questions?

23 EDQM Upcoming Events CPhI India (Stand D65), November 2017, Mumbai > Book a One-to-One Session on CEP Procedure Ph. Eur. Training Session (Chemicals), May 2018, Croatia Events Calendar: PRDD 2017 EDQM, Council of Europe. All rights reserved. EDQM existing webinars Webinar on Elemental Impurities Webinar on Electronic Submissions for CEP applications PRDD 2017 EDQM, Council of Europe. All rights reserved. 23

24 Webinar on How to get acceptance of CEP Revisions quickly Question & Answers Florence Schuliar, Scientific assistant Andrew McMath, Head of Section for Revisions Ciaran Feeney, Principal Scientific Assistant Certification of Substances Department, EDQM, Council of Europe. PRDD 2017 EDQM, Council of Europe. All rights reserved. Thank you for participating in EDQM Webinar on How to get acceptance of CEP Revisions quickly 13 November 2017 PRDD 2017 EDQM, Council of Europe. All rights reserved. 24