Sultan Ghani WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Variations Maintenance of Prequalified Products

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Variations to a medicinal product Throughout the lifecycle of a medicinal product, the Marketing Authorisation holder –is responsible for the product which circulates on the market place –is required to take into account technical and scientific progress and make any amendments required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods –may wish to alter / improve the medicinal product or to introduce additional safeguards

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Variations to a medicinal product Such amendments have to be approved by the Competent Authority Same principles apply to a Pre-qualified product -WHO Pre-qualification team should be informed of any changes by means of an application for a variation -Definition: a variation to the terms of a Pre-qualified FPP dossier means an amendment to the contents of the documents, such as they existed at the moment the product was listed as Pre-qualified

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Variations to a Pre-qualified medicinal product Guidance on variations to a Pre-qualified dossier Adopted by the WHO Expert Committee on Specifications for pharmaceutical preparations in October 2006, applicable since January 2007, published in WHO Technical Report Series (TRS) 943, as Annex 6. -Inspired technically and structurally from the EU guideline on dossier requirements for type IA and IB notifications but adapted to the WHO Prequalification environment

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. WHO PQ guidance on Variations to a Pre-qualified medicinal product -Applicable only to APIs and excipients manufactured by chemical synthesis or semi-synthetic processes and FPPs containing such APIs and excipients -Applicable to Multisource (generic) FPPs that have been pre-qualified by WHO -NOT APPLICABLE to Variations to FPPs licensed by DRAs of ICH regions and associated countries and listed as Pre-qualified. - These variations should be also approved by corresponding original DRAs however WHO PQ should be notified about nature and approval of change

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Study variation guideline before dossier submission Helps in planning the submission Helps in preparing the dossier, e.g. different batch sizes, multiple API sources, refer to the variation guideline for the documentation requirements. A change made to a dossier while application for prequalification is still ongoing is considered additional data. 3 categories of changes –Notifications (mainly administrative) –Minor changes (minor impact on quality) –Major changes (major impact on quality) But not always as the option is used by "default" Certain variations are considered "so major" that a new application is necessary

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Guidance on Variation to a prequalified dossier To facilitate classification of various types of changes, the variation guide is composed of 4 Annexes -Annex I: lists minor changes, including notifications (N) + minor changes -Annex II: definition and examples of major changes -Annex III: changes that make a new application /extension application necessary -Annex IV: stability requirements for variations and changes to Pre- qualified FPPs

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Guidance on Variation to a prequalified dossier Definition of changes -Minor change is a variation which can be found listed in Annex I. There are 40. -Major change is a change to the documentation which is - neither a minor variation within the meaning of preceding definition - nor a change for which the submission of a new dossier would be necessary

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Guidance on Variation to a prequalified dossier ANNEX I – Minor changes - Each change is numbered and subcategories depicted by letters and numbers. Conditions necessary for a given change are outlined for each subcategory and listed below each change. Documentation to be submitted is identified including all parts of the dossier that are affected by the variation according to the structure of the Pharmaceutical Quality Information Form (PQIF)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Guidance on Variation to a prequalified dossier ANNEX I – Minor changes Points to consider ● A justification should always be given why the change needs to be introduced ● Some changes affect the pharmaceutical particulars in the Summary of Product Characteristics (SmPC), labelling and/or package leaflet/insert. Modification of these documents are to be considered part of the change. ● Some changes are consequential therefore the application for variation should include documentation for all concerned variations: e.g. Minor change in the manufacturing process of FPP along with change in batch size, Variations

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Guidance on Variation to a prequalified dossier ANNEX I – Minor changes Minor changes listed in annex I are divided in 2 categories  Notifications designed by letter "N" ● Evaluation in 3 months ● Considered as approved if no correspondance by WHO with the applicant has been initiated within 3 months ● If validity of the change cannot be acknowledged, correspondence will be started before the period of 3 months  Other minor changes in annex I

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Annex I – Minor changes For Example: Variation No. 1—a notification

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Annex I – Minor changes List of administrative changes -Var 1 - Change in the name and/or address of the supplier of the prequalified product "N" -Var 2 - Change in the name of the finished pharmaceutical product (FPP) -Var 3 - Change in the name and/or address of a manufacturer of the active pharmaceutical ingredient (API) where no European Pharmacopoeia certificate of suitability (CEP) is available "N" -Var 4 - Change in the name and/or address of a manufacturer of the finished pharmaceutical product (FPP) "N" -Var 7 - Deletion of any manufacturing site (including for an API, intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place) "N"

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Annex I – Minor changes Var 27: Minor change in supplier of packaging components or devices; spacer devices for metered dose inhalers are excluded Conditions 1. No deletion of packaging component or device. 2. The qualitative and quantitative composition of the packaging components/device remain the same. 3. The specifications and quality control method are at least equivalent. 4. The sterilization method and conditions remain the same, if applicable Documentation 1, 2 and 3.

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Annex I – Minor changes Experience with the Variation Guide in PQ –Only few types of variation predominantly occur  Addition of FPP manufacturing site (No.5)  Change in batch size of FPP (No.29)  Extension shelf life of FPP (No.39)  Addition of new source of API (No.12 or No. 13)

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Annex I – Minor changes Addition of new source of API (No.12 or 13)  Variation 12 Change in the manufacturer of the API or final (ultimate) key intermediate in the manufacturing process of the API  Variation 13 Submission of a new or updated Ph. Eur. Certificate of Suitability (CEP) for an API or starting chemical material/reagent/intermediate in the manufacturing process of the API Very frequent case in post-MA and also in post- prequalification - availability of APIs sources - to secure supply of APIs/ avoiding shortages - to optimise API costs

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Annex I and II – Minor and Major changes Variations to the API when APIMF procedure is referred to - Changes to the open part of the APIMF should be reported by the manufacture of API to the applicant in order that the applicant can file a variation - Changes to the restricted part of the APIMF should be reported directly to WHO PQ

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. ANNEX II – Major changes Major change - exceeds the scope of minor changes as listed in annex I OR - exceeds/does not comply with the conditions to be fulfilled along with the change - still does not reach the scope of a line extension/ new application -Examples - Change in the manufacturing process of the API - Change in the composition of the finished product - Change of immediate packaging of the product -It is the applicant's responsibility to provide the relevant documentation (parts of the dossier affected by the change) to demonstrate that the major change will not affect the quality of the pre-qualified product and therefore will not have an impact on safety and efficacy of the product

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. ANNEX III – New application necessary Some changes are so important which make submission of a new application/ line extension application necessary -Changes to the API - change of the API to a different API - inclusion of an additional API to a multi-component product - removal of one API from a multi-component - change in the dosage strength of one or more APIs

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. ANNEX III – New application necessary Changes to the pharmaceutical form/dosage form - change or addition of a new pharmaceutical form: e.g. change from tablets to an oral solution (for paediatric use) Change or addition of a new route of administration This would imply a change in the pharmaceutical form

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. PQ variation guideline Annex IV Stability requirements for variations and changes to Pre-qualified FPPs -Responsibility of the pre-qualified supplier to investigate whether or not the intended change will have an impact on the quality characteristics of APIs and /or FPPs and consequently on their stability. -Test conditions and duration of studies described in Annex IV

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Annex IV - Stability requirements for variations to Pre-qualified FPPs Major changes requiring generation of new stability data -At least 1 st production batch to be placed on long term stability testing using the approved protocol -Stability studies should be always continued to cover the entire shelf life accorded -Results should be made available to WHO on request and WHO should be informed immediately in case of OoS results

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. Future revision of the WHO PQ guide on Variations -Need to render it more flexible -Creation of annual report for minor variations similarly to USFDA and Canadian system of changes. EU is going to change also the regulation and guidelines to create an annual report. -Variations which do not require any prior approval -Need for clarification for some of variations e.g. -Introduction of new sources of API when there is use of APIMF procedure -Addition of item on change in sources of starting materials of API (very popular in PQ) -Systematic inspection of FPP new manufacturing sites by WHO if not inspected or shown compliant by inspections of ICH authorities -Minor variations in nature would not be anymore classified as major just by default which is actually the case

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. CONCLUSION ● Any change to the content of the pre-qualified dossier should be reported to WHO PQ ● The change should not adversely affect the quality, safety and efficacy of the pre-qualified product ● Recommendation for all variations files - Position correctly the variation, submit necessary data - Justify always the change - Present comparison of the already accepted/present aspect and the proposed change in tabular format ● No fees charged to date. Enjoy! ☺☻ ☺☻

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E. THANK YOU

WHO Prequalification Programme of Priority Essential Medicines, October 2010, Abu Dhabi, U.A.E.