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Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines , Jakarta, October 2009

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Page 1: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Variations to Prequalified Medicines

Rutendo Kuwana

Workshop on WHO prequalification requirements for reproductive health medicines ,

Jakarta, October 2009

Page 2: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20092 |

Variations to a medicinal productVariations 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 safeguard

Page 3: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20093 |

Variations to a medicinal productVariations 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

Page 4: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20094 |

Variations to a Pre-qualified medicinal product

Variations to a Pre-qualified medicinal product

Guidance on variations to a Pre-qualified dossier

http://www.who.int/prequal/

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

Page 5: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20095 |

Scope of WHO PQ guidance on Variations to a Pre-qualified medicinal product

Scope of 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 the change

Page 6: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20096 |

Few considerationsFew considerations

The guideline helps in planning the submission and in preparing the dossier, refer to the variation guideline for the documentation requirements, e.g. different batch sizes, multiple API sources…

A change made to a dossier while assessment is still ongoing is considered as 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

Page 7: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20097 |

Guidance on Variation to a prequalified dossierGuidance 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

Page 8: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20098 |

Guidance on Variation to a prequalified dossierGuidance 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

Page 9: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 20099 |

Guidance on Variation to a prequalified dossierGuidance 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)

Page 10: Variations to Prequalified Medicines Rutendo Kuwana Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200910 |

Guidance on Variation to a prequalified dossier ANNEX I – Minor changes

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 30 + 29

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200911 |

Guidance on Variation to a prequalified dossier

ANNEX I – Minor changesGuidance 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 correspondence 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

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200912 |

Annex I – Minor changesAnnex I – Minor changes

For Example: Variation No.1—a notification

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200913 |

Annex I – Minor changesAnnex 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"

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200914 |

Annex I – Minor changesAnnex I – Minor changes

Var 27: Minor change in supplier of packaging components or devices; spacer devices for metered dose inhalers are excluded

Conditions1. 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

Documentation1 ,2 and 3.

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Annex I – Minor changesAnnex I – Minor changes

Experience with the Variation Guide in PQExperience 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)

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Annex I – Minor changes Addition of new source of API (No.12 or 13)

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

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200917 |

Annex I and II – Minor and Major changesAnnex 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

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ANNEX II – Major changesANNEX 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

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ANNEX III – New application necessaryANNEX 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

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ANNEX III – New application necessaryANNEX 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 administrationThis would imply a change in the pharmaceutical form

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200921 |

PQ variation guidelineAnnex IV

PQ variation guidelineAnnex 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

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Annex IV - Stability requirements for variations to Pre-qualified FPPs

Annex IV - Stability requirements for variations to Pre-qualified FPPs

Major changes requiring generation of new stability data

- At least 1st 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

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200923 |

Future revision of the WHO PQ guide on Variations

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. Consideration of inspection of API sites if not yet inspected

- Minor variations in nature would not be anymore classified as major just by default which is actually the case

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CONCLUSION 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

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Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 200925 |

Acknowledgement

Dr Maryam Mehmandoust – WHO PQP, Geneva for preparing this presentation