Pharmaceutical Development
Training Workshop on Pharmaceutical
Development with focus on Paediatric
Formulations
Protea Hotel
Victoria Junction, Waterfront
Cape Town, South Africa
Date: 16 to 20 April 2007
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Slide 1
April 2007
Introduction to the WHO Prequalification
programme and Regulatory aspects
Post- registration Variations
Presenter:
Maryam MEHMANDOUST, PhD
Pre-qualification programme: Priority
Essential Medicines
WHO- HTP/PSM/QSM
e-mail:
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Slide 2
April 2007
mehmandoustm@who.int
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 safeguard
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Slide 3
April 2007
Variations to a medicinal product
Such amendments have to be approved by the
Competent Authority
Same principles apply to a Pre-qualified product/dossier
WHO Pre-qualification team should be informed of any changes by
means of application for a variation
Definition: a variation to the terms of a Pre-qualified dossier means
an amendment to the contents of the documents, such as they
existed at the moment the product was listed as Pre-qualified
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Slide 4
April 2007
Variations to a Pre-qualified
medicinal product
Guidance on variations to a Pre-qualified dossier
http://www.who.int/prequal/ , see under Information for applicants
then Pre-qualification guidelines then medicinal products
Adopted by the WHO Expert Committee on Specifications for
pharmaceutical preparations in October 2006,
applicable since January 2007
- Inspired technically and structurally from the EU guideline on
dossier requirements for type IA and IB notifications but
adapted to the WHO Prequalification environment
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Slide 5
April 2007
Reminder on the EU system of variations
to medicinal products for human use
- EU Commission Regulations 1084/2003 and 1085/2003 including
● annex I (list and conditions for minor variations/notifications)
● annex II (changes leading to an extension application)
separate guideline on dossier requirements for type IA and IB
notifications (conditions and documentation required)
- Regulation introduced in 2003 to
● simplify the procedures for execution and follow up of minor
changes
● reduce the administrative workload of the competent authorities
● without reducing guarantees in terms of the quality, safety and
efficacy of medicinal products
Commission Regulation (EC) N0 1085/2003 of 3 June 2003 concerning the examination of variations to the terms of a marketing authorisation for
medicinal products for human use and veterinary medicinal products falling within the scope of council Regulation (EEC) N0 2309/93
NTA, Guideline on dossier requirements for Type IA and IB notifications, Revision 1, July 2006
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Slide 6
April 2007
Reminder on the EU system of variations
to medicinal products for human use
- Some EU Member states have adopted the same system
for application to national procedures some others not
- Proposals have recently been made to revise the current
system for a "Better Regulation"
● application to national authorisations in all Member States
● less prescriptive and more flexible regulatory approach by
introduction/application of design space, risk management, …
ICH Q8- Q9-Q10
● "tell and do" notifications (IA) would become "do and tell"
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Slide 7
April 2007
Reminder on the EU system of variations
EU Regulation categorises variations into 3 types
1. Type IA notifications (very minor) - listed in annex I of the
Regulation
2. Type IB notifications (minor) - listed in annex I
3. Type II variations (major)
any change to the documentation proposed by the marketing
authorisation (MA) holder which is not a type IA or a type IB
notifications and which is not regarded as an extension to the MA
(new application) : by default becomes a type II variation
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Slide 8
April 2007
Reminder on the EU system of variations
Different types of variations differ in timetables for validation and
acceptance, sometimes different fees (for national procedures)
- Type IA notifications (very minor): 14 days
- Type IB notifications (minor): 30 days
- Type II variations (major): 60 days
a variation that cannot be deemed to be a minor variation or an
extension of the MA
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Slide 9
April 2007
Reminder on the EU system of variations
Notifications
- A variation notification normally concerns only one variation
- Consequential variations: linked between each other and
unavoidable e.g. change in a test procedure and in the specification
- Parallel variations: not linked between each other but simply occurs
at the same time e.g. registration of 2 new manufacturing sites
- The EU notifications IA and IB apply to adult formulations and to
paediatric formulations equally
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Slide 10
April 2007
WHO Guidance on Variations to a
Pre-qualified dossier
- 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 including paediatric formulations
- Variations to FPPs licensed by DRAs of ICH regions and
associated countries and listed as Pre-qualified, should be also
approved by corresponding original DRAs however
WHO should be notified about the approval of the changes
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Slide 11
April 2007
WHO Guidance on Variations to a
Pre-qualified dossier
To facilitate classification of various types of changes, the
variation guide is composed of 4 annexes
- Annex I: lists 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 Prequalified FPPs
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Slide 12
April 2007
WHO Guidance on Variations to a
Pre-qualified 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
can neither be deemed to be a minor variation within the
meaning of preceding definition (therefore exceeding the
frame of a minor change) nor to be a change for which
the submission of a new dossier would be necessary
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Slide 13
April 2007
WHO Guidance on Variations to a
Pre-qualified dossier
Minor changes listed in annex I
1. 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 cannot be acknowledged, correspondance will be
started before the period of 3 months
2. Other minor changes in annex I
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Slide 14
April 2007
WHO Guidance on Variations to a
Pre-qualified dossier
3 points to consider
- For all changes that are not considered as notifications, prior
approval by WHO is always necessary before the change can be
implemented
- A justification should always be given why the change needs to
be introduced
- In case the change also implies a change in the pharmaceutical
particulars in the Summary of Product Characteristics (SmPC),
labelling and/or package leaflet/insert, this also forms part of the
change.
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Slide 15
April 2007
WHO Guidance on Variations to a
Pre-qualified 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)
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Slide 16
April 2007
WHO Guidance on Variations to a
Pre-qualified dossier
ANNEX I – Minor changes /example of a notification
administrative change
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Slide 17
April 2007
WHO Guidance on Variations to a Pre-qualified dossier
ANNEX I – Minor changes
List of administrative changes
Var 1 - Change in the name and/or address of the supplier of the prequalified product
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
Var 4 - Change in the name and/or address of a manufacturer of the finished
pharmaceutical product (FPP)
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)
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Slide 18
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 8: minor change in the manufacturing process of the API
Conditions
1. No change in qualitative and quantitative impurity profile or in physicochemical
properties
2. The route of synthesis remains the same, i.e. intermediates remain the same
Documentation
1. Replacement of the relevant pages of the dossier according to the structure as listed in
the PQIF and of the prequalified Drug Master File (where applicable), including a direct
comparison of the prequalified process and the new process.
2. Batch analysis data (in comparative tabular format) of at least two batches (minimum
pilot scale) manufactured according to the prequalified and the proposed process.
3. Copy of prequalified specifications of the API.
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Slide 19
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 8: minor change in the manufacturing process of the API / Discussion
The Pre-qualified applicant/ supplier should be able to have access to the
appropriate information in order to judge about the 1st condition i.e.
There is no change in qualitative and quantitative impurity profile or in physicochemical properties of the API
● Impurity profile: ordinary organic and inorganic impurities, residual solvents,
catalysts residues, highly toxic impurities
● Physico-chemical impurities such as particle size (if applicable), polymorphism (if
applicable)
In order to fulfil condition 1
Either no confidential issue between the applicant / supplier to prequalification
and the API manufacturer and data given in the dossier OR If confidential issue,
the information should be submitted in the framework of the APIMF procedure
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Slide 20
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Variations concerning introduction of a new source / a new
manufacturer of the API
Var 12
Change in the manufacturer of the API or final (ultimate) key
intermediate in the manufacturing process of the API
Var 13
Submission of a new or updated Ph. Eur. Certificate of
Suitability 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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Slide 21
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 12: Change in the manufacturer of the API or final (ultimate) key
intermediate in the manufacturing process of the API
Conditions
1. The specifications (including in-process controls, methods of analysis of all materials),
method of preparation (including batch size) and detailed route of synthesis are identical to
those already prequalified.
2. Where materials of human or animal origin are used in the process, the manufacturer does not
use any new supplier for which assessment is required of viral safety or of compliance with
the current WHO Guideline on Transmissible Spongiform Encephalopathies in relation to
Biological and Pharmaceutical Products or the Note for Guidance on Minimizing the Risk of
Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal
Products or an equivalent guideline of the ICH region and associated countries.
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Slide 22
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 12: Change in the manufacturer of the API or final (ultimate) key intermediate in
the manufacturing process of the API
Documentation
1. Replacement of the relevant pages of the dossier according to the structure as
listed in the PQIF.
2. A declaration from the supplier of the prequalified FPP that the route of synthesis,
quality control procedures and specifications of the API and key (ultimate)
intermediate in the manufacturing process of the API (if applicable) are the same
as those already prequalified.
3. Either a TSE European Pharmacopoeia certificate of suitability for any new
source of material or, where applicable, documentary evidence of absence of TSE
risk material
4. Batch analysis data (in a comparative tabular format) for at least two (minimum pilot
scale) batches of the API from the prequalified and proposed manufacturers/sites.
5. The application should clearly outline the ”prequalified” and “proposed”
manufacturers.
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Slide 23
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 12: Change in the manufacturer of the API or final (ultimate)
key intermediate in the manufacturing process of the API
Discussion
The Pre-qualified applicant/ supplier should be able to have access to the
appropriate information in order to judge about the 1st condition and be
able to provide documentation 2 which is only limited to a "declaration".
The 1st condition and the 2nd documentation together make that actually there
should be no confidential issue between the pre-qualified applicant and
the already approved API manufacturer and the future one
i.e. no use of confidential dossier such as DMF/API master file.
See differences with the EU guide
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Slide 24
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 12: Change in the manufacturer of the API or final (ultimate)
key intermediate in the manufacturing process of the API
Problems
From a general point of view, it is difficult to fulfil condition 1
i.e. 2 manufacturers of API who manufacture an API in the
same details: specifications (including in-process controls,
methods of analysis of all materials), method of preparation
(including batch size) and detailed route of synthesis
In most of the cases, the change would be a major change
Remark applicable to the EU guideline equally
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Slide 25
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 13: Submission of a new or updated CoS
Conditions
1. The finished product release and end-of-shelf-life specifications remain the same.
2. Unchanged additional (to European Pharmacopoeia) specifications for impurities and product
specific requirements (e.g. particle size profiles, polymorphic form), if applicable.
3. The API will be tested immediately prior to use if no retest period is included in the European
Pharmacopoeia certificate of suitability or if data to support a retest period is not provided.
4. The manufacturing process of the API, starting material /reagent /intermediate does not include the
use of materials of human or animal origin for which an assessment of viral safety data is required.
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Slide 26
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 13: Submission of a new or updated CoS /
discussion of conditions
1. The finished product release and end-of-shelf-life specifications remain the same.
Preferable to check the feasibility on 1 batch of FPP
2. Unchanged additional (to European Pharmacopoeia) specifications for impurities and
product specific requirements (e.g. particle size profiles, polymorphic form), if
applicable. Attention to particle size and /or polymorphic forms if not covered by CoS
3. The API will be tested immediately prior to use if no retest period is included in the
European Pharmacopoeia certificate of suitability or if data to support a retest period
is not provided. If no retest period on the CoS, then stability data should be provided
as complementary data or parallel variation 15: change in the re-test period of API
4. The manufacturing process of the API, starting material/reagent/intermediate does
not include the use of materials of human or animal origin for which an assessment
of viral safety data is required. Viral safety is not assessed within CoS scheme for
instance.
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Slide 27
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 13: Submission of a new or updated CoS /
discussion of conditions
Condition 2: Unchanged additional (to European Pharmacopoeia)
specifications for impurities and product specific requirements (e.g. particle
size profiles, polymorphic form), if applicable.
Explanation Note
Unchanged additional specifications for impurities refer to new additional
impurities
Excluded from this condition in EU practice
- Tightened impurities
- New residual solvents class II and class III complying with their option I ICH limits
(nfg ICH Q3C)
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Slide 28
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Introduction of a new source/ new manufacturer of API is often a
major change
The worst case would be an API
- administered by oral route in a solid form/ suspension
- insoluble in water and in acid pH
- narrow therapeutic margin
- used in a prolonged release form e.g. carbamazepine, ritonavir
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Slide 29
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Introduction of a new source/ new manufacturer of API is often a
major change
Critical points related to co- existence of different sources of API
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Physico-chemical characteristics which may have an impact on pharmaceutical quality
and in-vivo performance of the FPP
● polymorphism: should be the same morphic form (if applicable, see ICH Q6A) ● particle size profile (if important, see ICH Q6A): identical method and norm used by
the FPP manufacturer
Common specifications
Purity general tests, related substances (if route of synthesis identical), degradation
impurities as inherent/ intrinsic to the substance
Different specifications
specific impurities related to one specific route of synthesis (related substances,
residual solvents, catalysts, … Norms and methods can be different
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Slide 30
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Introduction of a new source/ new manufacturer of API is often a
major change
Critical points to the attention of FPP manufacturers related to co- existence of
different sources of API
● Check the feasibility on at least one lot of the FPP with the new source of API
● Try to keep master of particle size determination method
● Perform comparative dissolution testing with a discriminatory method ● Harmonise as much as possible the specifications of different sources of API
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Slide 31
April 2007
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Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 5: Replacement or addition of a manufacturing site for part or all of the
manufacturing process of the FPP
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Slide 32
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 5: Replacement or addition of a manufacturing site for part or all of the
manufacturing process of the FPP
Conditions
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1.
Satisfactory inspection in the last three years either by WHO or a drug regulatory
authority (DRA) in the International Conference on Harmonisation (ICH) region and
associated countries.
2.
Site appropriately authorized by a NDRA (to manufacture the pharmaceutical form and
the product concerned).
3.
Product concerned is not a sterile product.
4.
Validation protocol is available or validation of the manufacture at the new site has been
successfully carried out according to the current protocol with at least three production
scale batches.
Slide 33
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 5: Replacement or addition of a manufacturing site for part or all of the
manufacturing process of the FPP
Documentation
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1.
Proof that the proposed site is appropriately authorized for the pharmaceutical form and
the product concerned:
– a copy of the current manufacturing authorization, a GMP certificate or equivalent
document issued by the NDRA.
– a GMP statement or equivalent issued by WHO or a Drug Regulatory Authority (DRA) in
the International Conference on Harmonisation (ICH) region and associated countries.
2.
The date of the last satisfactory inspection concerning the packaging facilities by WHO or
drug regulatory authority (DRA) in the International Conference on Harmonisation (ICH)
region and associated countries, in the last three years.
3.
Date and scope (indicate if product specific, if related to a specific pharmaceutical form,
etc.) of the last satisfactory inspection.
4.
The batch numbers of batches ( 3) used in the validation study should be indicated and
validation protocol (scheme) to be submitted.
Slide 34
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 5: Replacement or addition of a manufacturing site for part or all of the
manufacturing process of the FPP /documentation (cont.)
5. The variation application should clearly outline the “prequalified” and “proposed” finished
product manufacturers.
6. Copy of prequalified release and end-of-shelf-life specifications.
7. Batch analysis data of three production batches and comparative data on the last three
batches from the previous site;
8. For semisolid and liquid formulations in which the API is present in non-dissolved form,
appropriate validation data including microscopic imaging of particle size distribution and
morphology.
9. For solid dosage forms data of comparative dissolution tests [refer to Supplement 1of the
Guideline on Submission of Documentation for Prequalification of Multi-source (Generic)
Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and
Tuberculosis] with demonstration of dissolution profile similarity, performed on the last
three batches from the previous site and the first three batches of the new site should be
submitted.
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Slide 35
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Var 5: Replacement or addition of a manufacturing site for part
or all of the manufacturing process of the FPP
discussion
For Var 5c)
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-
3 production batches for PQ versus 1 production batch and 2
pilot scale for EU
-
Documentation 9 on comparative dissolution testing for PQ
instead of GMP compliance for manufacturing sites of API
for EU
-
The French national regulation on variations has added an
additional condition that the manufacturing process should
be the same on the claimed new sites, PQ has added
documentation 9: comparative dissolution testing.
Slide 36
April 2007
Variations to a Prequalified dossier
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
What to do if the condition 2 is not fulfilled?
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Slide 37
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes
Position correctly the variation !
- Why the condition 2 is not fulfilled?
- Is it a change in supplier in reality?
- Apply for a minor variation 26 together with a
consequential variation 27: change in supplier
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Slide 38
April 2007
Variations to a Prequalified dossier
ANNEX I – Minor changes correct positioning
Var 26: Minor change in the qualitative and/ or quantitative composition of the
immediate packaging material
Conditions
1. The product concerned is not a sterile product.
2. The packaging type and material remain the same (e.g. blister to blister).
3. The proposed packaging material must be at least equivalent to the prequalified material in
respect of its relevant properties.
4. Relevant stability studies in accordance with the relevant guidelines have been started with at least
two pilot scale or production scale batches and at least three months' stability data are at the
disposal of the applicant….
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Slide 39
April 2007
Variations to a Pre-qualified dossier
ANNEX II - Major changes
Exceed the scope of minor changes as listed in annex I or they
exceed/do not comply with the conditions to be fulfilled along
with the change, but still do not cover the changes listed in
annex III
Examples
- Change in the manufacturing process of the API
- Change in the composition of the finished product
- Change of immediate packaging of the product
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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Slide 40
April 2007
Variations to a Pre-qualified dossier
ANNEX III - Changes making a new application
/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 dose of one or more APIs
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Slide 41
April 2007
Variations to a Pre-qualified dossier
ANNEX III - Changes making a new application
/extension application necessary
Changes to the pharmaceutical form/dosage form
- change or addition of a new strength / potency
- change or addition of a new pharmaceutical form: change from
tablets or capsules to an oral solution (for paediatric use)
Change or addition of a new route of administration
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Slide 42
April 2007
Variations to a Pre-qualified dossier
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.
When stability data required, the choice of test conditions defined in
annex IV refers to the guideline on the submission of
Documentation for Prequalification of Multi-source (Generic) FPPs
used in the treatment of HIV/AIDS, Malaria and Tuberculosis (main
generic guide)
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Slide 43
April 2007
Variations to a Pre-qualified dossier
ANNEX IV - Stability requirements for variations and
changes to Pre-qualified FPPs
Minor changes as listed in annex I
- minimum set of stability data to be submitted is defined in annex I
- comparison of the new results, obtained in accelerated and long
term conditions, to the stability results obtained on the unchanged
API / FPP
- to ensure that the change does not negatively impact the stability
profile – that the specification limits of the API / FPP are still met at
the end of the proposed retest period / shelf life.
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Slide 44
April 2007
Variations to a Pre-qualified dossier
ANNEX IV - Stability requirements for variations and changes to
Pre-qualified FPPs
Major changes: 3 examples dealt with in annex IV
Change in the manufacturing process of the API
if quality characteristics (eg physical characteristics, impurity profile) of the API
are changed in such a way that stability may be compromised, comparative
stability data required in accelerated and long term conditions on the API before
and after the change:
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API known to be stable
3 months on 1 batch of at least pilot scale
API known to be unstable
6 months on 3 batches of at least pilot scale
Slide 45
April 2007
Variations to a Pre-qualified dossier
ANNEX IV - Stability requirements for variations and changes to
Pre-qualified FPPs
Major change: change in the manufacturing process of the API (cont.)
if quality characteristics of the API are changed in a way that it may impact the
stability of the FPP, additional stability data obtained in long term and accelerated
testing :
3 months on 2 batches of at least pilot scale batches of FPP
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-
Physical quality characteristics: crystallinity and/or polymorphic state –if
applicable- and charcteristics derived from crystallinity such as solubility,
hygroscopicity, etc.
-
Chemical quality characteristics: impurity profile including degradation products
Slide 46
April 2007
Variations to a Pre-qualified dossier
ANNEX IV - Stability requirements for variations and
changes to Pre-qualified FPPs
Definition of a stable API
An API is considered as stable if it remains within the initial
specifications when stored at 25°C/60% RH or 30°C/65% RH,
respectively, for 2 years and at 40°C/75% RH for 6 months and
such data are available from the API manufacturer that applies for
change.
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Slide 47
April 2007
Variations to a Pre-qualified dossier
ANNEX IV - Stability requirements for variations and changes to
Pre-qualified FPPs
Major change: change in composition of the finished product
-
Conventional dosage forms (conventional solid dosage forms, solutions) AND
When the API is known to be stable
Comparative stability data, at least 6 months duration on 2 pilot scale FPP batches
-
Critical dosage forms (eg prolonged release) OR API known to be unstable
Comparative stability data, at least 6 months duration on 3 pilot scale FPP batches
See definition of a pilot scale batch: 1/10 of production batch or 100 000 units whichever greater
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Slide 48
April 2007
Variations to a Pre-qualified dossier
ANNEX IV - Stability requirements for variations and
changes to Pre-qualified FPPs
Major change: change on immediate packaging of the
finished product
If less protective packaging or risk of interaction for semisolids or liquid dosage forms
Comparative stability data in accelerated and long term conditions for
at least 6 months on 3 pilot batches of FPP
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Slide 49
April 2007
Variations to a Pre-qualified dossier
ANNEX IV - Stability requirements for variations and changes 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 as
described in 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 or in case of OoS results
Guideline on stability testing for applications for variations to a marketing authorisation, CPMP/QWP/576/96
Rev 1
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Slide 50
April 2007
CONCLUSION
● Any change to the content of the pre-qualified dossier should be reported to WHO PQ team
● The change should not adversely affect the quality, safety and efficacy of the pre-qualified
product
● New experience and challenge in implementation of the guideline on variation for WHO prequalification team of assessors
● Same for applicants and suppliers to
- understand the system and its mechanism,
- position correctly the variation and to submit necessary data
- not forget to apply for consequential variation when applicable and submit the
corresponding documentation to avoid unnecessary additional data requested and
additional rounds of assessments
● For instance, no fees in PQ Programme
- Seriousness of applicants in the claimed variations
● No timetable except for those called notifications in WHO guidance
main difference in major and minor changes is the extent of documentation submitted
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Slide 51
April 2007