Pharmaceutical Development with Focus
on Paediatric formulations
WHO/FIP Training Workshop
Hyatt Regency Hotel
Sahar Airport Road
Andheri East, Mumbai, India
28 April 2008 – 2 May 2008
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Presented by:
Birgit Schmauser, PhD
Federal Institute for Drugs
and Medical Devices (BfArM)
b.schmauser@bfarm.de
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
In this presentation:
 Changes to a dossier after prequalification
 Classification of Changes
 Dossier requirements according to Guidelines
 Examples
 Conclusion
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 Changes made to a dossier after prequalification are
variations to the prequalified dossier
 Variations are subject to approval because they may
impact the pharmaceutical quality
 Implementation of a system to regulate variations was
deemed necessary for the prequalification project
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 Variations to a melody
Mozart, Sonata, KV 331, I
 ....“What are more striking than the
differences, however, are the
similarities.
So similar, indeed, are the above
variations to the original theme
that they give the impression of
being ornamentations
not just of the theme itself but of an
even simpler melodic outline, of which
Mozart´s original theme is perhaps
itself an ornamentation”....

From: Piston, DeVoto, HARMONY,
4th edition, W. W. Norton and Company
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 Various systems to handle variations exist in the ICHregion
– Decision for PQ-project
• EU-system seemed most suitable:
Build up knowledge & experience initially
Give assistance by a corresponding guideline adapted for PQ
purposes
Open for future modifications by outcome of assessments and
experience
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 Guide on Variations to a prequalified product dossier
(http://mednet3.who.int/prequal/info_general/documents/TRS943/TRS943.pdf#page=121)
– Gives assistance in how to adequately document variations
 It is in the interest of all to handle variations in a
time-saving and efficient manner
This presentation is intended to assist in clarifying potential
problems and/or misunderstanding around variations
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Guide on Variations to a prequalified product dossier
(Variation Guide)
 Three categories of variations according to their potential
impact on pharmaceutical quality
– Notification (mainly administrative, some potential impact on quality)
– Minor change (potential minor impact on quality)
– Major change (potential major impact on quality)
 Certain variations are considered „so major“ that a new
application (line extension) is necessary
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Variation Guide
 Timelines for the different types of variations
– Notifications (N)
• If no objection is received by WHO within 3 months the variation
can be considered approved
– Minor changes
• Based on satisfactory documentation of the variation WHO will
inform applicants on approval
– Major changes
• Based on evaluation of documentation of the variation WHO will
inform applicants on approval
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Variation Guide
 FOCUS on minor variations
– Lists types of variations that are subject to notification or approval
• Appendix 1
– Gives assistance in identifying the intended change
• Particular conditions to be fulfilled
– Gives assistance in documentation to be provided
• Appendix 1
 SCOPE of major changes and line extensions
– Appendix 2, Appendix 3
 GENERAL ASSISTANCE in (additional) stability requirements
for all changes (N, minor, major)
– Appendix 4
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 Prequalification of FPPs
 Prequalification of APIMFs (since 2007)
Variation Guide addresses conditions & documentation
requirements in case of a variation to both API and FPP
Scenario 1 (Variation Guide)
– FPP/API is affected by the variation (without use of APIMF-procedure)
Scenario 2 (Variation Guide and Guideline on the APIMF-procedure)
– APIMF is affected by the variation
• 3.4 Changes and updates to the APIMF (mainly administrative)
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Exception
The Variation Guide is not applicable to FPPs that are
prequalified based on the assessment of a DRA of the
ICH-region and associated countries
(Innovator Guideline)
Variations on these types of FPPs are approved by the
respective DRAs of the ICH region and associated countries
and WHO is notified subsequently
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
“Regulatory” clarification
 A change made to a dossier after it has been
prequalified is considered a variation
 A change made to a dossier while application for
prequalification is still ongoing is considered
additional data
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Variation versus additional data
 No difference from a technical point of view
– Changes made to a dossier within PQ must be adequately
documented and communicated
• Before prequalification
– Evaluation of its impact on quality
– Prequalification of the correct/up-to-date characteristics
• After prequalification
– Evaluation of its impact on quality
– Update of prequalified characteristics
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 Enjoy advantages
– Grouping of dossiers affected by a variation 
• A single variation application may be filed if more than one dossier is
affected by the same variation
– Grouping of variations affecting a dossier  
• Different types of variations affecting the same dossier may be grouped
within one variation application
– No fees charged to date     
not enyoyed by applicants within the parent EU-system
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
General considerations for variation applications (I)
– Justification/background why changes need to be
introduced
– Comparison of „present/prequalified“ and „proposed“
state in tabular format (transparency)
– “ Replacement of the relevant pages of the dossier
according to the structure listed in the PQIF “
Parts of the dossier that are affected by the variation need to be
resubmitted according to the structure of the pharmaceutical quality
information form (PQIF)
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Example for „Justification/Background“
– „Replacement of an excipient with a comparable
excipient“
• In order to avoid incompatibilities of magnesium stearate
with ethambutol-HCl we intend to exchange magnesium
stearate with stearic acid
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 „Justification for using variable „types of equipment“
 We are using different
types of umbrellas
for protection against
light as they have
proven to
perform „equivalently“
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Example for a „Comparative Table“ (replacement of Mg stearate)
Present
3.2.P.2 Pharmaceutical development
as is
Proposed
- Comparability of the replaced excipient is
demonstrated
- Comparative dissolution profiles of batches with old
and new excipient presented
- Justification for not submitting a new bioequivalence
study provided
- No interference with finished product test method
observed
3.2.P.3.2 Batch formula
as is
- The new composition is presented
3.2.P.4 Control of Excipients
as is
- CoA of stearic acid attached together with a copy of
the monograph and data on TSE-safety
3.2.P.5 Control of FPP
as is
- CoAs of three batches are presented
3.2.P.8 Stability
as is
- Stability studies with three production scale batches
were started
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
General considerations for variation applications (II)
 Consequentiality
– SmPC consequentially needs to be changed, if affected by
the change
• e.g. change in pharmaceutical attributes listed in the SmPC/container
label (manufacturing site, container material, excipients etc.)
– Additional variation applications to be filed if „effected“ by the
original variation application
• e.g. change in manufacturing site may necessitate adaptation of batch
size due to equipment needs
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Specific considerations
– Conditions frame a particular variation
– In case all conditions are met the variation is considered
minor
– In case one of all conditions is not met the variation is
considered major
Documentation requirements beyond those of Variation Guide
Essential to clarify whether the conditions are met
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Condition No. 1:
– You must proceed at a minimum velocity of 30 miles/hour
It is essential to clarify whether the conditions are met
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
 Experience with the Variation Guide in PQ
– Variations that are “minor in nature” are classified major
because they are “not listed as minor” variations
– Only few types of variation predominantly occur
 Potential future perspective
– Complementary parts of the SUPAC-Guidelines may be
adopted
– Experience with annual reports from requalification
– Variations within design space require that FPPs are
prequalified based on design space
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Examples
 Notifications
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
4
Change in the name and/or address of the
Conditions to be
manufacturer of the finished pharmaceutical product
fulfilled
1
Conditions
- 1 The manufacturing site remains the same
Documentation
- 1…, - 2…
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Birgit Schmauser | April 2008
Documentation
to be supplied
1, 2
N
Dossier maintenance including Variations
9
Change in batch size of API or intermediate
Conditions to be Documentation
fulfilled
to be supplied
a)
Up to 10-fold increase compared to the
prequalified batch size
1, 2, 3
1, 2
N
b)
Downscaling
1, 2, 3, 4
1, 2
N
c)
More than 10-fold increase compared to the
prequalified batch size
1, 2, 3
1, 3, 4
Conditions
-1 No changes to the manufacturing methods other than those necessitated by scale-up,
e.g. use of different sized equipment
-2 Test results of at least two batches according to the specifications should be available
for the proposed batch size
-3 The change does not affect the reproducibility of the process
-4 The change should not be the result of unexpected events arising during manufacture or
because of stability concerns
Documentation (-1…, -2…, -3…, -4…)
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Examples
 Minor changes
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
26
Change in the qualitative and/or quantitative
composition of the immediate packaging
material
Conditions Documentation
to be fulfilled to be supplied
a)
Semisolid and liquid pharmaceutical forms
1, 2, 3, 4
1, 2, 3, 4, 5
b)
All other pharmaceutical forms
1, 2, 3, 4
1, 4, 5
1, 3, 4
1, 2, 3, 4, 5
N
Conditions
1- The product concerned is not a sterile product
2- The packaging type and material remain the same (e.g. a different blister, but same type)
3- The relevant properties of the proposed packaging material must be at least equivalent to
those of the prequalified material
4- Relevant stability studies with the relevant guidelines have been started with at least two pilotscale or production scale batches, and at least three months´ stability data are at the
disposal of the applicant. Assurance is given that these studies will be finalised and that the
data will be provided immediately to WHO if outside specifications or potentially outside
specifications at the end of the prequalified shelf life (with proposed action)
Documentation (-1…, -2…, -3…, -4…, -5…)
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
26
Change in the qualitative and/or quantitative
composition of the immediate packaging
material
Conditions Documentation
to be fulfilled to be supplied
a)
Semisolid and liquid pharmaceutical forms
1, 2, 3, 4
1, 2, 3, 4, 5
b)
All other pharmaceutical forms
1, 2, 3, 4
1, 4, 5
1, 3, 4
1, 2, 3, 4, 5
 All dosage forms
– Sterile FPPs are handled as major variations
 Semisolid and liquid preparations
– Change in type/material of packaging material: major variation
 All other dosage forms
– Change type/material of packaging material: minor variation but extended
documentation requirements (1 – 5)
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Birgit Schmauser | April 2008
N
Dossier maintenance including Variations
12
Change in the manufacturer of the API or
final (ultimate) key intermediate in the
manufacturing process of the API
Conditions to be Documentation
fulfilled
to be supplied
a)
Change in site of the already prequalified
manufacturer (replacement or addition)
1, 2
1, 2, 3, 4, 5
b)
New manufacturer (relacement or addition)
1, 2
1, 2, 3, 4, 5
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 or EU or ICH Guidelines on TSE...”
Documentation (-1…, -2…, -3…, -4…, -5…)
- 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.
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
12
Change in the manufacturer of the API or
final (ultimate) key intermediate in the
manufacturing process of the API
Conditions to be
fulfilled
Documentation
to be supplied
a)
Change in site of the already prequalified
manufacturer (replacement or addition)
1, 2
1, 2, 3, 4, 5
b)
New manufacturer (relacement or addition)
1, 2
1, 2, 3, 4, 5
 How to verify that the specifications/method of preparation/detailed
route of synthesis are the same as those already prequalified?
– Comparison of API-data of prequalified and proposed API-manufacturer by the
FPP-manufacturer
• Available from the API-part of the dossier/OP of APIMFs/DMFs
• Tabular presentation of data (documented evidence)
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Examples
 Major changes
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Appendix 2
 Major changes
– Exceed the scope of minor changes
– Do not yet reach the scope of line extensions
 Most likely the following cases occur:
– Change in the manufacturing process of the API
– Change in the composition of the FPP
– Change to the immediate primary packaging of the FPP
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Appendix 2
 Major changes
– Documentation requirements
• Replacement of particular sections affected by the change
– Generic Guideline
• Potential implications of the change on the FFP
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Appendix 3
 Changes that afford a new application / line extension
– Changes to the API
• Replacement, addition, removal, change of dose
– Changes to the pharmaceutical form / dosage form
• From immediate release to delayed or modified release and vice
versa
• From liquid to powder for reconstitution and vice versa
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Appendix 4
 Stability requirements for changes to prequalified
FFPs
– Scope and design of stability studies for variations based
on knowledge and experience acquired on APIs and FPPs
• Stability profile, supportive data, data on primary batches
– Investigations on potential impact of changes on stability
of API/FPP are at the responsibility of Applicants
– Stability studies required due to changes are to be
continued up to the proposed shelf life
• WHO to be informed on deviations immediately
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Appendix 4
 Minor changes
– Comparison of stability data of the changed product to
stability data of unchanged product
• Evidence of unchanged quality characteristics
 Major changes
– Stability studies depending on
• the nature of the change
• the characteristics of the API/FPP
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Appendix 4
 Major changes
– Changed manufacturing process of API
• Changed quality characteristics of API?
– Changed stability profile of API?
Impacted stability profile of FPP?
– Changed composition/container of FPP
• Critical dosage form or unstable API?
– Changed container of FPP
• Risk of interaction/less protection by packaging?
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
Summary
 Variations to a prequalified product dossier need to be
approved by WHO because they may impact the quality of the
FPP
 Most variations occurring in PQ are reflected in Appendix 1 of
the Variation Guide (minor changes)
 Major changes afford a more thorough documentation
approach and evaluation procedure to ensure unchanged
quality characteristics
 The concept of the Variation Guide reflects a risk-basedapproach
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Birgit Schmauser | April 2008
Dossier maintenance including Variations
THANK YOU
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Birgit Schmauser | April 2008