Transcript Concent application

Content of the
application for a CEP
Hélène BRUGUERA
Deputy Head
Certification of Substances Division
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
1
Send an application to EDQM
•
Process to obtain a CEP: outlined in
Resolution AP-CSP(07) 1
•
“Content of the dossier”:
–
–
•
Chemical purity (revised May 2007)
TSE risk
See docs on web site www.edqm.eu
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EDQM, Council of Europe
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How long does it take?
• Timeframes:
– Applicant notified by EDQM on the assessment
conclusion
• Within 5 months of receipt of new dossier
• Within 4 months of receipt of additional information
– Responses expected
• within 6 months for original demand
• within 3 month for any subsequent demand
– Responses assessed within 4 months
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The situation
• Mean time to obtain a CEP (chemical): 20
months
• 3% of CEPs obtained after 1st evaluation
• 70% of CEPs: 2-3 rounds
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
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How can I speed up the granting
of my CEP for chemical purity ?
•
•
•
•
Send a complete application
Submit a good technical documentation
Prepare a good QOS
Hints
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
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Send a complete application
• Application form (for new application)
www.edqm.eu
• Dossier in English preferably (or
French); 1 copy;
• Quality Overall Summary
(electronic+paper)
• Samples of 1 or 2 commercial batches
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At receipt
• Validation of application: check of completeness
• If application receivable: dossier nr allocated + clock
start
• New applications blocked if deficient:
– Missing pieces (form, declarations, dossier,…)
– Technical reasons:
• Refer to the current Ph. Eur monograph
• Description of route of synthesis and/or impurity profile of
the starting material
• Use of Class I solvents without proper justification and
control
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• Technical reasons (cont)
– Suitable information on impurities, solvents,…
– Presence of validation data
– Quantitative method to replace a non-specific TLC
test of the monograph
– Sterile substances: validation of the sterilisation
• If application not receivable: dossier nr allocated but
clock does not start. The company has 6 months to
submit info + clock start
• 30% of new applications blocked in 2007 (most of
them unblocked)
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
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How can I speed up the granting
of a CEP for chemical purity ?
•
•
•
•
Send a complete application
Submit a good technical documentation
Prepare a good QOS
Hints
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
9
Administrative info (applic.
form)
• Name and addresses of the parties involved (all
sites)
• Declarations (GMP, Willingness to be inspected, Use
of animal (TSE risk or other origin) / human material)
• History of the substance (give details)
• Retest period requested ?
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Technical documentation
• PA/PH/CEP (04) 1: Content of dossier for chemical
purity
• <=> 3.2.S of CTD
– General information
– Route of synthesis
– Impurities, solvents, catalysts
– Control of the substance (specification and
methods)
– Analytical validation-suitability of the monograph
– (Stability is optional)
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3.2.S.2.2 Manufacturing Process
•
•
•
•
Flow chart
Detailed description of the process, including
quantities
Maximum/typical batch size and yields
Describe any reprocessing/recovery of materials
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Semi-synthetic products:
 Fermentation steps involved in synthesis of starting material
– Characterisation of fermented starting material, incl. detailed
impurity profile, compliance with the general monograph
1468
– Carry-over of fermentation impurities
– Use TSE risk substances in manufacture?
• Different sites, different manufacturing methods or
alternatives, reprocessing, in one dossier:
– impurity profile of final substance unchanged
– detailed information
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3.2.S.2.3 Control of Materials
• Starting materials:
TOP 2 deficiency in 2007
– Propose and justify which substance(s) is the starting
material(s) e.g. incorporated as a significant structural
fragment into the structure of the final substance. Is the
substance purchased or manufactured in-house ?
– Short steps synthesis: description of its route of
synthesis, and detailed impurity profile (related
substances, reagents, solvents, catalysts)
– Suitable specifications - limits for impurities, solvents,…
– Description of carry-over of its impurities to the final
substance
– Where more than one supplier is used batch results for the
final substance manufactured from the different suppliers
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3.2.S.2.3 Control of Materials
• Describe specifications for all reagents,
solvents used
– Purity tests for solvents (e.g benzene in toluene, acetone,
ethanol)
– Specifications for pure and recovered solvents
– Quality of water
• Include specification of recovered materials if
any
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3.2.S.3.2 Impurities
Need to address:
•
•
•
•
Organic impurities
Inorganic impurities (catalysts,…)
Residual solvents
Genotoxic impurities
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3.2.S.3.2 Organic impurities
• Discussion on impurities should cover:
– Potential impurities, origin, correspondence with
transparency list of the monograph and individual
impurity results
– Use of monograph nomenclature or correlation
with monograph nomenclature required
– Which impurities are actually present? Levels
found in production batches (actual data needed) chromatograms
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Organic impurities (cont)
Need to address:
• Suitability of the method(s) of the
monograph for the detection of all
impurities present in the material
• If the monograph is not suitable then
need to supplement it with an additional
(validated!) method
• Set appropriate limits
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3.2.S.3.2 Residual solvents
 ICH guideline Q3C
 CPMP Concept paper (2003)
• Data for ALL solvents used during synthesis (incl.
1st steps)
• Batch results + typical chromatograms
• Solvents likely to be present/used in the last
steps
• justified limits (ICH or lower)
• validated test methods
• mentioned on CEP (+ method appended)
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3.2.S.3.2 Other impurities
• Demonstrate the absence of particular
reagents in the final substance or set a limit
• Demonstrate absence of residues of catalysts
or set a limit
– EMEA draft guideline on catalysts
(CPMP/SWP/4446/00)
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3.2.S.3.2 Genotoxic impurities
TOP 1 Question in 2007
• Cf NfG CPMP/SWP/5199/02 since 01/2007
• Applicable to:
• substances not yet marketed in Europe
• new routes of synthesis
• Specific discussion with regard to genotoxic
impurities:
• Look for potential genotoxicity (structural alerts)
• Consult literature and databases
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GTI (cont)
• Principles:
– Data available on maximal exposure
– TTC approach (1.5 g/day)
– Tox tests (AMES)
• Analytical (sensitive) methods to show residual levels
• Demonstrate absence (<30% of max exposure or
TTC) or justify a limit
• The use of the substance may be taken into
consideration
==> « Questions and Answers » to be published on
EMEA website
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3.2.S.4 Control of Drug Substance
•
•
•
•
•
Refer to the right monograph and its tests
Include additional/alternative tests if necessary
Use quantitative method for related substances
Appropriate limits for impurities, solvents,…in
accordance with the process and relevant guidelines
- General monograph 2034
Adequate methods description -> format to be
appended to the CEP
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3.2.S.4 Control of Drug Substance
For monographs which still include a
non-specific & non-quantitative TLC method:
suitably validated QUANTITATIVE method for related
substances & suitable limits for impurities to be
proposed in the application
IPA-EDQM Mumbai 11/2007 ©2007
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3.2.S.4 How to set limits for related
substances
• Impurities of the monograph: limits of the monograph
• “Other detectable impurities” of the monograph are known
substances detected by the method but NOT normally present
above the identification threshold from general monograph
(2034).
• Additional impurities (any impurity not on the
transparency list) : apply the general monograph
(2034)
- Individual limits for specified impurities
- Individual limits for identified non-qualified
impurities
- Limit for unspecified impurities
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Limits for related substances
• For products out of the scope of the
general monograph 2034 (antibiotics,
peptides,…):
– Characterise the impurity profile
– Apply the principles of the general monograph
(limits for specified, unspecified, total impurities)
– Propose justified limits (not necessarily ICH Q3A)
 on the CEP
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Qualification of Additional Impurities
• Qualification by use
– History of the product:
– Consistency with manufacturing capability
– Shown to be present in other products
already approved in Europe
• Qualification by toxicological data
• Or limited to qualification/identification
threshold
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3.2.S.4.3 Method validation
• All in-house methods should be validated (incl. nonroutine methods)
ICH Q2B for methodology
Typical chromatograms
• Cross-validation against Ph. Eur methods:
comparative results obtained from the same
samples
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3.2.S.4.4 Batch data
– Should be in line with specification
– Details on batches tested (batch nr, size, dates of
manufacture, analysis)
– Numerical figures (“complies” not appropriate)
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3.2.S.5 Reference Standards or materials
• Use the Ph. Eur. standards (EPCRS) or provide
traceability to these standards and certificates for the
in-house standards used
3.2.S.6 Container closure system
• Provide a description of the commercial packaging
• Provide specification for all materials used
• Reference compliance with appropriate guidelines
(i.e. EMEA CHMP Plastic Primary Packaging
Materials (CPMP/QWP/4359/03))
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3.2.S.7 Stability
Option !
 EMEA guideline “Stability testing of existing active substances”
 EMEA guideline on “Declaration of storage conditions for
medicinal products”
•
•
•
•
ICH conditions incl accelerated
Study description - relevant parameters
Detailed results
Validation of in-house methods (stability
indicating)
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3.2.S.7 Stability
• Proposed retest period and storage conditions:
– In accordance with stability results (real time +
accelerated)
– Extrapolation possible (according to ICH)
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
32
How can I speed up the granting
of a CEP for chemical purity ?
•
•
•
•
Send a complete application
Submit a good technical documentation
Prepare a good QOS
Hints
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
33
The QOS
• QOS = Quality Overall Summary
• Summary of the application highlighting
the key points+suitability of the
monograph
• The expert can be anyone having sufficient
knowledge/experience in the topic, i.e. from
the applicant’s company
• CV of the expert to be appended
IPA-EDQM Mumbai 11/2007 ©2007
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The QOS (cont)
• Use template of QOS available on
EDQM website
– Helps to prepare the QOS
– Helps for the assessment report
• Submit electronic QOS (Word) to
EDQM in addition to paper copy
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
35
How can I speed up the granting
of a CEP for chemical purity ?
•
•
•
•
Send a complete application
Submit a good technical documentation
Prepare a good QOS
Hints
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
36
Hints
• The dossier should be Clear, Concise,
Readable, Obtained from recent data
• The e-QOS should be in line with the dossier
• Follow recommendations described in
“Content of the dossier” + “TOP TEN
deficiencies”
• Technical Advice procedure, workshops,…
• Submit electronic files
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Electronic submissions
Electronic dossier (new appl., revisions,
add info): pdf files welcome
– e-QOS obtained from EDQM template
(Word)
– Paper copies still required if > 10 pages
– Dropbox to exchange files
– EDQM sends requests for info by e-mail
IPA-EDQM Mumbai 11/2007 ©2007
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Additional information
• Submit in time and in 2 parts:
– Questions/Anwers document addressing
all deficiencies. To be submitted
electronically + paper copies
– Updated sections of the dossier as
annexes (electronic + paper)
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And also…
• Timetables noted on the letter of
acknowledgement of receipt
• No AR for additional info, but treated in
time
• Do not contact EDQM before the
expected dates
• No possibility of « special fast track »
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You have got the CEP, it is not
finished….
The CEP has to be maintained through
the Revision system
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Revisions/Renewals of
CEPs
Hélène BRUGUERA
Deputy Head
Certification of Substances Division
IPA-EDQM Mumbai 11/2007 ©2007
EDQM, Council of Europe
43
Basic principles for maintaining a
CEP
• Any change (administrative or
technical) to be reported to EDQM for
approval  Revised CEP granted
• Holder to inform customers and/or authorities with
revised CEP
• Original CEP: valid 5 years. Need to apply for
renewal in time.
• After renewal, CEP valid for an unlimited period,
provided the dossier is kept up-to-date
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Revisions of CEPs:
Background
• Based on EU Regulations on Variations to
Marketing Applications
• Guideline on requirements on revision /
renewal of CEPs (PA/PH/CEP (04) 2)
• New procedures for management of revision /
renewal of CEPs (PA/PH/Exp. CEP/T (04) 18)
• Available on EDQM website
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Guideline on Requirements:
documentation
• Application form (specific for revisions)
• Technical data:
– Justification of change
– Assurance that the conditions are fulfilled
– Updated pages of the dossier
– Specific supporting documents
– COMPARATIVE DATA - Full batch results
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Types of changes
•
•
•
•
•
Notifications
Minor changes
Major changes
Renewal
Update following revision of the
monograph / regulatory change
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Notifications
• Change in holder, manufacturer references: holder
name, address (no move),...
• Change in batch size by ≤ x 10
• Minor changes to test procedures (no changes in
performances - few cases in practice)
• Tightening limits (methods not affected)
• Post-stability commitment data
• Deletion of information from CEP: manuf. site, retest
period, country of origin for TSE
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Notification
Timescales and Fees
• Simple
2 weeks/500 euros
• Multiple (max. 3) 30 days/1000 euros
Workflow:
• No Acknowledgement of Receipt
• Letter sent to advise that either the notifications has been
accepted as valid or has been rejected - No demand for
additional information sent
• Revised CEP only issued when the information on the CEP is
changed (i.e. and address)
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Typical minor changes
• Minor change in manufacture
• Up scaling > x10
• Change in specification (new or replaced test
parameter)
• Change/Addition of manufacturing site
• Change from a TSE risk to a non-TSE risk
material
• Change/Addition of retest period on CEP
IPA-EDQM Mumbai 11/2007 ©2007
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Minor Change
Timescales and Fees
• Single
• Multiple (max. 3)
1 month /1000 euros
2 months /1500 euros
Workflow:
•
•
•
•
•
Acknowledgement of Receipt sent within 5 days
One demand for additional information sent if neccessary
Holder has 30 days to respond to this demand
EDQM has 30 days to evaluate the response
Revised CEP issued or demand for revision rejected
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Major changes
• Any changes not included in the
guideline (or conditions not fulfilled)
• Examples (chemical):
– Introduction of new reagents, solvents
– Alternative process ( Spec of the final substance
identical, otherwise new certificate)
– Process replaced
• Examples (TSE):
– Addition of new source countries or suppliers of
materials
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Major Change
Timescales and Fees
• Single
3 months /1500 euros
• Multiple (max. 3, 1 major) 3 months /1500 euros
Workflow:
•
•
•
•
•
Acknowledgement of Receipt sent within 5 days
One demand for additional information sent if necessary
Holder has 30 days to respond to this demand
DCEP has 30 days to evaluate the response
Revised CEP issued or demand for revision rejected
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Consolidated Revision
Timescales and Fees
• Multiple revisions (> 3)
4 months/2500 euros
Workflow:
•
•
•
•
•
Acknowledgement of Receipt sent within 5 days
One demand for additional information sent if necessary
Holder has 30 days to respond to this demand
DCEP has 30 days to evaluate the response
Revised CEP issued or demand for revision rejected
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Monograph revision
• Revised monographs published 3 times a
year
• EDQM gives instructions to the holders:
– Compliance with the monograph
– Suitability of the monograph
• Timescales and Fees
90 days/No fee
• Revised CEP issued if necessary after
approval
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Renewal
• Holder shall apply about 6 months prior to expiry date
• Declaration that no change occurred or
• Updated dossier (CTD) with comprehensive list of
changes
– General Monograph “Substances for
Pharmaceutical Use”
– Recent European quality guidelines: eg impurities,
residual solvents, residual catalysts
 Not an administrative job!
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Renewal
Timescales and Fees
•
4 months /1500 euros
Workflow:
• Acknowledgement of Receipt sent within 5 days
• 120 days to evaluate the request
• Revised CEP issued, demand for additional information sent or
demand for revision rejected
• If Demand for additional information sent
• Holder has 30 days to respond to this demand
• EDQM has 30 days (90 for TSE) to evaluate the response
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Common deficiencies
• Change in the analytical method: N7/R3
• Replacement of a solvent: Major
• Change of strain in fermentation
process: Major
• New supplier of starting material when
route of synthesis is not identical: Major
• Alternative process: if the specs are
changed : New application
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What to do with a revised CEP
• CEP ref number incremented
– RX-CEP 2007-001-Rev YY
• Provide a copy to customers
• Update of relevant Marketing
Applications  Type IA variation in
most cases
(cf. European regulations)
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 Thank you !
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