Assimetries in technical data for
registration applications in multiple
markets and the advantages of the
standardization based in international
model: CTD/ECTD (ICH)
J Sousa
Coimbra, Portugal
1.Brief notes about EU
2. CTD
3. Type of MA/procedures
4. Evaluation process
5. Strengths/Weaknesses
Summary
1. Brief notes about EU
2. CTD
3. Type of MA/procedures
4. Evaluation process
5. Strengths/Weaknesses
Summary
EU means
27 Member States
500 milion citizens
23 official languages*
4 326 243 Km² (115 hab./km² )
General overview: Brief notes about EU
1993: the Single Market is
completed with the 'four
freedoms': movement of goods,
services, people and money
1995: Schengen’ agreements:
gradually allow people to travel
without having their passports
checked at the borders
General overview: Brief notes about EU
A brief history…
There are no importations/exportations within UE;
Once released in EEA, batches are allowed all over the UE;
Mutual Recognition Agreements
General overview: Brief notes about EU
This means that:
Decentralized Agency comes
into operation
European Medicines Agency (EMA)
Main responsibility: protection and promotion of public and
animal health, through the evaluation and supervision of
medicines for human and veterinary use
Decentralised agencies
scientific evaluation of MA applications;
Monitoring the safety of medicines
Stimulate innovation and research in the
pharmaceutical sector
Functions
European Medicines Agency (EMA)
Medicinal Products for Human Use
Pharmacovigilance Risk Assessment
Committee
Medicinal Products for Veterinary Use
Orphan Medicinal Products
Herbal Medicinal Products
Paediatric Committee
Advanced Therapies
Scientific Committees
European Medicines Agency (EMA)
How it works
The Agency brings together the scientific resources
of over 40 national competent authorities in 30 EU
and EEA-EFTA countries in a network of over 4,000
European experts
CHMP* - Committee for Medicinal Products for Human Use
responsible for preparing opinions on questions concerning
medicines for human use
European Medicines Agency (EMA)
CHMP - Working Parties
1. Quality Working Party (QWP)
2. Efficacy Working Party (EWP)
3. Safety Working Party (SWP)
4. ….
The Agency has a number of working parties and related groups,
which can be consulted by the Agency's scientific committees on
scientific issues relating to their particular field of expertise
European Medicines Agency (EMA)
1. Preparation, review and update of quality guidelines;
2. Provision of scientific advice on general and product-specific
matters relating to quality;
3. Resolution of national divergences regarding the assessment of
quality issues;
4. International co-operation on quality-related matters
Quality Working Party (QWP)
European Medicines Agency (EMA)
1.Brief notes about EU
2. CTD
3. Type of procedures
4. Evaluation process
5. Strengths/Weaknesses
Summary
A common format for the technical documentation will
significantly reduce the time and resources used to compile
applications and will ease the preparation of electronic
submissions
CTD
How to solve
Difference in the regulatory requirements in the various
countries, hampers the development of a global regulatory
strategy for MAAs
The problem
Regulatory reviews and communication with the
applicant will be facilitated by a standard document of
common elements
Exchange of regulatory information among regulatory
authorities will be simplified
CTD
Advantages
Through the ICH process, considerable harmonization has
been achieved among the three regions in the technical
requirements for the registration of pharmaceuticals
However, until now, there has been no
harmonization of the organization of a submission
CTD
Each region has its own requirements for the organization
of the technical reports in the submission and for the
preparation of the summaries and tables
Diagrammatic Representation
of the ICH
Common Technical Document
(CTD)
CTD
This module should contain documents specific to each
region.
Content and format can be specified by the relevant
regulatory authorities.
Type and number of annexes: considerable differences
within ICH
CTD
Module 1.
Administrative Information and Prescribing Information
Module 2 should begin with a general introduction
to the pharmaceutical, including its pharmacologic
class, mode of action, and proposed clinical use.
Module 2. Common Technical
Document Summaries
CTD
Module 3. Quality
Information on Quality should be presented in the
structured format described in the guidance M4Q.
Module 4. Nonclinical Study Reports
The Nonclinical Study Reports should be presented in the
order described in the guidance M4S.
Module 5. Clinical Study Reports
The human study reports and related information should be
presented in the order described in the guidance M4E .
CTD
1.Brief notes about EU
2. CTD
3. Type of MA/procedures
4. Evaluation process
5. Strengths/Weaknesses
Summary
Types of MA
Stand alone
Generics
Hybrids
Well established use
…….
Types of procedures
National Procedure
Centralised Procedure
Mutual Recognition Procedure
Decentralised Procedure
National application, for a single country
The MAA must follow the national
regulations and should be submitted to
the Health Authority of that country for
evaluation
Products that fall outside the scope for
a mandatory centralised procedure
Aim for a national license
Marketing Authorisation
Applicable for
National Procedure
Type of procedures
Marketing Authorisation
Community license, from a single application,
a single evaluation and a single authorisation
Evaluated by EMA, through CHMP, where a
(Co-) Rapporteur is appointed among its
members, who performs the scientific
evaluation and prepares an assessment
report to the CHMP
210 + 36 days (normal assessment) or 121-150
days (accelerated assessment), excluding
clock-stops
Centralised Procedure
Type of procedures
Biotechnology medicines
New active substances AIDS,
cancer, neurodegenerative
disorders, diabetes, auto-immune
diseases and/or other immune
dysfunctions and viral diseases
Orphan medicines
Mandatory for
Type of procedures
Centralised Procedure
Significant therapeutic, scientific
or technological innovation
Interest of public or animal health
Aim for all Member States
Applicable for
Generic Drugs
Generics of medicines authorised
via centralised procedure
Public interest
Centralised Procedure
Type of procedures
Marketing Authorisation
MRP among MS of their respective national MA
Product already authorised by one MS in
accordance with the NP is submitted to several
other CMS, A RMS is defined, who evaluates the
MAA dossier and prepares the AR on behalf of
the CMSs, for their analysis and discussion
Type of procedures
Mutual Recognition Procedure
No agreement
90 + 30 days
CMDh intercedes
Already existing national MA
Aim for several countries
Mutual Recognition Procedure
Type of procedures
Applicable for
How others look to your previous
evaluation?
How different would be a 2nd
wave?
National evaluation
Simultaneous authorisations in more than one MS,
for products that haven’t been yet authorised in any
EU MS
The MAA dossier is submitted to the RMS and to the
CMSs in parallel
The RMS prepares a draft AR in consultation with
the CMSs. The AR is the basis for the RMS and
CMSs to agree the terms for the marketing
authorisation
Decentralised Procedure
Types of procedures
No agreement CMDh intercedes
210 – 270 + 30 days (excluding clock-stops)
Marketing Authorisation
Products that fall outside the scope
for a mandatory centralised procedure
Aim for several countries
Applicable for
Types of procedures
Decentralised Procedure
How others look to your PrAR?
How deal with Day 100, 160,…
questions?
National evaluation
1.Brief notes about EU
2. CTD
3. Type of MA/procedures
4. Evaluation process
5. Strengths/Weaknesses
Summary
Different pharmaceutical legislation and regulations among different regions;
Different evaluation process (National calendars);
The Guidelines “open way”;
“Major” versus “minor” concerns
The evaluation process
Drawbacks
The evaluation process
Portugal
Administrative evaluation
Distribution to experts according scientific area
Evaluation
Major objections/points to clarification
Possible 2nd wave of questions
Meeting of CAM
Final decision
1.Brief notes about EU
2. CTD
3. Type of MA/procedures
4. Evaluation process
5. Strengths/Weaknesses
Summary
1. What do we have in common?
2. Why discrepancies still exist?
Strengths/Weaknesses
Two questions araise
Common points
Identical technical framework;
Working Parties
Information share
Quality Guidelines
CTD with only one separate Module
Friendly atmosphere
Technical expert backgroud
The same focus: drug quality
Bounds to harmonization
Major opinion conflicts
3.2.S DRUG SUBSTANCE
1. COS/CEP
2. DMF
3. Ph. Eur. Standard
4. Other Pharmacopeias
5. Other informative sources
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
Does API shows polymorphism?
Is the particle size relevant?
Major opinion conflicts
3.2.S DRUG SUBSTANCE
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Description of Manufacturing Process and Process Controls
What should be enclosed on the restricted part?
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development
Major opinion conflicts
Major opinion conflicts
Starting material
Agency Manufacturer
3.2.S.3 Characterisation
3.2.S.3.1 Elucidation of Structure and other Characteristics
3.2.S.3.2 Impurities
Organic solvents below ICH requirements?
Genotoxic impurities?
Major opinion conflicts
3.2.S.4 Control of Drug Substance
3.2.S.4.1 Specifications (internal, Ph. Eur, others?)
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification
Major opinion conflicts
3.2.S.5 Reference Standards or Materials
Are impurities standard identified?
3.2.S.6 Container Closure System
Is the secondary package funtional?
Major opinion conflicts
3.2.S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
Retest period acceptable?
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
Is commitment accepted if the minimum time is not reached?
3.2.S.7.3 Stability Data
What type of batches have been used?
Major opinion conflicts
3.2.P DRUG PRODUCT
Major opinion conflicts
Ph. Eur. has no finished product monographs
3.2.P DRUG PRODUCT
3.2.P.1 Description and Composition of the Drug Product
Major opinion conflicts
Composition of flavours
Differentiation between strengths
3.2.P.2 Pharmaceutical Development
3.2.P.2.1 Components of the Drug Product
3.2.P.2.1.1 Drug Substance
3.2.P.2.1.2 Excipients
Is there any reason to check mutual compatbility?
Major opinion conflicts
3.2.P.2.2 Drug Product
3.2.P.2.2.1 Formulation Development (Biowaivers)
3.2.P.2.2.2 Overages
3.2.P.2.2.3 Physicochemical and Biological Properties
3.2.P.2.3 Manufacturing Process Development
3.2.P.2.4 Container Closure System
3.2.P.2.5 Microbiological Attributes
3.2.P.2.6 Compatibility (Is the SmPC accordingly?)
3.2.P.2 Pharmaceutical Development
Major opinion conflicts
3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
3.2.P.3.2 Batch Formula
3.2.P.3.3 Description of Manufacturing Process and Process Controls
Is terminal sterilization better than aseptic process?
3.2.P.3.4 Controls of Critical Steps and Intermediates
3.2.P.3.5 Process Validation and/or Evaluation
Is it our formulation critical?
Can I submit a commitement?
Major opinion conflicts
3.2.P.4 Control of Excipients
3.2.P.4.1 Specifications
Are them described in Ph. Eur? And if not?
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of Analytical Procedures
3.2.P.4.4 Justification of Specifications
3.2.P.4.5 Excipients of Human or Animal Origin
3.2.P.4.6 Novel Excipients
Major opinion conflicts
3.2.P.5 Control of Drug Product
3.2.P.5.1 Specification(s)
Divisibility, impurities level, organic solvents,
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
3.2.P.5.4 Batch Analyses
3.2.P.5.5 Characterisation of Impurities
Is it enough cross reference to S part?
3.2.P.5.6 Justification of Specification(s)
Major opinion conflicts
3.2.P.6 Reference Standards or Materials
3.2.P.7 Container Closure System
Major opinion conflicts
3.2.P.8 Stability
3.2.P.8.1 Stability Summary and Conclusion
Bulk stability; in use stability
3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment
3.2.P.8.3 Stability Data
Particular storage conditions
Major opinion conflicts
Type IB/II
What is a “minor manufacturing change”?
Why reduce shelf life?
What is a “minor analytical change”?
Does a composition change mean new BD/BE study?
Major opinion conflicts
Variations
Questions?
Thank you!
