EU and US Procedures for API Registration - Commonalities and Differences

The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
API
Registration
Pharma and Food Materials
Regulatory Management
Life Science
EU and US Procedures for API Registration -
Commonalities and Differences

The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

Agenda
1
2
3
Introduction
Common requirements
Overview EU
Overview US
4
5
Special Aspects
Elemental imp., Watch outs,
Fees, Submission roadmap
Takeaways

ICH – International Conference on Harmonization
agreed on a harmonized format to present data for
drug product submission:
Common Technical Document (CTD)
API information presented in
 Module 1: regional information
 Module 2: Summaries
 Module 3: Quality
CTD – Harmonized Format
API Registration-Part of Drug Product Registration
Structure of CTD
Module 1
Module 3 Module 4 Module 5
2.1
2.2
2.3
2.4 2.5
2.6 2.7
1.0
Quality
Nonclinical
Study Reports
Clinical
Study Reports
ICH M4 Guideline
 individual
 harmonized
European
Union
United States Japan
API Registration Requirements | 31 Oct 20195

Harmonized Format and Pictures
Focus on CTD Module 3: Quality
Description of API quality is embedded in the overall Quality Module
S1 General Information
S2 Manufacture
S3 Characterization
S4 Control of Drug Substance
S5 Reference Materials
S6 Container Closure System
S7 Stability
3.1 Table of contents
3.2 Body of data
S Drug substance
P Drug product
A Appendices
R Regional information
3.3 Key Literature References

Registration of APIs in Drug Products
USA
Pharmaceutical
part of drug
dossier
(Module 1, 2 & 3)
US-DMF
Type II
European Union
Pharmaceutical
part of drug
dossier
(Module 1, 2 & 3)
ASMF (European DMF) CEP
Applicants part
(open part)
Restricted
part
(closed part)
CEP
Certificate
of Suitability
European
Pharmacopoeia

API –
Registration
Requirements
EU

Focus Europe
Three types of information
possible:
1. pharmaceutical part of a drug
product dossier.
Europe
Pharmaceutical
part of drug
dossier
(Module 2 & 3)
Applicants part
(open part)
Restricted part
(closed part)
CEP
Certificate
of Suitability
No.

Focus Europe
2. ASMF
Active Substance Master File,
 contains the same information
for the API as Module 2 & 3 of
the drug dossier.
 applicants part, also known as
open part, and a
 restricted part, also known as
closed part.
 The restricted part contains
core know-how and is not
provided to the applicant, but
only to the authorities.
Europe
Pharmaceutical
part of drug
dossier
(Module 2 & 3)
Applicants part
(open part)
Restricted part
(closed part)
CEP
Certificate
of Suitability
No.

Focus Europe
3. CEP or
Certificate of Suitability to the
monographs of the European
Pharmacopoeia.
 Requires Ph. Eur. substance
monograph
 Certifies that the quality of an
API can be suitably controlled by
the relevant monograph
 Provides additional acceptance
criteria as required
 Dossier content confidential
 Certificate shared with applicant
Europe
Pharmaceutical
part of drug
dossier
(Module 2 & 3)
Applicants part
(open part)
Restricted part
(closed part)
Certificate
(= positive
assessment)
content
Regardless of which kind of
submission is chosen, the basic
information is the same.
CEP
Certificate
of Suitability
No.

Certificate of Suitability to the Monographs of the European
Pharmacopoeia
CEP Types
Certificate of chemical purity /
microbiological quality
Certificate for herbal drugs and
herbal drug preparations
TSE Certificate
“Herbal CEP” “TSE CEP”
1 2 3
“Chemical CEP”
CAUTION:
Often Confusion due to fact that there is more than one type of “CEP”

Pharmacopoeia
CEP Types
Certificate of chemical purity /
microbiological quality
Certificate for herbal drugs and
herbal drug preparations
TSE Certificate
“Herbal CEP” “TSE CEP”
1 2 3
“Chemical CEP”
Specific Ph. Eur. monograph required
 Certifies that the quality can be suitably controlled by
− the specific Ph. Eur. Monograph and
− the certified additional acceptance criteria (if needed)
 Evaluation based on the specific data supplied by the manufacturer
 GMP declaration required (for each manufacturing site)
General monograph on
products with TSE risk
 Demonstrates compliance to
the general Monograph 1438
PRODUCTS WITH RISK OF
TRANSMITTING AGENTS OF ANIMAL
SPONGIFORM ENCEPHALOPATHIES
 Only for products with TSE risk
 Specific Ph. Eur. monograph for
the substance not necessary

Pharmacopoeia
Searchable on the EDQM Website
https://extranet.edqm.eu/publications/recherches_CEP.shtml
Example of returned information

The CEP procedure is not intended for:
Out of Scope
CEP -
Out of
scope
No batch certificate
 A CEP is not for compliance of
certification of batches
Not for Biologicals
 The CEP procedure is not
applicable to Biological
substances
No GMP certificate
 A CEP is not a GMP certificate,
nor does it replace it.
 The applicant submits a self
declaration to apply GMP
 Inspection is not a prerequisite
TSE CEP ≠ quality certification
 A TSE CEP does not certify that
the quality of the substance is
suitably controlled by a specific
monograph

How to make CEP dossier available for Drug Product assessment?
CEP Declaration of Access
If an Applicant wants to develop a drug
product using the API
 On a CEP copy the CEP holder will fill in
the Declaration of Access *
The Declaration
1) grants the authority access to review the
CEP dossier
2) grants the Applicant the right to
incorporate the CEP in their drug dossier.
3) Certifies that no changes to the
operations have been made since the
latest version of the CEP
CEP Holder
(API Manufacturer)
Authority
Applicant
(Drug Product
Manufacturer)
authorized
CEP
(Filled CEP copy)
Incorporates
authorized CEP
in the DP
application
➔ May rely on the CEP
or review the dossier
together with the DP
application
* also referred to as “authorized CEP”

CEPs are widely accepted
Member States of the Ph. Eur. Convention
CEP acceptance
 38 member states of the
Convention on the Elaboration of a
European Pharmacopoeia
 Others states, at the discretion of
the authorities in those countries
(e.g. Canada, Australia, New
Zealand, Morocco, Tunisia, Saudi
Arabia, South Africa, S. Korea, …),
- additional documents may be
required
Source: https://www.edqm.eu/sites/default/files/medias/images/maps/europe-carte-membres-observateurs-
bilingues_the_republic_of_north_macedonia.png
https://www.edqm.eu/en

Centralized
Assessment
No different dossier
versions in various
countries.
Advantages
of the CEP Procedure
Transparent
Lifecycle
CEP coding: information
about renewal and
revision status.
Simplified
Variation
Procedure
For the MAH:
Processing of CEP
revisions/renewals are
minor variations
(administrative, type IA)
Convenient
for MAH, drug product
and API manufacturer.

Differences between CEP and ASMF
CEP
ASMF
Chemical CEP / Herbal CEP
 pharmacopoeial substances only,
 active substances or excipients
TSE CEP
 any substance
with TSE risk
Active substances only
 New or pharmacopoeial
 Not applicable to excipients

20
Summary
CEP - ASMF
Scope
Competent authority
Make dossier available
for DP assessment
Assessment of dossier
Applicant gets
chemical / herbal:
Ph. Eur. monograph
CEP
EDQM
Stand alone
Declaration of Access:
enter Applicant & DP in access
box of the certificate
CEP, incl. annex(es)
National Authority/EMA
(corresponding to DP)
ASMF
Letter of Access (LoA)
Combined with DP
API (new / existing)
Applicant’s Part

API –
Regulatory
Requirements
US

Registration of APIs in drug products
USA
Pharmaceutical
part of drug
dossier
(CMC Section)
US-DMF
Type II
Europe
Pharmaceutical
part of drug
dossier
(Module 2 & 3)
Open part
(applicants part)
Closed part
(restricted part)
CEP
Certificate
of Suitability
European
Pharmacopoeia

Registration of APIs in drug products
USA
Pharmaceutical
part of drug
dossier
(Module 1, 2, 3)
US-DMF
Type II
USA:
1. pharmaceutical part of a drug
product dossier.
2. US-DMF Type II
Drug substance, intermediates, or
materials used in their preparation
Only the DMF Type II refers to APIs.
There are other DMF-types ...
e.g. Type III: Packaging material
Type IV: Excipients
Type V: Manufacturing site, etc.
… they have nothing to do with APIs.

How to make API dossier available for Drug Product assessment?
Letter of Authorization (US)
If an Applicant wants to develop a drug
product using the API
 the DMF holder will issue a
Letter of Authorization (LoA)*
The LoA does two things:
1) grants the FDA authorization to review
the DMF
2) grants the Applicant the right to
incorporate the DMF by reference in
their drug dossier
The Applicant gets a copy of this LoA and
the FDA obtains a copy via electronic
gateway
DMF Holder
(API Manufacturer)
Authority
Applicant
(Drug Product
Manufacturer)
LoA
addressed
to FDA
LoA
copy
Incorporates
LoA copy in the
DP application
➔ reviews API dossier
together with the
DP application
* similar procedure in the EU for ASMFs: „Letter of Access“ - Both Letter of
Authorization (US) and Letter of Access (EU) are commonly called “LoAs”API Registration Requirements | 31 Oct 201924

Specific to the United States
Highlighting Differences with EU requirements
 .
Regional Information
Module 1
Procedural
Specifics
Other registration
requirements
1 2 3
Include
Environmental
Assessment
Submit Product Label
with storage conditions
+ expiry/retest date
Contact name of
on-site individual
Appoint US Agent for
submission (foreign DMF
holders)
Annual Report
FDA Inspection
Drug
Establishment
registrations
GDUFA self-identification
and GDUFA fees for APIs
in generic drug products

Special aspects:
- Elemental Impurities
- Watch outs
- Fees, submission roadmap

New requirements
Elemental Impurities Guideline
Finalized
International ICH Q3D: Finalized Dec 2014
EU: June 2016 new DP - Dec 2017 existing DP
US: published as FDA document in Sept. 2015
- Applicalbe to new DP as of June 2016
Japan: implemented April 2017
 Prepare a risk assessment
 Develop risk based controls for Elemental Impurities
 Consider max daily dose and route of administration of drug product

Water,
solvents
Perspective of drug product manufacturer
Risk Assessment For the Drug Product perspective of drug
pr manufacturer
Elemental impurities
in drug product
Drug
substance
(API)
Manufacturing
equipment
Excipient 1
Primary
packaging
material
Excipient 2
source
materials
source
environment
materials
manufacturing
process
manufacturing
process
environment
most likely
sources
Lower risk
Risk Assessment for Elemental Impurities

Elemental Impurities
Filing expectations for APIs
Elemental
Impurities Risk
Management
Summary in the file
Component Approach
 Risk assessment at the
level of the substance
Consider contributions from
manufacturing
 Catalysts/reagents,
 Raw materials,
 Process
Update of
 Impurity profile (3.2.S.3.2)
 Justification of Specification
(3.2.S.4.5)
If required, include test method
and validation for controlled EI
FDA expects updates to
DMFs (first annual report
after ICH Q3D
implementation)
USA
Regulators encourage
to use ASMF or CEP
procedures to supply
information
EU

Outcome of the Risk Management Summary in the CEP Annex
Elemental Impurities Information
API for dermatological DP for
topical application
 max daily dose possibly
exceeding 10 g
Elemental
Impurities
Provision of a Risk
Management Summary
is optional,
If provided, the
necessary information
is appended to the CEP
 level of
contamination
 Route of
administration
API for oral or parenteral
application
 max daily dose ≤ 10 g

CEP users’ perspective
Watch outs for CEPs
Retest Period
Provision of a Risk Management Summary on Elemental Impurities
is optional. CEP containing this information support the EI risk
assessment for the drug product.
Accepted test methods: included in the CEP annex (e.g. tests for
residual solvents or additional related substances)
Older CEPs (issued before September 2011) might not include
information about packaging materials.
Submission of stability studies is not a requirement for CEP
applications. If not included, stability data for APIs need to be
provided (or developed).
Container Closure System
Additional Controls

Fees for registration, application
Costs
 New applications from 5000 €
for simple chemical certificate
 Revision fees from 1000 € to
3000 €
 New MF registration = $1,248
 MF update = $541
 Letter of access = $176
 2019 GDUFA for generic APIs:
 Application fee* for Type II
DMF = $55,013
*application fees are paid upon first
submission and only paid once
Health Canada
DMFs
FDA
API DMFs1 2 3
CEP Certificate
of Suitability
Applications
33

Electronic Submissions Gateway (ESG)
 Central transmission point for sending
information electronically to the FDA
 Agency-wide solution for accepting
electronic regulatory submissions.
 eCTD is the standard and accepted
electronic format for DMFs
E-submission Roadmap
Electronic Submission Gateways
eSubmission Gateway and eSubmission Web
Client
 Secure submission of regulatory information to
National Competent Authorities and EMA.
 support all types of applications for human and
veterinary medicines
 The use is mandatory
http://esubmission.ema.europa.eu/esubmission.htmlhttps://www.fda.gov/industry/electronic-submissions-gateway
Common European Submission
Portal (CESP)
 Portal to submit electronic documents to
EDQM via a secure gateway
https://www.edqm.eu/sites/default/files/pa_ph_cep_13_67_2r.pdf
FDA EMA
EDQM

End of Paper Submissions
eCTD Roadmap
EU authorities and US FDA set binding timelines for eCTD submissions
Rough overview:
Procedure 2016 2017 2018 2019-2020
ASMF*
CEP
US-DMF
EDQM
EMA (human DP)
May 2018: eCTD for all
Binding guidance requires e-submission of
NDAs, ANDAs, BLAs and DMFs in eCTD format
US-FDA
eCTD only for all
CP human ASMF
submissions
eCTD only for new MAA’s
in MRP
no paper submissions
for new CEP applications
2020: eCTD only
for all CEP
applications
2018 Q1: eCTD only for all EU submissions
eCTD only for new
MAA‘s in DCP
*Are expected to follow the format of the DP submission
eCTD only
for new CEP applications
No pdf revisions/renewals,
only NeeS or eCTD

Advantages of eCTD submissions
Adaptable
XML
back-
bone
eCTDFast Navigation
Transparent
Life
cycle
6
5
4
Allows use of documents for
submission in other regions
Immediate receipt of
submission via
e-submission gateway
Search functionality +
tracking ability for entire
submission
37
1
2
3
Allows agencies to view
dossier in cumulative fashion
Improves Reviewer‘s
efficiency
Easy to track previous
document versions
 Improved archiving
Living dossier
Accessibility to
documents across
modules
Hyperlinks

Takeaways
Submission Types for API
information
LoA Process to make API
information available
CEP (chemical)
Special Aspects
 2 Types in US: DMF type II,
 3 Types in Europe: ASMF, CEP,
 Letter of Authorization (US-DMF), Letter of Access (EU-ASMF)
 Declaration of Access for CEPs
 Certifies that the quality can be suitably controlled by the Ph. Eur.
monograph + the additional criteria outlined in the certificate
 Advantageous procedure for pharmacopoeial APIs
 EU and US regulators encourage to supply useful information about
the API for the DP risk assessment
 Fee structures across regions differ significantly
 The long roadmap for eCTD comes to a close with implementation
imminent for 2020
or full CMC part in DP dossier

Thank You!
Questions?

Head of Pharma Registrations
Pharma and Food Materials
Life Science | Regulatory Management
bretta.lichtenhan@milliporesigma.com
Dr. Ulrich Reichert, M.D.R.A.
Head of Pharma and Food Materials
Life Science | Regulatory Management
ulrich.reichert@emdgroup.com
Bretta Lichtenhan
Ulrich Reichert
The vibrant M is trademark of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners. Detailed information on trademarks
is available via publicly accessible resources.
© 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

EU and US Procedures for API Registration - Commonalities and Differences

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