Post on 15-Jun-2018
Registration of APIs in drug products
USA
Pharmaceuticalpart 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 – Not mandatory
… they have nothing to do with APIs.
Regulatory Trends of API in EU & USA1
2 Regulatory Trends of API in EU & USA
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 *
The LoA does two things: 1) grants the FDA authorization to review
the DMF2) grants the Applicant the right to
incorporate the DMF by reference in their drug dossier.
The Applicant gets a copy of this LoA, the original goes directly to the US FDA.
DMF Holder(API Manufacturer)
Authority
Applicant (Drug Product Manufacturer)
LoAoriginal
LoAcopy
Incorporates LoA copy in the DP application
reviews API dossier
together with the DP application
* similar procedure in the EU: „Letter of Access“
4 Regulatory Trends of API in EU & USA
New requirements
Elemental Impurities Guideline
Fin
ali
ze
d
InternationalICH Q3D: Finalized Dec 2014Transitional period ≥36 M for exist. products
EU: June 2016 new DP Dec 2017 existing DP US: published as FDA document in Sep 2015 - expected to be applied to new DP as of June 2016
Japan: implements from April 2017
• Prepare a risk assessment• Develop risk based controls for Elemental Impurities• Consider max daily dose and route of administration of drug product
Scope of
ICH Q3D
Elements added intentionally(reagents, catalysts)
Elements introduced by interaction (e.g. with process materials, equipment or container closure system)
Elemental impurities may occur naturally
(e.g. starting materials from natural sources – mined excipients)
Specified, unless removed
consistently
Natural Sources: Added by Interaction:
Impurity profile Risk
Assessment
5
ICH Q3D covers all potential sources of contamination with elements (metals) in the drug product.
Elemental Impurities - Scope of ICH Q3D Guideline
Impurity profile Risk Assessment
Regulatory Trends of API in EU & USA
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
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
Regulatory Trends of API in EU & USA6
Elemental Impurities
Filing expectations for API
Elemental Impurity Risk Assessment
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 to update DMFs (first annual report after ICH Q3D implementation)
USA
Regulators encourageto use ASMF or CEP procedures to supply information
EU
Regulatory Trends of API in EU & USA7
Regulatory Trends of API in EU & USA9
Focus USA
GDUFA - Generic Drug User Fee Amendments
2012: Tremendous Backlog in Generic Drug approval
Missing resources (reviewers and inspectors, >900 FTEs)
Industry: $1.5 billion over 5 years -> US $300 m per year
Submission fee (one-time)
Facility fee (yearly)
Foreign facilities to pay differential of US$ 15 k
Designed to speed access to generic drugs
Fewer inspections for more compliant manufacturers
Program will lead to “Level Playing Field”
Backlog: Fees: Objective:
1 2 3
ANDA $76,030PAS $38,020DMF $42,170
Facility
Domestic API $40,867Foreign API $55,867Domestic FDF $243,905Foreign FDF $258,905
10 Regulatory Trends of API in EU & USA
• Pay DMF fee at least 6 months prior to submission of the ANDA (prior to first LoA issuance for generic drug product)
• Useful checklist for DMF completeness
• Formal + Content aspects
• CA does not replace the full scientific review
Procedure:
• Positive: DMFs found complete will be identified on FDA’s public Web site
• Negative: Incomplete letter to DMF holder and authorized party
• Submit amendment to correct deficiencies
• Resubmit a complete update
Outcome:
Finalized Guidance
Completeness Assessment
How We Support?
GMP Compliance
• API – ICH Q7A GMP• Excipients – EXCiPACTTM GMP/GDP Certificate, audit report
Emprove® Dossier - Excipients• Support customers with EMPROVE® dossier for excipients to easy customer’s registration process.
• CTD format, self assessments, declaration, certificate, elemental impurity, residual solvents
Emprove API• EU Directive 2011/62• CEP/ASMF of EMEA, DMF of US FDA• Site acknowledged with US FDA, GDUFA fee paid
Multi-compendial compliance
Quality Agreements, Change control agreements
Merck Life Science – Your partner for effective risk mitigation