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“

US

USP ELEMENTAL IMPURITIES

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

US

GDUFA

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?

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

Thank you!