Meredith Ge

Head of Regulatory Management APAC, Merck Life Science

Oct 28th, 2016 Bangkok, Thailand

US & EU

REGULATORY TRENDS OF API AND EXCIPIENTS

Introduction of Industry Guidelines on API and Excipients

EU

• 1.1 Falsified Medicines Directive

• 1.2 Formalized Guidline on Risk Assessment for Excipients

• 1.3 EXCiPACTTM & Rx 360 Consortium

• 1.4 CEP/ASMF

US

• 2.1 USP Elemental Impurtities

• 2.2 DMF

• 2.3 GDUFA

Agenda

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EUROPE

FALSIFIED MEDICINES DIRECTIVE

Directive on Falsified Medicinal Products – 2011/62/EU is an amendment of the Directive 2001/83/EC, regulating medicines in Europe

Designed to prevent the infiltration of fake medicinal products within the legal distribution chain in Europe

EU Falsified Medicines Directive Directive 2011/62/EU*

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*Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products

Regulatory Trends of API in EU & USA

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Safety Features

• Safety features on prescription and critical non-prescription products

• To verify authenticity, and identify individual packs

• QP has to ensure safety features are affixed

• Delegated acts setting out detailed rules

• Technical specification of safety features to be defined

• Tracking system to be defined

Supply Chain & GDP

• New Draft GDP Guide -Manufacturers,

• Distributors and brokers have to be registered

• Distributors and brokers need to have Quality System

• Improved product recall or withdrawal system

• Expanded to to recall medicinal products from patients

• Patient and consumer organisations to be kept informed about enforcement activities

• Obligation to inform authority and MAH immediately if any suspicion of products being falsified

API & Excipient Control

• New “QP Declaration“ Template

• New GMPs for APIs? Delegated acts concerning GMP and GDP for active substances

• APIs imported only if standards of GMP at least equivalent to EU

• Mandatory audits of manufacturers and distributors GMP & GDP

• List of foreign countries with GMP equivalent to EU

• GMP to be applied for excipients based on risk assessment

• Regulation to be developed by EU Commission

Internet Sales

• Combat illegal sale of medicinal products via Internet

• Awareness campaigns

• Common logo

• Websites should be linked to authority websites

• List of Internet salers –nationally and on an EU basis

EU Falsified Medicines Directive | Directive 2011/62/EU – the 4 Pillars

Regulatory Trends of API in EU & USA

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Compliance to EU GMP Guide, Part II (ICH Q7)

Manufacturers of active substances for use in medicines must follow EU standard GMP, regardless whether the substances are produced in the EU or imported from third countries

Registration

Importers, manufacturers and distributors of active substances must be registered with the relevant competent authority as a broker of medicinal products

Verification

Drug manufacturers must verify that their suppliers comply

with GMP and GDP (good distribution practices).

New Requirements for API Suppliers

Regulatory Trends of API in EU & USA

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Directive 2011/62/EU

Active substances shall only be imported if, inter alia, the active substances are accompanied by a written confirmation from the competent authority of the exporting third country which … confirms that the standards of good manufacturing practice and control of the plant are equivalent to those in the EU.

“White list”

The requirement of a written confirmation is waived for third countries listed on a waiver list by the European Commission (Switzerland has been adopted).

As part of this, the commission is to establish a list of foreign countries with GMP systems equivalent to those of the EU.

Final version of the Template has been issued in July 2012

“Written confirmation” for APIs

Regulatory Trends of API in EU & USA

EUROPE

FORMALIZED GUIDLINE ON RISK ASSESSMENT OF EXCIPIENTS GMP

What is the challenge dealing with excipients?

Different source

Petrochemicals

Fine Chemicals

Agriculture

Minerals

Animal Origin

Biotechnology

Different compliance standards and focus of the manufacturer

• ISO 9001:2008• EXCiPACT• EU GMP for APIs (Eudralex vol IV

part 2)• 21 CFR parts 210 and 211/ • HACCP • GMP for finished pharmaceuticals

Evolution of Excipients GMP & The Third Party Audit9

Current Challenges

Good Manufacturing practice (GMP) in bothEurope and the USA are only for ActivePharmaceutical Ingredients (API)

However, excipients pose asmuch of a hazard to the end

patient as the API

Excipients have no such legal requirement!

Due to the globalization of thePharmaceutical Industry the supply chain

is becoming more and more complexSub standard pharmaceutical

raw material on the market

Counterfeit Medicines have resulted in many tragedies

Evolution of Excipients GMP & The Third Party Audit10

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Guidelines on the formalized risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use

(2015/C 95/02)

• Published by the EU Commission March 21, 2015

• Risk assessment be carried out for excipients for authorized medicinal products by March 21, 2016

EU Guideline on Risk Assessment for Excipients

EU Guidelines on the risk assessment for GMP for pharmaceutical excipients

EU Guidelines on the risk assessment for GMP for pharmaceutical excipients

3 important sections

Chapter 2 – Determination of appropriate GMP based on type and use of excipient

Chapter 3 – Determination of excipient manufacturer’s risk profile

Chapter 4 – Confirmation of application of appropriate GMP

EU Guideline on Risk Assessment for Excipients

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Risk Assessment for Excipients

Drug Product Manufacturer

Determine and assess the risks for each excipient

Consider the Application of the Excipient

• Dosage form

- Route of administration

• Functionality

• Potential impact on critical quality

attributes of the drug product

• Quantity, daily intake

Consider Risks from Manufacture / Supply

• Quality Management System

• Contamination potential

- Impurities

- TSE, viral safety

- Microbiological / endotoxin

• Dedicated equipment / facilities

• Environmental control and storage conditions

• Supply chain complexity

EU Guidelines on the risk assessment for GMP for pharmaceutical excipients12