regulatory aspects and impurity profiling of ... · 2/14/2018 bms confidential — for internal use...

BMS Confidential — For Internal Use Only2/14/2018 1

Regulatory Aspects and

Impurity Profiling of Pharmaceutical Products

Dr. Naresh SharmaDeputy Drugs Controller (India)

Indira Gandhi International Airport, Delhi Central Drugs Standard Control Organization (CDSCO) ,

Ministry of Health & Family Welfare, Govt. of India www.cdsco.nic.in

BMS Confidential — For Internal Use Only

Indian Pharmaceutical Industry(Snap Shot)

2/14/2018 2


Indian Pharmaceutical Industry – A Profile

Size of the Industry USD 32 Billion

Export USD 17 Billion

Domestic market USD 15 Billion

Growth Rate 10-12%

Imports USD 5 Billion

Exported to More than 200 countries

Volume of Production 3rd Largest in the world

Value of production 10th in the world2/14/2018 3


Indian Pharmaceutical Industry – A Brief Profile

Type of Manufacturing Unit Number of Units (Approx)

Formulations 4900

Active Pharmaceutical Ingredients 1500

Vaccines 30

Medical Devices 350

Miscellaneous (Surgical dressings, Blood

banks, Disinfectants etc)

2850

Other Industry

Cosmetics 2300

Ayurveda, Unani 4800

Homeopathy 1000

Whole sale and Retails 800,000


Global Presence


Indian pharmaceutical industry – global presence

USFDA Approved sites

(Formulations + API)

262

EDQM approved sites

253

COPP holding sites 1300 (approx)


Exports to different regionsS.No Region % of total exports

1 North America 27

2 EU 18

3 Africa 18

4 Middile East 7

5 Asean 6

6 Latin American Countries

6

7 CIS 6


Central Drugs Standard Control Organisation

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CDSCO H.Q. FDA Bhawan , New Delhi


New Building-CDSCO Mumbai

CDSCO Zonal Offices -Mumbai & Hyderabad

New Building-CDSCO Hyderabad


Mumbai

New Delhi

Chennai

CDSCO North Zone (Ghaziabad)

Kolkata.

CDSCO West Zone (Mumbai)

CDSCO South Zone (Chennai)

CDSCO East Zone (Kolkata)

CDSCO, HQCDSCO – Geographical Location Zonal /Sub Zonal Offic es(11)

Hyderabad

Ahmadabad

Port Offices / Airports : 11Laboratories : 8

29 States

6 Union Territories

CDSCO Zone (Ahmadabad)

CDSCO Zone (Hyderabad)

•Proposed Sub Zonal Offices : Guwahati•Proposed Port Office at Vishakhapattnam

CDSCO Sub Zone (Bangaluru)

Bangaluru

Ghaziabad

CDSCO Sub Zone (Chandigarh)

Chandigarh

Jammu

CDSCO Sub Zone (Jammu) GoaCDSCO Sub Zone (Goa)CDSCO Sub Zone (Indore)

Indore


Drugs is in concurrent list of Indian Constitution

It is governed by both Centre and State Governments under the Drugs & Cosmetics Act, 1940


Legal Enactments to Regulte Import, Manufacture & Sale of Drugs

Drugs and Cosmetics Act,

1940

Drugs and Cosmetics

Rules, 1945 made under the

Act

Drug Price Control Order (DPCO), 1995

Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954


CDSCO

• National Drug Regulatory body• Under Ministry of Health and Family

Welfare• Headed by Drugs Controller General Of

India• On behalf of Central Government• Functional NRA by WHO • Nodal agency for all international activities• Coordination among States2/14/2018 14


Central Drugs Standard Control Organization

Indian Drug Regulatory System: Government of India Ministry of

Health &

Family Welfare

DGHS

Central Drugs

Standard

Control

Organization

(CDSCO)

Ministry of

Science &

Technology

Indian Council

of Medical

Research

(ICMR)

Council of

Scientific &

Industrial

Research

(CSIR)BARC

(Radioactive)

Ministry of

Chemicals &

Petrochemicals

National

Pharmaceutical

Pricing

Authority

(NPPA)Department of

Chemical &

Petrochemicals

(DCP)

Department of

Pharmaceutical

s

Ministry of

Commerce &

Industry

Patent Office

Dept. of

Commerce &

Pharmexil

Controller

General of

Patent

DGFT

Ministry of

Environment &

Forest

GEAC-[Genetic

Engineering

Approval

Committee]

Department of

Biotechnology

r-DNA Advisory

Committee

Review

Committee

Genetic

Manipulation


Drugs and Cosmetics Act and Rules

Objective:

To ensure safety, efficacy and quality of

Drugs

Biologicals

Medical Devices

Cosmetics

Veterinary Drugs.

2/14/2018 16


Implementing Authorities:

�Central Government:

�Central Drugs Standard Control

Organization(CDSCO)

�State Governments:

�State Drug Licensing Authorities

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Drugs and Cosmetics Act

Principle:“through system of licensing”

Basic Philosophy:�Manufacturers are responsible for quality of drugs

manufactured by them�Government Regulatory Agencies will monitor the

quality of drugs by ■ periodic inspections of the manufacturing and sales

premises for confirmation to the provisions of Drug s & Cosmetics Act

■ monitoring the quality of drugs moving in the market by carrying out post market surveillance.


Regulated under the Act:

Act

Manufacture Import Sale Distribution

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Regulated under Rules

New Drugs

ExportsClinical Trials

2/14/2018 20


Legal Framework

Legal Framework in Medicines:

�Drugs Law:

�Regulation:

�Import,

�Manufacture

�Sale, distribution

�Penalties

�Statutory authorities

Guidelines

Orders

2/14/2018 21


Import of Pharmaceutical products

• Registration of the product and site with NationalRegulatory Authority mandatory before importinto the country

• Overseas manufacturing sites have to comply tothe WHO requirements of GMPs

• Registration is valid for three years• Site registration fee -1500 USD, product fee-1000

USD• Provisions for Site inspection• Quality monitoring at the port of entry• Major imports APIs, Blood products, MD etc

22


Control on Manufacture

• Application to the concerned State• Review and pre inspection• After complete compliance, Licence will

be granted• Quality Surveillance • Suspension or Cancellation , if any

violations• Legal action, if any violation

2/14/2018 23


IPC

� Autonomous Institution of the Ministry of Health

and Family Welfare, Government of India.

� Created to set standards of drugs in the country.

� Basic function to update regularly the standards of

drugs commonly required for treatment of diseases

prevailing in this region.

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Composition of IP Commission

IPC

Secretariat

IPL

Governing Body

General Body

Scientific Body

IPC

25


Mandate

• To publish new edition and addenda of the Indian

Pharmacopoeia.

• To publish the National Formulary of India.

• Certification and distribution of IP Reference Substances.

• National Coordination Centre (NCC) for running

Pharmacovigilance Programme of India (PvPI)

• To establish working relations with other similarly placed

institutions at National and International level.

• To organize educational programs, skill development and

research activities.

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Legal Status of Pharmacopoeia

Indian Pharmacopoeia (IP), or any part of it, has got

legal status under the Second Schedule of the Drugs &

Cosmetics Act, 1940.

Standards of Drugs included in IP – Standards of

Identity, Purity and Strength as specified in the IP for

the time being in force as mandated in Drugs &

Cosmetics Rules 1945.

2/14/2018 27


Control on Manufacture

• Application to the concerned State• Review and pre inspection• After complete compliance, Licence will

be granted• Quality Surveillance • Suspension or Cancellation , if any

violations• Legal action, if any violation

2/14/2018 28


Publication of Indian Pharmacopoeia

(By IP Committee)

Edition Year

I IP-1955

Supplement 1960

II IP-1966

Supplement 1975

III IP-1985

Addendum 1989 & 1991

IV IP-1996

Addendum 2000

Vet Supplement 2000

Addendum 2002

(By IP Commission)

Edition Year

Addendum 2005

V IP-2007

Addendum 2008

VI IP-2010

Addendum 2012

VII IP-2014

Addendum 2015

Addendum 2016

VIII IP-2018


Monographs Development

30


Development of IP Reference Standards (IPRS)

31

Chemical Reference Standards


Development of Impurity Standards

32


Forced Degradation

33


Why Forced Degradation ?

34

• Forced degradation is a powerful tool usedroutinely in pharmaceutical development to

�Determine “developability” of a compound

�Develop stability-indicating methods that leadto quality stability data

�Understand degradation pathways &mechanisms of the drug substance and drugproduct

BMS Confidential — For Internal Use Only35

�Anticipate and prevent stability problems

for both API and DP

�Support expiry dating period, packaging,

and storage statement in labeling




It is recognized that some degradation

pathways can be complex and that under

forcing conditions decomposition

products may be observed which are

unlikely to be formed under Accelerated

or Long term testing”


Types of Degradation

Forced degradation studies of the drug

substance include appropriate solution

and solid-state stress conditions. e.g. :

� Acid/Base hydrolysis

� Heat

� Humidity

� Oxidation

� Photostability


Impurities

38

Pharmaceutical impurities are the organic and inorganic unwanted chemicals which are found in active pharmaceutical ingredient after synthesis or develop during formulation development .

Identification, isolation and characterization of impurity.


ICH Guidlines

39

The Guidelines of impurity profiling in ICH are

Impurities in New Drug Substances Q3A (R2)Impurities in New Drug Products Q3B (R2)Impurities: Guideline for Residual Solvents Q3C (R5)Guideline for Elemental Impurities Q3D


USFDA Guidlines

40

The Guidelines of impurity profiling in USFDA are(A) Impurities in New Drug Substances Q3A 16(B) Impurities in New Drug Products Q3B (R2) 17(C) ANDAs: Impurities in Drug Substances(D) ANDAs: Impurities in Drug Products he


RISK

41


Risk

42

�Lack of investigation of known/unknown degradation products

◦ Toxic degradation products (Doxorubicin cardio-toxicity may be caused by its metabolite doxorubicinol)

◦ Metabolites (metabolite of imipenem, Thienamycin M1 causes cleavage of the molecule)


Probable Factors

43

�Inappropriate Storage�Hold time�Vendors for API�Excipient incompatibility�Ions leachables�pH �Instruments�Aging both API and API Formulations.�The presence of these unwanted chemicals

even in small amounts may influence the efficacy and safety of the pharmaceutical products


QUALITY AND INDIA

44


The WHO NRA re-benchmarking exercise, from 13-17 Februa ry 2017 , was aimed at assessing the status of the India vaccine regulatory system

Successful Re -benchmarking of the National Regulatory Authority (NRA) of India


Maturity level


• Focus on strengthening Pharmacovigilance Programmeof India (PVPI) and integrating Public HealthProgrammes

■ Universal Immunization Programme- Immunization Technical Support Unit (UIP-ITSU) for monitoring of Adverse Event Following Immunization

■ National Vector Borne Disease Control programme (NVBDCP)

■ Revised National Tuberculosis Control Programme(RNTCP)

■ National AIDS Control Organization (NACO)■ Indian Medical Association (IMA) ■ Indian Council of Medical Research (ICMR)■ National Accreditation Board of Hospitals (NABH)■ National De -worming Programme

Strengthening Pharmacovigilance in India - Integration with PHPs


■ Quality assurance and standards of medical products , including labs - (Network of National Control Laboratories –NCL networks are included) Coordinator: Thailand

■ Good Regulatory Practices including GMP, GDP etc. (may include mapping activities, what exists in existing platforms) Coordinators: Indonesia and India

■ Information sharing platform – India (explore utilizing existing systems, we may additionally explore use of social media tools, such as twitter for quick communications) Coordinator: India

■ Vigilance for medical products Coordinators: India and Thailand

South East Asia Regulatory Network (SEARN) –short/ medium term priorities

BMS Confidential — For Internal Use Only 49

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