Post on 20-Jul-2019
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 – 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
BMS Confidential — For Internal Use Only
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
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Indian pharmaceutical industry – global presence
USFDA Approved sites
(Formulations + API)
262
EDQM approved sites
253
COPP holding sites 1300 (approx)
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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
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New Building-CDSCO Mumbai
CDSCO Zonal Offices -Mumbai & Hyderabad
New Building-CDSCO Hyderabad
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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
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Drugs is in concurrent list of Indian Constitution
It is governed by both Centre and State Governments under the Drugs & Cosmetics Act, 1940
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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
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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
BMS Confidential — For Internal Use Only
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
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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
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Implementing Authorities:
�Central Government:
�Central Drugs Standard Control
Organization(CDSCO)
�State Governments:
�State Drug Licensing Authorities
2/14/2018 17
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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.
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Regulated under the Act:
Act
Manufacture Import Sale Distribution
2/14/2018 19
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Regulated under Rules
New Drugs
ExportsClinical Trials
2/14/2018 20
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Legal Framework
Legal Framework in Medicines:
�Drugs Law:
�Regulation:
�Import,
�Manufacture
�Sale, distribution
�Penalties
�Statutory authorities
Guidelines
Orders
2/14/2018 21
BMS Confidential — For Internal Use Only
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
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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
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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.
2/14/2018 24
BMS Confidential — For Internal Use Only2/14/2018 25
Composition of IP Commission
IPC
Secretariat
IPL
Governing Body
General Body
Scientific Body
IPC
25
BMS Confidential — For Internal Use Only
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.
2/14/2018 26
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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
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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
BMS Confidential — For Internal Use Only
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
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Development of IP Reference Standards (IPRS)
31
Chemical Reference Standards
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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
Why Forced Degradation ?
BMS Confidential — For Internal Use Only36
Why Forced Degradation ?
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”
BMS Confidential — For Internal Use Only37
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
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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.
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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
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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
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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)
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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
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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
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• 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
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■ 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