DIA International Conference “Quality of Active Pharmaceutical Ingredients”pharmexcil.com/data/uploads/API_Quality_from_Indian_Perspective.pdf · “Quality of Active Pharmaceutical

Nandkumar Chodankar Ph D TechDIA pACI Chair & DIA Board Member

DIA International Conference

“Quality of Active Pharmaceutical Ingredients”In collaboration with EMEA, EDQM, EU, FDA

& WHO

Disclaimer: The views expressed in this presentation are the personal opinions of the speaker and do not necessarily represent the views of the Organization

Presentation Flow

Objectives of Regulations

History of Indian regulatory requirements

Acts & rules - which regulates Indian Pharmaceutical Industry

Requirements for the Quality of API

Regulatory approval processes

2/34Nandkumar Chodankar Ph D Tech6th Sept. 2009

Objective of Regulation- Quality

The Objective of Drugs & Cosmetics Act is to ensure that public (consumers) are supplied with safe and efficacious drugs and cosmetics.

Responsibility of Manufacturers: Are responsible for quality of drugs manufactured by them.

Responsibility of the Government Regulatory Agencies:Responsible to monitor the quality of drugs by periodic inspections of the manufacturing and sales premises for confirmation to the provisions of Drugs & Cosmetics Act and monitoring the quality of drugs moving in the market by carrying out post market surveillance.


History: Pre- Independence

1927 Henry Gidney’s resolution to legislate the manufacture and sale of drugs.

1930 Govt. appointed R. N. Chopra Committee to control menaceof spurious, adulterated, misbranded drugs. (Cinchona bark)

1931 Committee submitted Report

1935 After passing Govt. of India Act, Drug became provincial subject.

1939 Introduction of Drug Bill

1940 Drugs Act enacted

1945 In order to provide procedures to the industry rules were made under Drug Act


1948 Pharmacy Act

1954 Drugs and Magic Remedies (Objectionable advertisement Act)

1955 Amendments to Drugs & Cosmetics Act, extension of definitions

1960 Amendments --- DTAB, Powers to central Govt., etc.

1962 Amendments ---- Cosmetics manufacture regulated, misbranded, import prohibited etc.

1964 Amendments ---- provision for Ayurvedic, Siddha.

1982 Widened scope & definition, empowered

1985 Narcotics Drugs and Psychotropic Act

1986 Powers to consumers to draw samples.

1995 Drugs Price Control Order (DPCO)

History: Post- Independence


Composition of Drugs and Cosmetics Act

Chapter I Definitions

Chapter II Statutory committees and laboratories

Chapter III Import of drugs and cosmetics

Chapter IV Manufacture of Drugs and Cosmetics

Chapter V Siddha and Unani drugs

Chapter VI Miscellaneous

Books on Standards: Indian Pharmacopoeia (Inclusion of HIV Drugs monographs)

Homeopathic PharmacopoeiaAyurvedic Pharmacopoeia and Indian Pharmacopoeia – Veterinary


Standards in Drugs and Cosmetics Act- Schedules

Schedule I Ayurvedic Drugs

Schedule II Other Drugs

Schedule S Cosmetics

Schedule R Condoms

Schedule F Vaccines

Schedule FF Standards for Ophthalmic Preparations

Schedule V Patent & Proprietary Medicines

Schedule O Standards for Disinfectant Fluids

Schedule M Requirements for Manufacturing

Schedule Y Requirements for New Drugs

Schedule P Requirements for Shelf Life and Storage Conditions


Requirement for the Quality of API

Schedule M discusses about the GMP operations

(especially Chapter IV)

Rule No. 69, Rule No.122 and Schedule Y covers the filing requirements for a manufacturing license of New Drug / approval


“Assumption can lead to disaster”

Schedule M1.General Requirements

Location & surroundings, Building and premises, Water System, Disposal of waste

2. Warehousing Area

3. Production area

4. Ancillary Areas

5. Quality Control Area

6. Personnel

7. Health, clothing andsanitation of workers

8. Manufacturing Operations and Controls

9. Sanitation in theManufacturing Premises

10. Raw Materials

11. Equipment

12. Documentation and Records

13. Labels and other Printed Materials

14. Quality Assurance


Schedule M15. Self Inspection and

Quality audit

16. Quality Control System

17. Specifications

18. Master Formula Records

19. Packing Records

20.Batch Packaging Records

21.Batch Processing Records

22.SOPs & Records for Receipt of materials, Sampling, Batch numbering, Testing

23. Reference Samples

24. Reprocessing and Recoveries

25. Distribution records

26. Validation and Process validation

27. Product Recalls

28. Complaints and Adverse Reactions

29. Site Master Files


Buildings & Facilities

Designed and constructed– To facilitate cleaning,

sanitizing, maintenance (incl. repairing), appropriate manufacturing operations (defined in physical areas or other control systems)

–To prevent mix-ups or contamination(chemical and microbiological)

Utilities: e.g. Water– “Quality of the water used

in the manufacture of APIs should be demonstrated to be suitable, for its intended use”

– Increasing purity of the API along the process increasing quality of the water- Finally Purified water


Process Equipment

Equipment shall be located, designed, constructed, adapted and maintained to suit the operations to be carried out

The layout and design of the equipment shall aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build-up of dust or dirt

To avoid accidental contamination, wherever possible, non-toxic / edible grade lubricants shall be used


MaterialsMaterial management


- All incoming materials shall be purchased from

approved sources

- Evaluation of suppliers of critical materials shall

be based on Historical experience,

Questionnaire, Analytical verification of samples,

Audit of the supplier

Receipt Quarantine Sampling Testing (min. Identity)

Reject ApprovedStorageReevaluation

Indian rules are somewhat silent on “acceptance of hazardous materials”

and does not define the starting material

Stages of production operations:Chemical: SynthesisPhysical: isolation/ purification/ drying/ …Packaging/ labeling- Critical operations to be

witnessed- Any deviation to be

documented/explained

In-process sampling and controls (IPC)– Purpose IPC: monitoring/

adjusting process (reaction completion, pH control, water content, etc)

– Sample size– Sampling method– Sampling procedure


Manufacturing

http://www.pharmaceutical-technology.com/contractors/contract/fine_foods/

Blending of intermediates or APIs“Combining materials with the same specifications to produce a homogeneous product” Blend should

– be traceable back to all individual batches– only contain individual batches that conform to

specifications No blending of OOS batches Blending should include testing of

parameters that may be affected: Particle size distribution Bulk density Tapped density

(May be we should include Color)

Manufacturing


Where reprocessing is necessary, written procedures shall be established and approved by the QA that shall specify the conditions and limitations of repeating chemical reactions. Such reprocessing shall be validated. (Scientific Rational is important)

If the product batch has to be reprocessed, an investigation shall be carried out into the causes necessitating re-processing and appropriate corrective measures shall be taken for prevention of recurrence.

Re-processed batch shall be subjected to stability evaluation. Recovery of the product residue may be carried out, if permitted,

in the master production and control records by incorporating it in subsequent batches of the product.

Reprocessing and Recoveries


Quality controlOut of specifications (OOS) results to be investigated according to SOP including e.g.,

– checklist of potential defects in laboratory– checklist of potential defects in production– check list of sampling and sampling devices– guidance on re-sampling and re-testing– testing of control (reserve) sample [RS, WRS and storage]

Standards

– Reagents and standard solutions with “use before” date– Primary reference standard: from documented source. If from

official source and if stored as stipulated: no testing necessary

– Secondary reference standards (working standards): compared (by testing) to primary standard prior to first use


Schedule L1 Effective from Nov. 2010 will answer many of the questions

Quality control

Stability monitoring Purpose: to confirm appropriate

storage conditions and retest or expiry date Samples stored in containers simulating market

containerNormally, first 3 commercial production batches, then

1 batch/year placed on the on-going stability program


Mention Expiration period instead of Retest period for APIs (?)

Qualification: DQ, IQ, OQ, PQ “Before starting process validation activities, appropriate qualification of facilities (rooms), equipment, systems (e.g., steam, gases, HVAC,...) should be completed”.

Validation of processesProcesses and procedures shall be established on the basis of validation study and undergo periodic revalidation to ensure that they remain capable of achieving the intended results

Validation of analytical methods– Degree of validation to be in relation to purpose of analysis

and stage of production process (see also ICH Q2A, Q2B)– Analytical methods from recognized pharmacopoeia: only

suitability for use

Validation


Change control

Any system needs to constantly be adapted/ optimized (deviations, OOS,..)Formal (written) proposal for changeApproval of change by Quality UnitImplementation of changeEvaluation of impact of the implemented change


Documentation All quality relevant activities should be

described (written procedures, instructions) and documented (records)

“Life cycle” of documents according to written procedure

– Issuance, review, approval, distribution, retention, withdrawal, revision history of documents

Records on major equipment use and cleaning including date, signature and– Use: product, batch-no.– Cleaning (sanitization, sterilization): SOP– Maintenance: preventative, during production, repair

Water System Qualification and trending21/34Nandkumar Chodankar Ph D Tech6th Sept. 2009

Records on materials: traceability, i.e., origin and use Master production/ control instructions

– To ensure uniformity from batch to batch– Issued and checked independently

Batch production/ control records– Should include all significant steps

Batch production/ control records review– To be performed accordingly to written procedure– Review of critical steps such as OOS reports and

deviation investigations and their impact on product quality, check for missing records, incomplete or illegible entries, compliance with specifications, … before batch release


Documentation

A typical Drug Development Cycle


Discovery

Development

API

Drug Product

Packaged product for market


Regulatory Authorities in India

Central Drug Regulatory Authorities

- CDSCO – Central Drugs Standard Control Organization

DCGI, DELHI – Drugs Controller General of India- CBN – Central Bureau of Narcotics NCI, GWALIOR –

Narcotics Commissioner of India

State Regulatory Authorities

- Each state is having state licensing authoritye.g., DCA, Andra Pradesh - Director of Drugs Control

AdministrationDC, Tamil Nadu – Director of Drugs Control FDA, PONDY – Licensing Authority,

Food and Drugs Administration


Drug Approval category in India:

New drug – First time in India

Approved new drug- Approved by DCG(I), but not more than 4 years old

Approved drug - Approved by DCG(I), but more than 4 years old

Approved drugs details are Available at < www.cdsco.nic.in >



New drug, Approved new drug Application

DCG(I), CDSCO

Form 44

Form 46A

Approval

Mfg. License application

Approved drug Application (more than 4 years old drug)

Form 24

State licensing authority

Mfg. License approval

Form 24

Form 25



Clinical trial

Chemical and pharmaceutical information.

Animal Toxicology

Animal pharmacology

Regulatory status in other countries

Marketing information

Post-marketing surveillance study


Data requirements for filing –

Schedule Y

Recently IPR status is also needs to be submitted along with the

Pharmaceutical category and route of administration.

Clinical Trials Clinical trials required to be carried out in the country

before a new drug is approved for marketing depend on the status of the drug in other countries.

If the drug is already approved/marketed and internationally available, Phase III trials are required

For new drug substances discovered in India, clinicaltrials are required to be carried out in India right fromphase I


Chemical and Pharmaceutical Information

Brief description of the drug and the therapeutic class

Physiochemical data

- Chemical name, Structure,

Empirical formula

Molecular weight

- Physical properties

Description, solubility, rotation, partition coefficient,

dissociation constant, crystalline / amorphous, water of

hydration, flow properties (even micro metrics)


http://www.public.iastate.edu/~pkeeling/block01.htm


Analytical Data

Elemental analysis

Mass spectrum

NMR spectra

IR spectra

UV spectra

Polymorphic identification

Particle size distribution

Crystalline / amorphous,

Water of hydration,

Flow properties (even micro metrics)

5.97

5

13.5

35

25.5

17

28.9

55

36.6

49

40.9

47

AU

0.000

0.005

0.010

0.015

0.020

0.025

0.030

0.035

0.040

Minutes

0.00 5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00 50.00



Complete monograph specification- Identification - Identity/quantification of impurities - Enantiomeric purity- Assay

Validations- Assay method - Impurity estimation method - Residual Solvents/ OVI estimation method



Stability studies

- Study on final release specification

3 batches:

Long term 30°C ± 2°C/ 65%RH ± 5%RH – 12 months

Accelerated 40°C ± 2°C/ 75%RH ± 5%RH – 6 months

Photo stability study on min of 1 batch is required


Quality System


Thank you!!!

Nandkumar Chodankar Ph D [email protected]


Back up Slides

GROWTH OF PHARMACEUTICAL INDUSTRY

1950-1960: Imports, Simple Formulations

(tinctures and mixtures)

1970-1980: APIs by chemical synthesis and

fermentation, different dosage forms

1980-1990: Growth and sophistication

1990-2000: Research, Biotechnology and Exports


REASONS FOR INITIATIVES

A) Globalization

B) New Technologies

C) New Therapies


REASONS FOR INITIATIVES CONTD..

A) Globalization

Opportunities in:

–Contract Manufacturing

–Contract Clinical Research

–Contract R & D.



–Contract Documentation & Testing.

–Neutraceuticals

–Herbal Medicines



B) New Technologies

–Vaccines

–Recombinant DNA

–Tissue Culture

–Cell Biology

–Fermentation

–Chemical Synthesis



C)New Therapies

–Stem Cells

–Genomics


INITIATIVES TAKEN BY THE GOVERNMENT

Upgradation of G.M.P. requirements (Schedule M)

Issuance of guidelines for clinical trials and bio-equivalance studies (GCPs)


INITIATIVES TAKEN BY THE GOVERNMENT CONTD..

Good Laboratory Practices for the Government as well as Private Testing Laboratories.

Concepts of DMF for drugs imported into the country.

G.M.P. for Ayurvedic Drugs.


IMPORTANT COMMITTEES CONSTITUTED BY THE GOVERNMENT

• HATHI COMMITTEE

• SPECIAL TASK FORCE AND

• MASHELKAR COMMITTEE


INITIATIVES IN THE PIPELINE

Guidelines for manufacture, sale and distribution of medical devices.

Guidelines for good distribution and storage practices for the hospitals.

Guidelines for manufacture of biotech products.


INITIATIVES IN THE PIPELINE CONTD..

Guidelines for some of the important G.M.P. components i.e. stability testing, validation requirements etc.

Guidelines for Neutraceuticals.


Documents

DIA International Conference “Quality of Active Pharmaceutical Ingredients”pharmexcil.com/data/uploads/API_Quality_from_Indian_Perspective.pdf · “Quality of Active Pharmaceutical