Phytopharmaceutical Drugs and GMP

Prof. Ramesh K. Goyal, Ph.D.

F.I.C., FICN., FIPS, FAMS, FIACS, FNASc., FSCH

(Former Vice Chancellor, The M. S. University of Baroda)

Vice Chancellor

Delhi Pharmaceutical Sciences & Research University

Changes in Practice of Medicine & IRs

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Empirical

Herbals

&

Minerals

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Before 1900 1900s-1970s 1970s–2000s 2000– 2020

1^st IR 2^nd IR 3^rd IR 4^th IR

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Chemicals

&

Biochemicals

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Industrial Production

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Genome

Health ATMs

Nanotech based

Biomarker Based DD

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Biotechnology

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Biologicals

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Immunological

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Systematic Drug Discovery

Availability of Medicines

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Modern Vs. Herbal Drugs

• Mostly single entity with structure known,
• Rigorously tested
• Meeting Regulatory requirements (Whose?)
• Clinical trials done
• Toxicity tests cleared then Why Pharmacovigilance?

[ 4^th-6^th largest cause of death in US ].

• Many times Number of active entities is not known,
• Time Tested?
• Safety & efficacy based on experiences of practitioners
• Used by large population
• MOA many times unknown.

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Why 4^th IR cannot be used to promote Ancient Systems of Medicine?

System Practiced Since

Ayurveda 6000 B.C.

Chinese herbals 5000 B.C.

Egyptian medicine 1600 B.C.

Chinese Yin Dynasty 1500 B.C.

Greek medicine 500 B.C.

Roman medicine 200 B.C.

Unani Tibb 1400 A.D.

Homoeopathy 1800 A.D.

Allopathy medicine 1800 A.D.

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Asia & Evolution of Different

Systems of Medicine

Digitalis Discovered Over 2 Centuries Ago

An Account of the Foxglove and Some of its Medical Uses

William Withering

1785

Cardiac glycosides (Digoxin, Digitoxin, etc.)

remained the mainstay for the treatment of Heart failure especially for the Congestive heart failure for

over two centuries

William Withering (1783)

“out of 158 patients 101 patients

with congestive heart failure

experienced relief following administration

of Digitalis purpurea (Foxglove) leaves”

Cardiac Glycosides

Advance Access Online Publication March 11, 2013

Progress in Traditional Medicine w.r.t

4^th Industrial Revolution

• Herbal Extracts
• Minerals
• Mechanical
• Tictures
• Powders

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• Isolation

Strychnine (1817)

Quinine (1820)

Nicotine (1828)

• Cultivation
• Packaging

Ethnopharm

• Tissue Culture
• Analytical
• Chromatography
• Standardization
• Botanicals
• WHO Recognition
• HTS
• Leads, Hits, Candidates

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• Reverse Pharmacology
• Nutraceuticals
• Asian Regulations
• Genomics
• Molecular Modeling
• HTS
• Leads, Hits, Candidates

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1^st Industrial Revolution in TM�The 18^th century, Pharmacognosy

• Johann Adam (1759-1809)
• Linnaeus (Naming and classifying plants)
• BUT At the end of the 18^th century,

crude drugs were still being used as powders, simple extracts, or tinctures

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2^nd Industrial Revolution in TM �The era of pure compounds�(In 1803, a new era in the history of medicine)

• Isolation of morphine from opium
• Strychnine (1817)
• Quinine and caffeine (1820)
• Nicotine (1828)
• Atropine (1833)
• Cocaine (1855)

3^rd Industrial Revolution in TM �Pharmacological Studies

• 1783-1855: Francois Magendie Isolation of Strychnine

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• 1813-1878: Claude Bernard Site of action of Curare

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• 1820-1879: Rudolf Buchheim Own lab at home: Site of action

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• 1907 John J. Abel (USA) Ephedrine from adrenal

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• 1937 A. J. Clark/ Receptor concepts

J. H. Gaddum (UK)

• 1940-60 Col. R. N. Chopra Herbal Drugs

(India)

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4^th Industrial Revolution in TM

Integrated Medical Research: Translation

Clinical Pharmacy & Translational Science

• Drug design
• Discovery
• Preclinical toxicity
• Biomarkers & molecular diagnostics
• Development
• Delivery systems

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• Clinical efficacy
• PK/PD Studies
• Side effects & ADEs
• Ineffectiveness
• Pharcogenomics
• Pharmacovigilence
• Applied therapeutics

Improving Human Health

Translation

DRUG

Pharmaceutical Development

Clinical Research

1^st to 4^th Change in Trend in the 20^th century�Production of natural drug products

1. Collection
2. Cultivation (commercial),
3. Collection, harvesting, drying, garbling, packaging, storage and preservation
4. Fermentation (Recombinant DNA technology or Genetically engineered drugs)
5. Cell-culture techniques
6. Biologics (prepared from the blood of animals)

2^nd to 4^th Change in Trend in the 20^th century �Isolation of Active Principles

1. Chromatography
2. Combinatorial chemistry
3. HPLC, LC-MS
4. Combinatorial biosynthesis

Biomarkers

Biomarker (Biological Marker): A characteristic that is measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention. Biomarkers may relate to efficacy, safety, differentiation etc.

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Surrogate Endpoint: A biomarker accepted by regulatory agencies as a substitute for a clinical endpoint (e.g. HIV load for the stage of AIDS, LDL level for the risk of coronary artery disease, blood pressure for the incidence of stroke & hemoglobin A1C for the control of diabetes).

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Diagnostic: A biomarker that has applicability in clinical use or patient management

Guidelines for the Ayurveda, Siddha, Unani Drugs

Documents required for the approval of premises� 

Herbal regulations in ASEAN countries�

Regulations for Herbal Drugs in Other Countries

Regulations in India

• 1911 Act of Patent and Designs : Allopathic medicines
• MNCs utilized for importing drugs

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• 1948 Foreign companies allowed to set up plants
• Formulations rather than bulk drugs

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• 1956, Manufacture of drugs from the basic stage
• 1972 Amendment of the Patent Act

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• 1988 D & C Act & Schedule – Y

Ministry of Health & FW: Allopathic System of Medicine�(Single molecule as drugs or Phytopharmaceuticals DCGI Route)�Ministry of AYUSH: Indian System of Medicine

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Y

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U

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H

Ayurveda

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Yoga & Naturopathy

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Unani

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Siddha

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Homeopathy

• Indian System of Medicine under Ministry of Health and Family Welfare (1995)

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• Renamed as Deptt. Of AYUSH (2003)

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• Ministry of AYUSH (2015)

Classification of drugs from Herbal Sources

• Classical Medicine
• Proprietary Medicine
• Phyto- pharma-ceuticals
• Pharma-ceuticals

Arjuna arista Himalaya LIV 52 Vincristine

Yograja Guggulu Dabur Vatika Nil Vinblastine

Narayana Taila Zandu Balm Morphine

Sarpagandha Churna Himalaya’s Serpina Reserpine

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Requirements for formulation to be classified as phytopharmaceutical drugs

Govt. of India: GAZETTE NOTIFICATION made public on 30th November, 2015

GSR 918 (E), issued by Ministry of Health & family Welfare, D & C Rule 122 EB

“Phytopharmaceutical drug” includes purified and standardised fraction with defined minimum four bio-active or phyto-chemical compounds (qualitatively and quantitatively assessed) of an extract of a medicinal plant or its part, for internal or external use of human beings or animals for diagnosis, treatment, mitigation or prevention of any disease or disorder but does not include administration by parenteral route.’

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Why Phytopharmaceuticals Regulations?

• Shrinking of NCE pipeline with Pharma MNCs
• Phytopharmaceutical concept may open new vista of drug discovery
• Being in line with regulations in USA, China, & other countries involving scientific basis and Standardization will have global recognition
• Will promote innovations & transform the concept of botanicals to drug formulations

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Why Phytopharmaceuticals Regulations?

• This regulation is expected to develop new drugs from botanicals in a scientific way and would help in the acceptance of the use of herbal products by modern medical profession.
• Phytopharmaceutical’s proposal would promote innovations and development of new drugs from botanicals, and would give boost to research in drug development for innovators, industry, and national laboratories and pharmaceutical research labs in India.

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Phytopharmaceutical Drugs ? �How does it differ from ASU drugs?

• Chapter IV of the D & C Act deals with drugs of Allopathic system.
• Chapter IV A deals with ASU drugs (restricted to drugs of texts of the First schedule of D & C Act)
• The definition, the D & C act does not include the words like TM, herbal drugs, herbal medicines, Phytomedicines, MCBT.
• Phytopharmaceuticals can be from any medicinal plants of the globe (not restricted to plants mentioned in the texts of Schedule First of D & C Act.)
• Leads for phytopharmaceuticals may have their origin not only in ASU but also in TCM, Kampo, ethnobotanicals tribal plant drugs or any plant of the globe.
• It does not encroach upon the wholistic approach of ASU drugs of Chapter IV A of D & C Act rather encourages innovative approach for new drug discovery for unmet needs
• NCE pipeline with pharma MNC’s shrinking drastically. Introduction of phytopharmaceuticals category of drugs open new hope of drug discovery from rich biodiversity of medicinal and aromatic plants.

Requirements for formulation to be classified as phytopharmaceutical drugs

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• Purified and standardized fraction with defined minimum four bio-active or phyto-chemical compounds

• Qualitatively and quantitatively assessed

• Obtained from an extract of a medicinal plant or its part

• For internal or external use of human beings or animals

• For diagnosis, treatment, mitigation or prevention of any disease or disorder

• Does not include administration by parenteral route.

Phytopharmaceutical Drug Development

Plant

Extraction

Extract/Fraction

Purification

TLC (Qualitative)

HPLC ( Quantitative)

Dosage – Oral/external but not parenteral

Human / Animal

Requirements for as ‘Phytopharmaceutical drugs Approval’: Part 1A

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1. Data to be submitted by the applicant

A brief description or summary of the phytopharmaceutical drug

Published literature on plant or phytopharmaceutical drug

Information on any contraindications, side effects

Published scientific reports on safety and pharmacological studies of phytopharmaceutical drug

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Present usage of the phytopharmaceutical drug

Identification, authentication and source of plant used for extraction and fractionation

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Phytopharmaceuticals Drugs…..

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Requirements for as ‘Phytopharmaceutical drugs Approval’: Part 1B

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2. Human or clinical pharmacology information

Published scientific reports on pharmacological studies including human studies or clinical studies or epidemiological studies

Pharmacodynamic information

Monographs, if any, published on the plant or product or extract or phytopharmaceutical

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Safety and Pharmacological information

• Animal toxicity and safety data:
1. 28 to 90 days repeat dose oral toxicity on two species of animals.
2. in vitro genotoxicity data
3. Dermal toxicity test for topical use products
4. Teratogenicity study (intended for use during pregnancy)

Part 4�Process for extraction and subsequent fractionation and purification

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• Quality specifications and test methods for starting material
• Details of packaging of the purified and characterized final product, storage conditions and labeling.
• Steps involved in processing

Other Parts�Phytopharmaceutical drugs….

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• 5
• Formulation of phytopharmaceutical drug applied for:

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• Manufacturing process of formulation:

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• Stability data:

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• 8
• Safety and pharmacological information:

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• 9
• Human studies:

Stability data

• Stability data of the Phytopharmaceutical drugs: stored at room temperature at 40 °C ± 2 °C , humidity at 75% RH ± 5% RH for 0, 1, 2, 3 and 6 months
• Stability data in dosage form or formulation: stored at room temperature at 40 °C ± 2 °C , humidity at 75% RH ± 5% RH for 0, 1, 2, 3 and 6 months in the packet intended for marketing.

Phytopharmaceuticals Drugs…..

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Regulatory

ASU drugs have been under the purview of Ministry of AYUSH

Phytopharmaceuticals are under the purview of CDSCO

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• 10
• Confirmatory clinical trials:

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• Regulatory status:

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• Marketing information:

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• Post marketing surveillance (PMS):

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• Any other relevant information:

Other Parts�Phytopharmaceutical drugs….

Comparision of Attributes of ASU Vs Phyto

What is Not Included Or Included Phytopharmaceuticals?

• One step extracts of Botanicals using any solvent & converted into powders

Steps involving more than one solvents for Fractionation

• Fixed Oils extracted from botanicals

Fractionated fatty acids from vegetable oils, fractionated distilled oils extracted from botanicals

• Extracts obtained by traditional methods using other solvents like vegetable oil, milk or clarified butter

Distilled oils or volatile components from botanicals

• Single step oleo-resin extracts
• Fractions or Purified Fractions tested for bioactivity or phyto-chemicals (4 Analytically assed) & At least one of the Phytopharmaceutical biologically assessed

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Summary

• Introduction of Phytopharmaceuticals as a new class of drug is an important, timely and progressive step

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• It would inculcate higher level of scientific inputs in herb based products

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• Phytopharmaceuticals may help as a booster dose for the Herb based drug business.

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Thank you

��Case Study�Scutellaria barbata D. Don as Phytopharmaceutical drugs……

Requirements for formulation to be classified as phytopharmaceutical drugs

“Phytopharmaceutical drug” includes purified and standardised fraction with defined minimum four bio-active or phyto-chemical compounds (qualitatively and quantitatively assessed) of an extract of a medicinal plant or its part, for internal or external use of human beings or animals for diagnosis, treatment, mitigation or prevention of any disease or disorder but does not include administration by parenteral route.’

S. barbata D. Don as Phytopharmaceutical drugs……

• Purified and standardised fraction: ethyl acetate
• Minimum four bio-active or phyto-chemical compounds
• Qualitatively assessed: Scutellarin, scutellarein, hispidulin and wogonin
• Quantitatively assessed: Scutellarin (27 µg/mg), scutellarein (20.16 µg/mg), hispidulin (13.02µg/mg) and wogonin (3.27 µg/mg)
• A medicinal plant or its part: Whole plant of Scutellaria barbata

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• Animals for diagnosis, treatment, mitigation or prevention: LACA mice, for the treatment of depression

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• Route: Oral