CURRENT REGULAT0RY ASPECT

FOR PHYTOPHARMACEUTICALS
IN INDIA

A.B.RAMTEKE (Consultant)
Clinical Development Service Agency
470, Udyog Vihar, Phase III,
Gurgaon
 Regulatory Authorities
Ministry of Ministry of Health State Licensing
Chem & Fertilizers Ministry of Health Authority
Health Secretary
Dept. of
AYUSH
Genetic /
Engineering Manufacturing ,
(DGHS)
(NPPA) Approval Committee
ISM&H Sales & Inspections
Dir. General of
National
Health Services
Pharmaceutical Ministry of Science
DBT
Pricing Authority & Technology
(CDSCO) Central
Drugs Standard
Control Org.
Pricing Regulations Review
Committee of
(DCGI) Gene
Drugs Controller Manipulation
General (India)
 Existing Structure & Composition of CDSCO
DCG (I)

CENTRAL INDIAN
CDSCO SUB ZONAL
ZONAL OFFICES PORT OFFICE DRUG TESTING PHARMACOPOEIA
(Head Quarter) OFFICES COMMISSION
LABORATORIES

•North Zone, •Delhi •CDL Kolkata

•New Delhi •Hyderabad •Ghaziabad
Ghaziabad •CIPL Ghaziabad
•East Zone, •Ahmadabad •Mumbai
Kolkata •CDTL Mumbai
•.Bangalore •Chennai
•West Zone, •CDTL Chennai
Mumbai •Kolkata
•RDTL Guwahati
•South Zone, •Hyderabad
Chennai •RDTL Chandigarh
•Ahmadabad

•New Drugs
•GMP Audits •Export •Testing of drug
•Biologics, CT •Coordination's
•Coordination's •Import •Samples
•Imports, Export •with States
•with States •Validation of
• Medical Devices •GMP Audits
•Test protocol
• Diagnostics
• Cosmetics
• Policy making.
Drug Definition (Drugs & Cosmetics Act, 1940)

• Section 3(a) [“Ayurvedic, Siddha or Unani drug”

includes all medicines intended for internal or
external use for or in the diagnosis, treatment,
mitigation or prevention of disease or disorder in
human beings or animals, and manufactured
exclusively in accordance with the formulae
described in, the authoritative books of
Ayurvedic, Siddha and Unani (Tibb) systems of
medicine, specified in the First Schedule;]
Authoritative text recognized by Drugs and
Cosmetics Act in India
• The traditional experience has been documented and
government of India in its wisdom has given regulatory
status to these preparations as Ayurvedic drugs and
there are more than 57 books recognized by
Government of India and is laid down under The First
Schedule of Drug and Cosmetic Act 1940
• The First Schedule has been inserted in regulatory book
more than 50years back and has been amended time to
time,
• The latest inclusion in 2010 was ayurvedic
pharmacopoeia of India and its parts.
Indian Pharmacopoeia (IP)
• Indian Pharmacopoeia Commission is an autonomous
body under Ministry of Health and Family Welfare,
Government of India, which publishes Indian
Pharmacopoeia,
• IP is the legally recognized book for standards of
medicines in India,
• It specifies the standards in terms of identity, purity and
strength of medicines,
• Therefore, Indian Pharmacopoeia (IP) laid down
monograph for herbs and herbal products to maintain
their quality.
Quality Standards of Indian Medicinal Plants

• Standards set as per WHO guidelines

• Use conventional and modern scientific
approach
• Developed at 4 national laboratories
• 4 Volumes on Indian Medicinal Plants:
(Next Slide)
MEDICINAL PLANTS MONOGRAPHS ON DISEASES
OF PUBLIC HEALTH IMPORTANCE
• ANCIENT KNOWLEDGE
• ALLOPATHY SYSTEM OF MEDICINE
• SCIENTIFIC STUDIES
• INTEGRATION OF LEADS
SOME THRUST AREAS
» FILARIASIS
» MALARIA
» KALA-AZAR
» LIVER DISORDERS
» DIABETES MELLITUS
» ANTIINFLAMMATION
» IMMUNOMODULATORS
• (Courtesy ICMR)
Role of AYUSH* in India
• Ø Medical Education management through Central Council of
Indian Medicines
• Ø Promote the cultivation of herbs
• Ø Promote the research work on Indian system of medicines
• Ø To lay down standards to maintain the quality of drugs
• Ø Develop regulation to promote the traditional system of
medicines
• Ø To provide financial subsidy to Small Scale Industries to promote
the manufacture of traditional drugs,
• Ø Regulate Clinical trials of these drugs to prove the safety and
efficacy
• Ø Amend the regulation for the betterment of the system in the
interest of general public,
* Department of Ayurveda, Yoga, Unani, Sidha and Homeopathy (AYUSH)
Approved Botanicals as Drugs (PhytoPharmaceuticals) by
DCGI
• Ø Guglip extract and tablets I.P. – standardized Guggulu
extract (Cammiphora mukul) – for cholesterol reduction,
Ø Gingko biloba tablets (Gingko biloba leaf extract)- for
treating short term loss of memory,
• Ø Gingseng tablet (Standardized Gingseng extract along
with vitamins and minerals)- for immunity and energy
• Ø Silymarin syrup and capsules –for treating liver
disorders,
• Ø Ginger capsules-standardized Ginger – for treating
chemotherapy induced nausea.
Drug Definition (Drugs & Cosmetics Act, 1940)
Section 3(b) “drug” includes—
• (i) all medicines for internal or external use of human beings or animals and all
substances intended to be used for or in the diagnosis, treatment, mitigation or
prevention of any disease or disorder in human beings or animals, including
preparations applied on human body for the purpose of repelling insects like
mosquitoes;
• (ii) such substances (other than food) intended to affect the structure or any
function of human body or intended to be used for the destruction of (vermin)
or insects which cause disease in human beings or animals, as may be specified
from time to time by the Central Government by notification in the Official
Gazette;]
• 2[(iii) all substances intended for use as components of a drug including empty
gelatin capsules; and
• (iv) such devices intended for internal or external use in the diagnosis,
treatment, mitigation or prevention of disease or disorder in human beings or
animals, as may be specified from time to time by the Central Government by
notification in the Official Gazette, after consultation with the Board ;]
Drugs & Cosmetics Act
• The Act Contains Part –I - five Chapters which includes 38
different Sections.
• Part II of the Act is –Drugs and Cosmetics Rules 1945,
• The D&C Rules contains 19 parts (Part XIX).
• Part X-A is for ‘ IMPORT OR MANUFACTURE OF NEW DRUG FOR
CLINICAL TRIALS OR MARKETING.
• There are currently 171 Rules, followed by Schedule A to Y
• Schedule Y is for” Requirements & Guidelines for permission to
import and /or manufacture of New Drugs for sale or to
undertake Clinical Trials”.
What Is Schedule Y
• It is “Schedule under Part X-A of Drugs & Cosmetics
Rule 1945 describe the information/data required
for approval in Clinical Trial and/or to import or
manufacture of new drug for marketing in India.
• It is outlined extensive study criteria in line with the
globally accepted formats such as ICH and US FDA
guidelines
• Refer to rules 122A, 122B, 122D, 122DA, 122DAA ,
122 DAB, 122 DD and 122E.
Important Appendices of Schedule Y
Appendix I

Data to be submitted to
- Conduct clinical trial
- Import and
- Manufacture of New Drugs for marketing in the
country
Appendix I – A

Data required for grant of permission

- To import and / or
- Manufacture new drugs already approved in the
country (Subsequent Applicants)

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Appendix II

- Structure
- Contents &
- Format for clinical study reports

Appendix III
- Animal toxicology
- Systemic toxicity studies
- Male fertility study
- Female reproduction & Dev toxicity study
- Local toxicity
- Allergenicity, hypersensitivity
- Genotoxicity
- Carcinogenicity

1
Appendix IV
- Animal pharmacology
Appendix V
- Informed consent
Appendix VI
- Fixed dose combination
Appendix VII
- Undertaking by the investigator
Appendix VIII
- Ethics committee
Appendix IX
- Stability testing of new drugs

1
Appendix X
- Contents of the proposed protocol for conducting
clinical trials
Appendix XI
- Data elements for reporting serious adverse
events occurring in a clinical trial.
Appendix XII
- Compensation in case of injury or death during
Clinical trial. (Rule 122 DAB) (GSR No. 53-E , 30th Jan 2013)

1
 Application Form 44
Form 44

(See Rules 122A, 122B, 122D and 122DA)

Application for grant of permission to import or
manufacture a New Drug or to undertake clinical trial.
I/We ______ of ______ hereby apply for grant of
permission for import and / or clinical trial or for
approval to manufacture of a new drug or fixed dose
combination or subsequent permission of already
approved new drug.

Contd:
Application Form 44 (contd.)
With Information / Data Required
1. Particulars of New Drug:
• Name of the drug:
• Dosage form:
• Composition of the formulation:
• Test specifications:
– Active ingredients:
– Inactive ingredients:
• Pharmacological classification of the drug:
• Indications for which proposed to be used:
• Manufacturer of the raw material:
• Patent status:
Application Form 44 (contd.)
1. As Per Appendix 1
• Chemical and pharmaceutical information
• Animal pharmacology
• Animal toxicology
• Human / clinical pharmacology
• Exploratory clinical trials
• Confirmatory clinical trials
• Bioavailability / Bioequivalence, dissolution
and stability data
 Application Form 44 (cont.)

• Regulatory status in other countries

• Marketing information:
– Proposed product monograph
– Drafts of labels and cartons
• Application for test license: (next page)
Test License To Import New Drug
For Testing / Clinical trial Purpose

• Application:
–Form 12 application
–Material justification plan
–Treasury Challan of Rs 100 for first
drug, followed by Rs 50 for
additional drug
– License will be in Form 11
 New Drug Approval Committee (NDAC)
• Since April 2011, Twelve New Drug Approval
Committees (NDACs) were constituted to advise
DCG(I) in matters related to review and
regulatory approval of clinical trials and new
drugs {except INDs} of 12 different therapeutic
categories.
• Details of the NDACs along with the names of
the committee members are posted at CDSCO
web-site www.cdsco.nic.in

cdsa
New Drug Advisory Committee (NDAC)
“ New Drug Advisory Committee” (NDAC) to advise DCG(I) in matter
related to review & regulatory approvals of clinical trials and new drug
(except IND) of following categories :

1. Antibacterial, Antiparasitic & Antiviral,

2. Analgesics, Anesthetics and Rheumatology,
3. Cardiovascular and Renal,
4. Dermatology and Allergy,
5. Gastroenterology & Hepatology,
6. Metabolism & Endocrinology,
7. Neurology & Psychiatry,
8. Oncology & Hematology,
9. Ophthalmology,
10. Pulmonary,
11. Reproductive & Urology,
12. Vaccines.
( Details regarding names & addresses of subject Experts may be seen at www.
cdsco.nic.in
GAZETTE NOTIFICATION (GSR 702 E)
• GSR 702 ( E) dated 24th October 2013 defines –
“ Phytopharmaceutical drug” includes processed
or unprocessed standard material derived from
plants or parts thereof or combination of parts of
plants, extracts or fractions thereof in a dosage
form for internal or external use of human being or
animals and intended to be used for diagnosis,
treatment, mitigation or prevention of any disease
or disorder in human beings or animals, but does
not include administration by parenteral route”.
GSR 702 ( E) dated 24th October 2013 (Contd)
“ APPENDIX I-B” –Data to be submitted along with
Application to conduct Clinical Trial or Import or
Manufacture of a Phytopharmaceutical drug in the country.
PART-1:
1. Basic Information: Summary of the drug , including
name, route of administration, dosage, therapeutic
class.
- Relevant Published literature, Scientific reports
including product as a traditional medicine.
Information on contraindications, side effects and
present usage of the product.
GSR 702 ( E) dated 24th October 2013 (Contd)

2. Human or Clinical Pharmacology information:-

- Published Scientific Reports in respect of
pharmacological studies, human clinical trials
relevant to the drug.
- Pharmacodynamic information (if available)
- Pharmacopeia Monographs, if any on product,
extract or plant.
GSR 702 ( E) dated 24th October 2013
PART –II – Data generated by Applicant:
1. Pharmacognostic description: Morphological, Taxonomical
identity , Natural habitat & geographical distribution of Plant (s),
Season or time of collection, list of growers / suppliers etc.
• Quality Specifications: (a) Foreign matter, (b) moisture content;
( c) volatile matter, if any (d)total ash (e ) acid insoluble ash, (f)
extractive value; (g) pesticide residue;(h) heavy metal
contamination; (i) microbial load; (j) aflotoxins, if any (k)
chromatographic finger print profile with phytochemical reference
maker/(s); (l) assay for active constituent(s) or characteristic maker
if active constituents are not known.
2. Processing of Extract or Phytopharmaceutical:
• Quality Specifications & Test methods for starting material.
GSR 702 ( E) dated 24th October 2013 (Contd)
• Detail steps used in processing of phytopharma;
• Details of packaging, storage and labeling,
3. Formulation of Phytopharmaceuticals drug applied for:
• Details of composition, unit dose, name, all excipients,
Tests for identification and Quality specifications…..
4. Manufacturing process of Formulation:
• Outline method of manufacture, dosage form, in-process
quality control tests, packaging steps & final packs.
5. Stability Data:
6. Safety & Pharmacological Information:
GSR 702 ( E) dated 24th October 2013 (Contd)

7. Animal Toxicity and Safety Data:

• 28 to 90 days repeat dose oral toxicity in two
species (rodent & non-rodent as per Schedule-Y)
• In-vitro Genotoxicity (Ame’s test –Schedule-Y),
• Dermal toxicity for topical use products,
• Teratogenicity study ( only for product intended
for usage during pregnancy ),
8. Human Clinical Trials : Phase- I, Phase-II and
Phase- III as per Schedule- Y.
GSR 702 ( E) dated 24th October 2013 (Contd)
9. Regulatory status : Status of product out-side
India,
10.Marketing Information : Details of Package-
Insert,
11.Post Marketing Surveillance (PMS): Furnish
Periodic Safety Update Reports (PSUR) every six
months, for first two years after approval
granted.
Comments / Suggestions on GSR 702 (E )
1. This is regulatory provisions of defining
phytopharmaceuticals ( botanical-based drug) and will
be regulated under Chapter IV of D & C Rules
2. A schedule providing requirements of scientific data on
quality, safety and efficacy to evaluate and marketing
authorization for plant based drug.
3. Ayurveda, Siddha, and Unani (ASU) drugs are currently
regulated under Chapter IV-A of D & C Rules, hence the
said GSR 702 (E) will not have any impact on ASU
regulation.
4. Phytopharmaceuticals would need to be evaluated for
safety (Toxicology) & Efficacy as per Schedule Y .
Comments / Suggestions on GSR 702 (E )

5. The word “ Unprocessed Standardized Material”

should be deleted from definition.
6. Details of contaminants limits should be based
on daily consumption instead of per dose
content. (2008).
7. Safety study ( animal toxicity) may be exempted
in case of extract from 100% water.
Challenges and future perspectives:

• Develop mechanisms to recognize and not block

the traditional use, at the same time assuring the
quality, safety and efficacy of medicinal plants.
• Build policies and regulations aligned with
traditional practices,
• Regulation of Phytopharmaceuticals as “new
drugs”, ( under Rule 122 E)
• Need to engage in workshops and training courses
and Exchange of information,
Contact for Suggestions / Comments
E mail - ramteke.cdsa@thsti.res.in