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1. Herbal drug regulations &
standardization
Ravish Yadav

2. Content
• Quality control of herbal drugs as per WHO guidelines.
• Herbal regulatory issue
• Safety parameters, toxicity concerns and herb- drug
interactions
• Herb patent case study
• Schedule T
• Schedule Y
• Proposed Schedule Z & shelf-life
• Standardization of marker of Phytoconstituents

3. Quality control of herbal drugs
(WHO guideline)
1. Authentication (stage of collection, parts of the plant
collected, regional status, botanical identity like
phyto-morphology, Microscopical and histological
analysis, taxonomical identity, etc.)
2. Foreign matter (herbs collected should be free from
soil, insect parts or animal excreta, etc.)
3. Organoleptic evaluation (sensory characters – taste,
appearance, odour, feel of the drug, etc.)
4. Tissues of diagnostic importance present in the drug
powder.

4. Quality control of herbal drugs
(WHO guideline)
5. Volatile matter
6. Moisture content determination
7. Chromatographic and spectroscopic evaluation.
9. Determination of heavy metals –
e.g. cadmium, lead, arsenic, etc.
9. Pesticide residue
10. Microbial contamination
11. Radioactive contamination

6. Regulation in India
• Herbal drugs are regulated under the Drug and Cosmetic
Act (D and C) 1940 and Rules 1945 in India, where
regulatory provisions for Ayurveda, Unani, Siddha medicine
are clearly laid down.
• Department of AYUSH is the regulatory authority and
mandate that any manufacture or marketing of herbal
drugs have to be done after obtaining manufacturing
license, as applicable.
• The D and C Act extends the control over licensing,
formulation composition, manufacture, labelling, packing,
quality, and export.
• Schedule “T” of the act lays down the good manufacturing
practice (GMP) requirements to be followed for the
manufacture of herbal medicines.

7. Regulation in India
• The official pharmacopoeias and formularies are
available for the quality standards of the medicines.
First schedule of the D and C Act has listed authorized
texts, which have to be followed for licensing any
herbal product under the two categories: ASU drugs &
Patent or proprietary medicines.
• In India, traditional medicines are governed by the
Drugs and Cosmetics Act of 1940 and the Drugs and
Cosmetics Rules of 1945. They regulate the import,
manufacture, distribution and sale of drugs and
cosmetics.

8. Regulation in India
• In 1959, the Government of India recognized the traditional Indian
systems of medicine and amended the Drugs and Cosmetics Act
to include drugs which are derived from traditional Indian
medicine.
• No products derived from traditional systems may be
manufactured without a licence from the State Drug Control
Authorities.
• Patent and proprietary medicines derived from the traditional
systems must contain ingredients which are mentioned in the
recognized books of the above systems, as specified in the Drugs
and Cosmetics Act.
• The government is advised by a special committee and an
advisory board for Ayurvedic, Siddha and Unani drugs.
Pharmacopoeia committees have been constituted to prepare
pharmacopoeias for all these systems

9. Regulation in US
• The botanical products are classified as a drug, food or
a dietary supplement by the United States Food and
Drug Administration on the basis of the claims or end
use.
• A product that is used to prevent, diagnose, mitigate,
treat or cure a disease would fall under the category of
drug.
• If the intended use of a botanical product is to affect
the structure or function of the human body, it may be
classified as either a drug or a dietary supplement.
• As per FDA, the drug must be marketed under an
approved New Drug Application (NDA).

10. Regulation in US
• FDA regulates the dietary supplements under the
Dietary Supplement Health and Education Act of 1994.
• These do not require premarket approval and it’s the
responsibility of the marketer to ensure the safety and
labelling compliance of their products with the
regulations.
• The claims need to comply with the regulatory
guidelines issued by the FDA.
• The manufacturing of dietary supplements should be
done as per the current GMP for dietary supplements

11. Regulation in Australia
• Therapeutic Goods Administration, the regulatory
agency of Australia, regulate herbal products under the
category of complementary medicine.
• Ayurvedic medicine, traditional Chinese medicine, and
Australian indigenous medicines are all covered under
this category
• Complementary medicines which do not require
medical supervision are permitted and have to be
entered on the Australian Register for Therapeutic
Goods (ARTG) before marketing

12. Regulation in Australia
• The low-risk medicines require to be listed while the
medicines for comparatively higher risk therapeutic
conditions require registration on the ARTG.
• Only evidence-based claims which are entered on the
ARTG are allowed.

13. Regulation in Canada
• Since January 1, 2004, Health Canada regulates herbal
remedies and traditional medicines such as Ayurvedic
medicine, under the natural health products
regulations.
• The regulations mandate that a manufacturer, packer,
labeler or importer need to have a prior registration
with Health Canada before commencing any such
activity.

14. Regulation in Canada
• The process involves registration of the manufacturing
site/s along with the products. Complete data on
product composition, standardization, stability,
microbial and chemical contaminant testing methods
and tolerance limits, safety and efficacy along with
ingredient characterization, quantification by assay or
by input needs to be submitted to Natural Health
Product Directorate (NHPD).
• The authority mandate that NHPs must comply with
the contaminant limits and must be manufactured as
per the GMP norms

15. Regulation in European union
• The European Medicine Agency have laid down two
ways of registration of herbal medicinal products:
• (1) A full marketing authorization by submission of a
dossier, which provides the information on quality,
safety and efficacy of the medicinal products including
the physicochemical, biological or microbial tests and
pharmacological, toxicological and clinical trials data;
under directive 2001/83/EC

16. Regulation in European union
• (2) For traditional herbal medicinal products, which do
not require medical supervision, and where evidence of
long traditional of use of medicinal products exists,
and adequate scientific literature to demonstrate a
well-established medicinal use cannot be provided, a
simplified procedure under directive 2004/24/EC exists.
• The evidence of traditional use is accepted as evidence
of efficacy of the product. However, authorities may
still ask for evidence to support safety.

17. Regulation in European union
• Quality control requirements require physicochemical and
microbiological tests to be included in the product
specifications. The product should comply to the quality
standards in relevant pharmacopoeias of the member state
or European Pharmacopoeia.
• The bibliographic evidence should support that the
product has been in medicinal use for at least 30 years out
including at least 15 years within the European community.
• The application for traditional use registration shall be
referred to the Committee for Herbal Medicinal Products, if
the product has been in the community for less than 15
years, but otherwise qualifies for the simplified registration
procedure under the directive.

18. Herb drug interactions
• Many medicinal herbs and pharmaceutical drugs are
therapeutic at one dose and toxic at another.
• Interactions between herbs and drugs may increase or
decrease the pharmacological or toxicological effects
of either component.
• Synergistic therapeutic effects may complicate the
dosing of long-term medications-
• E.g. herbs traditionally used to decrease glucose
concentrations in diabetes1 could theoretically
precipitate hypoglycaemia if taken in combination with
conventional drugs.

19. Herb drug interactions
• E.g. herbs traditionally used to decrease glucose
concentrations in diabetes1 could theoretically
precipitate hypoglycaemia if taken in combination with
conventional drugs.
• Herbal medicines are ubiquitous: the dearth of reports
of adverse events and interactions probably reflects a
combination of under-reporting and the benign nature
of most herbs used.
• increase or decrease the effect of a blood thinner such
as Warfarin and lead to either a bleeding episode or
formation of a dangerous clot;

20. Herb drug interactions
• decrease the effect of a blood pressure medication,
leading to high blood pressure and a stroke;
• decrease the effect of an anti-infection agent, letting
the infection get out of control; or
• increase the effect of an anti-diabetes drug and plunge
blood sugar to dangerously low levels.

21. Herb drug interactions
Garlic
• Allium sativum (garlic) decreased the area under the
plasma concentration-time curve (AUC) and maximum
plasma concentration of saquinavir, but not ritonavir
and paracetamol (acetaminophen), in volunteers.
• A. sativum increased the clotting time and
international normalised ratio of warfarin and caused
hypoglycaemia when taken with chlorpropamide.

22. Herb drug interactions
Ginkgo
• Ginkgo biloba (ginkgo) caused bleeding when
combined with warfarin or aspirin (acetylsalicylic acid),
raised blood pressure when combined with a thiazide
diuretic and even caused coma when combined with
trazodone in patients.

23. Herb drug interactions
Ginseng
• Panax ginseng (ginseng) reduced the blood
concentrations of alcohol (ethanol) and warfarin, and
induced mania when used concomitantly with
phenelzine (MAOI), but ginseng increased the efficacy
of influenza vaccination.

24. Herb drug interactions
St. john’s wort
• Hypericum perforatum (hypericum; St John's wort)
decreased the blood concentrations of ciclosporin
(cyclosporin), midazolam, tacrolimus, amitriptyline,
digoxin, indinavir, warfarin, phenprocoumon and
theophylline, but did not alter the pharmacokinetics of
carbamazepine, pravastatin, mycophenolate mofetil
and dextromethorphan.

25. Herb drug interactions
St. john’s wort
• Cases have been reported where decreased ciclosporin
concentrations led to organ rejection. Hypericum also
caused breakthrough bleeding and unplanned
pregnancies when used concomitantly with oral
contraceptives.
• It also caused serotonin syndrome when used in
combination with selective serotonin reuptake
inhibitors (e.g. sertraline and paroxetine).

26. Patent case study
• Pharmaceutical compositions comprising hemp and
turmeric to treat pain and inflammation
• WO 2015171445 A1
• ABSTRACT
• The present invention comprises compositions
comprising therapeutically effective amounts of CBD
and curcumin in various combinations to treat pain.
CBD and curcumin are preferably from natural sources.
A method of using the combination of CBD and
curcumin compositions to treat pain is also described.

27. Patent case study
• Publication number WO2015171445 A1
• Publication type Application
• Application number PCT/US2015/028718
• Publication date 12 Nov 2015
• Filing date 1 May 2015
• Priority date 6 May 2014
• Inventors Mewa Singh
• Applicant Mewa Singh
• Export Citation BiBTeX, EndNote, RefMan

28. Patent case study
WHAT IS CLAIMED :
• 1. A composition for treating pain comprising a
therapeutically effective amount of cannabidiol (CBD)
and curcumin.
• 2. The composition of claim 1, further comprising at
least one of: magnesium or ginger.
• 3. The composition of claim 1, wherein the CBD and
curcumin comprises natural sources of CBD and
curcumin.
• 4. The composition of claim 1 , wherein the natural
source of CBD comprises CBD producing hemp and
the natural source of curcumin comprises turmeric.

29. Patent case study
5. The composition of claim 4, wherein the CBD comprises
a liquid or a powder extract of a cannabis plant and the
curcumin comprises a liquid or a powder extract from a
turmeric root.
6. The composition of claim 5, wherein the CBD extract
comprises at least 80% (w/w) CBD to total cannabinoid
content.
7. The composition of claim 5, wherein the curcumin
extract comprises at least 2% by weight curcuminoid
content.
8. The composition of claim 5, wherein the weight ratio of
CBD extract to curcumin extract comprises about 1 : 1 to
about 1 :5.

30. Patent case study
9. The composition of claim 5, wherein the weight ratio of
CBD in the CBD extract and curcuminoid in the curcumin
extract comprises about 1 : 1 to about 1 : 10.
10. The composition of claim 5, wherein the composition
comprises a water soluble dosage form.
11. The dosage form of claim 10, wherein the dosage form
comprises a capsule, tablet or liquid.
12. The dosage form of claim 11 , wherein the dosage form
comprises a capsule.

31. Patent case study
13. A method of treating pain comprising: a) selecting a
patient in need of treatment for pain; b) administering to
the patient a therapeutically effective amount of CBD and
curcumin, wherein the patient is treated.
14. The method as claimed in claim 13, wherein the pain
comprises acute pain, chronic pain, or acute and chronic
pain.
15. A method of treating pain comprising administering to
a patient the composition of claim 1.
16. A method of treating pain comprising administering to
a patient the composition of claim 2.

32. Patent case study
17. A method of treating pain comprising administering to
a patient the composition of claim 4.
18. A method of treating pain comprising administering to
a patient the composition of claim 5.
19. A method of treating pain comprising administering to
a patient the capsule of claim 12.

33. • Trade-Related Aspects of Intellectual Property Rights
• GI geographical indication

34. Schedule T
The Good Manufacturing Practices (GMP) are prescribed as
follows in Part I and Part II to
ensure that:
I. Raw materials used in the manufacture of drugs are
authentic, of prescribed quality and are free from
contamination.
II. The manufacturing process is as has been
prescribed to maintain the standards.
III. Adequate quality control measures are adopted.
IV. The manufactured drug which is released for sale is
of acceptable quality.

35. Schedule T
• To achieve the objectives listed above, each licensee shall
evolve methodology and procedures for following the
prescribed process of manufacture of drugs which should
be documented as a manual and kept for reference and
inspection. However, under IMCC
• (Indian Medicine Central Council Act, 1970) Act 1970
registered Vaidyas, Siddhas and Hakeems who prepare
medicines on their own to dispense to their patients and
not selling such drugs in the market are exempted from
the purview of G.M.P.

36. Schedule T
• PART-I
• GOOD MANUFACTRING PRACTICES
• Factory Premises:
• The manufacturing plant should have adequate space for:-
(i) Receiving and storing raw material
(ii) Manufacturing process areas
(iii) Quality control section
(iv) Finished goods store
(v) Office
(vi) Rejected goods/drugs store

37. Schedule T
• General Requirements:
• Location and surroundings
• Buildings
• Water supply
• Disposal of waste
• Containers’ cleaning
• Stores
• Raw materials
• Packaging material
• Finished goods stores

38. Schedule T
• Working space
• Heath, clothing, sanitation and hygiene of workers
• Medical services
• Machinery and equipment's
• Batch manufacturing records
• Distribution records
• Record of market complaints
• Quality control

39. Schedule T
• Requirement for Sterile product
• Manufacturing areas
• Precautions against contamination and mix

40. Schedule T
• Requirement for Space for ASU
• 200 sq. feet: Asava, Arishta, Churna /
Nasya/Manjan/Lepa/Kwath Churn Sufoof (powder)
• 150 sq. feet: Kupi pakava/Ksara/ Parpati/Lavana Bhasma
Satva/Sindura Karpu/ Uppu /Param, Panak, Syrup / Pravahi
Kwath Manapaku,
• 100 sq. feet: Anjana/Pisti, Pills/Vati /Gutika, Matirai and tablets,
Kajal, Capsule, Marham, ointment, Pak/Avaleh/Khand/
Modak/Lakayam, Ark Tinir, Sura, Taila, Ghrit ney, Aschyotan /
Netra Malham, Panir/Karn Bindu/Nasabindu, Habb (Pills) and
tablets, Arq,

41. Schedule Y for Herbal Drugs
• All of the fundamental ethical principles of human participation in research
apply equally to herbal remedies and research involving these compounds.
• Consent must be obtained, subject selection must be equitable, risks and
benefits must be weighed and must be favourable to the potential
participant, and experimental design must be sound.
• Concerns that particularly apply to clinical trials with herbal products
include:
• Product adulteration (has it been documented?)
• Interactions between herbal remedies and other entities (rarely understood)
• Reproductive and organ toxicity data (may be minimal)
• Prior dose finding (likely to be incomplete).

42. Schedule Y for Herbal Drugs
• Category 1: already in use for more than 5 years
• Category 2: in use for less than 5 years
• Category 3: new medicines.
• For the herbal remedies and medicinal plants that are to be clinically
evaluated for use in the Allopathic System and which may later be used in
allopathic hospitals, the procedures laid down by the office of the Drugs
Controller General of India for allopathic drugs should be followed.
• When an extract of a plant or a compound isolated from the plant has to be
clinically evaluated for a therapeutic effect not originally described in the
texts of traditional systems or, the method of preparation is different, it has
to be treated as a new substance or new chemical entity (NCE) and the same
type of acute, sub acute and chronic toxicity data will have to be generated
as required by the regulatory authority before it is cleared for clinical
evaluation.

43. Schedule Y for Herbal Drugs
• An extract or a compound isolated from a plant, which has never been in use
before and has not ever been mentioned in ancient literature, should be
treated as a new drug, and therefore, should undergo all regulatory
requirements before being evaluated clinically.
• The document also provides general guidelines on clinical trials of herbals,
toxicity studies, need for standardization, and compliance with GCP in all
clinical trials.
• Some of the recommendations are:
• Clinical trials should be carried out with herbal preparations only after
standardization and identification of markers to ensure that the substances
being evaluated are always the same.
• Plants and herbal remedies should be prepared strictly in the same way as
described in the literature while incorporating GMP norms for
standardization.

44. Schedule Y for Herbal Drugs
• Herbal remedies, Phase 1 studies must be undertaken to check Maximum
tolerarated dose (MTD) & Early Measurement of Drug activity.
• If there are reports suggesting toxicity or when the herbal preparation is to
be used for more than 3 months, toxicity studies (4-6 weeks toxicity study in
2 species) are needed for phase 2 trials.
• For Phase 3 trial toxicity studies (4-6 weeks toxicity study in 2 species) are
needed.
• Ethical guidelines (patient information, informed consent, protection of
vulnerable populations etc) for biomedical research should be followed.
• Clinical trials should to be approved by the appropriate scientific and ethical
committees of the concerned Institutes.
• Clinical trials should be carried out only when a competent Ayurvedic,
Siddha or Unani physician is a co-investigator.

45. Herbal Drug Regulations
• Schedule Z: Proposed: Requirements and Guidelines for permission to
manufacture of ASU Drugs for sale or to undertake clinical trials
• Updated shelf life

46. Marker standardization
• Volatile Oil: Eugenol
• Glycoside: Digitoxin
• Resin: Curcumin
• Flavonoids: Quercetin
• Irridoids: Gentiopicroside

47. Marker standardization
Volatile Oil: Eugenol
• Species: Cinnamomum zeylanicum
• Eugenia caryophyllus
• TLC Mobile Phase
• Toluene: Ethyl acetate (93:7)
• Detection: Vanillin H2SO4 & Visible light
• Observation: Pinkish red spot
• Rf value: 0.9
• Eugenol oil on treatment with KOH, produces Potassium
eugenate crystals

48. Marker standardization
Glycoside: Digitoxin
• Species: Digitalis lanata
• Digitalis purpurea
• TLC Mobile Phase
• Ethyl acetate: Methanol: Water (81:11:8)
• Detection: Kedde reagent & Visible light
• Observation: Grey to Violet grey color spot
• Detection: SbCl3 & UV-365
• Observation: Dark blue fluorescence
• Rf value: 0.05-0.95
• Keller-killiani test for Cardiac glycoside

49. Marker standardization
Glycoside: Glycyrrhizin (K+ salt)
• Species: Glycyrrhiza glabara
• TLC Mobile Phase
• Chloroform: Methanol: Water (64:50:10)
• Detection: UV 254 nm
• Rf value: 0.25-0.3- Glycyrrhizin
• Detection: Anisaldehyde H2SO4 reagent
• Observation: Pink-violet spot
• Rf value: 0.24- Glycyrrhizin
• 0.6-0.8 - Liquiritin

50. Marker standardization
Resin: Curcumin
• Species: Curcuma longs
• Curcuma domestica
• TLC Mobile Phase
• Cholorofrom: Ethanol: Glacial acetic acid (95:5:1)
• Detection: UV-365
• Observation: Yellow
• Rf value: 0.3 – bisdemethoxycurcumin
• 0.5-0.55 – demethoxycurcumin
• 0.6 – curcumin

51. Marker standardization
Flavonoids: Rutin
• Species:
• TLC Mobile Phase
• Ethyl acetate: Formic acid: Glacial acetic acid: Water
(100:11:11:26)
• Detection: UV-365
• Observation: Yellow orange
• Rf value: 0.4 – Rutin
• Shinoda test for Flavonoids

52. Marker standardization
Irridoids: Gentiopicroside
• Species: Gentiana lutea
• TLC Mobile Phase
• Ethyl acetate: Methanol: Water (77:15:8)
• Detection: Vanillin H2SO4 & Visible light
• Observation: brown-violet spot
• Rf value: 0.45 (gentiopicroside)
• Detection: UV 245 nm
• Rf value: 0.4 – swetiamarine
• 0.45 – gentiopicroside
• 0.8 – amarogentin