Requirement WHO GMP guidelines for herbal drugs and herbal formulations

1. WHO GMP COMPLIANCE:
Mr.Shrikant Deshmukh
Dept:Regulatory(QA)
Pharmanza Herbal Pvt. Ltd.

2. Boswellia Serrata : Boswellia Serrata is a gum resin extracted from a tree,
which is sometimes burnt (the entire species of Boswellia is commonly known
as Frankinsence) Extracts of Boswellia Serrata have been clinically studied
for osteoarthritis and joint function, particularly for osteoarthritis of the
knee. Positive effects of Boswellia in some chronic inflammatory diseases
including rheumatoid arthritis,bronchial asthma, osteoarthritis, inflammatory
bowl disease .
Dose of B. Extract : 300-400 mg (Twice a day).
Active Ingredient :
1.α-Boswellic acid
2.β-Boswellic acid
3. 3-Acetyl- α-Boswellic acid
4. 3-Acetyl- β- Boswellic acid
5. Acetyl-11-keto- β- Boswellic acid ( AKBA)

3. Formulation product of Boswellia Serrata
Name: wokvel
Dosage form of Product: Tablet
Composition:
Quantity Category
Boswellia serrata extract 333 mg Active
Excipient :
Maize Starch 60 mg Binding agent
MCCP 50 mg Anticaking agent or Emulsifier
Di basic calcium phosphate 55 mg Flowing agent
Talcum powder 20 mg Protective agent
Sodium starch gluconate 15 mg Disintegrating agent
Magnesium stearate 20 mg Lubricant
n

4. Indications:
Osteoarthritis
Recommended Dosage:
Adult: 1– 2 tablets thrice daily or as directed by the physician
Presentation:
Tablets: Strips of 10 x 3 tablets.
Storage: Store in cool and dry place.stored out of reach of children.
Clinical Use: Wokvel is clinically shown to increase joint function and
flexibility while decreasing joint pain in patients with osteoarthritis.
Shelf Life: Best before 36 months from date of MFG.

5. CDSCO ( Central Drug Standard Control Organization )
1. The CDSCO of india is main regulatory body for regulation of
pharmacuetical, medical devices and clinical trials.Head office of CDSCO
is located in NEW DELHI and functioning under the control of
directorate general of health services , ministry of health and family
welfare Government of India.
Functions
1.Approval of new drugs and Clinical trials.
2. Import Registration and Licensing.(e.g-Licensing of Blood Banks,Vaccines
and some medical devices.)
3.Amendment to D&C Act and Rules.
4.Participation in WHO GMP Certification Schemes
5. Banning of drugs and cosmetics.
6. Grant to test licence,personal licence,NOC’S for export.
7. Publication of Indian Pharmacopoeia.
8.Monitoring adverse drug reactions
9. Licensing of manufacturing site for drugs including API and finished
formulation.
10. Recall of substandard drugs
11. Licensing for establishment of sale and distribution of drugs

6. Drug Controller General of India (DCGI)
1. He/She is a responsible for approval of New Drugs,Medical devices and
Clinical trials to be conducted in India which is appointed by Central
Government. and advised by Drug Technical Advisory Board (DTAB) and the
Drug Consultative Committee ( DCC).
WHO GMP CERTIFICATE
The application for grant of WHO GMP Certificate of Herbal product shall be
made to respective Zonal /Sub Zonal officers as per the requirement.The
COPP will be issued by Zonal/ Sub Zonal officers on behalf of Drugs Controller
General ( India) after inspection and satisfactory clearance by CDSCO officers
as per WHO-GMP Guidelines.

7. Zonal office Sub –Zonal office Central Drug Testing Laboratories
1.Mumbai
2.Kolkata
3.Chennai
4.Ghaziabad
5.Ahmedabad
6.Hyderabad
These are involved in
GMP audits and
inspection of
Manufacturing Unit.
1.Chandigarh
2. Jammu
3. Bangalore
These centre co-ordinate
with state
Drug control authorities
under their jurisdiction
for uniform standard of
inspection and
enforcement.
1.Kolkata
2.Mumbai
3.Chennai
4. Kasauli
5.Guwahati ( Regional)
6. Chandigarh ( Regional )
These laboratories are responsible
for quality control of drugs and
cosmetics in the country.

8. Introduction of WHO
1. It is specialized agency of United Nation (UN).
2. Established on 7th Apr 1948.
3. Who’s logo was chosen by the first world health assembly in 1948. The logo
consist of United Nation’s symbol surmounted by a staff with a snake coiling
around it. The staff with the snake has long been a symbol of medicine and
medical profession.
History of WHO
1.Constitution coming into force on the first ‘World Health Day’ (7 th APR 1948),
when it is ratified by 26 member state.
2. Under the control of IHC (International Health Conference).
3. In 1948,WHO had 56 member.

9. Structure and Governance for WHO
Regional offices and Regions of the WHO:
1. Africa: HQ: Brazzaville,Congo
2. America: HQ: Washington, USA
3. Eastern MED:HQ:Cairo,Egypt
4. Europe: HQ: Copenhagen,Denmark
5. South East Asia: HQ: New Delhi, India
6.Western Pacific: HQ: Manila,Philippines

10. Objective of WHO
Attainment by all people of the world a level of health that will permit them
to lead a socially & economically productive life.
Responsibility
1.solving Global health matters
2.Shaping the health research agenda (Schedule)
3. Setting norms and standards
4.Providing technical supports to countries
5.Monitoring and assessing health trends

11. WHO GMP Minimum Documents Checklist For Herbal Drug Products
1. Site Master File
2. Air Quality
3. Water Quality Manual
4. Standard testing procedures and specifications for raw materials,packaging
material ,Intermediate and Finished Products.
5.Market Complaints Record
6. Calibration Record
7.Process Validation
8.Analtical Method Validation
9.Clinical Validation
10.DQ/IQ/OQ/PQ
11. Internal Quality Audit Reports
12. Medical Check up record of Employees
13. Master Formula Record

12. WHO GMP Minimum Documents Checklists For Herbal Drug Products
14. Batch Manufacturing Record
15. Batch Packing Record
16. List of Machines and Equipment For Production and QA
17. List of Competant Technical Staff
18. Latest FDA Approved Plan
19. Approved Vendor List and Vendor Evaluation Record
20.Employee Training Record
21. Pest Control and Premises Maintenance Record (Sanitation ,Cleaning etc.)
22. Cloth Washing and Laudering Record
23. Preventive and Breakdown Maintenance Record
24. All Other Records as per WHO guidelines

13. Site Master File
It is a document which gives complete and factual information regarding
site of manufacturing plant. this document should not be very massive and
brief.
Content
1. Information about organization
2. Manufacturing activities at the site
3. Name and address of the site
4. Type of product manufactured at site
5. Description of plant and site
6. Employee details
7. Quality management system-I.Quality policy II.Responsibilities of QA

14. Air Quality
1. An air supply filtered through high-efficiency particulate air filters (HEPA)
under positive pressure, regardless of whether flow is laminar or non laminar.
2. HEPA filter (0.3 micrometers) generally tested for efficiency at the filter
manufacturing site using a thermally generated dioctylphalate ( DOP) aerosol
3. In Production area, Cold DOP test used for leak testing and pinhole
detection.
Water Quality Manual
It should include
1. Chemical and Microbiological Specifications
2. Sampling instructions
3. Testing Procedure
4. Responsible persons
5. Training requirements

15. Standard testing procedures for raw materials, packaging materials,intermediate
and finished products
A.Raw materials in the storage area should be labeled one which contains
following information
1.The designated name of product and the internal reference if applicable
2. Batch no. Given by supplier on receipt,batch no. Given by the maufacturer,if
any,documented so as to ensure tracebility.
3. The status of contents (e.g.released,rejected,returned,recalled,in quarantine).
4.Where appropriate,an expiry dateor a date beyond which retesting is necessary.
B. Packaging material should be issued for use only by designated personnel
followed an approved and documented procedure-
1.Each delivery or batch of printed or primary packaging material should be given
a specific reference number or identification mark.

16. 2. Outdated or obsolete primary packaging material or printed packaging
material should be destroyed or it’s disposal recorded.
3. All products and packaging materials to be used should be checked on
delivery to the packaging department for quantity ,identity and conformity
with the packaging instructions.
C. Intermediate and bulk products
1. It should be kept under appropriate conditions .
2.Intermediate and bulk products purchased as such should be handled on
receipt as though they were starting materials.
D. Finished products
Finished products should be held in quarantine until their final release by QA
department. then it is stored in storage department for further shipment.

17. Market Complaints Record
1.All market complaints should be carefully reviewed by designated person.
2. It should be recorded with all original details and throughly investigated.
3. Complaints records should be regularly reviewed for any indication of any
specific problems that require attention and might justify the recall of
marketed products.
Calibration records
All instruments and equipments should be routinely calibrated,inspected
or checked according to standard written procedure to assure proper
performance.Written records of calibration checks and inspection should
be maintained.
Process Vaidation
It is a documentary evidence for production process gives assurance about
that processes consistently capable of delivering quality products.

18. Analytical Process validation
Method validation is the process used to confirm that the analytical procedure
employed for a specific test is suitable for its intended use. Results from method
validation can be used to judge the quality, reliability and consistency of analytical
results; it is an integral part of any good analytical practice.
Cleaning validation
Documented evidence to establish that cleaning procedures are removing
residues to predetermined levels of acceptability, taking into consideration factors
such as batch size, dosing, toxicology and equipment size.
DQ/IQ/OQ/PQ
1.Design Qualification (DQ) : Documented evidence that the premises, supporting
systems, utilities, equipment and processes have been designed in accordance
with the requirements of GMP.
2. Installation Qualification (IQ) : installation qualifi cation (IQ) The performance of
tests to ensure that the installations (such as machines, measuring devices,
utilities and manufacturing areas ) used in a manufacturing process are
appropriately selected and correctly installed and operate in accordance with
established specifications

19. 3.Operational Qualification (OQ)
Documented verification that the system or subsystem performs as intended
over all anticipated operating ranges.
4.Performance Qualification (PQ)
Documented verifi cation that the equipment or system operates consistently
and gives reproducibility within defined specifications and parameters for
prolonged periods.
Internal Quality Audit Reports
The main purpose of audit report to evaluate the manufacturer’s compliance
with GMP in all aspects of production and QC. It should be designed to
detect any shortcomings in The implementation of GMP and to recommend
any necessary actions.
Master Formula
A document or set of documents specifying the starting material with their
quantities and packaging materials, t ogether with the description of the
procedures and precautions required to produce specific quantity of finished
product as well as the processing instructions including the in-process controls.

20. Batch manufacturing records
1. It should be prepared for each intermediate and API/formulation and should
include complete information relating to the manufacturing and control of each
batch.
2. The batch manufacturing record should be checked before issuance to assure
that it is the correct version and a legible accurate reproduction of the
appropriate master production instruction.
3. Before any processing begins, a check should be performed and recorded
to ensure that the equipment and workstation are clear of previous
products, documents, or materials not required for the planned process and
that the equipment is clean and suitable for use.
4.These records should be numbered with a unique batch or identification number
and dated and signed by QA department when issued.

21. Batch Packing Record
1. It should be kept seperate for each batch or part batch processed.
2. It should be assigned by unique identification number or version number
before issuance by QA department.
3. Before any processing begins, check shall be performed and recorded to
ensure that the equipment and work station are clear of previous products,
documents or materials not required for the planned process are removed
and that equipment is clean an suitable for use.
4. After checking all relvant parameters Qa person will gives line clearance
for further packaging activity.afer completion of packaging activity should
be reviewed by operation as well as QA person.

22. WHO Guidelines for regulation of herbal drug products and herbal
formulation in India
These guidelines aim to propose to member states a framework for facilitating
the regulation of herbal medicines/ products
They cover the following issues:
• Classification of herbal medicines
• Minimum requirements for assessment of safety of herbal medicine
• Minimum requirements for assessment of the efficacy of herbal medicines
• Quality assurance of herbal medicinal products
• Pharmacovigilance of herbal medicinal products
• Control of advertisements of herbal medicinal products

23. WHO Guidelines For the purpose of quality control of herbal drugs/herbal
formulation
World Health Organization has prepared accordingly guidelines. The
objectives put forth are provisions for recommended general test methods
and also the general limits for contaminants for herbal drugs. A typical
monograph for herbal drugs as per WHO guidelines is as follows:-
MONOGRAPH TITLE
1. Botanical
2. Physicochemical
3. Pharmacological
4. Toxicological

24. Botanical
Sensory Evaluation:- Visual Macroscopy / Touch / Odour / Taste
Foreign Matter:- Foreign plants, foreign animals, foreign minerals etc.
Microscopy:- Histological observation, Histochemical detection,
measurements etc.
Physicochemical
Ash:- In hot water, cold water and ethanol
Extractable Matter:- LOD, Azeotropic
Volatile Oils:- By steam distillation

25. Pharmacological
Bitterness Value:- Units equivalent to bitterness of standard solution of
quinine hydrochloride.
Haemolytic Activity:- On ox blood by comparison with standard reference
saponin
Astringency:- Fraction (tannins) that bind to standard hide powder
Swelling Index:- In water
Foaming Index:- Foam height produced by 1 gm material under specified
conditions.
Toxicological
Pesticide Residues:- Total organic chloride and total organic phosphorus
Arsenic:- Stain produced on HgBr₂ paper in comparison to standard stain
Heavy metals:- Cadmium (0.3 mg /kg)and Lead (10 mg/kg) as per Who
guideline

26. Microbial load
Microbes Crude drugs
for
Processing
Internal
Use
Topical
Use
1. Salmonellae - nil nil
2. Enterobacter
iacae
- 103 10⁴
3. Total Aerobic - 10⁵ 10⁷
4. E.Coli 10⁴ 10 102
Afflatoxins:- Totally free from it .
Radioactive contaminants :- As per recommendations of International
atomic energy agency (IAEA), Vienna, Austria. (wherever applicable
only)

27. Determination of pesticide residues as per Who Guidelines
An ARL (in mg of pesticide per kg of plant material) can be calculated on
the basis of the maximum acceptable daily intake of the pesticide for
humans (ADI), as, recommended WHO, and the mean daily intake
(MDI) of the medicinal plant material.
ADI = maximum acceptable daily intake of pesticide (mg/kg of body
weight); E = extraction factor, which determines the transition rate of the
pesticide from the plant material into the dosage form; MDI = mean daily
intake of medicinal plant product. 60 in Numerator = adult body weight;
100 in Denominator= Consumption factor.
ARL= ADI X E X 60/ MDI X 100

28. Some example of Pesticides
Chlorinated hydrocarbons : BHC, DDT
Chlorinated phenoxyalkanoic acid herbicides: 2,4-D; 2,4,5-T
Organophosphorus pesticides: malathion, methyl parathion, parathion
Carbamate insecticides: carbaryl (carbaril)
Dithiocarbamate fungicides: ferbam, maneb, nabam, thiram, zineb
Inorganic pesticides: calcium arsenate, lead arsenate
Miscellaneous: ethylene dibromide, ethylene oxide, methyl bromide

29. References
1. WHO Traditional Medicine Strategy: 2002–2005. Geneva, World Health
Organization, 2002 (WHO/EDM/TRM/2002.1).
2. Quality control methods for medicinal plant materials. Geneva, World Health
Organization, 1998.
3. WHO guidelines on good agricultural and field collection practices (GACP) for
medicinal plants. Geneva, World Health Organization, 2003.
4. International pharmacopoeia, 4th ed., Vol. 1. Geneva, World Health
Organization, 2006.
5. International pharmacopoeia, 4th ed., Vol. 2. Geneva, World Health
Organization, 2006.