ZAMBIA MEDICINES REGULATORY AUTHORITY

GUIDELINES ON APPLICATION FOR

REGISTRATION OF HERBAL
MEDICINES

First Edition
Table of Contents

Page
Foreword……………………………………………………………………....3
Acknowledgments………………………………………………………….....4
Introduction…………………………………………………………………….5
Abbreviations…………………………………………………………………...6
Definitions………………………………………………………………….…...7
PART A: General requirements……………………………………………..10
PART B: Summary of product characteristics……………………………...17
PART C: Quality requirements……………………………………………...18
PART D: Safety data………………………………………………………....26
PART E: Efficacy data………………………………………………………...27
PART F: Application form………………………………………………….....28
Foreword
There has been a marked increase in the use of herbal medicines in the recent
past. Herbal medicines are not only used for primary health care of the poor in
developing countries but also in countries where conventional medicines are
predominant in the national health care system.

With the expansion in the use of these medicines world wide, quality, safety and
efficacy have become a challenge both to medicines regulatory authorities and
the public. These guidelines have been developed to provide requirements in
support of quality, safety and efficacy in respect of herbal medicines meant to be
placed on the Zambian market.

One of the means for ensuring that a herbal medicinal product meets the
required standards of quality, safety and efficacy is by conducting product
specific pre-marketing assessments to determine whether the product should be
registered.

Submission of adequate documentation on quality, safety and efficacy of a herbal

medicine will enable the PRA to use the information and other factors to assess
the suitability of the product for the intended use.

Compliance to these guidelines in the submission of applications will facilitate the

speedy processing and evaluation of the applications and subsequent
registration of the products. This will enable the product prospective licence
holders to market their products on time and make them available to the
consumers in a timely manner.

It is therefore my sincere hope that these guidelines will provide the necessary
information in preparing and submitting documents for registration of herbal
medicinal products in Zambia.

Finally, I wish to urge our esteemed readers and applicants to read this first
edition of guidelines carefully and make as many suggestions as possible so that
we have a version of the guidelines that are commensurate with current
practices.

Dr S.M. Miti
PERMANENT SECRETARY
Ministry of Health
Acknowledgments

The Ministry of Health (MoH) and the Pharmaceutical Regulatory Authority (PRA)
wish to acknowledge the immense contributions of individuals and originations
that constituted the Technical Working Group in developing these guidelines. The
principal contributors for this guidance document were:

1. Professor Karashani: Ethics & Research Committee, UTH

2. Ms Esnat Mwape: Director General, PRA
3. Dr Yona Sinkala: Veterinary Surgeon, Dept. of Veterinary
& Livestock Development, Lusaka
4. Dr G. Chishimba: Medical Practitioner, National AIDS Council
5. Ms Anne Zulu: Pharmacist, Medical Stores Limited
6. Dr K Choongo: Lecturer, UNZA School of Veterinary Medicine
7. Ms Loyce Lishimpi: National Profession Officer, WHO
8. Mrs Bernice C. Mwale: Director-Product Registration, PRA,
9. Mr. Felix P. Chizu: Regulatory Officer, PRA
10. Dr Zuma Munkombwe: Regulatory Officer, PRA
11. Mr. Pelekelo Mangisha: Assistant Regulatory Officer, PRA

The MoH and PRA would further like to thank the World Health Organisation
(WHO) for providing financial and technical support to the development of these
guidelines.

Ms E. Mwape
DIRECTOR-GENERAL
Pharmaceutical Regulatory Authority
Introduction

The Pharmaceutical Act No 14 of 2004 requires that products intended to be marketed in

Zambia meet appropriate standards of good quality, safety and efficacy. Also they
should be manufactured in facilities, which comply with cGMP requirements. One of the
means for ensuring that Herbal Medicinal products meet the required standards of good
quality, safety and efficacy is by conducting product specific pre-marketing assessments
to determine whether the product should be registered.

These Guidelines have been prepared to provide information to applicants who intend to
register Herbal Medicinal products in Zambia.

This document has been developed by the Pharmaceutical Regulatory Authority (PRA)
to provide guidance to applicants on the content and format of the Chemistry and
pharmaceutical data of such products required for their complete scientific evaluation for
quality, safety and efficacy. These guidelines also indicate the order of the material to
be submitted and the minimum requirements for product registration. Compliance to
these guidelines in the submission of applications will facilitate the speedy processing
and evaluation of the application and hence the product licensing. This will enable the
prospective licence holders to market their products on time and make them available to
the consumers. In view of this, applicants are advised to read these guidelines carefully
and adhere in full to the prescribed instructions.
Abbreviations
µg Microgram
API Active Pharmaceutical Ingredient
ATC Anatomic Therapeutic Chemical classification
AUC Area under the plasma concentration time curve
BE Bioequivalence studies
BP British Pharmacopoeia
CASR Chemical Abstract Service Registry Number
cGMP current Good Manufacturing Practices
CI Confidence Interval
Cmax Maximum plasma concentration
CV Coefficient of Variation
e.c Enteric coated
f.c Film coated
FDC Fixed Dose Combination
FP Finished Product
GCP Good Clinical Practice
GLP Good Laboratory Practice
GMP Good Manufacturing Practice
GS General Sale
HPLC High power Liquid Chromatograph
i.m Intramuscular
i.v Intravenous
INN International Non-proprietary Name
IP International Pharmacopoeia
IR Infra red spectroscopy
IU International Unit
IUPAC International Union for Pure and Applied Chemistry
JP Japanese Pharmacopoeia
M.R Modified Release
mg Milligram
ml Millilitre
MRA Medicines Regulatory Authority
P Pharmacy
Ph. Eur European Pharmacopoeia
POM Prescription Only Medicines
PRA Pharmaceutical Regulatory Authority
RF values-Retention factors
RH Relative Humidity
s.c Sugar coated
SPC Summary of Product Characteristics
SR Sustained release
TE Therapeutic Equivalence
TLC Thin layer chromatography
Tmax Time to reach maximum plasma concentration
USP United States Pharmacopoeia
VICH International Conference on Harmonization of Technical
WHO World Health Organization
Definitions

Active pharmaceutical ingredient (API) means a substance or compound that is

intended to be used in the manufacture of a pharmaceutical product as a therapeutically
active compound (ingredient).

Authority Means the Pharmaceutical Regulatory Authority established under

Section 4 of the Pharmaceutical Act No 14 of 2004.

Bio-equivalence Two pharmaceutical products are bioequivalent if they are

pharmaceutically equivalent or alternatives and their bio-availabilities (rate and extent of
availability), after administration in the same molar dose, are similar to such a
degree that their effects can be expected to be essentially
the same.

Composition Composition in relation to a Herbal medicinal product means the

ingredients of which it consists, proportions, degree of strength, quality and purity in
which those ingredients are contained.

Container Means a bottle, jar, box, packet, sachet or other receptacle which
contains or is to contain in it, not being a capsule or other article in which the product is
or is to be administered or consumed, and where any such receptacle is or is to be
contained in another receptacle, includes the former but does not include the latter
receptacle.

Container labelling
Means all information that appears on any part of a container, including
that on any outer packaging such as a carton.

Established active pharmaceutical ingredient

Means APIs which are subject of the current pharmacopoeias or those well documented
in the literature and generally recognized as safe and effective for use as a medicine.

Excipient
Means any component of a finished dosage form which has no therapeutic
Value

Expert report
Means a summary and interpretation of data, with conclusions, prepared
by an independent competent person.

Finished product
Means a product that has undergone all stages of production, including
packaging in its final container and labelling

Formulation
Means the composition of a dosage form, including the characteristics of its
raw materials and the operations required to process it.

Herbal Medicine means any medicinal product that contains, as active ingredients,
aerial or underground parts of plants other plant material or combination thereof,
whether in a crude state or as plant preparations and includes herbal medicines which
contain, organic or inorganic active ingredients and are processed or packed in such a
manner that they appear like medicines under the western system but do not include
medicines containing plant materials combined with chemically defined active
substances, or chemically isolated constituents of plants.

Immediate release dosage form

Means a dosage form that is intended to release the entire active ingredient
on administration with no enhanced, delayed or extended release effect.

Impurities include by-product of synthesis arising from side reactions products in

starting materials etc., residual solvents and reagents, trace elements arising from other
sources and products of degradation

Innovator (or pioneer) pharmaceutical product

Means a pharmaceutical product which was first authorized for marketing
(normally as a patented product) on the basis of documentation of efficacy,
safety and quality

Label Means any tag, brand, mark, pictorial or other descriptive matter, written,
printed, stenciled, marked, embossed or impressed on or attached to a
container of any Medicines

Manufacture Means production, quality control, release and packaging of a product.

Manufacturer Means a firm that is engaged in the manufacture of products

New active pharmaceutical ingredient Means a Medicine (active ingredient), including

its salts, esters, derivatives, etc. or biological agent, which is not a subject of current
pharmacopoeias.

Pharmacopoeia Includes but not limited current edition of the British Pharmacopoeia,
European Pharmacopoeia, United States Pharmacopoeia, International Pharmacopoeia
and Japanese Pharmacopoeia.

Pharmaceutical alternatives Two or more medicinal products are said to be

pharmaceutical alternatives if they contain the same active ingredients, but which may
differ in salt, esters, dosage forms, strength and/ or route of administration.

Pharmaceutical equivalents Products are pharmaceutical equivalents means products

that contain the same amount of the same active substance(s) in the same dosage form;
if they meet the same or comparable standard; and if they are intended to be
administered by the same route.

Retention fee
Means a fee paid annually to maintain product licence.

Shelf life Specifications

Means the combination of physical, chemical, biological and microbiological test
requirements that an active ingredient should meet up to its retest date or a Medicines
product should meet during its shelf life.

Shelf Life
Means the combination of physical, chemical, biological and microbiological test
requirements that determine whether a Medicines product is suitable for release at the
time of its manufacture

Therapeutic equivalence
Two pharmaceutical products are therapeutically equivalent if they are pharmaceutically
equivalent and, after administration in the same molar dose, their effects with respect to
both efficacy and safety essentially the same, as determined from appropriate
bioequivalence, pharmacodynamic, clinical or in vitro studies.

WHO-type certificate
Means a certificate of pharmaceutical product of the type defined in the WHO
Certification Scheme on the Quality of Pharmaceutical Products Moving in International
Commerce

Proprietary name
Means the (trade or brand) name, which is unique to a particular Medicines and by
which it is generally identified (and by which it is registered in the country of
manufacture).

Approved/ INN / generic name

In relation to Medicines mean the internationally recognized non-proprietary name of
such Medicines.

Dosage form
Means the form in which the Medicines is presented, e.g. solution, suspension,eye
drops, emulsion, ointment, suppository, tablet, capsule, etc. For injections, the type of
presentation (e.g. vial, ampoule, dental cartridge, etc), and the type of content (e.g.
powder for reconstitution, solution, suspension, oily solution, etc.) shall also be stated.

Description of the product

means a full visual description of the Medicines including colour, size, shape and other
relevant features, e.g. „black and red gelatin capsule with marks “Amp -250”, „pink film
coated tablets with word “PAN” embossed on one side‟ etc.

Commercial Presentation
Means the final product pack as it will be presented in the market (e.g. 10 ampoules of
2ml each, 10 blister packs of 10capsules each, etc.)

Prescription Only Medicine (POM)

The products in this category are available from pharmacies/dispensaries only.
All products in the above three categories are available upon presentation of a
prescription from a prescriber to a licensed pharmacy/dispensary.

Pharmacy Medicine (P)

These products are available from licensed pharmacies only.

General Sales Medicines (GS)

Medicines in this category are available in pharmacies, dispensaries and all licensed
trade supermarkets.

Strength of the medicinal product

Means the content of the active ingredient expressed quantitatively per dosage unit, per
unit of volume or mass or weight according to the dosage form;

Immediate packaging
Means container or other form of packaging, which is immediately in direct contact with
the medicinal product;

Outer packaging
Means the packaging into which is placed the immediate packaging;

Labelling
Means the information contained on the immediate or outer packaging;

Package insert
Means a leaflet containing information for the prescriber and the dispenser;

Patient information leaflet

Means a leaflet containing information for the patient;

Product licence Holder means a person or company under whom a medicinal product
has been registered. This party is responsible for all aspects of the medicinal product
including quality, safety, efficacy and compliance with conditions of registration.
 PART A. GENERAL REQUIREMENTS

All application shall be made by submitting a duly filled in application form

accompanied with information as prescribed in these guidelines.
All documents shall be in English language
Where original licences are in another language, copies shall be presented
together with certified English version.

Applicants

An application for registration of herbal medicines can be made by owner of the

product (an individual, body corporate, partners or registered business)
responsible for the manufacture or to whose order the product is manufactured
for sale in Zambia.

The applicant shall be responsible for the product information supplied in support
of his/her application for registration and amendments thereof.

Responsible local Distributor

Every applicant who is not resident in Zambia shall nominate a licensed

pharmaceuticals importer in Zambia to be responsible local distributor. Every
nominee shall submit a power of attorney as evidence of his/her nomination.

Responsibilities of local Distributor, applicant and manufacturer

The responsibilities of the local agent, applicant and manufacturer shall be –

i. To monitor the product on the market and inform the Authority immediately
after the detection of any problem relating to registered product such as
serious manufacturing defects which may endanger public health.
ii. The Local Distributor shall facilitate communication between the applicant and
the Authority on matters relating to the product
iii. Handle product recalls according to Pharmaceutical Regulatory Authority
Recall procedures.
iv. Detect and report adverse drug reactions or events to the Pharmacovigilance
Unit of the Pharmaceutical Regulatory Authority

Applications

A separate application is required for each product, i.e. products containing the
same ingredients but made to a different specification (in terms of strength or
content of active ingredients, dosage form, etc) or by a different manufacture.

However, product other than injectable, made by the same manufacturer to the
same specifications, strength (content) of ingredients and form, but differing in
packaging or pack size requires only one application but separate stability
studies reports should be submitted for each packaging material and container
differing in technical specifications

Applications shall be made by submitting a dully filled in application form which

shall be accompanied with:

i). Complete documentation as per these guidelines supported by

independent expert reports on quality, safety and efficacy.

All ingredients must comply with specification prescribed either in

International & national Herbal medicines Pharmacopoeias. In-house
specification may be acceptable if justified by validation reports

ii). Original Licence of Pharmaceutical Product (WHO-type) from the Drug

Regulatory Authority of the country of origin of the product. This shall be
accompanied with approved product information.
iii). Prescribed Non refundable fee per product to be imported or produced
locally.
iv). Three commercial samples of each package size being applied for
registration or sufficient samples to carry out quality control tests as
declared in the dossier whichever is higher. The samples must be in the
form and container in which they will be marketed.
v). An appropriate and complete index / list of the various chapters and
documents of submission.
vi). Current Site Master File

It should be noted that the above fees may be changed as shall be prescribed
under the Fees and Charges Regulations.

Application for amendment of a registered product

Whenever a product licence holder wishes to make any amendment to a

product he must apply to and obtain approval from the Authority in respect of
a registered product before introducing it is Zambia. An application for
amendment shall be made on an Application Form for Amendments and shall
be accompanied with:

i). Detailed description of the amendment with supporting reasons

ii). Samples of the amendments
iii). Prescribed non refundable amendment fee.
Application for renewal of registration

Application for renewal of registration of products shall be submitted at least

90days before expiry date of registration.

Renewal of registration shall be made on a Renewal Application Form which

shall be accompanied with:

iv). Consolidated report of all changes if any (reported and unreported)

which had been with respect to product during the validity of its
registration.
v). Report of additional adverse drug reactions if any detected during the
lifetime of the product.
vi). Five commercial samples of each package size being applied for
registration or sufficient samples to carry out quality control tests as
declared in the dossier whichever is higher. The samples must be in
the form and container in which it shall be marketed.
vii). Prescribed Non refundable renewal application fee per product to be
imported or for produced locally.
viii). Current Site Master File.

Documentation

Paper type and binding

Data shall be presented on A4 and 80g/m2 paper with readable letters of at
least 12 font sizes. Every page shall be numbered sequentially.

Extension sheets, tables, diagrams and other supporting documents shall be

as far as possible be of the same size, well annotated, numbered and
appropriately referenced or cross referenced.

All chapters must be bound separately and arranged sequentially in or more

file covers depending on the number of pages contained in a chapter.

However, if two or more chapters are bound in a single file, cover marked
dividers should separate them. The binding shall be in such a manner as to
allow chapters to be detached for evaluation by different experts.

The file cover should be of hard, non-collapsible biodegradable material.

Lever arch files and spring files are not permissible. The thickness should be
expandable or reducible depending on the thickness of the contents. The
allowable file size is A4 size.
Official References, Texts

When direct reference is made to specification, quality control procedures,

test methods, data etc. in official compendia, texts or standard publication
other than the current pharmacopoeias, reprints or authenticated copies of
relevant pages shall be enclosed. References to pharmacopoeias should
specify the year of issue.

Expert Reports

Expert reports shall accompany documentation on quality, safety and

efficacy. All copies should be authenticated by authorised signatories and
stamped officially by the applicant.

Manuals

An applicant may have several products which are pharmaceutical similar and
the same data may be applicable to these products e.g. specifications for
named ingredients, standard analytical methods or test protocols.

In order to avoid unnecessary duplication, this information may be assembled

in the form of a manual for e.g. “Manual – Specifications for Ingredients” or
“Manual Analytical Methods and Test Protocols”.

One hard copy a manual and CD-ROM if any should be submitted together
with the first application. In subsequent applications appropriate reference
may then be made to the “Manuals”.

Such manuals must be clearly headed with the company name, title e.g.”
Manual – Specifications for Ingredients” and date of compilation. The
Authority must be notified of any change of particulars in the manuals.

Binding of manuals should be such as to allow convenient up-dating, revision,

additions or removals.

Cross Reference between Products

There shall be no reference of particulars or documentation between on

product and another (Other than reference to above-mentioned “Manuals”)
except in the following circumstances:

i) Two or more products in the same pharmaceutical dosages form containing

the same active ingredient in different strengths or
ii) Two or more products in the same pharmaceutical dosage form containing a
mixture in different strengths of the same two or more active ingredients in the
same proportion.

Separate application forms are required for each product but supporting
documentation if similar, may be cross-referenced provided the application for
registration of these products are made at the same time, or within five years of
the application for registration of the first product in the group. Appropriate
reference must be clearly stated.

Submission, payment of fees and processing of applications

Submission of application

All application accompanied by prescribed fees shall be addressed and

submitted in person or by courier to: The Director General, Pharmaceutical
Regulatory Authority, Plot No. 6903, Tuleteka Road, Rhodespark, P.O Box
31890, Lusaka, Zambia

When an application has been received, an acknowledgement will be issued

together with reference number for each product.

Payment of Fees

Fees shall be paid into the following bank account:

Name of Account: Zambia Medicines Regulatory Authority

Name of Bank: Standard Chartered Bank, North-end Branch
Cairo Road. Lusaka, Zambia

US Dollar Bank Account No 8700211468100

ZMK Bank Account No. 0100122033800
Swift Code: SCBL2MLX
Processing of applications

Processing of applications shall only be done on complete applications,

incomplete applications shall not be processed. The Authority may during
evaluation of the product request for clarification or additional data or samples
and the applicant is obliged to comply. Once a query has been raised, the
processing may be halted until the query has been clarified.

The processing of an application takes about 180days. Immediately after the

processing is completed applicants will be informed.

The Authority as part of the evaluation of the product may conduct pre-
registration Good manufacturing process (GMP) inspection to verify
compliance thereof. The applicant shall bear the cost of conducting pre-
registration GMP inspection.

Registration

When a product is found to have complied with all the prescribed registration
requirements, the applicant will be informed to that effect. A product licence
together with such conditions as the Authority may determine shall be issued.

A duplicate of the licence may be issued upon request and on payment

prescribed non refundable fee.

Validity of registration

The registration of a product shall be valid for five (5) years unless sooner
suspended, cancelled or revoked by the Authority or terminated by the
registration holder. The validity of registration shall be subjected to payment
of prescribed annual retention fees product one year after a product is
registered.

Termination of product registration

The Authority may by giving in writing refuse, suspend, cancel or revoke the
registration of a product or amend the conditions of its registration.

The product licence holder may by giving a 60 days written notice and
reasons to the Authority terminate the registration of registered product.

Appeals
 Any person aggrieved by decision of the Authority in relation to any
application for registration of a herbal medicines may take representation to
the Authority, whereby he shall submit information and arguments to convince
the Authority to reconsider its decision. However, if after reconsideration of
the application, the Authority still rejects the application, the applicant may
appeal to the Minister

PART B. SUMMARY OF PRODUCT CHARACTERISTICS

The following summary of product characteristics shall be submitted for every

application: -

1. Trade name and dosage form of the product

2. Physical description of the product

3. Botanical name or any other name, family of the plant(s) from which the
drug(s) has been extracted including plants part(s) used. Synonym if available
should be given. The English name if available shall be provided. For locally
produced products the local name and geographical distribution shall be
provided.
4. Plant used whether wild or cultivated
5. Brief pharmacology of the medicines
6. Therapeutical indications
7. Dosage regimen and route of administration
8. Brief toxicological information of the medicine
9. Contra-indications
10. Warnings and precautions
11. Drug Interactions

12. Adverse reactions

13. Side Effects

14. Shelf-life and storage conditions

15. Presentation or pack size(s)

PART C. QUALITY REQUIREMENTS

The following information shall be submitted in support of the quality of herbal

medicines:

1. Raw material specifications and details of analytical methods to test

compliance to these specifications should be described. Where references to
pharmacopoeial specifications and analytical methods are given, full photocopies
of those references (monographs) should be supplied. Such pharmacopoeias
include the British Herbal Pharmacopoeia, Ayurvedic Pharmacopoeia of
India, or the list of WHO herbal monographs.

In all other cases specifications and analytical methods should be described

for the processed material and the crude material from which it is processed
as follows:

(a) Crude plant parts or plant material/non-plant material:

 Definition:
 name of plant
 part of plant
 Nature/condition of material: whole, powdered, fresh, dried, etc.

 Authentication: confirmation of:

 Correct geographical origin
 Correct stage of growth

 Absence of foreign matter:

 other plant parts or materials
 soil, stones, dust
 insects and other animal matter (as determined by microscopy,
macroscopy, chromatography - see below).

 Microscopic characteristics confirming identity:

 qualitative features
 quantitative features, e.g. stomatal number
  Radioactive contamination limits: arising from environmental
pollution or microbial decontamination procedures.

 Assay: for materials containing constituents of known therapeutic

activity, or known unique (marker) compounds. Non-specific assay
methods for groups of compounds may be used where specific
assay methods are not available for single compounds.
 Conformation to a pharmacopoeial monograph

 A copy of the manufacturer‟s or supplier‟s certificate of analysis

should be attached to confirm conformation to these specifications

(b) Processed plant materials/non-plant materials (extracts,

tinctures, comminutions etc):

Definition: liquid, solid, etc

Organoleptic characteristics:

macroscopy
smell
taste
texture
colour
 Chromatographic profile using more than one method:
 to confirm presence of unique compounds (markers)
 to confirm characteristic TLC chromatogram
 to confirm characteristic HPTLC chromatogram (TLC +
densitometry = HPTLC)
 Water content (for hygroscopic materials)

 Ash values: indicate extent of contamination with inorganic

material. Determined by incineration. Values include acid insoluble
and sulphated ash

 Volatile matter: for plants containing volatile oils. Determined by

steam distillation
 Powdered material – test method and acceptable limits for particle
size, distribution
 If the product is a mix of plant materials, the supplier must provide
evidence that each component plant has been individually tested.
 Heavy metal limits: from environmental pollution and pesticides

 Microbial contamination limits: microbial contamination arises from

cultivation, harvesting, processing and storage:
  confirmation of absence of E. coli, S. aureus, P. aeruginosa and
salmonella
 limits for aflatoxins (fungal toxins)

 Residual solvents from processing

 Pesticide residue limits: arising from cultivation (FAO and WHO

limits)

 Extractive values: extraction by different solvents indicates

proportion of polar and non-polar components

 Assay: for materials containing constituents of known therapeutic

activity, or known unique (marker) compounds. Non-specific assay
methods for groups of compounds may be used where specific
assay methods are not available for single compounds

(c) Inactive ingredients: as per pharmacopoeial monograph, or in-house

monographs where no pharmacopoeial monographs exist.

2. Whereas fresh plant materials are to be used, processing should

commence as soon as possible after harvesting. If processing cannot be
initiated within a few hours, harvesting should not be done under damp
weather conditions when plants are wet or covered with dew. If the delay
in processing will be greater than 8 hours, the plant material will need to
be stored under appropriate conditions to conserve the medicinal
properties, preferably refrigerated and used within 48 hours.
3. Comprehensive details of the procedures involved in the various
stages of manufacture, including packaging (e.g. a description of the
type of equipment, duration of treatment, etc.) should be given.

4. Analytical, microbiological and other in-process control procedures

together with the frequency and sequence in which they are carried out
during the manufacturing process should be stated.

5. Summarised specifications of the final product should be given, i.e.

the acceptable limits of all the physical, chemical and (where applicable)
microbiological parameters. A full description of analytical and other
control procedures carried out to ascertain the final product specifications
should also be given. The following specifications and relevant analytical
methods should be described:
6. Specifications and test methods (for all dosage forms)
 Description of dosage form
 Identity
 Assay: specific or non-specific; stability-indicating
  Impurities
 degradation product of active raw materials
 microbial limits

7. Additional tests for specific dose-forms

Hard Gelatin capsules and tablets (coated & uncoated)

a) Dissolution/Disintegration
b) Hardness & friability
c) Uniformity of content and mass (dosage units)
d) Water content

Oral liquids
a) Uniformity of content and mass
b) pH
c) Microbial limits
d) Antimicrobial preservative content
e) Antioxidant preservative content
f) Extractable from container/closure system
g) Alcohol content
h) Dissolution for suspensions and powders for suspension
i) Re-dispensability for suspensions.
j) Viscosity for suspensions or viscous solutions
k) Specific gravity for suspensions or viscous solutions
l) Water content for powders for reconstitution.

Where analytical procedures in various parts of the application coincide,

these procedures may be reflected in one part and may be subsequently

referred to, provided that the relevant page and paragraph are clearly

identified. Reference only to standard books of reference will not be

acceptable.

Omission of any of the above specifications and tests should be well-

justified.
Brief description of the finished product

8. Herbal medicines Stability

 Evidence of Stability should be submitted as follows:

8.1 Stability studies on imported finished product should:

(i) be on the market pack
i) have a detailed protocol
ii) have summarised results
iii) have conclusions on:
 proposed storage conditions
 proposed shelf life
 in-use storage conditions and shelf life

 Labelling recommendations should be stated as follows:

 Store under normal storage conditions (15oC - 30oC)
 Store between 2oC - 8oC (i.e. refrigeration, no freezing)
 Store below 8oC (i.e. refrigeration)
 Store between –5oC - OoC (i.e. in a freezer)
 Store below –18oC (i.e. in a deep freezer)
Note that these recommendations must be present on the product
samples submitted with the application.

 Stability studies on local finished product:

 All local products should have a shelf life of not more than one
year.
 copy of certificate of analysis one year from the date of
manufacture should be submitted

Accelerated stability data (6 months) and real time stability studies

conducted for minimum of 12 months should be submitted together with
the application. However, studies should continue to the end of the
proposed shell-life (a written commitment to this effect should be made by
the applicant).

The following are the guidelines on submission of the stability data

INSTRUCTIONS EXPLANATORY NOTES

Accelerated stability studies

1. These studies shall be conducted at
Give brief description of the 40+2oC/75%RH for six months at a
accelerated stability conducted sampling frequency of initial 1, 2, 3 and
to establish the effects of the 6 months in humidity chambers.
increase of change of the rate
of chemical degradation and 2. The parameters to be examined,
physical change of a drug using number of batches, sampling plan, type
exaggerated storage of packaging and analytical test
conditions. procedures shall be similar to those
 under real-time stability (see below).

3. Accelerated stability data results shall

enable proposition of a tentative shelf-
life of 24months, which shall later be
confirmed by completed real-time
stability studies.

4. The requirement of orientation of

containers and container closure
systems is equally applicable here as is
the case for real time stability studies.
Real time stability studies

Describe briefly the real time

stability studies performed to 1. Real time stability studies should be
establish the shelf-life and conducted under controlled conditions in
storage conditions of the stability chambers and not open
product. shelves.

2. They should be carried out under zone

III of the world climatic conditions
(hot/dry) which are fixed at
25+2oC/65+5%.
3. Sampling should be done at initial 3, 6,
9, 12, 18, 24, 36 etc. Months to
establish the stability characteristics of
the drug product.
4. Samples from three different batches,
which are randomly selected to
represent the whole batch, should be
issued for the study.
5. Attributes (parameters) to be tested
should be those susceptible to change
and are likely to influence the quality,
safety and efficacy of the
pharmaceutical product. These
parameters should be at least cover:
a. Appearance for all dosage forms

b. Assay (Stability indicating) for all

dosage forms
 c. Degradation products / impurities
for all dosage forms.

d. Physiological properties such as

disintegration, hardness, particle
matter etc, for all solid dosage
forms.

e. Dissolution for all solid and semi

solid oral dosage forms.

f. Microbial limits for all dosage

forms.

g. pH for liquid preparations.

6. A description of the sampling plan used

to select the samples from the test batch
for storage and subsequent testing
should be given.

Provide results of stability 7. For liquids, dispersed systems and

studies for the three batches semi-solid products, samples should be
tested. stored in upright, horizontal and inverted
positions to ensure full interactions with
all primary packaging materials.

1. Results should be presented in tabular

form or graphs (wherever possible).
2. Acceptable criteria should be fixed for
each test included in the stability study.
The criteria can be in the form of
numerical limits if results are
quantitative (e.g. assay degradation
products, particle size and viscosity).
For qualitative tests, the criteria can be
pass or fail (e.g. odour, colour,
appearance).
3. Analytical test procedures shall be fully
validated and assay shall be stability
indicating. For products with official
monographs, the procedures in the
current edition of the official compendia
 stipulated in these guidelines will apply.

9. Labelling Requirements

9.1 Information on the label

Every immediate container of any product shall be affixed with a label

bearing the following particulars pertaining to the contents of such
container in clearly legible and indeligible letters in English

i. Proprietary / trade name

ii. Local names based on the seven official local languages for locally
manufactured herbal medicines.
iii. Dosage form of the product
iv. Quantitative list of active ingredient(s) in the container expressed in the
appropriate unit or volume of the pharmaceutical product.
v. Name and address of manufacturer
vi. In case of contract manufacturing, the name and address of
manufacturer printed in the same letter size as those of the registrant
as follow: “Manufactured for ….(name and address of registrant) by
…..(name and address of manufacturer)”.
vii. Distribution category

viii. Precautions ( e.g. the instruction:

“Shake well before use or “For external use only”, where
applicable)
ix. Indications and recommended dosage of the pharmaceutical product
x. In case of products for injection, route of administration by suitable
words or abbreviations such as im, iv, etc.
xi. The batch or lot number of the product
xii. The manufacturing and expiry date of the product
xiii. Zambian product registration number
xiv. The name and concentration (content) of preservatives, where present
xv. Storage instruction and shelf-life and the instruction “keep out of the
reach of children”.

In case the product‟s package bears both the immediate container label and
outer container label, the above requirements shall apply to the outer label as
well.

9.2 Requirements for package inserts

Each package of a product shall be accompanied by a package insert as a
separate entity or as an integral part of the package on which the following
information is printed in legible letters in English both under the headings
specified below:

i. Name and dosage form of the product

ii. Identification (description of the product and package)
iii. Quantitative list of active ingredients in a dosage unit or suitable mass
or volume or unit of the product.
iv. Indications
v. Dosage regimen and directions for use.
vi. Contraindications
vii. Side effects and adverse reactions
viii. Drug interactions
ix. Precautions and warnings
x. Symptoms and treatment of overdose
xi. Presentation (packing and pack size)
xii. Storage instructions and shelf-life
xiii. Name and address of manufacture and country of origin
xiv. Date of publication of the insert

PART D. SAFETY DATA

The requirement for submission of safety data is applicable for products

which are not official in current editions of pharmacopoeia and for herbal
medicines which are not listed in the current WHO Monographs on Selected
Medicinal Plants.
a) For products of long-term traditional use: bibliographical (documentary)
evidence of safety should be submitted including the following:

i) Evidence of long-term use (in terms of decades)

ii) Specification of the system of traditional medicine, disorders
treated, numbers of users and countries of use (as found in
literature, monographs, etc)
iii) Indication of the lack of toxicity problems over the documented
period of time
iv) If toxicity problems are revealed by the documentation, toxicological
studies should be done to determine safe dosage, and risk
assessment made and presented in the dossier
v) Details of the potential for misuse, abuse or dependence
vi) Bibliographical evidence sources include reference literature
(textbooks, journals etc), case reports, pharmacopoeial
monographs
 vii) In the case of local products where there may not be much
bibliographical evidence available, the applicant should write a
summary clearly confirming the safety of the product.

b) For foreign products where there is no bibliographical evidence of

safety in long-term use: toxicological studies proving safety are
necessary, and should be submitted in the dossier.
c) Non clinical studies
Provide full information to support safety of the herbal medicines by
submitting results of the following tests.
i). Acute toxicity tests using at t least two species one of them being a
non rodent.
ii). Subacute toxicity tests
iii). Chronic toxicity tests
iv). Mutagenic tests using salmonella (Ames test) or other tests
v). Teratogenicity tests if a product is to be administered to pregnant
women
vi). Immuno toxicity (test for allergic reactions)
vii). Carcinogenicity tests
viii). Reproductive toxicity tests

For each of the above tests applicants will be required to provide protocol
or study plan and amendments bearing signatures of study director and
quality assurance person.
i) Name of study director, principal investigators, their qualifications and
full addresses
ii) Details of all tests items including transportation, storage formulation
data and quality control data.
iii) Information on tests system (supplier, animal husbandry, species,
justification for use, strain).
iv) Curriculum vitae (CV) of all personnel involved in the study
v) Copies of standard operating procedures and revisions if any for
each of the tests.
vi) Copies of all raw data including procedures and revisions if any for
each of the tests.
vii) Copy of final report on safety of the product signed by the study
director and quality assurance person.

An independent expert report critically examining data and making considered

opinions supported with references from peer review literature should be
provided.

PART E. EFFICACY DATA

The requirement for submission of efficacy data is applicable for products which
are not official in current editions of pharmacopoeia and for herbal medicines
which are not listed in the current WHO Monographs on Selected Medicinal
Plants. It shall be noted that only those therapeutic uses which are established
through clinical studies are acceptable for herbal medicines listed in the current
WHO monographs on Selected Medicinal Plants. The rest of the herbal
medicines shall be required to provide evidence of efficacy as outlined below.
Evidence should be submitted as follows:

a) Pharmacological and clinical effects of active ingredients and their

active constituents if known should be described, and should be
relevant to the main indications of the product

b) For products with long-term traditional use, used for minor disorders or
non-specific indications or for prophylactic use: bibliographical evidence
of efficacy should be submitted, e.g. literature (textbooks, journals etc),
case reports, pharmacopoeial monographs

c) For products without bibliographical evidence of efficacy in traditional

use: reports of clinical studies proving efficacy

d) Combination products: for new combinations of active ingredients, the

therapeutic justification, compatibility and dose range should be given.
For well established combinations, photocopies of references in
traditional texts (eg. Ayurveda, traditional Chinese) will be acceptable
as evidence of efficacy

e) In the case of local products where there may be little or no

bibliographical evidence available, the applicant should write a
summary clearly explaining the efficacy of the product.
PART F. APPLICATION FORM

PHARMACEUTICAL REGULATORY AUTHORITY

APPLICATION FORM
For registration of Herbal Medicines for Human use in Zambia

For official use only

Date of receipt of application:

Application Number:

In completing this form and preparing of dossiers for submission to the

Authority, the applicant is advised to refer to the guidelines on registration
of Herbal Medicines for Human use in Zambia.

1. Product Particulars

1.1. Product Name:-

1.2. Therapeutic Indications for the Product:-

1.3. Pharmaceutical Dosage Form

1.3.1 Dosage and Route of administration:-

1.3.2 Container, closure and administration devices:-

1.3.3 Package sizes:-

1.3.4 Shelf life:-

(i) The shelf life of the product in each of the different package type(s) and sizes:-

(ii) The shelf life after first opening of container where applicable:-

(iii) The shelf life after reconstitution:-

1.3.5 Storage conditions:-

1.3.6 Categories for Distribution

Prescription only Herbal Medicines

Pharmacy Herbal Medicines

General Sales herbal Medicines

Other information
2. Product composition

Name (INN) of Reason for Quantity Unit Reference standards

inclusion
Names of
ingredients
i.
ii.
iii.
iv.
v.
vi.
vii.

3. Status of/ Registration in the Country of Original Development and /Registration

Number and Date, Where Applicable, Country of Manufacture:-

4. Registration Status for this herbal Medicines in the SADC Member States and in
Other Countries

4.1 Registered: Country:

Date of registration:
Proprietary name:

4.2 Pending: Country:

Date of submission:
Application number:

Country:
4.3 Rejected: Date of rejection:
Application number:
Reason for rejection:
 Country:
Date of withdrawal:
4.4 Withdrawn (by applicant before registration) Reason for withdrawal
Proprietary name:

Country:
Date of registration:
4.5 Withdrawn (by applicant after registration) Date of withdrawal:
Reason for withdrawal
Proprietary name:

Country:
Date of withdrawal:
4.6 Suspended/ revoked/ cancelled/Withdrawn by Reason for withdrawal
competent authority Proprietary name:

5. Details of Applicant (who must be the prospective holder of the product licence)

Name:

Physical Address:

Postal Address:

Country:

Phone: Fax: Mobile: E-mail:

5.1 Details of a Distributor/local agent (who must be appointed by the applicant and
submit evidence of power of attorney)

Name:

Physical Address:

Country:

Phone: Fax: Mobile: E-mail:

5.2 Manufacturer(s), site(s) for the pharmaceutical dosage

NAME (each site ACTIVITY –Dosage form SITE (Physical Name, address &
involved in the compounding (for each Address, Phone and qualifications of key
manufacture of the stage where applicable, Country) personnel
dosage form) including labelling)

5.3 Source(s) manufacturer(s) of Active Pharmaceutical Ingredient(s)

Name:

Physical Address:

Postal Address:

Country:

Phone: Fax: Mobile: E-mail:

6. Declaration by an Applicant:

I, the undersigned certify that all the information in this form and all accompanying
documentation is correct. I further certify that I have examined the following statements and I
attest to their accuracy.

I also agree that I am obliged to follow the provisions of the Pharmaceutical Regulatory
Authority which relate to Herbal Medicines.

All the documentation referred to in this licence is available for review during a GMP
inspection.

Name:

Qualification:

Position in the company: Official

Date stamp
Signature:

Date:

References

 WHO/AFRO guidelines for registration of herbal medicines