Registered Herbal Drug

A detailed process for product registration in Malaysia is available at http://npra.moh.gov.my/ The document below has been compiled specific for natural product or Health supplement only.

A. INTRODUCTION

Under the CDCR 1984, Regulation 7(1): Except as otherwise provided in these Regulations, no person shall manufacture, sell, supply, import, possess or administer any product unless

(a) The product is a registered product; and
(b) The person holds the appropriate licence required and issued under these Regulations.

Under the CDCR 1984, Regulation 2: “Product” means:

(a) a drug in a dosage unit or otherwise, for use wholly or mainly by being administered to one or more human beings or animals for a medicinal purpose; or
(b) a drug to be used as an ingredient of a preparation for a medicinal purpose.

The following criteria may be used as criteria to assist in the classification of products:

  • The primary intended purpose of the product
  • The primary mode of action/ the principal mechanism of action by which the claimed effect or purpose of the product is achieved;
    • Medical device is based on function by physical means, e.g. mechanical action, creation of a physical barrier or replacement or support of organ or body function
    • Drug is based on pharmacological, immunological or metabolic action in/on the body

(c) Active ingredients, indication and pharmaceutical dosage form (these are the main criteria for classification of the drugs)

Registration process includes quality control, inspection and licensing as well as post-registration of medicinal products as illustrated below:

fig 1
Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://npra.moh.gov.my/index.php/guidelines-central 24 September 2014.

The applicant for product registration shall be known as Product Registration holder (PRH) and must be locally incorporated company, corporate or legal entity with permanent address and registered with Companies Commission in Malaysia (with the scope of business related to the health/pharmaceutical product).

For registration of products, only web-based online submissions via QUEST at  https://quest3plus.bpfk.gov.my/front-end/login.php shall be accepted. However, applicant must first register a membership for QUEST system with National Pharmaceutical Control Bureau and purchase a USB Token that contains a User Digital Certificate, from Digicert Sdn. Bhd., which shall be installed to the applicant’s computer. The processing fee and any other charges shall be paid in the form of bank draft/banker’s cheque/money order/postal order made payable to “Biro Pengawalan Farmaseutikal Kebangsaan”.

The process of registration via QUEST 2 will undergo screening process by the Screening Officer. Applicant may need to print the online form as stated in semi manual procedure of screening and submit to:

Ketua Unit Produk Semulajadi,
Pusat Pendaftaran Produk,
Biro Pengawalan Farmaseutikal Kebangsaan,
Lot 36, Jalan Universiti,
46200 Petaling Jaya, Selangor.

Details of the registration process are demonstrated as below:

Fig 2
Note: The figure was extracted from Circular Bil (28) dlm. BPFK/PPP/06/04 Jld. 6 available at http://portal.bpfk.gov.my/newsmaster.cfm?&action=news&menuid=52&searchcategory=Circulars&search=yes access on 24 September 2014.

B. PRODUCT REGISTRATION PROCESS- EVALUATION

Evaluation of the application is dependently on the product’s category. There are two types of methods applied in the evaluation process that known as full evaluation or abridge evaluation.

fig 3b
fig 3a
Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.
Product to be registered under Natural Product or Health supplements with general or nutritional claim or functional claim category must provide dossier consist of elements as below:

GENERAL REQUIREMENTS FOR ABRIDGED EVALUATION

Step 1:  Product validation

Step 2: 

  • Section A: Product particulars
  • Section B: Product formula
  • Section C: Particulars of packing
  • Section D: Label (Mock-up) form immediate container, outer carton, proposed package insert
  • Section E: Particulars of product owner, manufacturer, importer and other manufacturer(s) involved and stored address
  • Section F: Supplementary documentation

In accordance to ASEAN ACTD/ ACTR or ICH guidelines, categories of product that require a Full Evaluation are:

  1. New Drug Products
  2. Biologics Products
  3. Health Supplements (High claims on disease risk reduction)

GENERAL REQUIREMENTS FOR FULL EVALUATION

Step I: Product Validation

Step II:

  • Part I: Administrative Data and Product Information
    • Section A: Product Particulars
    • Section B: Product Formula
    • Section C: Particulars of Packing
    • Section D: Label (Mock-up) For Immediate Container, Outer Carton, Proposed Package Insert
    • Section E: Supplementary Documentatio
  • Part II: Quality of Product
    • Section P: Drug Product (Finished Product)
    • Section S: Drug Substance
  • Part III: Nonclinical Document
    • Section A: Table of Contents
    • Section B: Nonclinical Overview
    • Section C: Nonclinical Written and Tabulated Summaries
    • Section D: Nonclinical Study Reports
    • Section E: List of Key Literature References
  • Part IV: Clinical Document
    • Section A: Table of Contents
    • Section B: Clinical Overview
    • Section C: Clinical Summary
    • Section D: Tabular Listing of all Clinical Studies
    • Section E: Clinical Study Reports
    • Section F: List of Key Literature References, Published Clinical Papers and Latest Periodic Safety Update Report (PSUR)

PART II: QUALITY CONTROL

Documents to be submitted are as below:

Documents to be submitted via online Quest system 1) Complete protocol of analysis (POA) for finished product including preservatives and diluents (if any) 2) Summary of Analytical Method Validation (AMV) include all the relevant validation characteristics, its acceptance criteria and results 3) Certificate of Analysis (COA) for active drug substance (1 batch) and recent batches of finished products (3 batches)  

Documents to be submitted as hardcopy: 1) Certificate of analysis for active drug substance (1 batch) and recent batches of finished product (3 different batches) 2) Complete protocol of analysis for active drug substances and finished product (including preservatives and diluents, if any) 3) Complete testing method for the AMV.

Complete results for the AMV with all relevant validation parameters, including acceptance criteria and supporting raw data (e.g. chromatograms, spectrums etc.)

Protocol of analysis (POA)

Details of test methods shall include the following items

i. List of equipment and apparatus; ii. List of chemical, reagents and media; iii.Preparation of solutions such as sample, standard, mobile phase, medium etc. iv.Setting up of analytical instrumentation v. System suitability tests (resolution, percentage of Relative Standard Deviation (%RSD), tailing factor and theoretical plate for High Performance Liquid Chromatography (HPLC)      and Gas Chromatography (GC) methods); vi. Complete formula for calculation and interpretation of results; vii. Specification or acceptance criteria

Analytical Method Validation (AMV)

Types of analytical procedures to be validated: a) Identification tests b) Quantitative tests for impurities’ content c) Limit tests for control of impurities d) Quantitative tests of the active ingredient in the sample (assay and dissolution) e) Pyrogen or Bacterial endotoxin test f) Sterility test g) Microbial Contamination Test h) Biological Assay of Antibiotics

Typical validation parameters for chemical tests:

fig4
Full validation for in-house methods
 Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.
fig 5
Partial validation for Compendial/ Pharmacopoeial methods
Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.
fig6
Typical validation characteristics for Microbiological Tests:
Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.

PART III: NON CLINICAL DOCUMENT

CONTENT OF NON CLINICAL STUDY REPORT:

For ASEAN member countries, the Study Reports of this part may not be required for NCE, Biotechnological Products and other Major Variation Products if the Original Products are already registered and approved for market authorisation in Reference Countries

1) Table of contents

2) Pharmacology

  •    Primary pharmacodynamics
  •    Secondary pharmacodynamics
  •    Safety pharmacology
  •    Pharmacodynamic drug interactions

3) Pharmacokinetics /ADME

  • Analytical methods and validation reports
  • Absorption
  • Distribution
  • Metabolism
  • Excretion
  • Pharmacokinetic drug interactions
  • Other pharmacokinetic studies

4) Toxicology

  • Single-dose toxicity (in order by species, by route)
  • Repeat-dose toxicity (in order by species, by route, by duration, including supportive toxicokinetics evaluations)
  • Genotoxicity
  • in vitro
  • in vivo (including supportive toxicokinetics evaluations)
  • Carcinogenicity (including supportive toxicokinetics evaluations)
  1. long-term studies (in order by species)
  2. short- or medium-term studies
  3. other studies
  • Reproductive and developmental toxicity (including range-finding studies and supportive toxicokinetics evaluations)
  1. Fertility and early embryonic development
  2. Embryofoetal development
  3. Prenatal and postnatal development, including maternal function
  4. Studies in which offspring (juvenile animals) are dosed and/or further evaluated
  • Local tolerance
  • Other toxicity studies (eg: antigenicity, immunotoxicity, mechanistic studies, dependence, metabolites, impurities)

5) Integrated overview and conclusions (supporting the safety of the product for the intended clinical use)

6) List of Key literature referrences

Non-Clinical Data as below are applicable to disease risk reduction claims:

(For new active ingredient, new combination of active ingredients and new dose)

fig7
 Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.

All information must be provided in the following format/ table:

fig8
 Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.

PART IV: CLINICAL DOCUMENT

Clinical Data as below are applicable to disease risk reduction claims:

(For new active ingredient, new combination of active ingredients and new dose).

fig 9
Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.

All information must be provided in the following format/table:

fig10
 Note: The figure was extracted from Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.

C) REGISTRATION OF NATURAL PRODUCTS

Natural products can be defined as:

a) Traditional medicine (as defined under the Control of Drugs and Cosmetics Regulations 1984): Any product used in the practice of indigenous medicine, in which the drug consist solely of one or more naturally occurring substances of a plant, animal or mineral, of parts thereof, in the unextracted or crude extract form, and a homeopathic medicine. It shall not include any sterile preparation, vaccines, any substance derived human parts, any isolated and characterized chemical substances.

b) Finished Herbal Product Finished herbal products consist of herbal preparations made from one or more herbs. If more than one herb is used, the term “mixture herbal product” can also be used. Finished herbal products and mixture herbal products may contain excipients in addition to the active ingredients. However, finished products or mixture herbal products to which chemically defined active substance have been added, including synthetic compounds and/ isolated constituents from herbal materials, are not considered to be herbal.

c) Herbal Remedy Any drug consisting of a substance or a mixture of substances produced by drying, crushing or comminuting, but without subjecting to any other process, a natural substance or substances of plant, animal or mineral origin, or any part of such substance or substances.

d) Homeopathic Medicine Any pharmaceutical dosage form used in the homeopathic therapeutic system in which diseases are treated by the use of minute amounts as of such substances which are capable of producing in healthy persons symptoms similar to those of the disease being treated.

General requirements for registration of natural products are simplified as below:

INGREDIENTS
Active ingredients Active ingredients are those substances that have a therapeutic role in the formulation. Substances that are included in the formulation as active ingredients must make a contribution to the proposed indications for the product. Where a claim links the presence of an ingredient to the product indication, that ingredient must contribute to that indication. The evidence may be scientific and or traditional.
Overages of active ingredients Overages may be used during manufacture. An overage is where the amount of an ingredient added during manufacturing that is greater than the nominated on the product label. Details of the overage used must be available.
New active ingredients/ new combination product The following information shall be required.
Product containing new single ingredient:
i) Extract form
   – Information on the taxonomy of the ingredient;
   – Techniques and methods in preparing/ processing the
     extract  and  subsequently the product;
   – Information on the use and safety of the ingredient
     and the product Quality standard.
 
ii) Powder/ Granules
  – Information on the taxonomy of the ingredient;
  – Techniques and methods in preparing/ processing the

      extract and subsequently the product;
  – Information on the use and safety of the ingredient
     and the product.
Product containing multiple ingredients (contains ingredients which are known to be used traditionally):
– The source of the product formulation;
e.g. Chinese Pharmacopoeia
– Proof or evidence of the use, traditionally.
Product containing multiple ingredients (contains ingredients which are not known to be used traditionally):
– Information on the use and safety of every new ingredient;
– Safety data on the new formulation;
– Regulatory status in other countries.
Premix Shall not be used in a traditional product formulation, as directed in circular Bil (71) dlm BPFK/02/5/1.3, 1 Jun 2007
Prohibited/ banned ingredients The following lists are prohibited/ banned ingredients which are not allowed in the formulation of natural products registered by the Authority:
Botanicals (and botanical ingredients) containing scheduled poisons as listed under the Poisons Act 1952;
Botanicals (and botanical ingredients) which are banned due to reported adverse event
Ingredients (botanicals and substance derived from animals) which are banned due to safety reasons.
Use of protected/ endangered ingredients A) PROTECTED/ ENDANGERED WILDLIFE SPECIES
It is the responsibility of the applicant to ensure that the ingredient(s) derived from wildlife species its parts and derivatives used in the formulation COMPLIES with the Wildlife Conservation Act 2010 (Act 716) and International Trade in Endangered Species Act 2008 (Act 686). A copy of the permit/ license shall be attached together with the application form for product registration.
 
Department of Wildlife and National Parks, Peninsular Malaysia Km. 10, Jalan Cheras, 56100 Kuala Lumpur, Tel: +603-90866800, Fax: +603-90753873
 
B) ENDANGERED BOTANICAL SPECIES
It is the responsibility of the applicant to declare the source of the botanical ingredient if it is listed under the International Trade in Endangered Species Act 2008 (Act 686). If the ingredient is from a local source, a special permit/ license shall be obtained from the:
 
Division of Protection and Quarantine of Plants, Department of Agriculture, Tingkat 1-3, Wisma Tani, Jalan Sultan Salahuddin, 50632 Kuala Lumpur. Tel: +603 – 20301400, Fax: +603 – 26913550.
Excipients – Excipients are substances used to assist in the manufacture of active substance into dosage forms suitable for administration to consumers. Each excipient ingredient included in a formulation must have a justifiable excipient role and shall be controlled by specifications. The intended use of an excipient shall be appropriate.
–  New excipient will require safety and/or other additional data to support the function in the product prior to addition into the Quest 3 database.
Indications “Traditionally used…. / “Digunakan secara tradisional….
Quality Control – Sample for testing shall be submitted to the Drug Analysis Division, NPCB within 14 working days of payment confirmation by the NPCB.
– Types of tests includes:
– Limit Test for Heavy Metals
– Disintegration Test
– Test for Uniformity of Weight (For tablet and capsules only)
– Tests for Microbial Contamination
Stability Data The objective of stability study is to determine the shelf-life, namely the time period of storage at a specified condition within which the drug product still meets its established specifications.

It consists of a series of tests in order to obtain an assurance of stability of a drug product, namely maintenance of the specifications of the drug product packed in its specified packaging material and stored in the established storage conditions within the determined time period.
Labelling – All labels and package inserts must be in Bahasa Malaysia or English.
– Requirements to be stated on the labels and package insert are as below:

State the weight per dosage form
State the quantity/content of active ingredients per dosage form
For products in liquid form (syrup), content of active ingredients shall be stated as below:
“Each ­___ ml (per dosage) product contains extract of the following ingredients”
Herb X = ___ mg
Herb Y = ____ mg

Check and correct all spelling/grammar and translations.
– All herbal/traditional products label shall state the general cautionary statement except for product with indication for men’s health or product for children use.
– Special precaution shall be given to ingredients taken during pregnancy. Pregnant women should consult their medical/traditional health care provider prior taking any herbal or traditional products. Unless otherwise supported, general cautionary statement:

“Pregnancy and breastfeeding: Insufficient reliable date”
Product Specific Requirements – Food patch which contains herbs with a health claim needs to be registered with the Authority.
– Herbal Tea.
– Homeopathic Products.
Note: The information was extracted from Appendix 5: Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.

 

D. REGISTRATION OF HEALTH SUPPLEMENTS

A Health Supplement (HS) means any product that is used to supplement a diet and to maintain, enhance and improve the health function of human body. It may contain one or more, or the following combination:

  1. Vitamins, minerals, amino acids, fatty acids, enzymes, probiotics, and other bioactive substances;
  2. Substances derived from natural sources, including animal, mineral and botanical materials in the forms of extracts, isolates, concentrates, metabolites;
  3. Synthetic sources of ingredients mentioned in (i) and (ii) may only be used where the safety of these has been proven.

All claims made for HS shall:

  • be consistent with the definition of HS;
  • enable consumers to make an informed choice regarding products;
  • not be misleading or false;
  • support the safe, beneficial and appropriate use of the product;
  • maintain the level of scientific evidence which is proportional to the type of claims;
  • be for health maintenance and promotion purpose only;
  • not be medicinal or therapeutic in nature, such as implied for treatment, cure or prevention of disease.

Types of HS claims are:

  • General or Nutritional claims;
  • Functional Claims (medium);
  • Disease Risk Reduction Claims (high).

For a HS product making a General or Functional Claim on vitamin(s) and/or mineral(s), it must contain minimum of 15% of the Codex Nutrient Reference Value (NRV) per daily dose of the vitamin(s) and/or mineral(s). Other ingredients must be substantiated by the evidences to which it has been supported. For a HS product making Disease Risk Reduction Claim, it must be substantiated by the evidences to which it has been supported.

Note: Always refer Drug Registration Guidance Document (DRGD) for latest substantiated evidences requirements.

Dossier requirements include:

The requirements are simplified as below:

SECTION APRODUCT PARTICULARS
SECTION BPRODUCT FORMULA
SECTION CPARTICULARS OF PACKING
SECTION DLABELLING REQUIREMENTS
SECTION EPARTICULAR OF PRODUCT OWNER, MANUFACTURER, IMPORTER AND OTHER MANUFACTURER
SECTIONSUPPLEMENTARY DOCUMENTS
Note: The information was extracted from Appendix 4: Drug Registration Guidance Document (DRGD) available at http://portal.bpfk.gov.my/index.cfm?&menuid=137 access on 24 September 2014.
in this scope
Research
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