9. Guideline For The Submission Of Protocol Of Analysis (POA)

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This guideline consists of general and specific requirements for the POA submission. The general requirements are referred to POA content whilst details of the test methods are illustrated in the specific requirements

9.1   GENERAL REQUIREMENTS

 a) The POA shall be written in Bahasa Malaysia or English only.

b) The POA shall contain the following information: 

    1. Name of product;
    2. Name and address of manufacturer;
    3. Name, signature and designation of authorized person;
    4. Effective date and Review date.

c) The POA shall comply with the following requirements : 

    1. To provide updated testing methods, shelf-life specifications and certificate of analysis for the intended product to be registered.
    2. References used must be clearly stated.
    3. The latest version of British Pharmacopoeia (BP) and United State Pharmacopeia (USP) shall be used as the main references.
    4. All tests and its specification listed in BP and/or USP in General Monographs and Specific Monographs shall be the minimum requirement.  However, a specific testing method for quantitative analysis shall be accepted.
    5. All test specifications set by the manufacturer shall be in line or more stringent than official pharmacopoeias (BP and USP).

d) Details of test methods shall include the following items:

  1. List of equipment and apparatus;
  2. List of chemical, reagents and media;
  3. Preparation of solutions such as sample, standard, mobile phase, medium etc.;
  4. Setting up of analytical instrumentation;
  5. 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);
  6. Complete formula for calculation and interpretation of results;
  7. Specification or acceptance criteria.

e) Photocopies or methods directly copied from pharmacopoeias shall not be accepted. In cases where test methods are adopted from official pharmacopeia, details of specifics requirements should be submitted.

f) All relevant data collected during chemical and microbiological testing such as chromatograms HPLC/ GC, test reports and formulae used for calculating should also be submitted.

g) All documents should be arranged and labeled accordingly.

 

9.2   SPECIFIC REQUIREMENTS

 

The specific requirements for test methods are based on type of tests and dosage forms of product as stated in Table IX below:

 

Categories

Type of Tests

Specific Requirements

 

Physical & Performance Tests

Physical test (friability, uniformity of weight, pH, etc)

 

Specific method for the intended analysis

Disintegration test

Specific method for related dosage forms

Dissolution test

 a)Dissolution parameters should include:

    1. type of apparatus
    2. type and volume of dissolution medium
    3. rotation rate
    4. temperature of solution
    5. sampling time

b) Complete formula for calculation especially for extended and delayed release products.

c) Method of analysis for example HPLC, UV, etc.

 

Quality Test

Identification test   such as color test, Fourier Transform Infrared (FTIR), Thin Layer Chromatography (TLC) etc.

 

Specific method for the intended analysis

Impurities/ degradation/ purity test

a) Analysis method should include:-

  1. Placebo solution (if any
  2. Relative retention times of impurities or degradation product

b) Complete formula for calculation

c) Method of analysis for example HPLC, TLC, etc.

Assay and uniformity of content

Specific method for the intended analysis

 

Biological Assay of Antibiotics

 a) Procedure for preparation of following solutions/ substances:-

  1. Culture medium
  2. Buffer solutions
  3. Diluents
  4. Microorganisms used in assay 

b) Detailed test method (diffusion or turbidimetric method), which  includes:

  1. Preparation of standard solutions (including steps to counteract the antimicrobial properties of any preservatives, etc present in the sample)
  2. Preparation of test solutions (including any steps to neutralize the antimicrobial properties of any preservatives, etc present in the sample)
  3. Test for Media Sterility and Growth Promotion Test
  4. Dilution schemes for test and standard solutions.
    • Application of test & standard solutions (volume, use of latin squares, etc.)
    • Incubation temperature & time
    • Interpretation of result
    • Detailed calculation for the test including ANOVA table and other data showing validity of test results.

 

 

 

 

Safety tests

Pyrogen Test

  1. List of depyrogenated or pyrogen-free apparatus, glassware and reagents
  2. Temperature recording system
  3. Retaining conditions of the animals
  4. Selection of animals for test
  5. Preliminary test/ Sham test procedure
  6. Detailed test procedure
  7. Volume and dose of injection
  8. Interpretation of test results

Bacterial Endotoxins Test (BET) or Limulus Amebocyte Lysate (LAL) Test

  1. Certificate of analysis for endotoxin and LAL (limulus amebocyte lysate) reagent
  2. List of depyrogenated or pyrogen-free apparatus, glassware and reagent
  3. Preparation of standard solutions, LAL reagent/ substrate, sample
  4. Detailed calculation for determination of maximum valid dilution (MVD)
  5. The product's endotoxin limit concentration (ELC) and source of information
  6. Detailed calculation for determination of endotoxin limit concentration if the ELC is not in BP, USP, JP or EP
  7. Detailed test procedure
  8. Calculation and interpretation of test result

Sterility Test

 

a) List of media and reagent

    1. Culture media
    2. List of rinsing solution, buffer solution and diluent
    3. Neutralizing agent (if any)

b) Preparation of media & Composition of Rinsing Buffer

c) Test for Media Sterility and Growth Promotion Test

d) Preparation of test sample (including steps to eliminate antimicrobial activity due to antibiotic samples or samples which contain preservatives).

e) Detailed test procedure for sterility test

  1. Quantity of sample / Volume of sample
  2. Membrane filtration / Direct inoculation
  3. Open System or Closed System (if uses Membrane filtration method)
  4. Volume of rinsing fluid

Microbial Contamination Test

Required for ALL non-sterile products

a) Preparation of media

b) Test for Growth Promoting, Inhibitory  and Indicative Properties of Media

c) Preparation of test sample (including neutralizing of preservatives for samples that contain preservatives)

d) Total Viable Aerobic Count

  •  Detailed test procedure for Total Aerobic Microbial Count TAMC) and Total Yeasts and Moulds Count (TYMC) by Plate Count, Membrane Filtration or Most-Probable Number (MPN) method.

e) Test for Specified Microorganisms

  • Detailed  test procedure for each specific microorganism tested (including identification and confirmation test)
  • Specification and acceptance criteria

For details, please refer circular;
Bil (4) dlm. BPFK/PKK/12/05.  Maklumat Lanjutan Tentang Spesifikasi Baru Untuk Ujian Kontaminasi Mikrobial (30 Mac 2010).

 

Quality Testing for Specific Ingredient

For a product containing specific ingredient such as Aphanizomenonflosaquae, Red Yeast Rice (Monascus purpureus), ingredient(s) derived from seafood and placenta, please refer to Appendix 4 and Appendix 5 for the testing requirement(s).

 

Note:
1. Finished product testing shall be conducted on every batch produced as per approved finished product specifications.

  • Manufacturer shall ensure that products manufactured locally or overseas are free from any contamination of Burkholderia cepacia. Please refer to these circulars for details:

Ref. (90)dlm.BPFK/PPP/01/03/ Jld. 2
Ujian Kontaminasi Burkholderia cepacia (19 December 2012).

  • Products are not allowed to send for gamma radiation treatment for the control of microbial contamination. Please refer to this circular for details:

Ref. (54)dlm.BPFK/02/5/1.3.
Aktiviti Pendedahan Produk Berdaftar kepada Sinar Gamma (18 April 2006)

National Pharmaceutical Regulatory Agency (NPRA)
Lot 36, Jalan Universiti, 46200 Petaling Jaya, Selangor, Malaysia.
  • Email: npra@npra.gov.my
  • Phone: +603-7883 5400
  • Fax: +603-7956 2924, +603-7956 7075

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