ANNEX A
Guidelines for the Submission of Protocol of Analysis
I. General Requirements
1. The Protocol of analysis must be in a standard format that contains information
as stated below:-
a. Product name
b. Name and address of manufacturer
c. Name, signature and designation of authorized person
d. Effective date
e. Review date
2. Protocol of analysis must consist of all test methods and specifications that are
carried out by the manufacturer. Standard pharmacopoeias, for example,
BP/USP can be used as references. The tests and specifications in the
pharmacopeias are the minimum requirements.
3. Photocopies of methods/ methods directly copied from pharmacopoeias are not
acceptable. Manufacturers can use methods from those standard references but
must have their own written and detailed procedure.
4. Manufacturers must confirm that all test methods in their protocol of analysis
perform as expected. Copies of chromatograms (HPLC/GC/TLC), UV spectrum
etc must be submitted together with the protocol of analysis.
5. Protocol of analysis must be properly ordered with proper numbering for all tests
and specifications.
6. All references stated in the protocol of analysis must be submitted and clearly
labeled.
7. Protocol of analysis submitted must be in either Bahasa Malaysia or English.
Protocol of analysis in other languages will be rejected.
8. An authorized copy of latest certificate of analysis for the product concern must
be submitted with the protocol of analysis.
1. Identification test
a. List of equipment and apparatus required.
b. List of chemical / reagents
c. Preparation of sample and standard solutions.
d. Details of method and procedures.
e. Specification and acceptance criteria
a. List of equipment required together with test parameters.
b. Sample preparation (if any).
c. Specification and acceptance criteria
3. Disintegration test
a. Equipment required
b. Test parameters
c. Test medium
d. Specification
4. Dissolution test
a. Equipment and apparatus required.
b. List of chemical / reagents required
c. Test parameters i.e. type and volume of dissolution medium, rotation rate,
temperature of solution and time.
d. Preparation of dissolution medium, preparation of sample and standard
solution (if any), etc.
e. Type and method of analysis (HPLC, UV, etc) and test procedures. For
example, if HPLC method is used, test method has to include the
preparation of mobile phase, brand and type of column used, run time,
detector used (UV, RI, etc), injection volume, system suitability test and
other parameters.
f. Typical chromatograms / UV spectrum for sample & standard solution,
system suitability etc.
g. Complete formula for calculation. For example, ‘slow release’ products
calculation must include quantity of active substance in the medium volume
which have been taken out for analysis.
h. Test specification
5. Impurities / degradation / purity test
a. List of equipment and apparatus required,
b. List of chemical and reagents required.
c. Preparation of sample and standard solutions.
d. Detailed method and procedures
e. Complete formula for calculation.
f. Typical chromatogram of system suitability test, sample & standard
solutions if applicable.
g. Specification / acceptance criteria.
6. Assay and uniformity of content
a. List of equipment and apparatus required,
b. List of chemical and reagents required.
c. Preparation of sample and standard solution
d. Detailed method and procedures
e. Complete formula for calculation.
f. Typical chromatogram/spectrum of system suitability test, sample &
standard solutions if applicable.
g. Specification / acceptance criteria.
7. Pyrogen / abnormal toxicity test
a. List of equipment, apparatus, glassware and reagents required.
b. Preparation of sample solution and injection dose.
c. Test method & procedure.
d. Test interpretation
e. Test specification
8. Bacterial Endotoxins Test (LAL)
a. List of apparatus, glassware and reagents required.
b. Preparation of standard solution, LAL reagent/substrate and sample.
c. Determination of MVD (Maximum Valid Dilution) and endotoxin limit.
d. Detailed test procedure.
e. Calculation and interpretation of test result
f. Test specifications.
9. Microbial Limit Test
9.1 Determination of microbial contamination test
i. List of apparatus and culture required.
ii. Preparation of test medium and growth promotion test.
iii. Sample preparation including method for neutralizing of preservatives
for samples that contain preservatives.
iv. Complete test procedure by ‘surface spread’ for bacteria and ‘pour
plate’ for fungi.
v. Colony counting
vi. Specification and acceptance criteria
9.2 Test for specified microorganisms and total viable aerobic count
i. List of apparatus and culture required.
ii. Preparation of test medium and growth promotion test.
iii. Sample preparation including method for neutralizing of preservatives
for samples that contain preservatives.
iv. Complete test procedure for each of specific microorganism involved.
v. Observation on colonies presence.
vi. Specifications and acceptance criteria.
10. Sterility test
a. List of apparatus required.
b. List of biological and chemical substance required:-
i. Culture medium
ii. List of rinsing solution, buffer solution and diluent
iii. Neutralizing agent (if any)
iv. List of specific type cultures required
c. Method used (e.g. membrane filtration method, direct inoculation,
etc)
d. Method of preparation of the following solutions/materials:-
i. Culture medium (e.g. Fluid Thioglycollate Medium and Soyabean
Casein Digest Medium).
ii. Rinsing solution, buffer solution and diluents.
iii. Neutralizing agent (if any).
iv. Microorganism culture
e. Growth promotion test for medium used in sterility testing (specific aerobes,
anaerobes and fungi).
f. Preparation of sample solution (including neutralizing procedure of
antimicrobial agent for antibiotic samples and samples which contain
preservatives).
g. Complete test procedure for sterility test.
h. Specifications and acceptance criteria.
i. Validation procedure & validation data (if applicable).
11. Microbiology assay
a. List of apparatus required.
b. List of biological and chemical substances required.
c. Procedure for the preparation of following solutions/substances:-
i, Culture mediums
ii. Rinsing solutions.
iii. Buffer solutions
iv. Diluents
v. Microorganism culture used in assay
d. Test method (e.g. agar diffusion, turbidimetric, randomized block, dose, etc)
e. Test procedure
i. Preparations of solutions containing antimicrobial agents which may be
present in the sample to be tested (if applicable).
ii. Preparation of standard solutions (including any steps to counteract
the antimicrobial properties of any preservatives, etc present in the
sample)
iii. Preparation of test solutions (including any steps to neutralize the
antimicrobial properties of any preservatives, etc present in the
sample)
iv. Dilution schemes for test and standard solutions.
v. Application of test & standard solutions (volume, latin squares, etc)
vi. Incubation temperature & time
vii. Procurement of test data.
f. Complete calculation for the test including ANOVA tablet and other data
showing validity of test results.
g. Specifications and acceptance criteria.
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