NPCB

MOH

National Pharmaceutical Control Bureau

MINISTRY OF HEALTH MALAYSIA

AMV Document Submission Guideline

& Common Problems

Centre for Quality Control|

National Pharmaceutical Control Bureau
Lot 36, Jalan Universiti, 46200 Petaling Jaya, Selangor

DL: +6.03.78835400 | F: +6.03.79567075 |

WS : www.bpfk.gov.my |

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PRESENTATION OUTLINE

1. Introduction
2. Analytical Method Validation (AMV)
3. Protocol of Analysis (POA)
4. Certificate of Analysis (COA)
5. The Requirement of AMV Document Submission
6. Common Problems
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INTRODUCTION
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Background

National Pharmaceutical Control Bureau, was set up in

October 1978.

This institution was established to implement quality

control on pharmaceutical products.
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Objectives of NPCB

 To ensure that therapeutic substances

approved for the market are safe, efficacious
and of quality.

 To ensure that the approved traditional

medicines and the notified cosmetic products
marketed are safe and of high quality.
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Core activities of Centre for Quality Control (CQC)

1. SAMPLE TESTING
a) Pre-registration of traditional products
b) Post-registration for pharmaceutical, traditional
and cosmetic products (surveillance program)
c) Screening of adulteration products (Enforcement
program)

2. EVALUATION OF PROTOCOL OF ANALYSIS

(POA) AND ANALYTICAL METHOD
VALIDATION (AMV) DATA
- Registration of pharmaceutical products
(1 January 2008)
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Analytical Method Validation (AMV)

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OVERVIEW OF ANALYTICAL METHOD VALIDATION (AMV)

DEFINITION
Validation is the proof needed to ensure that an analytical method can
produce results which are reliable and reproducible and which are
fit for the purpose intended.

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
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Purpose of Analytical Method Validation (AMV)

• Identification of sources and quantitation of

potential errors.

• Determination if method is acceptable for intended

use

• Establish proof that a method can be used for

decision making
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When methods need to be validated or revalidated?

1. Before their introduction into routine use

2.Whenever the conditions change for which the method

has been validated (e.g., samples with a different matrix)

3. Whenever the method is changed and the change is

outside the original scope of the method
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OVERVIEW OF ANALYTICAL METHOD VALIDATION (AMV)

Plan Collection Good

of data AMV
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Guidelines for AMV

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What are the type of analytical procedures to be validated?

Identification

Assay (content & dissolution measurement only)

Impurities (quantitative & limit test)

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What are the parameters/validation characteristics to check for

those analytical procedures?

Specificity
Accuracy
Precision (repeatability, intermediate)
Linearity & Range
Detection Limit
Quantitation Limit
Robustness
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System Suitability Testing (SST)

Test to verify the proper functioning of the operating system.

i.e., the electronics, the equipment, the specimens and the analytical
operations

The example of SST in HPLC system:

1. Minimum resolution of 3.0 between the analyte peak and internal
standard peaks.
2. Relative Standard Deviation (RSD) of replicate standard injections
of not more than 2.0 %
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Validation vs Verification

Validation requirement = Non compendial methods (in-house)

Verification requirement = Compendial methods

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Validation Requirement – Non compendial / in house method

Parameter Identification Testing for Impurities Assay /

Dissolution /
Content
Quantitative Limit
Accuracy - + - +
Precision – Repeatability - + - +
Precision – Intermediate - + - +
Precision
Specificity + + + +
Detection Limit - - + -
Quantitation Limit - + - -
Linearity - + - +
Range - + - +
Robustness - + - +

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Validation vs Verification

Validation requirement = Non compendial methods (in-house)

Verification requirement = Compendial methods

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Compendial method

Users of analytical methods described in USP are not

required to validate accuracy and reliability of these
methods, BUT merely verify their suitability under actual
conditions of use.

system suitability testing

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Verification Requirement for Compendial method: (Ideally)

Parameter Identification Testing for Impurities Assay /

Dissolution /
Content
Quantitative Limit
Precision – Intermediate - + - +
Precision
Specificity + + + +
System suitability testing

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Good validation data should have ;

 Validation protocols / methods

 Acceptance criteria
 Results
 Raw data
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1. Validation protocol / method

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1. Validation protocol / method

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2. Acceptance Criteria
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3. Results
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4. Raw data
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PROTOCOL OF ANALYSIS (POA)

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PROTOCOL OF ANALYSIS (POA)

The way of performing the analysis

Describe in detail the steps necessary to perform

each test
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General requirement of POA for finished product

Product name
Name & address of manufacturer
Name, signature & designation of authorized person
Effective date
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General requirement of POA : Example

Product name

Name & address of

the manufacturer

Name, signature Effective date

& designation
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POA for finished product

1. It must be in Bahasa Malaysia / English

2. It contain all the updated test methods & the shelf life
specifications
3. Methods must be described in detailed procedures
1. - equipment/ reagent/ standards required
2. - detailed dilution for standard / sample solution
3. - detailed preparation of mobile phase/ diluent/ medium
4. - system suitability test (resolution, %RSD, tailing
factor, theoretical plate)
5. - complete formula for calculation and interpretation of the
results
6. - chromatogram
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POA for finished product

4. The latest BP / USP shall be used as the main

references.
5. Photocopies or methods directly copied from
pharmacopoeias will not be accepted
6. All test specifications set by the manufacturer shall be
in line or more stringent than BP / USP
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POA for finished product

The manufacturer can set the

specification in line (90.0 – 110.0%)
or more stringent (95.0 – 105.0 %)

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Certificate of Analysis (COA)

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Certificate of analysis

Finished product
3 batches

Active Pharmaceutical Ingredient(s)

1 batch

Note :
The test specifications must be listed in the certificate as
well as actual results obtained
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The Requirement of AMV Document

Submission

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Requirements

1. Protocol of analysis for finished product (POA)

2. Certificate of analysis for finished product and

active pharmaceutical ingredient(s) (COA)

3. Analytical method validation documents

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Documents to be submitted via online Quest system

E9 Complete protocol of Analysis for finished product including

preservatives (if any)

E10 Summary of AMV which include all the relevant validation

characteristics, its acceptance criteria and results

E11 Certificate of analysis for active drug substance (1 batch) and recent
batches of finished product (3 different batches)
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Requirements

 submit through the Quest System

 hardcopy version sent to Laboratory Services
Section

Note :
If the file is too big, then a summary of the
validation data may be uploaded but the hardcopy
version has to be a complete set of documents.
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Documents to be submitted as hardcopy

1. Certificate of analysis (COA)for active drug substance (1 batch)

and recent batches of finished product (3 different batches)

2. Complete protocol of analysis (POA) for finished product (including

preservatives, if any)

3. Complete testing method for the AMV

4. Complete results for the AMV with all relevant validation parameters,
including acceptance criteria and supporting raw data (e.g.
chromatogram, spectrums etc)
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Additional
1. A cover letter consisting of the following information should be
enclosed with every hard copy documents submission;
i) Name of product
ii) Reference Number / Protocol Number
Iii) Contact person (name/email address/ telephone no.)
iv) Name and address of company

2. Documents submitted should be well organized and indexed

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Common Problems in Submitting the

Documents

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Common problems in submitting the document : COA

1. COA of active ingredient not available

2. Incomplete number of COA of finished product
3. Incomplete information on COA
- no specification
- the results was written as “complies” or “conform”
(esp. for the results for Related Substance /
Particulate matter)
1. The specifications are too lenient
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Common problems in submitting the document : COA

The manufacturer can set the

specification in line (90.0 – 110.0%)
or more stringent (95.0 – 105.0 %)

x
DO NOT set the
specification too
lenient than this!!
e.g. 85.0 – 115.0 %
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Should write the

actual value e.g
0.01 ppm

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Common problems in submitting the document : POA

Protocol of analysis

 Methods are directly copied from pharmacopeias

 Methods are not updated to current pharmacopeias
 Critical test are not performed ( dissolution, related
substance/impurities)
 Test parameters are listed in COA but not found in POA
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Common problems in submitting the document : AMV

Validation Data

 Methods are not validated as per ICH guidelines

 Validation protocol is not provided. Only provide
validation report
 Different test methods in POA and protocol validation
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Common problems in submitting the document : AMV

Validation Data

 Test method for validation was not mentioned

 No acceptance criteria
 Raw data not given / manufacturer refuse to
give the raw data
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