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Sunday, June 12, 2011

Guidance from different agencies(Source:(cGALP))

Guidance document on part 11-Electronic signature & Electronic record & Computer System Validation(CSV)

FDA guidance - General principles of software validation

Computer System Validation(CSV)

21 CFR Part 11 -FDA


NEW: Validation of Computerised Systems - Core Document

NEW: Annex 1: Validation of computerised calculation systems: example of validation of in-house software - Spread sheet/Microsoft Excel

NEW: Annex 2: Validation of Databases (DB), Laboratory Information Management Systems (LIMS) and Electronic Laboratory Notebooks (ELN)

NEW: Annex 3: Validation of computers as part of test equipment

GAMP 4 to GAMP 5 –Summary

Stability study

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. Stability testing is a routine procedure performed on drug substances and products. It is involved at various stages of product development.

In early stages, accelerated stability testing (at relatively high temperatures and/or humidities) can be used as a “worst case” evaluation to determine what types of degradation products may be found after long-term storage.

Testing under more gentle conditions (those recommended for long-term shelf storage), and slightly elevated temperatures, can be used to determine a product’s shelf life and expiration dates.

In these types of studies, the product is analyzed at regular intervals for various parameters, which may include assay of the active ingredient, measurement of known degradation products, dissolution time, appearance, etc.

Stability Guidelines


Quality Guidelines : (Stability)

Q1A(R2): Stability Testing of New Drug Substances and Products

Q1B: Photostability Testing of New Drug Substances and Products

Q1C: Stability Testing for New Dosage Forms

Q1D: Bracketing & Matrixing Designs for Stability Testing of Drug Substances & Drug Products

Q1E: Evaluation of Stability Data

Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV - This Guideline withdrawn on June 8, 2006


Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms Annex 5, WHO Technical Report Series 863, 1996

Item 10.1 TRS 937:
Item 10.1, WHO Technical Report Series 937, 2006

Update, Item 11.1 TRS 908
Item 11.1, WHO Technical Report Series 908, 2003

Stability testing of active pharmaceuticals ingredients and finished pharmaceuticals products - Annex 2

WHO Technical Report Series 953, 2009


Consultation of Stability studies in a global environment


Guidance for industry


Stability testing of new drug substances and products



Australian Regulatory Guidelines for Complementary Medicines(ARGCM)


TGA : Questions & answers on the stability testing of Listed complementary medicines

Read More


Stability study of drug product

Read More


Stability testing of drug substances and pharmaceutical products

Read More

Decision Tree for Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances or Products (excluding Frozen Products)

Case 1 : No significant change in accelerated

a) No or little change in long term and accelerated

Extrapolation (Y) = up to 2X, but not exceeding X + 12 months;

or if refrigerated, Y = up to 1.5X, but not exceeding X + 6 months

b) Change in in long term & acclerated

i)If backed by statistical analysis and relevant supporting data;

Extrapolation (Y) = up to 2X, but not exceeding X + 12 months;

or if refrigerated, Y = up to 1.5X, but not exceeding X + 6 months

ii)If backed by relevant supporting data;

Extrapolation (Y) = up to 1.5X, but not exceeding X + 6 months;

or if refrigerated, Y = up to X + 3 months

Case 2 : Significant change within 6 month accelerated

a) if refrigerated, and significant change within 3 months - No extrapolation

b) if refrigerated, and no significant change within 3 months- No extrapolation

c) if not refrigerated and significant change at intermediate - No extrapolation

d) if not refrigerated and no significant change at intermediate condition

i) If backed by relevant supporting data:Y = up to X + 3 months

ii) If backed by statistical analysis and relevant supporting data

Y = up to 1.5X, but not exceeding X + 6 months


"Significant change" for a drug substance is defined as failure to meet its specification

In general, "significant change" for a drug product is defined as:

1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures;

2. Any degradation product’s exceeding its acceptance criterion;

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form:

4. Failure to meet the acceptance criterion for pH; or

5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

FIP Position Paper on Qualification of Paddle and Basket Dissolution Apparatus -To read click the link FIP Position paper dissolution

FDA publishes guidance document on capillary Electrophoresis

The ICH Steering Committee recommends that the analytical procedures described in the official pharmacopoeial texts, Ph. Eur. 2.2.47. Capillary Electrophoresis, JP General Information. Capillary Electrophoresis, and USP General Information Chapter <1053> Biotechnology-derived Articles – Capillary Electrophoresis, can be used as interchangeable in the ICH regions. To view the guidance, CE FDA Guidance

Uncertainty of Measurement-Part 1: General OMCL Policy for implementation of Measurement of Uncertainty in Compliance Testing

Uncertainty of Measurement-Part 2: OMCL Policy on the Estimation and Application of Uncertainty in Analytical Measurement

Implementation of ISO/ISE 17025 by Agilent technoligies

To get the copy of Analytical instrument qualification from Agilent technologies click the link - Analytical Instrument Qualification

Guidance for UK Manufacturer’s Licence and Manufacturer’s Authorisation (for Investigational Medicinal Products) Holders on the use of UK Stand Alone Contract Laboratories

This document:

• Defines a stand alone contract laboratory in relation to quality control testing of medicinal products.

• Provides guidance as to when a contract laboratory must be named on a manufacturer’s licence for relevant medicinal products for human and veterinary use and/or a manufacturer’s authorisation for investigational medicinal products.

• Is applicable to all manufacturing licence holders, i.e. import, export, herbals and specials.

• Provides guidance as to when a contract laboratory is not required to be named on a manufacturer’s licence or authorisation.

• Outlines the MHRA’s criteria for inspection of contract laboratories.

This guidance can be downloaded by clicking Guidance .

A primer for Good laboratory Practice and Good Manufacturing Practice - For Analytical Laboratories

WHO good practice for pharmaceuticals quality control laboratory(draft)

Analytical Balance

NIST - weight and measurement-calibration procedure

NIST - Weight classification

Balance calibration procedure

A guide for Proper weighing of lab balance by Mettler

HPLC Column comparison

To find out alternative column for your column of interest.

HPLC Column comparison - USP Database

HPLC Troubleshooting guide

From waters

From sigma-aldrich

Instrument calibration

1. Disolution Apparatus 1 & 2 - Mechanical calibration

Procedure - FDA procedure - Dissolution - Mechanical calibration

Calibration of Dissolution Apparatus 1&2

Recently FDA has released a new guidance on Calibration of disolution apparatus 1 & 2. This guidance document more emphasis on enhanced mechanical calibration than chemical performance verification test. This guidance also recommends to manufacturer take appropriate control to handle recognised source of significant variablity during dissolution testing like dissolved gases, vibration and vessel dimensions. For more information go through the link .Guidance to industry -Dissolution

Dissolution procedure toolkit

USP released the version 2 of dissolution tool kit procedure for mechanical calibration and performance verification test apparatus 1 & 2. The dissolution toolkit provides a description of best practices associated with the mechanical calibration and performance verification test for the USP basket and paddle dissolution apparatuses and test assemblies.This second version of the dissolution toolkit represents a continuing effort to provide detailed information describing the procedures that if used will assure a properly qualified dissolution test assembly. For more information click Disolution Toolkit Procedure Version-2.

To refer version-1 click Dissolution Toolkit version-1

Further USP established a new acceptance criteria for current lot of Prednisone tablet. For more information click the link Performance of Equipment to Test Dissolution of Medications Further Assured

2. Prednisone tablet for PVT - New lot - P1I303

Prednisone Tablet for PVT - New lot released on March 2010

Prednisone Tablet for PVT - A new lot is released on March 01, 2010 Lot No.P1I300 valid through Feb 29, 2012 with test procedure an optional two stage test and calculation example. On April 30, 2010, Lot P0E203 will no longer be official.

Note: There was an error in the initial USP certificate dated Feb.22, 2010. It is now corrected. For corrected certificate click Prednisone Tablet for PVT - New lot released on March 2010.

Instrument Qualification

Qualification of Equipment (Core document)

Annex 1: Qualification of HPLC Equipment

Annex 2: Qualification of GC Equipment

Annex 3: Qualification of UV-Visible Spectrophotometers

Annex 4: Qualification of IR Spectrophotometers

Annex 5: Qualification of Automatic Titrators

NEW: Annex 6: Qualification of piston pipettes

Result & Reports

Evaluation & Reporting of Results

Concept paper on Storage Conditions during Transport

This paper is concerned with challenges related to the maintenance of appropriate transit conditions during transport as products move through all stages of the manufacturing and wholesale distribution system from active substance through the wholesale distribution system to ensure that patients and animals receive safe and efficacious medicinal products.

From a product’s perspective, transport is a mobile form of storage but where there are weaker controls than storage in fixed sites – therefore similar levels of controls should exist. Compliance at all stages of manufacture and distribution becomes more important as the number of transport stages increase, including transport (i.e. import) into the EU. Several examples have been seen where sea-freight significantly exceeds 30 days. Any increases in the length of time and/or the climactic challenge at each stage will also impact on compliance. It is also increasingly difficult to be aware of and to assess the cumulative effects of adverse incidents at different stages.

Many sites of manufacture are now located in tropical zones and/or where transport infrastructure may be difficult. Therefore the challenges arising from transport between such sites and from these sites to the EU may take finished products, or their earlier stages of manufacture, outside of the conditions defined in the EU Marketing Authorisation for storage of the product. Also, the risk of freezing during transport and the effects on the products should be considered.

It is important to understand the susceptibility of different products at the different stages and whilst the principles of quality risk management would be applied on a product by product basis at each stage of manufacture and transport would be expected, the reality is that different products and different product stages are frequently co-shipped. It is therefore evident that a simple set of readily understood general rules should apply to transit conditions to reduce this complexity and risk of error.

Although widely acknowledged, there is no explicit requirement for the need to conduct transport studies under worst case conditions and no requirement for routine monitoring during transport.

Primer for GLP & GMP for Analytical Lab - Agilent

Top ten deficiencies found during first assessment of new applications from October to December 2009 - EDQM

This document is a summary of the main questions resulting from the first assessment of new applications for Certificates of Suitability (CEP) for chemical purity. It is based on the content of 108 deficiency letters sent to the applicants on applications treated from October to December 2009.

The Top 10 questions are listed below with additional recommendations regarding EDQM requirements added. By including these recommendations - together with the requirements described in the EDQM Guideline "Content of the dossier for chemical purity" PA/PH/CEP (04) 1 (current version) which is available on our website - applicants can improve the quality of their dossiers with a view to facilitating and speeding up the granting of their CEP.

TOP 1 (3.2.S.2.2) / (3.2.S.2.3): Redefinition of starting material

TOP 2 (3.2.S.2.3): Absence of discussion on the carry-over of impurities/by-products from key materials

TOP 3 (3.2.S.2.3): Absence of discussion for Class 1 solvent as contaminant of another solvent

TOP 4 (3.2.S.3.2): Genotoxic impurities

TOP 5 (3.2.S.4.4): Absence of comparison of the quality of the final substance obtained with starting materials from different suppliers

TOP 6 (3.2.S.2.3): Incomplete specifications for the declared starting materials

TOP 7 (3.2.S.4.3): Suitability of the monograph to control the impurity profile of the final substance

TOP 8 (3.2.S.6): Specification for container closure system

TOP 9 (3.2.S.3.2): Compliance with the requirements of the Ph. Eur General Monograph 2034: limit for unspecified impurities

TOP 10 (3.2.S.2.3): Solvent recovery

For more information click the weblink


How to do document - New revised APIC guide - GMP for API

It describes the intrepretation of ICH Q7 with revision in quality management, personnel & agents,brokers,traders,distributors,repackers and relabellers - Version 6.

How to do document-Intrepretation of ICH Q7 -Verison 6 -Revised

Example of Quality Risk Management (QRM) Implementation by PIC/S

An informal working group within PIC/S has developed an example of methodology for the implementation of Quality Risk Management (QRM) in industry. For download example

EU GMP Guide chapter-7 revised - Outsourced activities -contract manufacturer and analysis

Chapter 7 of the EU GMP Guide "Contract Manufacture and Analysis" has been revised and was published on the GMP-information site of the European Commission on 9 November 2010.

Reasons for changes: in view of the ICH Q10 guideline on the Pharmaceutical Quality System, Chapter 7 of the GMP Guide has been revised in order to provide updated guidance on outsourced GMP regulated activities beyond the current scope of contract manufacture and analysis operations. The title of the Chapter has been changed to reflect this.

WHO guideline on Quality Risk Management

This guideline will align with the general framework described within other current international papers on this subject.

Principles of quality risk management- Four primary principles of QRM are:

•the evaluation of the risk to quality should be based on scientific knowledge and
ultimately link to the protection of the patient;
• QRM should be dynamic, iterative and responsive to change;
• the level of effort, formality and documentation of the QRM process should be
commensurate with the level of risk; and
• the capability for continual improvement and enhancement should be embedded in the QRM process.

Change in ICH classification of residual solvent - Cumene(Isopropyl Benzene) - From class 3 to class 2

Cumene is listed in the ICH Q3C(R4) guideline in class 3. A revision to the ICH Q3C(R4) guideline is proposed in which it is recommended that cumene be placed into class 2 to take account of new toxicity data.

To go through draft guideline and send comment click Draft guideline

Out-Of-Specification (OOS)

Investigation is must for any product failures to find out the root cause and Corrective And Preventive Action(CAPA). USFDA come up with definite guidance on this subject. This guideline helps to handle OOS data and procedure for investigation. For more information refer the below link. FDA Guidance - OOS

Out-Of-Trend(OOT) Analytical Results

OOT means an analytical result which fall with in the specification limit but does not follow with in the trend or unexpected result. Normally any analytical result which fall in Out-Of-Specification requires a detailed investigation to find a root cause failure and folowed by a currettive And Preventive Action(CAPA).

Though regulation demands investigation to be completed with in thirty days but most of the cases industries fails to complete the investigation with in stipulated period to find root cause. Meanwhile its end up with few more failures. To avoid such things happen the current practice starts investigation when results appear to be out-of-trend.

The following links help to know more about OOT

Identification of OOT-Stability results

Identification of OOT-Stability results-part-2

Revised Annex 13 on Investigational Medicinal Products (IMP) coming into operation
The European Commission has published on the EudraLex - Volume 4 webpage the new Annex 13 (Investigational Medicinal Products) of the EU Guidelines to Good Manufacturing Practice. The new Annex is coming into force in July 2010.


Part 2 EU GMP Guide on APIs Will No Longer Be Identical to ICH Q7
The European Commission published a revised Part 2 text on GMP for APIs which will enter into force by 31 July 2010.


A template for API quality agreement

This Quality Agreement template was developed by the Bulk Pharmaceutical Task Force (BPTF), an affiliate organization of the Society of Chemical Manufacturers and Affiliates (SOCMA), as a guide for drafting a Quality Agreement relating to the manufacture and release of substances regulated by the Food and Drug Administration. The template is based on the collective experience of industry members. This can be downloaded by clicking Quality agreement template

WHO released draft guidance for production and control of specified starting material

Specified starting material means any substance which is primarily or mainly used as a starting material for the production of an API, but which could be used directly as an API.

This guideline is intended to assist applicants or MA holders in assessing the required level of quality of “specified starting materials” that will be used for the manufacture of an API. It is also intended to help API master file holders (APIMF) in the compilation of their APIMFs

The control of the “specified starting materials” should be designed to detect isomeric or other impurities which are potentially reactive and could be carried through to the final product of the synthesis.

For more information click WHO guideline

Verification of Compendial Procedures - Changes Planned in the USP General Chapter <1226> -USP 35

In the Pharmacopeial Forum from November/December 2010, the USP proposed to revise the General Chapter <1226> Verification of Compendial Methods.

Changes planned are as below. USP planning to implement in USP 35.

  • The word "method" should be replaced by "procedure"

  • Aims to clarify the purpose and the scope of the verification process. "The verification process for compendial test procedures is the assessment of whether the procedure can be used for its intended purpose, under the actual conditions of use for a specified drug substance and/or drug product matrix."

  • "The process of assessing the suitability of a compendial analytical test procedure under the conditions of actual use may or may not require actual laboratory performance of each analytical performance characteristic."

The following will be added to the points which must be taken into consideration for the Verification of Compendial Procedures:

  • drug substance's synthetic route

  • method of manufacture for the drug product

  • effect of the matrix on the recovery of impurities

  • suitability of chromatographic conditions and column

  • appropriateness of detector signal response

The revision of the General Chapter <1226> Verification of Compendial Procedures should be published in the USP 35.

Clarification not provided by USP is "Whether the laboratory needs to prove the performance of each validation parameter for the assessment is left open".

Analytical Method Development

HPLC method development guide

Selecting right chiral column

GC column selection guide

Analytical Method Validation

Primer for validation of analytical method - Agilent technoligies

Validated analytical method only can give accurate results. Validation of analytical method is must for pharmaceutical analytical laboratory.

There is guideline for analytical method validation from ICH & US FDA.

ICH-Q2(R1)- Validation of Analytical Procedures - Text and Methodology


US FDA draft guidance on analytical procedures & method validation

FDA-Analytical method validation

EDQM guideline

EDQM-Validation of analytical procedure

Method validation - Particle size - Laser diffraction - Malvern application note New

Analytical Method Transfer

There is no definite guidance from USFDA on this subject. Recently USP has come up with a stimuli article on this subject. For more information refer the link below.

Transfer of analytical procedures-A new general information chapter


WHO draft guideline - Refer page 14

An article on analytical method transfer

Challenges in analytical method transfer

Auditing pharmaceuticals quality control Laboratory

Auditing quality control laboratory is must for continuous improvement and regualotory requirements. It helps to keep QC laboratory in high compliance level and maintain best practices through continuos improvement by training and gap analysis.

There is a guideline from US FDA for inspection pharmaceuticals QC laboratory it includes chemical lab and Micro lab.

Pharmaceutical Quality Control Labs

Guide to inspection of pharmaceuticals quality control laboratory

Audit check list for Pharmaceutical Quality Control Labs by PICScheme


Microbiological Pharmaceutical Quality Control Labs

Guide to inspection of microbiological pharamaceuticals quality control lab

  • NEW: Standard ‘Aide-Mémoire’ for the Mutual Joint Audit of Official Medicines Control Laboratories*

    GMP-Common Deficiencies-MHRA

    Auditing Guide from APIC

    World Health Organization Public Inspection Reports (WHOPIR)

    The World Health Organization Public Inspection Reports (WHOPIR) is a summary of the inspection report of

    • a manufacturing site for Active Pharmaceutical Ingredients (APIs);

    • a manufacturing site for Finished Products (FPs);

    • an organization such as a Contract Research Organization where a bioequivalence study or other clinical study had been performed (CROs);

    • a quality control laboratory

    The WHOPIR reflects the inspection report and gives a summary of the observations and findings made during the inspection, but excludes confidential proprietary information. It indicates also the date and duration of the inspection as well as the scope of the inspection.

    The reported inspection reports are from India & china companies. Few examples are Ranbaxy, Cipla, Matrix, Lupin, IPCA, Aurobindo, Sitec lab,Vimta lab etc

    To view/read the WHO inspection report click WHO inspection reports


    Harmonization of microbial limit test - pharmtech

    Objectionable microorganism Vs Specified microorganism

    How to Determine if an Organism is “Objectionable”

    Presentation - USP -Micro

    Presentation - USFDA -Micro

  • USP revised the general chapter <85> Bacterial Endotoxins Test

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