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PHARMACEUTICAL
QUALITY ASSURANCE

Alok Ghosh
Ex-President – Global Technical Operations, Lupin Limited, Mumbai
Adjunct Professor, Adamas University, Kolkata

ARYAN PUBLISHING HOUSE

181/3, Canal Street (Shreebhumi), Kolkata – 700048
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 Dedication
This book is dedicated to my late parents Maya Rani Ghosh
and
Benoy Moy Ghosh
.
 Preface
India has emerged as a major player in Pharmaceutical manufacturing in last 25-
30 years. Indian companies not only made India as self-sufficient in affordable
medicines but also a major supplier to other countries including USA, Japan and
many countries in Europe. India is considered today as the Pharmacy of the World.
The focus on quality and adhering to the requirements of leading regulatory
agencies like USFDA , UKMHRA , WHO etc. has brought India in today’s position of
a major exporter of pharmaceuticals.
The practice of world class Quality Assurance has played crucial role for India to
come to this position. Hence it is important for Pharmacy students to understand the
basics of Quality Assurance to prepare them for future professional work.
After retiring from corporate job with a Pharmaceutical Company, I decided to get
associated with an educational institution. While associating myself with Adamas
University, Kolkata, I had a chance to go through the syllabus on Pharmaceutical
Quality Assurance taught in Pharmacy degree course. The urge to write a book on
Quality Assurance started during Covid 19 lock down period, when I was confined to
my home in Mumbai. My colleague during my professional career with Lupin ,Ms
Nilanjana Basu readily agreed to help me. The flow charts and schematic diagrams
along with constructive review of the chapters were done by Nilanjana. Without her
active participation, the book would not have been completed on time for publication.
The syllabus on Pharmaceutical Quality Assurance has been changed to make
students industry ready. While writing this book, I approached from Industry perspective
with an intention to trigger the curiosity in students to the subject of Quality
Management.
I would be extremely happy to receive the feedback and suggestions on the book
by students and teachers for inclusion in future edition.
Sincere thanks to Ayan Dey and Ayan Chatterjee of Aryan Publishing House for
publishing the book and Mr Amitava Roy to take extra care in reading and correcting
the manuscript.
Finally, special thanks to my wife Ms Alpana Ghosh for her unstinted
encouragement to write the book

December 2020 Alok Ghosh

.
 SYLLABUS
CHAPTER-1
(i) Atomic and
.
CONTENTS
CHAPTER 1 : ?? 1-114
1.1 Ato

.
.
UNIT–1
.
 Chapter 1

Quality Assurance and

Quality Management Concepts
1.1 Good Manufacturing Practices (GMP)
Good Manufacturing Practice or GMP is a concept where all activities in
Pharmaceutical operations are conducted based on science and logic. Pharmaceuticals
is a knowledge-based industry where knowledge of science is essential to
manufacture products with quality, efficacy and safety. GMPs are the series of
principles that a company follows during manufacturing processes. It is the quality
management that ensures that the products are consistently produced and controlled
to the quality standard prescribed for product.
GMP guidelines are laid down by different regulatory authorities with an aim to
maintain minimum standards which are to be fulfilled during manufacturing of
products. Compliance to GMP is mandatory before any product is approved for
marketing. Usually the word “current” is prefixed with the GMP guidelines to show
the latest or current practices followed instead of superseded practices. GMP
encompasses both manufacturing and quality control (laboratory) activities in an
organization and commonly covers 5 Ps – People, Premises, Processes, Procedures
and Products.
The most frequently used GMP guidelines referenced by pharmaceutical
companies are –
(a) The US 21CFR 210 Current Good Manufacturing Practices for Drugs in general
and 21CFR 211 Current Good Manufacturing Practices for Finished
Pharmaceuticals and 21CFR Part 11 for compliance to Electronic Documentation.
(b) The Guide to Good Manufacturing Practice for Medicinal Products by the
European Union.
(c) The ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical
Ingredients
(d) The World Health Organization Guideline on GMP
(e) Schedule M “Good Manufacturing Practices and Requirements of Premises, Plant
and Equipment for Pharmaceutical Products “– The Drugs and Cosmetics Act
and Rules, India

13
14 Pharmaceutical Quality Assurance

(f) PICs (Pharmaceutical Inspection Co-operation Scheme) Guide to Good

Manufacturing Practice for Medicinal Products.
(g) Rules and Guidelines for Pharmaceutical Manufacture and Distributors
commonly known as The Orange Guide by Medicines and Healthcare Products
Regulatory Agency (MHRA) Inspectorate of United Kingdom.
Although every regulatory authority has their own guidelines but the principle
of good manufacturing practices are essentially same in all these guideline.

1.2 Quality Assurance and Quality Control

In the overall concept of Total Quality Management (TQM), Quality Assurance
(QA) and Quality Control (QC) are two facets of maintaining the quality of product.
Many times, the terms, QA and QC are used interchangeably, however, both the
functions are distinctly different, though interrelated.
Quality Assurance is defined in ISO 9000 as “part of quality management focused
on providing confidence that the quality requirements will be fulfilled”. This is
planned and systematic activity implemented within the Total Quality Management
to demonstrate that the product and service will fulfill the requirement of quality,
efficacy and safety of the product. The function of QA ensures that the good
manufacturing practices are followed always while manufacturing the product.
Quality Control is inspection and structured testing of the input materials, in-
process materials and finished products as a part of quality management to ensure
that the marketed product meets with the applicable specifications. While Quality
Assurance is over all monitoring of validated procedures, Quality Control is the
testing of the product at various stages of manufacturing to ensure that the product
is safe and meets the acceptance criteria.
Following schematic diagram explains the importance and relationship of Total
Quality Management, Quality Assurance and Quality Control.

Relationship between Total Quality

Management, Quality Assurance and
Quality Control

Total quality
Management (TQM)

Quality
Assurance

Quality
Control
Pharmaceutical Quality Assurance 15

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. Schedule M deals with—
(a) Good Laboratory Practice (b) Good Manufacturing Practice
(c) Good Clinical Practice (d) None of the above
2. The responsibilities of Quality Control is –
(a) Analysis of Finished Product
(b) Analysis of Raw Materials
(c) Both a & b
(d) Manufacturing of Pharmaceutical Products
3. Quality is actually—
(a) Customer needs (b) Customer Satisfaction
(c) Fitness of use (d) None of the above
4. Quality Assurance is—
(a) Testing of products (b) overall monitoring of manufacturing
(c) Ensure procurement of materials (d) None of the above

Keys for Multiple Choice Questions

1 (b), 2 (c), 3 (c), 4 (b)

➥ Long Questions
1. What is Good Manufacturing Practice?
2. What are the roles of Quality Assurance?
3. What are the roles of Quality Control?
 Chapter 2

Total Quality Management (TQM)

2.1 Introduction & Definition
Total Quality Management or TQM is a management concept designed to
continuously improve the quality of manufactured products and improve customer’s
delight. Quality Management Systems for TQM have been successfully applied for
over eight decades to improve quality, customer satisfaction and efficiency at
organizations. While TQM was not originally designed for Pharma or highly
regulated industries, it created a sustained influence on current good manufacturing
practices (CGMP), ISO standards and ICH Q10 guideline for Pharmaceutical Quality
Systems.
The Quality Management Systems (QMS) of Pharmaceutical Industries simplify
complex CGMP and compliance requirements to implement TQM.
The new quality paradigm for Pharmaceutical Industries, as defined in ICH Q10
guideline is a risk-based approach. Organizations are encouraged to move beyond
using GMP check lists and embrace TQM practices which encompasses the R&D to
manufacturing life cycles. The guideline specifies to improve quality management
to follow following steps –
1. Quality is built into the processes instead of trying to improve with additional
testing or inspections
2. Rigorous modern science is used throughout the product life cycle.
3. Quantitative risk management is used to enable effective decision making
4. Organizations employ statistical interpretations to assure knowledge
management and transfer
5. The industry adopts an integrated approach to development, manufacturing
and quality.

16
Pharmaceutical Quality Assurance 17

There are eight (8) elements of Quality Management for Pharmaceutical

companies–
1. Customer Focus
2. Leadership
3. Employee’s involvement
4. Process approach
5. Systemic management
6. Continuous improvement
7. Evidence based decision making and
8. Communications

2.2 CUSTOMER FOCUS

The primary focus of a quality management system is to exceed customer’s
expectation. Understanding the customer’s expectation in the present and future is
the necessity for success. A customer focused culture can offer a host of benefits
including greater brand valuation, customer loyalty and increased market share.
Establishing a strong focus on the customer has clear benefits for quality driven
organizations in any industry especially in verticals such as pharmaceuticals where
customer’s expectations are changing rapidly. While many professionals understand
the value of creating a customer obsessed culture, however, to fulfill a complete
customer’s satisfaction is often hard to achieve.
Start up and scale ups in pharmaceutical industry often have an advantage when
it comes to establishing a customer centric culture. Many firms in the R&D phase of
the product life cycle were founded based on passion for helping patients and yet
have not lost sight of the customer delight. The genuine desire to help patients
should be integral to pharmaceutical quality management system. An effective
pharmaceutical quality system should encourage pharma companies to make
decisions to improve the quality of products and speed of delivery.

2.3 LEADERSHIP
Leadership is an integral part for a strategic and systemic approach to quality
driven organizations. The management team is responsible for refining the
organization’s vision, disseminating the purpose and encouraging the employees to
engage with the quality goals. In a pharmaceutical organization, the leadership team
is tasked with creating a culture of quality by imbibing transparency, integrity and
inspiring excellent performance.
18 Pharmaceutical Quality Assurance

A strategic approach to pharma leadership allows a company to become forward

looking. Instead of focusing on immediate objectives, management review efforts
are driven by a clear road map for improvements. Decisions are made based on
informed information, accurate documentation for risk management and clear quality
objectives.
An evolved leadership in a pharmaceutical organization plays a crucial role in
helping employees to take a systemic approach to achieving both short term and
long-term quality objectives by providing transparency, ease of access to information
and improving communications.

2.4 Employee’s involvement

The employees involved in pharmaceutical manufacturing are now required to
make decisions based on data throughout the product life cycle. A quality
management system must provide the comprehensive picture and analysis
capabilities to avoid the risks of any assumptions. Data can help leadership decide
where changes makes sense and when immediate changes are necessary to protect
product quality.
Changes are costly, but the quality risks from incomplete analysis can be even
more expensive for pharmaceutical organizations. A quality management system
should provide a full scope of data from a variety of sources to help the quality unit
and leadership identify root causes. Pharmaceutical quality management systems
should provide transparency into outcome to measure impact.

2.5 Process Approach

A process-based approach is a core principle of quality management system with
increased impact specific to pharmaceutical system. A process centered approach
involves the development of clear SOPs for every role and responsibility in the
organization, but it also requires pharma organizations to shift their focus to the
entire product life cycle.
Process centered quality management systems are crucial for regulatory
compliance in pharmaceutical industries. Process approach provide transparency
throughout the product life cycle and clear guidance for supply chain partners to
adopt a risk-based approach to quality management. Pharmaceutical organizations
should consider following supports for developing quality management system .
- Vendor’s risk assessment and audit
- Monitoring, documenting and reviewing manufacturing performance statistically
- Establishing written quality guidelines and SOPs and
- Ensure qualified and well-trained employees are involved in manufacturing
Pharmaceutical Quality Assurance 19

2.6 Systemic Management

Quality Management Systems consist of a framework for the governance of
interrelated processes. Transparency throughout the product life cycle is necessary
to Total Quality Management. An organization can only optimize products and
performance by understanding how a system produces results. Transparency of
information can be supported by a comprehensive Quality Management System
which comply with cGMPand ICHQ10.
The critical elements of a developed integrated Quality Management System
should support following –
(a) Quality Policy
(b) Personnel
(c) Development and implementation
(d) Manufacturing
(e) Documentation
(f) Facilities and equipment
(g) Self-Inspection
(h) Management responsibilities
(i) Evaluation of Vendors
(j) Vendor’s production and analysis
(k) Risk Analysis
(l) Monitoring and control
(m) Compliance and Recall
(n) Continuous measurement, analysis and improvement

2.7 Continuous Improvement

Continuous improvement is critical to the success of organizations in any industry.
For pharmaceutical industries, constant improvement is imperative for survival.
Generally pharmaceutical companies are always on intense pressure to meet strict
regulatory requirements and changing customer expectations. A formalized approach
to improvements can allow organizations to meet standards capturing new
opportunities and requirements.
Efforts to improve continuous improvement should focus on developing greater
internal efficiencies, meeting current and emerging customers’ requirements and
adapting changing market conditions. Quality management system can enable
20 Pharmaceutical Quality Assurance

leadership to create improvement objectives and discover opportunities based on

real time data.
A pharmaceutical quality management system can enable continuous
improvement by –
- Providing a centralized system for creating improvement objectives
- Elevating employee education on SOPs, best practices and improvement goals
- Assessing employee training performance to assure competency
- Tracking and auditing progress toward meeting quality standards

2.8 Evidence Based Decision Making

The decision making based on fact or evidence is fundamental to total quality
management. It is expected any decision based on analysis and evaluation of data
are more likely to produce an informed decision. Driving quality improvements and
effectively addressing root cause of failure and establishing corrective and preventive
actions (CAPA) to eliminate potential repetition of same or similar failure .
Data driven decision making is not a new concept for pharmaceutical companies.
The industry has long embraced periodic measurement and management review of
quality to get deeply involved with day to day issues. What’s new however is the
clear focus in ICH Q10 for companies to shift to risk-based management methods
based on real time data insights.

2.9 Communications
Effective relationships and communications are crucial to achieving the alignment
of people, processes and technology. Systems for communication should support
real time, productive dialogue between leadership, quality, manufacturing, vendors
and supply chain. Recent shifts in regulatory responsibilities have made it more
critical than ever for pharmaceutical organizations to communicate effectively with
the employees.
A quality driven organization must pool and share information, expertise and
resources with relevant interested parties, provide success metrics and channels for
feedback and refine methods for collaboration.
A developed quality management system should support regular communications,
monitor and distribute information based on role defined on real time basis.
Pharmaceutical Quality Assurance 21

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. TQM is a __________ tool in pharmaceutical industry
(a) Corrective (b) Managerial
(c) Preventive (d) Behavioural
2. How many elements are in Quality Management under TQM?
(a) Seven (b) Ten
(c) Eight (d) Five
3. Which ICH guideline deals with Quality Management?
(a) Q10 (b) Q7
(c) Q8 (d) Q5
4. Which element is not part of TQM?
(a) Customer Focus (b) Continuous Improvement
(c) Profit (d) Communications

Keys for Multiple Choice Questions

1 (b), 2 (c), 3 (a), 4 (c)

➥ Long Questions
1. What is Total Quality Management?
2. What are the benefits following Total Quality Management?
3. What are the eight elements of Total Quality Management?
 Chapter 3
International Council for
Harmonization of Technical
Requirements for Pharmaceuticals for
Human Use (ICH)
3.1 Introduction
As the regulatory requirements for Pharmaceuticals increased and as countries
and supply chain became increasingly globalized, an urgent need of harmonization
of systems and procedures with the aim to satisfy regulatory authorities in major
importing and exporting countries became necessary. The international Council for
Harmonization of Technical Requirements for Pharmaceuticals or commonly called
ICH was formed in Switzerland with an aim to bring together regulatory authorities
and pharmaceutical industry to discuss and finalize scientific and technical aspects
of pharmaceutical manufacturing and product registration.

3.2 History
As Europe became more and more a common market by joining many European
countries in European Union (EU), EU felt the necessity of forming a platform to
discuss harmonization of processes within Europe. In 1980, EU started harmonizing
regulatory requirements within European countries. However, between Japan, Europe
and USA, many companies had been supplying products from one country to other
and needed understanding of each other’s regulatory requirements. So, the scope of
ICH was expanded in 1990 to include USA and Japan. The objective was to discuss
and agree the scientific aspects of each country’s product registration requirements
and find a way to finalize a harmonized process acceptable by each country.
However, in the new millennium (2000), more and more countries outside the
region of USA, EU and Japan like India and China started registering products in
advanced countries like USA, Japan and Europe. This happened when advanced
countries started promoting generic medicines to reduce health care cost in their
respective countries encouraging pharmaceutical companies from China and India
for generic product registrations. So, in 2015 ICH has gone through major reforms

22
Pharmaceutical Quality Assurance 23

and changed the name as The International Council for Harmonization of Technical
Requirements for Pharmaceuticals for Human Use and became a legal entity in
enforcing guidelines for pharmaceutical exporting countries. India and China, both
countries are major supplier of pharmaceuticals today.However, both countries are
still not member of ICH. They have been given participation right as observer.

3.3 Structure
The ICH comprises of four governing bodies –
(i) ICH Assembly
(ii) ICH Management Committee
(iii) Medical Dictionary for Regulatory Activities (MedDRA) Management
Committee.
(iv) ICH secretariat
ICH Assembly organizes meetings involving all member and observer countries
to arrive at decisions on adoption ICH Guidelines, admission of new members and
observers and finalize budgets.
The ICH Management Committee finalizes the Working Groups (WG) and looks
after administrative and financial matters
The Medical Dictionary for Regulatory Activities or MedDRA manages the
standardized medical terminology to be used by member countries and its
dissemination.
The ICH secretariat is in the hub of all activities by managing day to day
management of ICH,coordinating activities of Assembly, Management Committee
and MedDRA.
The Working Groups (WG) are formed when a new topic is taken up for
harmonization for drawing up an ICH Guideline. The meetings are normally
happening twice in a year at Geneva to create concept papers, business plan and
interim reports. The interim reports are accessible to general public through the ICH
website.

3.4 The Process of Harmonization

The process of harmonization follows five steps –
(i) Consensus Building
(ii) Confirmation of consensus and draft endorsement by regulatory authorities
on the technical documents
24 Pharmaceutical Quality Assurance

(iii) Consultation between regulatory authorities

(iv) Adoption of an ICH Guideline
(v) Implementation
Consensus Building–Based on the objective of concept paper, the WG prepares
a consensus draft Technical Document. If all the members of WG agrees on the
draft, then they approve by signing the draft technical document submit to ICH
Assembly for adoption.
l Confirmation and endorsement : Once ICH Assembly agrees that the draft
technical document is based on sound technical and scientific knowledge, the draft
document then processed for regulatory consultation. The final confirmation and
endorsement are done when regulatory members of ICH assembly endorse the draft
document.
l Consultation between regulatory authorities : This process comprises of three
distinct stages.
l Stage 1- The Guideline having the scientific consensus becomes the subject of
regional regulatory consultation in the ICH regions. During this time,industry
associations (likePDA, ISPE etc.) and other non – member regulatory authorities can
also provide their comments for acceptance.
l Stage 2- After obtaining all comments during the consultation process the
Expert Working Group finalizes a consensus report which is called Experts Draft
Guideline (EDG)
l Stage 3- The Expert Draft Guideline(EDG) after reaching consensus are then
signed off by all members of WG and placed to members of ICH Assembly with a
request to adoption.
l Adoption of an ICH Harmonized Guideline : This is the step 4 for adoption
of harmonized ICH guideline.The Regulatory Members of the ICH Assembly agree
that there is enough scientific consensus on the draft guideline and recommend
adopting the guideline.
l Implementation : This is the fifth and final step of implementation of the
harmonized ICH Guideline. The ICH guideline moves immediately to the final step
of the process that is regulatory implementation. The information of regulatory
actions taken, and the implementation date is reported to the ICH Secretariat. The
final report is also published in ICH web site.
Pharmaceutical Quality Assurance 25

3.5 Type of ICH Guidelines

The ICH Guidelines are classified into four categories commonly known as QSEM
guideline.
1. Q – Quality Guideline
2. S – Safety Guideline
3. E – Efficacy Guideline
4. M- Multidisciplinary Guideline
In this chapter special emphasis will be given only to Quality Guideline.

The complete list of harmonized ICH Quality Guidelines as finalized are given
below -

l A -ICH Q1
Q1A (R2) Stability Testing of New Drug Substances and Products
Q1B Stability Testing: Photo Stability Testing of New Drug
Substances and Products
Q1C Stability Testing for New Dosage Forms
Q1D Bracketing and Matrixing Designs for Stability Testing of
New Drug Substances and Products.
Q1E Evaluation of Stability Data
Q1F Stability Data Package for Registration Application for
Climatic Zones III and IV

l B. ICH Q2
Q2(R1) Validation of Analytical Procedures: Text and Methodology

l C. ICH Q3
Q3A(R2) Impurities in New Drug Substances
Q3B(R2) Impurities in New Drug Products
Q3C(R5) Impurities : Guideline for Residual Solvents
Q3D Impurities : Guideline for Elemental Impurities

l D. ICH Q4
Q4 Pharmacopoeias
Q4A Pharmacopoeial Harmonization–Details about the
harmonization of Pharmacopoeias like USP, JP and EP.
26 Pharmaceutical Quality Assurance

Q4B Evaluation and Recommendation of Pharmacopoeial Text

for use in the ICH Regions
Q4B (Annex 1 (R1) Residue on Ignition / Sulphated Ash
General Chapter
Q4B Annex 2(R1) Test for Extractable Volume of Parenteral Preparation
General Chapter
Q4B – Annex 3(R1) Test for Particulate Contamination: Sub visible Particles
General Chapter
Q4B -Annex 4A(R1) Evaluation and Recommendation of Pharmacopoeial texts
for use on microbiological examination of non-sterile
products microbial enumerations test.
Q4B-Annex 4B(R1) Evaluation and Recommendations of Pharmacopoeial texts
for use on microbiological examination of non-sterile
products: Test for specified microorganisms
Q4B-Annex 4C(R1) Microbiological Examination of Non-Sterile Products:
Acceptance Criteria for Pharmaceutical Preparations and
Substances for Pharmaceutical use General Chapter.
Q4B-Annex 5(R1) Disintegration Test General Chapter
Q4B-Annex 6 (R1) Uniformity of Dosage Units General Chapter
Q4B-Annex 7 (R2) Dissolution Test General Chapter
Q4B-Annex 8 (R1) Stability Test General Chapter
Q4B-Annex 9 (R1) Tablet Friability General Chapter
Q4B-Annex 10 (R1) Polyacrylamide Gel Electrophoresis General Chapter
Q4B-Annex 11 Capillary Electrophoresis General Chapter
Q4B-Annex 12 Analytical Sieving General Chapter
Q4B Annex 13 Bulk Density and Tapped Density of Powders General
Chapter
Q4B Annex 14 Bacterial Endotoxin Test General Chapter
Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived
from Cell Lines of Human and Animal Origin.
Pharmaceutical Quality Assurance 27

Q5B Quality of Biotechnology Products : Analysis of the

Expression Construct in Cells used for Production of r-DNA
Derived Protein Products
Q5C Quality of Biotechnological Products: Guidelines for Stability
Testing of Biotechnological/Biological Products
Q5D Derivation and Characterization of Cell Substrates used for
Production of Biotechnological /Biological Products
Q5E Comparability of Biotechnological/Biological Products
Subject to Changes in their Manufacturing Process.
Q6A Specifications : Test Procedures and Acceptance Criteria for
New Drug Substances and New Drug Products: Chemical
Substances
Q6B Specifications : Test Procedures and Acceptance criteria for
Biotechnological / Biological Products
Q7 Good Manufacturing Guide for Active Pharmaceutical
Ingredients
Q8(R2) Pharmaceutical Development
Q9 Quality Risk Management
Q10 Pharmaceutical Quality System
Q11 Development and Manufacture of Drug Substances
(Chemical Entities and Biotechnological/Biological Entities)
Q12 Life Cycle Management
Q13 Continuous Manufacturing of Drug Substances and Drug
Products

3.6 ICH Stability Testing Guideline

Stability testing of products is an important criterion to establish that the product
is stable and safe for use during its entire shelf life period. During development
phase, stability of the product should also be established before the product gets
technologically transferred into manufacturing for routine production.Because of
the varying climatic conditions of different countries, it is important to develop a
harmonized procedure approved by the regulatory authorities which should be
followed for stability testing.
28 Pharmaceutical Quality Assurance

The stability study establishes the retesting period of drug substances, expiry
period of finished dosage forms and their storage conditions during the retesting/
storage period. ICH Q1 describes the harmonized procedure of stability testing
acceptable by the regulatory authorities. The ICH Guideline Q1A(R2) titled Stability
Testing of New Drug Substances and Products principally describes the procedure
to be followed. Within ICH Q1, other Guidelines cover other important aspect
including evaluation and finalization of data package for submission to regulatory
authorities for product approval. The other Guidelines in ICH Q1 dealing with
related areas of stability studies are as follows –
Q1B – Stability Testing: Photo Stability Testing of New Drug Substances and
Products
Many Drug Substances or Products are light sensitive. By carrying out
Photosensitive stability studies it is established whether the product is light sensitive
and would require any special packaging.
Q1C – Stability Testing for New Dosage Forms
This guideline describes the procedure for stability studies for any new dosage
form unlike conventional tablets, capsules, injections, ointments, solution etc.
Q1D – Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products
Normally a product is packaged in multiple configurations. For example, if a
product is packaged in 30’s count bottle, 100’s count bottle, 250" s count bottle,500"
s count bottle and 1000’s count bottle, the guideline allows to carry out bracketing
of the packs. In this case, carrying out bracketing stability of only extreme counts
at 30’s and 1000’s will also encompass other count bottles.There by reducing
substantial stability study workload. Similarly, matrixing principles also can be
applied during stability studies. For example, a product A is a tablet having 1mg,
2mg, 5mg, 10mg and 20mg strengths. While designing stability protocols, one can
propose carrying out stability studies of extreme strengths like 1mg and 20mg or
skipping stability stations of some strengths based on an approved protocol.In this
case, if both 1mg and 20mg strength are found to be stable, then other strengths are
also considered stable. However, in cases of designing of stability protocols utilizing
bracketing or matrixing, one should take prior approval of regulatory authorities.
Q1E – Evaluation of Stability Data
This guideline is intended to provide recommendations on how to use stability
data generated in accordance with the ICH guideline “Q1A(R2) Stability Testing of
New Drug Substances and Products” . The guideline describes when and how
extrapolation can be considered when proposing retest period of a drug substance
or shelf life period of a drug product that extends beyond the stability data available
Pharmaceutical Quality Assurance 29

under the long-term storage condition. The guideline recommends statistical

regression analysis of quantitative stability data to establish the retest period of
drug substances or shelf life period of drug products.
Q1F – Stability Data Package for Registration Application in Climatic Zones III
and IV.
ICH has classified the entire world in four zones namely Zone 1, Zone II,Zone III
& Zone IV where the conditions of temperature and relative humidity for stability
studies vary.Subsequently Zone IV was also divided into Zone IV A and IVB. The
regulatory authorities of Zone III &IV expect the stability data for submission for
product approval should be carried out at more stringent conditions. For example,
in Zone IVB (Hot& high humidity), the real time stability studies should be carried
out at 30 °C and 75% RH rather than normal condition of 25 °C and 60%RH. The
zone classification is based on the temperature and humidity conditions prevailing
in the location. The higher is the temperature and humidity the greater are the
chances of product degradation.
Example of Zone III countries (Hot and dry) – Iran,Iraq, Sudan etc.
Example of Zone IV countries (Hot and humid) – Brazil,India,Indonesia,
Philippines etc. Within the countries in Zone IV, some areas have been divided
between Zone IVA and IVB based on the requirements of respective regulatory
authorities. The difference between stability conditions are only in Relative Humidity
conditions (Zone IVA – RH 65% & Zone IVB -RH 75%)
Normal Testing Frequency & Storage Conditions for Drug Substances and
Dosage Forms during Stability Studies

General case Study Storage Condition Testing Frequency Minimum Time Period
Months covered By data at the
time of Submission
Long Term Temp 25 C± 2° 0, 3, 6, 9, 12, 18, 12 Months
Stability C 24, 36 Annually
RH 60% ± 5% there after if
Or required
Temp 30 C±2°
C
RH 65% ± 5%

#Intermediate Temp 30 C ± 0, 6, 9 & 12 6 Months

Stability 2°C
RH 65% ± 5%
*Accelerated Temp 40+2oC 0, 3, 6 6 Months
Stability RH 75% + 5%
30 Pharmaceutical Quality Assurance

* It is up to the manufacturer to decide whether Long Term Stability Studies are

performed at 25C ±2 C/60%RH± 5% RH or 30 C± 2 C/ 65% RH ± 5% RH.
# As a result of “significant change” at the accelerated storage condition,
manufacturer is required to carry out stability studies at Intermediate conditions.
The Stability Study should always be conducted in final marketed packs for both
Finished Dosage Forms and Drug Substances.However,for Drug Substances,
miniature packs of final packing having same shape and contact surfaces are allowed
for conducting stability studies.
The Drug regulatory authorities require stability data obtained from both
accelerated and real time conditions. Based on the stability study data shelf life of
a product is established after considering the climatic zones where the product is to
be marketed .The storage conditions recommended by the manufacturer on the basis
of stability data should guarantee the quality , efficacy and safety of the product.
ICH classifies four climatic zones which are to be considered for designing the
protocol for stability studies. The climatic zone IV is further divided into Zone IVA
and IVB, based on difference of humidity conditions.
® Zone 1 - Temperate
® Zone II – Subtropical/Mediterranean
® Zone III – Hot/dry
® Zone IVA – Hot humid / tropical zone
® Zone IVB – Hot / Higher humidity
The following table explains the different climatic zones, countries falling in
respective zones and the real time stability conditions should be followed as per
ICH guideline
Climatic Zones Countries Real time stability conditions
Zone I Japan, United Kingdom,Northern Temperature 25°C±2°C RH
Europe,Russia,USA, Canada etc. 60% ±5% RH
Zone II Southern Europe, Japan, USA Temperature 25°C±2°C RH
60% ±5% RH

Zone III Iran, Iraq, Sudan, Saudi Arabia etc. Temperature 30°C
±2°C RH 35% ±5% RH
©Zone IV Brazil, Ghana, India, Indonesia, For Zone IVA Temperature
Philippines etc. 30°C±2°C RH 65% ±5% RH/
For Zone IVB Temperature
30°C ±2°C RH 75%±5% RH
Pharmaceutical Quality Assurance 31

©In Zone IV, within a country based on the climatic conditions, some regions are
classified as Zone IVA and Zone IVB. Between Zone IVA and IVB, only the humidity
conditions (RH) vary
For all climatic zones, the accelerated stability study condition is same I, e
Temperature 40°C ±2°C and RH 75% ±5% RH for a period of 6 months.
In stability study, the effect of variations in temperature,humidity, light intensity
and partial vapour pressure on the pharmaceutical products are investigated. The
storage conditions are often such that the temperature is higher than the average
meteorological data for a country. For some dosage forms,especially,liquid and semi
solids, the study design should also include subzero temperatures e.g. - 10 to – 20
C( freezer ) , freeze -thaw cycles or temperatures in the range of 2-8 C . For some
products effect on exposure to light also needs to be investigated.
The samples collected for stability studies should be representative of entire pilot
or commercial batch with predetermined schedule.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. ICH Q7 guideline deals with—
(a) Quality Risk Management (b) Good Manufacturing Practice in API
(c) Pharmaceutical Development (d) Pharmaceutical Quality System
2. ICH Q 8 guideline deals with—
(a) Pharmaceutical Development (b) Quality Risk Management
(c) Pharmaceutical Quality System (d) Life Cycle Management
3. Guideline of evaluation of stability data can be found in __________ICH guideline –
(a) Q1E (b) Q3
(C) Q5 (d) Q9
4. ICH Q6 guideline actually deals with—
(a) Impurities (b) Specification
(c) Stability (d) Quality System
5. ICH Q9 guideline deals with—
(a) Pharmaceutical Development (b) Quality Risk Management
(c) Quality System (d) Process Development System
6. The full form of ICH is—
(a) International Committee on Health
(b) International Committee for Harmonization
(c) International Council for Harmonization
(d) Institute of Concurrence on Health
32 Pharmaceutical Quality Assurance

7. ICH Q1C deals with—

(a) Evaluation of Quality Control Data (b) Evaluation of Stability Data
(c) Stability Testing of new dosage form (d) None of the above
8. The basic objective of ICH is—
(a) To promote public health (b) To assure profit of product
(c) Guideline for using animal in test (d) None of the above
9. Guideline of residual solvents can be found in ____ ICH guideline –
(a) Q3C (b) Q4
(c) Q2 (d) Q3
10. Zone IV B as per ICH is—
(a) Hot/dry (b) Hot/Higher humidity
(c) Subtropical/ Mediterranean (d) Temperate
11. India falls in following classification—
(a) Zone 1 (b) Zone II
(c) Zone IV (d) Zone III
12. Stability of accelerated condition is carried out at—
(a) 40 C/75% RH (b) 30 c/ 75% RH
(c) 40C/65% RH (d) None of the above
13. Long term stability for Zone II is carried out at—
(a) 30C/ 65% RH (b) 25 C / 60 % RH
(c) 25 C/ 75% RH (d) None of the above
14. India falls by ICH classification in—
(a) Zone I (b) Zone II
(c) Zone III (d) Zone IV

Keys for Multiple Choice Questions

1 (b), 2 (a), 3 (a), 4 (b), 5 (b), 6 (b), 7 (c), 8 (a),
9 (a), 10 (b), 11 (c), 12 (a), 13 (a), 14 (d)

➥ Long Questions
1. What is full form of ICH and explain why it was formed?
2. Describe the process of harmonization adopted for ICH guidelines
3. Name the classification of QSEM guidelines
4. What are the ICH Quality guidelines?
5. What are different conditions maintained for stability studies?
6. How are Zone I, II,III & IV differentiated ?
7. What are the countries mentioned in Zone I & Zone IV ?
 Chapter 4

Quality by Design (QbD) :

Definition & Overview

4.1 Definition & Overview

Quality by design (QbD) is a concept first outlined by quality expert Joseph
Juran, who believed that quality could be planned, and that most quality failures
and quality problems relate to the way quality was designed in the first place.
The regulatory agencies expect that the manufacturers completely understand the
product through thorough understanding of the processes based on science. The
concept of Quality by design (QbD) helps the manufacturer to understand their
product and processes.
International Conference of Harmonization (ICH) published the guideline ICH
Q8 on “Pharmaceutical Development” in 2005 where recommendation was made to
pharmaceutical industries to adopt QbD while developing new product.As per ICH,
QbD is defined as a systematic approach to product development that begins with
predefined objectives of the product with complete understanding of processes and
process controls, based on sound science and quality risk management.
Evolution of concept of Quality by Design : First guideline on QbD came into
existence with the publication of ICH Q8 “Pharmaceutical Development” in
November 2005. In November 2008,the guideline ICH Q8 was revised asICH Q8
(R1) with the addition of the Annex to the parent guideline. While the original
guideline was a 7 pager with fundamental details on Pharmaceutical Development
of Drug Substances and Drug products, their container closure system along with
the manufacturing process development, the R1 version came up with further
refinement and inclusion of terminologies like QTPP (Quality Target Product Profile),
CQA (Critical Quality Attribute), Risk Assessments, Design Space, Control Strategy
and the concept of Product Life Cycle management with Continual improvement.
The guideline was further revised (R2) in August 2009 after correcting (corrigendum)
certain nomenclature of diagrams.

33
34 Pharmaceutical Quality Assurance

Effective January 2013, USFDA has made mandatory for drug manufacturers to
implement Quality by Design (QbD) in drug development and submit data in their
Abbreviated New Drug Applications (ANDA) [Module 3 Quality 3.2. P.2
Pharmaceutical Development.] in line with the guideline ICH Q8.

4.2 Elements of QBD program

As per expectation of the regulatory agencies, pharmaceutical product
development should include, at a minimum, the following elements :
1. Quality Target Product Profile (QTPP) – This is the profile of a product where
quality parameters are determined which must be present in the product. The
scope of profile should include, its intended use, route of administration,
intended dosage form , strength , factors influencing bio availability , container
closure system and stability.
2. Critical Quality Attributes (CQAs)- Once QTPP is determined, then CQA of
the product needs to be identified. CQAs are the specifications of parameters of
the drug product – physical, chemical, biological or microbiological. The
parameters must fall within the range of specification, so that those product
characteristics having an impact on the product quality can be studied and
controlled. This is one of the first major area in the actual work of product
understanding.
3. Critical Material Attributes (CMA’s)- CMA is the specification or parameters
of the drug substance, and excipients which are identified for delivering desired
quality of product.This includes selecting the type and amount of those materials
to deliver drug product with the desired quality as part of the product
development. This is the second major area of product understanding.
4. Critical Process Parameters (CPP) – After selecting an appropriate
manufacturing process, it is important to identify and document CPPs of the
process as part of process development. The process must specify CPPs and the
limits which need to be followed during manufacturing. Identifying and
specifying the limit of CPP is considered as understanding of the process.
5. Control Strategy (CS) is Identification and documentation of the critical control
points for the product and its process with performance of appropriate risk
assessment performance that is based on recommended control of the product
during manufacturing.
Pharmaceutical Quality Assurance 35

Examples of CMAs, CPPs & CQAs for development of a tablet dosage form
CMAs CPPs CQAs
Particle size of the APIs Amperage of end point of Description of tablet
granulation in a granulator
Polymorphism Inlet, outlet temperature of Hardness, Friability&
FBD, CFM of FBD Thickness
Moisture content RPM of tablet compression Tablet weight and
machine variability

Specific grade of excipients Compression force of LOD/Moisture content

compression machine

Bulk/Tapped density RPM of force feeder of Disintegration test

compression machine

Impurity profile Temperature during Dissolution profile

granulation

4.3 Tools for QBD

Based on the requirements, the followings are generally used as tools amongst
others, for achieving Quality by Design (QbD) :
1. Risk Assessment: The common Risk Assessment Tools (FMEA/ Ishikawa or
Fishbone)are utilized to understand objectively which of the list of parameters
are most critical for product performance
Failure Mode Effect Analysis (FMEA) – It is a quality planning tool used to
identify reasons for failure and their causes. FMEA technique does not solve the
problem but helps in identifying. The terminology FAILURE means a component or
system is not meeting its design standard. Example – tablets are not meeting hardness
specification.The MODE means how a failure of component or system occurs.
Example –Some tablets fail hardness specification limit whereas majority of tablets
meet specification. The EFFECT is the consequence of failure. Example – Some
tablets with low hardness will break during transportation leading to customer
complaints. The ANALYSIS of FMEA determines Risk Priority Number (RPN) in
a scale of 1-5, higher is the number greater is the risk.
RPN = Severity X Occurrence X Detection
Where Severity is assessment of seriousness of potential failure in a scale of 1to5.
Occurrence is the likelihood of the incident repeating in a scale of 1 to 5. Higher
the number more chances of the failure to reoccur. Detection is the ability of the
36 Pharmaceutical Quality Assurance

system to detect the failure in a scale of 1 to 5. Here again, the higher the number
greater is the chance that the defect can go out unnoticed.The least RPN score could
be 1 (no or minimal risk) and the maximum RPN score could be 125 ( maximum risk
or critical defect)Normally, after corrective and preventive action, RPN is recalculated
to ensure that the system or procedure will run as per design space.
Ishikawa Diagram or Fish Bone Diagram–Karou Ishikawa, a Japanese engineer
reinvented the idea of a fish bone diagram to identify the reasons for failure. He
successfully used the diagram to resolve problems in Kawasaki Shipyards, where he
was employed. The process of using fish bone was known to quality professionals
since 1920s, however Ishikawa first used it effectively to solve problems. In Ishikawa
or fish bone diagram all problems or defects are divided into following areas
documenting and aligning with the fish bones.
(a) Personnel, (b) Materials, (c) Measurements, (d) Environment, (e) Methods
(f) Machines.
A cross functional team brainstorm and list down all possible reasons documenting
along with the fishbone categorizing in their respective groups. Example – whether
the hardness failure of tablet was due to Personnel, or the way it is measured, or the
method is defective or the hardness tester malfunctioning etc. Once all the possible
reasons are identified, one by one each reason were tested and eliminated till the
only reason for failure is identified. Based on the identified defect, corrective and
preventive actions are taken.
Ishikawa or Fishbone Diagram
Factors contributing to Hardness fallure in Tablet
Measurements Material Personnel
Calibration
of Hardness
Tester Granule Quality Shifts
Misplacement of
tablet in Hardness tester Lubricants used Training

Malfunction of Tester Flowability of Ganules Operator

Hardness not
meeting the
Control electronic specifications
Humidity Method of Testing failure

Die Punch Jamming

Temperature SOP not followed
Speed of Table machine

Environment Methods Machine

Pharmaceutical Quality Assurance 37

4.4 Design Space

This is established after carrying out range of studies (Design of Experiments)
along with manufacturing experiences at various scales in R&D. At R& D the
experimentation is done at lab scale followed by going to manufacturing set up and
execute at higher scale of operation.Generally statistical tools such as Design of
Experiments (DOE) is used while finalizing the process.

4.5 Process Analytical Technology (PAT)

PAT is defined as a system for designing, analyzing and controlling manufacturing
through timely measurements and interventions( i,e during actual processing) of
critical quality and performance attributes of raw and in process materials with the
goal of ensuring final product quality. Today, many of the devices and software’s
are commercially available which helps the manufacturer to monitor the established
parameters online without resorting to conventional analysis interrupting the
processes. Any deviation from the set limits can stop the process automatically and
corrections can be applied. Implementation of PAT helped manufacturer to improve
efficiency with lowering of process time, reduction of personnel and avoiding
conventional testing by quality control department.

4.6 Flow Chart of Quality by Design (QBD)

1 2 3
Identify Finalize Finalize
QTTP CMA CQA

4 5 6
Finalize Set up DOEs to Define design space
CPP establish relationship with an end product
between CQA & CPP and desired QTTP

7
Identify sources Continually monitor
of variations and to ensure consistent
control variation Quality
38 Pharmaceutical Quality Assurance

QbD remains at the core of quality framework as detailed throughguidelines

ICHQ8, ICH Q9,ICH Q10 and ICH Q11 and a crucial part for overall sustainability
of quality.

4.7 Expectation of Regulatory Authorities

By implementing QbD, regulatory agencies are emphasizing following paradigms–
1. The quality must be built in to the product and not by additional testing or
inspections
2. Utilization of science through out the product life cycle.
3. Quality risk management should be the key enabler through out the product
life cycle.
4. Robust product quality system with appropriate knowledge management assures
quality through out product life cycle and
5. An integrated approach to development, manufacturing and quality management
helps both manufacturer and regulatory agencies.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. QbD stands for—
(a) Quality by Design (b) Quality beyond Design
(c) Quality before Design (d) Quality by Decision
Pharmaceutical Quality Assurance 39

2. PAT stands for—

(a) Process Analytical Technique (b) Product Analytical Technique
(c) Both a & b (c) Process Approach Technique
3. QbD is covered in ______ of ICH guideline –
(a) Q7 (b) Q8
(c) Q10 (d) Q 1
4. QTPP in QbD stands for—
(a) Quality Target Product Profile (b) Quality Top Product Profile
(c) Quality That Product Profile (d) Quality Target Perfect Product
5. FMEA is a –
(a) Quality planning tool (b) Quality Control technique
(c) Both a & b (d) Risk assessment tool
6. Ishikawa Diagram helps in ——
(a) Identifying the problem (b) Raw material analysis
(c) Disposal of batches (d) Predict failure
7. Pharmaceutical manufacturing following QbD is aimed at
(a) Pharmacologically active products (b) Consistent product quality
(c) High quality (d) None of the above
8. QbD helps in ————
(a) Optimizing Operating Conditions (b) Minimizing Parameter Analysis
(c) Maximizing Personnel Efficiency (d) None of the above

Keys for Multiple Choice Questions

1 (a), 2 (a), 3 (b), 4 (a), 5 (d), 6 (a), 7 (b), 8 (a)

➥ Long Questions
1. Define the terms QTTP, CMA, CQA & CPP
2. What are the advantages of following QbD during development ?
3. What is FMEA and how it is followed ?
4. What is PAT and its advantages ?
 Chapter 5

ISO 9000 & ISO 14000

5.1 Overview
In a globalized world where goods and services from one country to another
move freely, it was important to set up a minimum standard on Quality System and
Environment Management which both the importing and exporting countries would
have consent and complied with. Both ISO 9000 and ISO 14000 series of standards
were originally derived from British standards. ISO 9000 was first implemented in
1987 following BS 5750 and ISO 14000 in1992 following BS 7750.
The fundamental difference is that ISO9000 deals with Quality Management
System (QMS) and ISO 14000 deals with Environment Management System (EMS).
Both the standards are not specifically for Pharmaceutical Industries but applicable
for any industry of any size involved in commerce.
ISO 9000 is defined as a set of international standards on quality management to
help companies effectively document the quality system elements to maintain an
efficient quality system. Companies apply and go through a process of certifying
and register their businesses as ISO 9000 compliant. Pharmaceutical companies are
heavily regulated by healthcare administration of different countries and normally
do not specifically go through a separate process of ISO 9000 registration. The
approval from regulatory authorities like USFDA,MHRA, EU etc. are enough for
Pharmaceutical companies to carry out their businesses. However, many of the
suppliers to Pharmaceutical companies can opt for ISO 9000 certification to prove
that they follow quality management system to maintain quality of their products.
For example, packaging materials, excipient manufacturing companies etc. normally
go for ISO 9000 certification to establish their creditability. However, the guideline

40
Pharmaceutical Quality Assurance 41

and steps described in ISO 9000 standards are completely in sync with Good
Manufacturing Practices followed in Pharmaceutical industries.
ISO 9000 was first published in 1987, by the international Organization for
Standardization (ISO), a specialized international agency for standardization having
members of national standard boards of more than 160 countries.
ISO 9000 is a family of quality management standards and ISO 9001 is a standard
within the family. The ISO 9000 family has gone through multiple revisions since
first implemented in 1987. The latest revision of ISO 9000 family in 2015 has three
standards -
1. ISO 9000 -Quality Management System - Fundamentals and Vocabulary
2. ISO 9001 - Quality Management System - Requirements
3. ISO 9004 - Quality Management System -Guidance to Achieve Sustained Success

5.2 Principle of Elements in ISO 9000

The ISO 9000 Quality Management is based on Seven principle elements of
Quality.
42 Pharmaceutical Quality Assurance

5.3 ISO 14000

ISO 14000 is a family of standards related to environment management that helps
the organization in:
A. Minimizing impact of the processes negatively to environment (air, water and
land)
B. Comply with applicable laws, regulations related to environment of the country.
C. Continuous improvement in processes and steps taken to protect environment
(air, water and land)
The ISO 14001 is the most important standard within the ISO 14000 series. ISO
14001 specifies the core set of standards used by large or small organizations for
designing and implementing an effective environmental management.
The basic principles of ISO 14001 are based on Plan - Do - Check - Act
(PDCA)cycle.
(a) Plan - Before implementation of ISO 14001, a review or gap analysis is carried
out of the organization's processes to identify all the deficiencies of the current
operation. This review assists the organization in establishing their
environmental objectives, goals and measurable targets. In the planning stage
development of control and management processes with legal requirements are
built into the policy.

4 2

(b) Do -During this stage the organization identifies the resources, the members
who would be responsible for the implementation of environment management
system. This includes establishing the documental procedures for operational
Pharmaceutical Quality Assurance 43

controls, management control, emergency preparedness and response. At this

stage training of employees are also important to ensure that they can implement
the necessary changes and document the changes. Communication and
participation at all levels including top management is also vital at this stage.
(c) Check - This is the stage when performance is monitored and measured to
ensure that the organization's environment targets and objectives are met.
Periodic internal audits are also carried out to ensure that the environment
targets are met as planned.
(d) Act - At this stage management review is done to ensure that the objective of
environment management system is being met and all communications are
appropriately carried out. Additionally, any corrective and preventive actions
or further improvement in the target as per changing regulatory environment
is also decided.

5.4 Principle of Elements in ISO 14001

In brief ISO 14001 environment management system contains following Five key
elements:

1. 3.
2.
Environment ® ® implementation
Policy Planning & Operation

¯
4 5
Checking & ® Management
Corrective Actions Review

5.5 Benefits of ISO 9000 & ISO 14000

ISO 9000 and ISO 14000 series were developed primarily to assist companies with
a framework for better quality management and environment management systems
respectively. In addition to improvements in performance, organizations can take
economic benefits including higher conformances to regulatory and legislative
requirements. The internationally recognized standards also help businesses
operating in multiple locations across the glove. Adaptation of ISO standards give
a competitive advantage against the organizations who do not implement
44 Pharmaceutical Quality Assurance

international standards. This also improves public perceptions of the business,

placing them in a better position to operate in international market. Overall ISO
certified organizations are considered as innovative and forward looking.

5.6 Steps for Registration

International Standards of Harmonization (ISO) does not participate in registration
and approval of ISO certification. ISO stipulates the standards and requirements for
approval.Various consultancy authorities having accreditation normally participate
in helping organizations in getting ISO certification.
The general flow chart for getting registration of ISO certification is as follows
1. Top Management Commitment : Top management commits to go for ISO
certification for various business reasons and employees are bought in. This
commitment is permanent in nature since the systems and procedures, resources,
investments and infrastructure would continue for foreseeable future. Even after
registration and certification is done, the systems and procedures would have
to be subjected for outside audit periodically, usually once in 3 years.
2. Prepare Quality Policy Manual for ISO 9001 or Environment Policy Manual
for ISO 14001 : Normally organizations recruit a consultancy agency at this
stage to work with the key personnel.
3. Prepare Standard Operating Procedures (SOP) : At this stage all the processes
and procedures are mapped and captured to write SOPs mimicking actual practices.
Consultancy agencies help in correcting existing practices and finalize SOPs
4. Train Personnel : All personnel involved in following procedures and processes
are trained
5. Hold internal audits : The internal audit or self-inspection helps the organization
to better prepare for external audits. After every internal audit, the deficiencies
and observations are critically evaluated, and corrective preventive actions put in
place. Before offering for external audits, an organization can undergo number of
internal audits to satisfy the management for preparedness.
6. Go through Registration Process : With the help of consultants, submit all
details as per ISO requirements and carry out external audits to the agency's
satisfaction. Once the organization is registered, normally every three years the
outside audits are carried out to keep the certification valid
7. Obtain Registration Certificate : Organizations normally display the certificate
in prominent places. The display usually states -A ISO 9001-2015 Certified
Company or A ISO 14001-2015 Certified Company (2015 refers the year of ISO
standards)
Pharmaceutical Quality Assurance 45

5.7 Flow chart for Registration

Management Commitment

Prepare Quality Policy Manual

Prepare related SOPs

Hold Internal Audits

Go through registration process

Obtain registration certificate

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. ISO is a ___________ organization
(a) Non Governmental (b) Governmental
(c) Semi Governmental (d) Public Sector

2. ____________ is the head quarter of ISO

(a) Geneva (b) Tokyo
(c) Paris (d) Washington

3. ISO 9000 deals with _______

(a) Quality Management (b) Environmental Management
(c) Both a & b (d) Legal Obligation

4. ISO 14000 deals with ________

(a) Quality Management (b) Environment Management
(c) Both a & b (d) Legal Obligation
46 Pharmaceutical Quality Assurance

5. The full form of ISO is

(a) International Standard Organization (b) International Specification Organization
(c) Institute of Standard Organization (d) International Specific Organization

6. PDCA cycle is part of —

(a) Implementation of ISO 9000 (b) Implementation of ISO 14000
(c) Approval of ISO 14000 (d) None of the above

Keys for Multiple Choice Questions

1 (a), 2 (a), 3 (a), 4 (b), 5 (a), 6 (b)

➥ Long Questions

1. Explain ISO and discuss its aims and principles

2. What are the seven principle elements of ISO 9000?
3. What are the benefits of ISO certification?
4. What are the five key elements of ISO 14001 implementation?
 Chapter 6

NABL Accreditation :
Principles and Procedures
6.1 What is NABL?
The full form of NABL is National Accreditation Board for Testing and
Calibration Laboratories (NABL).NABL is an autonomous body under the aegis of
the Department of Science and Technology, Govt of India and registered under the
society’s act 1860. The scope of NABL was originally established with the objective
of providing accreditation to testing and calibration laboratories, later extended to
include operation of clinical laboratories in India.
NABL is a constituent Board of Quality Council of India (QCI). QCI is a registered
society under the Societies Registration Act, 1860. Department of Industrial Policy
and Promotion, Min. of Commerce and Industry, Govt of India is the nodal
Department for QCI.
In early 2000, NABL established links with international bodies - Asia Pacific
Laboratory Accreditation Cooperation and International Laboratory Accreditation
Cooperation. This has imparted international recognition to NABL accredited
laboratories of India.

6.2 Why Accreditation is required?

Accreditation is the formal recognition, authorization and registration of a
laboratory that has demonstrated its capability, competence and credibility to carry
out the tasks it is claiming to be able to do. The accreditation provides feedback to
laboratories as to whether they are performing their work in accordance with
international criteria for technical competence.
NABL accreditation of a laboratory is an approach to improve customer confidence
in the test reports issued by the laboratory.
The accreditation is a procedure by which an authoritative body (NABL) gives
formal recognition of technical competence of a laboratory for specific tests and
measurements by an independent assessment following international standards. This
is the certification by which an authoritative body gives formal recognition that a
body or person is competent to carry out specific tasks.
47
48 Pharmaceutical Quality Assurance

Accreditation is currently granted to test & calibration laboratories according to

ISO/IEC 17025 and for medical laboratories against ISO 15189 standards.

6.3 Principles of NABL accreditation

The principle of NABL accreditation is that the certificate of analysis or certificate
of conformance issued by an accredited or recognized laboratory is acceptable
globally. With globalization, the trade and commerce are happening between various
countries without any restrictions of borders or boundaries. So,it is important that
the test report provided by an exporting company or agency is recognized by the
importing company of another country without any doubts about the conformity of
quality.
NABL website gives the names of NABL accredited calibration laboratories in the
various fields of accreditation.
The accredited laboratories can print the seal of approval of NABL on their
certificates issued.
The following mark appear on certificates that are accredited by NABL

6.4 Accreditation Procedures

Once a laboratory decides to apply for NABL accreditation, a responsible person
is nominated within the organization as QUALITY MANAGER who is familiar with
the functioning of the laboratory. The task of quality manager is to coordinate all
activities seeking accreditation with NABL. The following is the general procedure
for getting accreditation–
1. Contact NABL secretariat with a request for accreditation
2. Get fully acquainted with all relevant documents and assessment procedure
and methodology for making an application.
3. Train personnel on quality management system and internal audit. NABL
authorities conduct various training to help the laboratories to understand the
principles and procedures.
Pharmaceutical Quality Assurance 49

4. Prepare QUALITY MANUAL as per ISO 15189 or ISO 17025 based on the areas
of operation of the laboratory.
5. Prepare standard operating procedures (SOP) for all activities covering
functioning of the laboratory.
6. Ensure that the laboratory can maintain environmental conditions 24/7
(temperature, humidity)
7. Ensure all instruments/equipment are calibrated. Only NABL accredited
agencies are recognized for calibration.
8. Ensure documentation control is in place. The documentation control procedures
must have specific format design,clear authorization guidelines, identification
of each documentation system with identification numbers, document review
and change control procedures, retention procedures and names of controlling
authorities.
9. Evaluate periodic internal audits to measure the readiness for an independent
third-party audit.
10. Ensure implementation of all aspects mentioned in Quality Manual.
11. Document all corrective and preventive actions
12. Conduct management review to abreast top management on preparedness
13. Apply to NABL for accreditation along with all documentation and appropriate
fees.

6.5 Granting Accreditation

1. The Quality Manual will be forwarded by NABL to a Lead Assessor to judge
the adequacy of the Quality Manual as to whether it meets ISO standards.
2. Thereafter the Lead Assessor will conduct a Pre-Assessment of the laboratory
for one day. Based on the Pre-Assessment report the laboratory may have to
take certain corrective actions, to be fully prepared for the final assessment.
3. It is essential for the applicant as well as accredited laboratories to satisfactorily
participate in Proficiency testing/ Interlaboratory comparisons/External quality
assessment programme as Asia Pacific Laboratory Accreditation Cooperation
(APLAC) Mutual Recognition Arrangement calls for mandatory participation in
such programs.
4. Finally, when the laboratory is ready, the LeadAssessor and a team of technical
assessors will conduct the final assessment. The number of technical assessors
will depend on the number of disciplines applied for. The accreditation process
involves a thorough assessment of all the elements of the laboratory that
contribute to the production of accurate and reliable test data.
These elements include staffing, training,supervision, quality control, equipment,
recording and reporting of test results and the environment in which the
50 Pharmaceutical Quality Assurance

laboratory operates. The laboratory may have to take certain corrective actions,
after the final assessment.
5. After satisfactory corrective actions are taken by the laboratory (within a period
of 3 months), the Accreditation Committee will examine the report and if
satisfied recommend accreditation.
The time required for the process of accreditation will depend upon the
preparedness of the laboratory andits response to the non - conformances raised
during the pre-assessment and final assessment. The total duration ranges between
6 and 8 months.

6.6 Surveillance and Re-Assessment

Accreditation to a laboratory shall be valid for a period of three years. NABL
shall conduct annual surveillance of the accredited laboratories. The laboratories
may enhance or reduce the scope of accreditation during surveillance.
The laboratories need to apply for renewal of accreditation, at least six months
before the expiry of validity of accreditation for which a re-assessment shall be
conducted.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. NABL stands for ——-
(a) National Accreditation Board for testing and calibration laboratories
(b) New Accreditation Board for Testing and Calibration Laboratories
(c) National Accreditation Bureau for Testing and Calibration Laboratories
(d) National Accreditation Board for Testing and Collaborative Laboratories
2. NABL Accreditation is pre requisite for approval by ____ for testing laboratories—
(a) USFDA (b) WHO
(c) CDSCO (d) None

Keys for Multiple Choice Questions

1 (a), 2 (d)

➥ Long Questions
1. What is full form of NABL?
2. Why NABL accreditation is important?
3. What are thesteps of accreditation procedure of NABL?
4. How the surveillance and re assessment done?
UNIT–1I
.
 Chapter 7

Organization and
Personnel
All pharmaceutical organizations should have enough qualified and trained
personnel to carry out their operations. The job responsibilities on a single person
should not be such that it impacts the performance to take honest and informed
decisions. There should be an organization chart clearly depicting the functions and
reporting relationship with each other within and outside the functions. In
pharmaceutical industry the role of quality function is important, and they have the
sole responsibility of approving or rejecting a batch. Hence, as per regulatory
requirements, quality function should be independent of other functions and
reporting to top management.

7.1 Personnel Responsibilities

Qualified, experienced and well-trained personnel are the key factor for any
pharmaceutical company’s growth and success. The development, maintenance and
control of quality management system is completely dependent on the personnel
employed. Hence, all personnel working in a pharmaceutical company must have
their job description and responsibilities defined to carry out their respective
functions efficiently.
The regulatory guidelines of various regulatory authorities specifically stress the
importance of personnel employed in pharmaceutical industries. For example,
USFDA in 21CFR Current Good Manufacturing Practice for Finished Pharmaceuticals
under sub part B describes in detail Organization and Personnel. WHO describes
the personnel requirement in Annex 3 of Good Manufacturing Practices for
Pharmaceutical Products. In India Schedule M describes about the personnel
requirement in Part 1 of Good Manufacturing Practices and Requirements of
Premises,Plant, and Equipment for Pharmaceutical Products.
The regulatory authorities place quality department at the hub of all activities in
manufacturing and give special emphasis on role and responsibilities. The quality
department is divided into quality control and quality assurance. Quality control is

53
54 Pharmaceutical Quality Assurance

involved into the testing of input materials, intermediate stages of products and
finished products, whereas quality assurance is involved in controlling all systems
and procedures including the batch review and self-inspection. Quality assurance
has the sole responsibility for approving or rejecting all procedures or specifications
affecting identity, strength, quality and purity of the drug product.
Every company should have a site master file clearly specifying the management
organization chart illustrating how quality assurance department fits into the overall
plant organization and how the department’s principles, directives and strategies
are applied in daily activities. Besides quality function,the other important functions
in pharmaceutical industry are production, engineering, warehousing, human
resource, purchasing etc. Each responsible person should have their job descriptions
written in enough details and authorized by their superiors.
Each person involved in manufacturing, testing, packing, maintaining equipment
and utilities, holding of inputs and drug products must have relevant education,
training and experience to perform the assigned jobs in compliance with GMP to
ensure that the drug product is effective and safe. The heads of the different functions
can have shared, complimentary and joint responsibilities like –
1. Responsibility of writing standard operating procedures (SOP) and other
documents, including periodic amendments.
2. Maintaining hygiene in the plant.
3. Monitoring and control of manufacturing environment
4. Validation of utilities, processes and equipment
5. Periodic calibration of all equipment and utilities
6. Storage and monitoring of input materials and finished products
7. Training on systems and procedures to maintain GMP.
The head of manufacturing generally has following responsibilities–
1. To ensure that products are produced and stored with appropriate
documentation having traceability.
2. To ensure that the manufacturing instructions and in process controls have
been followed as designed.
3. To ensure that the manufacturing documentations are evaluated and signed by
authorized persons.
4. To ensure that the maintenance of the premises and equipment are carried out
regularly.
5. To ensure that all validations and calibration are carried out as per plan and
records available
6. To ensure that all personnel involved in manufacturing are trained.
Pharmaceutical Quality Assurance 55

The head of quality function generally has following responsibilities –

1. To approve or reject, starting input materials, in process materials and finished
products.
2. To ensure all required testing are carried out as per approved specifications
3. To evaluate batch manufacturing and packaging records for its completion and
compliance.
4. To approve sampling procedures, specifications, test procedures and quality
control/quality assurance procedures
5. To ensure that all validations including analytical procedures and calibrations
of analytical equipment are carried out and documented.
6. To carry out regular self-inspections.
7. To ensure that all personnel involved in quality function are trained
Based on the size and complexity of the pharmaceutical plants, some of the job
responsibilities of head of manufacturing and head of quality functions can be
delegated to appropriate authorized persons.

7.2 Personnel Training

Under quality management system appropriate training programme should be
developed to cover training needs of an employee, provision of training to satisfy
the training need and effectiveness of training. Each employee must have his or her
individual training records detailing the types of training undertaken and the
evaluation of training performance.
Visitors or untrained personnel preferably should not be allowed inside
manufacturing areas. If it is unavoidable, then they must be given training in advance
particularly about personal hygiene and protective clothing.They should not be left
alone and must always be accompanied and supervised.
Following are the types of training generally undertaken for employees-
1. Induction training programme for newly recruited persons – The trainees are
given an overview of company’s policies, over all organization structure and
functions
2. Training on standard operating procedures –The specific SOPs related to the job
descriptions of the employee are explained.
3. On job training –This is to improve the skill of the employee in executing job.
For example, training on how to run a tablet compression machine.
4. Training on GMP – This is to educate the employees on the overall concept of
GMP.
5. External training –Sometimes external experts are brought in to train employees
on a specific area or employees are sent to attend workshops or seminars to
acquire expertise in specific areas.
56 Pharmaceutical Quality Assurance

All trainings of an employee must be documented and preserved. All training

records must be signed and identified by trainer and trainee.

7.3 Personnel Hygiene

All personnel employed must undergo health examination prior to appointment
and periodic routine checkups during their tenure with the organization.Personnel
involved in critical operations like examination or checking of products should also
be subjected to eye examination.
Practicing high level of personnel hygiene should be utmost importance amongst
the personnel involved in manufacturing of products.Steps should be taken to ensure
that no person with infectious diseases or exposed lesions on the body can engage
in handling and manufacturing of products. All persons entering in manufacturing
area should also wear freshly laundered protective garments appropriately designed
to avoid exposure of any body part while handling pharmaceutical products.
Eating, drinking, chewing, smoking or storage of food, drink, smoking materials
etc. are strictly prohibited in manufacturing areas. Direct contact with the product
during manufacturing with the exposed hand must also be avoided. All personnel
handling the products and equipment should use protective hand gloves and face
masks.
Personnel should be instructed to use hand washing and sanitizing facilities
frequently while involved in manufacturing of products. In general, any unhygienic
practice within the manufacturing area where the product might get adversely
affected and contaminated must be avoided.

7.4 Personnel Records

Personnel records are records pertaining to the employees of an organization.
The records are complete history of employees since his joining the organization up
to current date detailing his or her performances, conduct and growth.Personnel
records are normally maintained by the Human resource department of the
organization.The record should have following details–
1. Employees’ name and educational qualification
2. Details of experience prior to joining the organization
3. Personal details like leaves availed, transfer record etc.
4. Record of any disciplinary action taken against the employee
5. Performance rating in yearly appraisals
Personnel records help the management to take decision on the development of
the employee.
Pharmaceutical Quality Assurance 57

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. Responsibity of writing Standard Operating Procedures ( SOPs) is—
(a) Quality Control Dept (b) Quality Assurance Dept
(c) Manufacturing Dept (d) Shared responsibility
2. Access to manufacturing areas should be restricted to ——
(a) Production Personnel
(b) QC Personnel
(c) Both Production & QC Personnel
(d) All authorized personnel who have legitimate reason for being there.
3. All personnel involved in manufacturing must be trained in –
(a) SOPs (b) GMP
(c) On Job Training (d) All of the above
4. Personnel record of an employee must have details –
(a) Employees political affiliation (b) Police record
(c) Sexual orientation (d) Name & educational qualification

Keys for Multiple Choice Questions

1 (d), 2 (d), 3 (d), 4 (d)

➥ Long Questions
1. What are the responsibilities of Quality head?
2. What are the responsibilities of Manufacturing head?
3. What are the shared responsibilities of Quality and Manufacturing?
4. Describe the areas all employees must undergo training?
5. What are details must be recorded in personnel record?
 Chapter 8

Premises : Design, Construction

and Plant Layout
Premises designing is a process by which machines, processes and utilities of a
factory are placed in such a way to achieve the greatest possible output of high-
quality product at the lowest possible cost.When a new premise is designed many
important aspects are taken into considerations.

8.1 Points to be Considered before Designing the Premises-

1. Segregation of different risks –for example locating the storage of flammable
or toxic substances outside the process area. Hazardous area classification for
flammable gases, vapour and dusts (static charges) to designate areas where
ignition sources are eliminated.
2. Location of new premises -The geographical location of the plant is an important
consideration. The site should be away from residential areas to avoid exposing
residents to any untoward emission or fire hazard but at the same time the
location should be easily accessible for the employees and materials to move in
and out.
3. Emergency services and escape routes of employees in case of emergency
4. The quality and type of construction – Do we need RCC building everywhere
or Any other type of construction will do
5. The optimum distances between plant and storage units, to reduce handling
time and cost.
6. Controlling access of unauthorized person within the premises.
Once the project team decides the overall design of the premises, it is time to
decide on constructing the facility. Civil Contractors are usually involved to construct
the buildings as per the design.

58
Pharmaceutical Quality Assurance 59

8.2 Main Considerations while Constructing a Facility –

1. Durability – The building must withstand all-natural variabilities for at least 50
years or more.
2. Comfort to operating personnel – The construction type should ensure that the
operating personnel are comfortable with the surrounding environment while
conducting their jobs.
3. Maintainability – The construction should be of high quality to have minimum
expenditure to maintain building fabrics.
4. Cost of construction – It is important to keep the cost within affordable budget.
Exorbitant construction cost will eventually impact the return on investment.
5. Timeline – It is extremely important to complete the construction work within
agreed timeline. If the completion of construction exceeds the agreed timeline,
will seriously impact the cost of the project.
Before initiating the construction, based on the overall design, the project team
finalizes the plant layout. While design of the plant is a holistic approach, the
finalization of plant layout is more granular exercise. The project team must co-
ordinate with marketing, manufacturing, quality and R&D team to understand the
requirements in detail. The layout should be helpful in delivering right quality with
optimum cost.
Plant layout is a plan of optimum arrangement of facilities in space, material
handling, intermediate storage, housing of equipment and operating personnel to
contain within the facility. Except the dedicated plants where a single product is
manufactured day in and day out, lay out planning in pharmaceutical industry is a
complex operation. It requires considerable expertise to ensure that the layout
delivers the effective utilization of personnel, equipment and space. One of the
challenges of layout plan in pharmaceutical industry is handling multiple products
with varying processes simultaneously, but with high efficiency and with full
compliance to current good manufacturing practices. The important considerations
in finalizing plant layout is unidirectional flow of personnel and materials as the
process goes on. This plan not only reduces the chance of contamination and
confusion but substantially improves efficiency and reduction of cost.Pharmaceutical
plant layouts have evolved over a period from single floor layout, double storied
layout and even multiple storied layout where material and processes flow vertically
utilizing space,energy conservation and material handling.
60 Pharmaceutical Quality Assurance
Pharmaceutical Quality Assurance 61
62 Pharmaceutical Quality Assurance

8.3 Objective of plant layout

1. Streamline the flow of personnel throughout the plant
2. Streamline the flow of materials throughout the plant
3. Minimize material handling
4. Maintain high turnover of in process inventory. Lower the in-process inventory
is better for efficiency
5. Maintain flexibility of arrangements and operations
6. Effective utilization of personnel, equipment and space
7. Minimize interruption of equipment
8. Reduce hazards affecting employees
9. Increase employee morale.

8.4 Maintenance of Plants

A plant requires regular maintenance to maintain its original constructed quality.
Plant maintenance is generally civil in nature rather than maintenance of electrical
and mechanical nature of equipment. The principle of preventive maintenance
procedure is followed while maintaining the pharmaceutical plants. At the beginning
of the year a schedule is created for the total maintenance work to be carried out
and accordingly the execution is done. Some part of maintenance work would need
involvement of external agencies like painting, hence advance planning is necessary
without disrupting the plant operation. The plant maintenance plan normally covers
following areas
1. External and internal painting of surfaces. Based on the criticality of the areas,
some areas like core process areas can get a fresh coat of painting yearly or the
external surface of the buildings fresh coat of paintings once in 2 -3 years. Any
cracks or crevices in the process area is considered violation of current good
manufacturing practices.
2. Fixing doors and windows – All doors, windows and fixtures should be
periodically evaluated and repaired. In pharmaceutical plants the doors are
particularly vulnerable due to continuous movement of personnel and materials.
3. Lights and fixtures – Pharmaceutical plants must be sufficiently illuminated
(minimum200 to 400 lux) based on the nature of operation performed. Hence all
the lights and fixtures must be evaluated and replaced periodically to ensure
proper illumination is maintained throughout the plant.
4. Stairs and pathways – The stairs and pathways should always be kept cleaned
and obstruction free to avoid safety hazard.
Pharmaceutical Quality Assurance 63

8.5 Sanitation in the plant

Pharmaceutical Industries must develop a cleaning and sanitizing program to
implement and maintain cleaning and sanitization of each piece of equipment, floor,
walls, ceilings, loading docks etc. It is not only important to clean an area or
equipment, but all accessible surfaces must also be sanitized. Many surfaces look
apparently cleaned but the plant must ensure that the surface is not going to
proliferate microbial contamination by effective implementation of sanitization
program. Cleaning is the process of removing product residue and other
contaminants like dirt, dust, grease etc. Cleaning is an essential step and precursor
of sanitization procedure. Sanitization procedure reduces the viable microorganisms
to an acceptable level.
All regulatory authorities have specified importance of cleaning and sanitization
in their guidelines.Cleaning and sanitization are part of current good manufacturing
practices.
The procedure developed by pharmaceutical companies must include validation
and monitoring program to ensure that the surfaces cleaned and sanitized does not
pose any potential health hazard.

8.6 Environmental Control and Control of Contamination

Environmental control of pharmaceutical facilities is essential to the manufacture
of quality products.Control of such conditions like airborne particles,
microorganisms, temperature, humidity, differential pressure between rooms
handling critical processes, direction of airflow within the facility, air velocity and
number of air changes and hygiene of operating personnel are crucial in maintaining
environmental conditions and contamination controls.
Therefore, design of plant and HVAC system, validation results and regular
monitoring is necessary to assure the quality and safety of pharmaceutical products.
The contamination in pharmaceutical industry are primarily of two types, chemical
and microbiological. A very effective validated cleaning and sanitization procedure
usually takes care of both types of contaminations. The contaminations can be
originated from any of the following sources –
1. Operating personnel – It is extremely important that all operating personnel
practice highest level of hygiene. While working in pharmaceutical industry, all
personnel working, at least in the process areas must remove street clothes and
foot wares and wear freshly laundered company provided dresses and foot
wares.
64 Pharmaceutical Quality Assurance

2. Production process – All production processes like manufacturing,filling,

packaging including campaign durations must be controlled to avoid
contamination.
3. Environment –Functioning of HVAC, pressure differentials between rooms,
humidity and temperatures, conditions of floor and walls are to be regularly
evaluated for fitness of purpose and to avoid contamination
4. Materials and Equipment –API, excipients, water used in products or the
equipment might also contribute contamination. For example, black particles in
starch used in product.
5. Airlocks and rooms – regular cleaning and sanitization of airlocks and rooms
are essential in controlling contaminations.

8.7 Utilities and Maintenance of Sterile Areas

USFDA, WHO and EU have classified sterile areas in four grades as per cleanliness
and microbial controls –
Grade Aor ISO 5 Area– This is highest risk zone of sterile manufacturing. This
is the zone where aseptic(sterile) products are filled and all aseptic connection and
disconnection works are carried out. This zone must have unidirectional airflow
through HEPA filters with air flow rate at least 0.36 to 0.54 meter per second. The
unidirectional flow in the zone must be established in dynamic condition (in
operating condition) by carrying out smoke test (air visualization test using glycerin
and water) and video graphed for evaluation of regulatory authorities.The air changes
recommended in this zone is at least 20 air changes per hour.
Grade B or ISO 6 Area - This is the background of Grade A zone. This area is
used for manufacturing and filtration of aseptic products through bacteria retention
filters (0.22 microns). The filtered solution of aseptic product, then transferred to
Grade A through a closed pipeline. Grade B area should always have negative air
pressure than that of Grade A area. Air can move from Grade A to B but never from
Grade B to A. The differential pressure between Grade A and Grade B should be
more than 0.05 inch of water when measured by magnehelic gauges.
Grade C & Grade D or ISO 7 & 8 - Less critical areas where preparative work
of sterile or aseptic preparations are carried out. For example, Loading of garments,
filters, production accessories etc. in double door autoclaves for sterilization. The air
Pharmaceutical Quality Assurance 65

quality of Grade C and GradeD are same except in Grade C, the air quality is
measured in dynamic condition (in operation) and Grade D in static condition.

Classification of Sterile Area

Aseptic Air Flow

Processing Area Direction
(APA) Class A or AIO5
Class B or AIO6
Class C or AIO7
Class D or AIO8

Note :
l Maximum Air Pressure in Class A (++++) followed by Class B (+++), Class
C (++) and Class D (+)
l Air Flow direction always is from A to B to C to D

Following is the general principles followed in manufacturing of sterile or aseptic

products using various Grades of zones.

Grade Examples of operations for terminally sterilized products

A Filling of Products. Connecting and disconnecting of sterile pipe lines.
C Manufacturing of products. Filtration of product for filling
D Preparative work for subsequent batches . Sterilization work of cleaned
accessories

Grade Examples of operations for aseptic products (not terminally

sterilized)
A Filling of Products. Connecting and disconnecting of sterile pipe lines
B or C Manufacturing of products. Filtration of products for filling
C or D Handling of components after washing

The maintenance and management of sterile areas are controlled by installing suitable
Heating Ventilation and Air Conditioning (HVAC) unit with the installing of HEPA
filters at terminal in-let air filters. The return air ducts must be from bottom of the
walls allowing complete flushing of room air with fresh HEPA filtered air.
The efficiency of HEPA filters should be checked for filter leakage and air flow
test as per guideline ISO 14644 once in every 6 months (recommended). However,
in no case the periodicity of testing HEPA filters should exceed 12 months.
66 Pharmaceutical Quality Assurance

Table -Maximum permitted airborne particle concentration in aseptic area

Maximum permitted numbers of particles per m3 greater

Grade At rest In operation

0.5mm 5.0mm 0.5mm 5.0mm

A 3520 20 3520 20

B 3520 29 352000 2900

C 352000 2900 3520000 29000

3520000 29000 Not defined

At rest–No production activity, no operating personnel present

In operation – Regular production activity with all relevant operating personnel
present.
The particle counting in sterile area is carried out by portable air sampler. The
requirement is to draw at least 1-meter cube of air per sampling location. Various
commercially available air samplers like Neutecare available for routine monitoring
of air borne particles.
As per regulatory guidelines of USFDA, WHO and EU, particle monitoring of
Grade A should be undertaken for the full duration of operation including equipment
assembly. It is also recommended to carry out similar particle monitoring of Grade
B except the frequency of monitoring may be decreased, say once in a week.
Beside particle counts, sterile areas including operating personnel should be
monitored microbiologically. Petri plates with microbiological media are exposed in
predetermined locations in Grades A,B,C & D zones for 3-4 hours and the plates are
incubated for growth to count the number of microbial colonies.The count of colony
in petri plates exposed in Grade A must be zero (no growth). For other zones,
individual organisation decide on acceptable limits based on trend data.However,
none of the plates after exposure should show presence of pathogens and fungus.
If any time pathogens or fungus have been identified, the entire sterile area must be
shut down and complete sanitization should be done by the approved procedure.
The facility should be allowed to function again once on retesting absence of
pathogens or fungus are confirmed.
Personnel working in critical areas of a sterile manufacturing plant must be
monitored while performing jobs and while coming out from critical areas. Following
types of personnel monitoring are normally carried out.
Pharmaceutical Quality Assurance 67

- Finger dabbing - The fingers of personnel touches a sterilized petri plate with
solid media. The petri plates are then incubated to evaluate microbial
contamination in hands(fingers).
- Garment evaluation – In sterile areas, personnel wear sterilized special garments
(cover all). The arm pits of fully garbed personnel are swabbed using sterilized
rodec plates to evaluate microbial contamination on their bodies
- Face swabbing – The face of the personnel especially the places above eyebrows
are swabbed to evaluate microbial contamination.
The other utilities used in sterile areas are water systems for both purified water
and water for injection. The water quality should be monitored daily for compliance
with the specifications for both chemical and microbiological.
As per risk profile of pharmaceutical products, sterile products have highest risk
profile as per USFDA. Accordingly, maintenance and monitoring of sterile area is
extremely important for pharmaceutical companies.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. HEPA filter needs _____ test for performance evaluation —
(a) LAL (b) ELISA
(c) SMOKE (d) None of the above
2. General ________ is required for illumination in manufacturing ——
(a) 200 to 400 lux (b) Less than 200 Lux
(c) More than 400 lux (d) None of the above
3. In Pharmaceutical Industry Grade A area is used in –
(a) Handling of components after washing (b) Aseptic filling
(c) Preparation of solution (d) All the above
4. HEPA filters are checked periodically as per guideline in –
(a) ISO 9000 (b) ISO 14000
(c) ISO 14644 (d) None of the above
5. Maximum permitted airborne particle of 0.5 micron size in Grade A dynamic condition is –
(a) 1000 (b) 3520
(c) 3675 (d) 2900
6. As per USFDA highest risk profile of dosage form is –
(a) Tablet (b) Topical product
(c) Sterile product (d) Vaccines
68 Pharmaceutical Quality Assurance

7. Rodec plates are used to check microbial contamination in –

(a) Garments (b) Table tops
(c) Arm pits (d) Environment
8. Water for Injection should be monitored –
(a) Daily (b) Weakly
(c) Monthly (d) None of the above

Keys for Multiple Choice Questions

1 (c), 2 (a), 3 (b), 4 (c), 5 (b), 6 (c), 7 (c), 8 (a)

➥ Long Questions
1. What are the major considerations while designing premises?
2. While constructing a facility, what are the main points one must look into?
3. Write down the objectives of plant layout.
4. What are main areas of plant maintenance?
5. What are the classifications of sterile areas?
6. How the personnel working in sterile area are monitored to avoid contamination?
 Chapter 9

Equipment and
Raw Materials

9.1 Equipment Selection, Purchase Specifications & Maintenance

Pharmaceutical Industry is one of the most regulated industry in the world. Every
aspect of manufacturing of a product is controlled by current good manufacturing
practices. Since a manufacturing equipment or a testing equipment is an integral
part of manufacturing, all equipment involved in manufacture must be complaint to
CGMP and ensure that the finished product is effective, compliant to specification
and safe. All regulatory authorities have specific guideline in selecting equipment
for manufacturing.
1. USFDA –21CFR under section 211.63 Equipment design, size and location
states “Equipment used in manufacture, processing, packing or holding of a drug
product shall be of appropriate design, adequate size, and suitably located to facilitate
operations for its intended use and for its cleaning and maintenance” .
Under section 211.65 Equipment construction states “ (a) Equipment shall be
constructed so that surfaces that contact components, in process materials, or drug
products shall not be reactive, additive or absorptive so as to alter the safety, identity
, strength , quality or purity of the drug product beyond the official or other
established requirements. (b) Any substances required for operation , such as
lubricants or coolants shall not come into contact with components , drug product
containers, closures, in-process materials , or drug products so as to alter the safety
, identity , strength , quality or purity of the drug product beyond the official or
other established requirements”.
Under section 211.67 Equipment cleaning and maintenance states “ a) Equipment
and utensils shall be cleaned , maintained and as appropriate for the nature of the
drug , sanitized and/or sterilized at appropriate intervals to prevent malfunctions
or contamination that would alter the safety, identity, strength, quality or purity of

69
70 Pharmaceutical Quality Assurance

the drug product beyond the official or other established requirements. b) Written
procedures shall be established and followed for cleaning and maintenance of
equipment, including utensils used in the manufacture,processing, packing or holding
of a drug product. These procedures shall include, but are not necessarily limited to
the following:
1. Assignment of responsibility for cleaning and maintaining equipment
2. Maintenance and cleaning schedules,including, where appropriate sanitizing
schedules.

n WHO GMP Guideline Annex 2 under section 13 Equipment states–

13.1 – Equipment must be located, designed, constructed, adapted and maintained
to suit the operations to be carried out. The layout and design of equipment must
aim to minimize the risk of errors and permit effective cleaning and maintenance in
order to avoid cross contamination,buildup of dust or dirt and in general,any adverse
effect on the quality of products.
13.1 Equipment should be installed in such a way as to minimize any risk of error
or of contamination.
13.6 Production equipment should be thoroughly cleaned according to a fixed
schedule.
13.8 Washing, cleaning and drying equipment should be chosen and used so as
not to be a source of contamination.
13.9 Production equipment should not present any hazard to the products. The
parts of the production equipment in contact with the product must not be reactive,
additive, or absorptive to an extent that would affect the quality of the product.
13.12 Non-dedicated equipment should be cleaned according to validated cleaning
procedures between being used for production of different pharmaceutical products
to prevent cross contamination.
The Indian Drug and Cosmetics Act 1940, under schedule M, Good Manufacturing
Practices and requirements of Premises, Plants and Equipment for Pharmaceutical
products,also specifically describes in detail about the type,installation, cleaning
and avoidance of contamination of equipment while using in pharmaceutical
manufacturing.
Overall, all regulatory guidelines highlight the importance of selection and
maintenance of pharmaceutical equipment in great details to ensure good
manufacturing practices are followed while manufacturing products.
Pharmaceutical Quality Assurance 71

9.2 Points are to be considered before selecting and purchasing of

equipment –
1. Cost of the equipment–While deciding to purchase an equipment, the first
point one must finalize is the budget for procurement. Many times, same
equipment by different manufacturer can vary in cost quite considerably. The
purpose is to have the best equipment that fits the budget without compromising
on quality.
2. Experience and reputation of the equipment manufacturer–It is always
preferred to go to an equipment supplier who has built reputation over the
years on performance of equipment, timely delivery and after sales servicing.
3. Suitability – Equipment selection must be suitable for the purpose of use. A
high degree of technical evaluation of the mechanism of operation of equipment
should always be carried out to determine suitability.
4. Constructability – Pharmaceutical equipment must be constructed to ensure
that all the contact surfaces are non-reactive with the product.Constructability
also should consider ease of installation and use.
5. Cost of running and maintenance- Cost of production is always an important
criterion in manufacturing pharmaceutical products. So, it is important to have
an overall assessment of running cost of the equipment and maintenance to
ensure that the cost of manufacturing does not increase appreciably.
6. Digital capabilities – Now a days, most of the pharmaceutical equipment are
fitted with software’s and other gadgets.It is important to involve people within
the organization who have expertise to understand the digital capability of the
machine and not merely evaluate mechanical or electrical capability.
7. Capacity – The capacity of output is an important criterion before selecting an
equipment. The purchased equipment should be able to handle the capacity
requirement over a considerable period. Hence, it is important to select an
equipment which can deliver the right capacity as per requirement.
8. Safety – This is an area must be studied in detail during selection of equipment.
Pharmaceutical equipment normally has multiple moving parts while running.
It is important that all moving parts remain covered by design while running
so that operators have no access to the moving parts.
9. Environmental health attributes – All equipment used in manufacturing must
be environment friendly. For example, a high noise making equipment must be
avoided while deciding a new equipment.
72 Pharmaceutical Quality Assurance

Once an equipment is decided for procurement, a purchasing specification is

finalized in consultation with the equipment supplier. The purchasing specification
must include all the requirements of the production department. The equipment
manufacturer must comply with the purchasing specification before delivering the
equipment to organization.
Once the equipment is received and qualified (IQ, OQ & PQ), the first step is to
write a standard operating procedure (SOP) in consultation with the user. The SOP
should cover operation, cleaning and maintenance of the equipment. Better the
maintenance of equipment, better would be the performance and overall efficiency.
In pharmaceutical industry for maintaining the equipment, principle of preventive
maintenance is followed. This means by preplanning maintenance of the equipment,
the organization is preventing the equipment from breaking down. Once the
equipment breaks down the cost of repair is normally high with disruption of
manufacturing activities. Hence, it is important that the organization must design a
very effective preventive maintenance programme.
In preventive maintenance program, at the beginning of the year all the equipment
and utilities are put into a schedule of periodic preventive maintenance. The schedule
should cover all the equipment with specific periodicity for maintenance. A
comprehensive check list is drawn for each equipment and the health of the machine
is evaluated in detail. If any change parts are to be replaced, it is also done during
preventive maintenance.All equipment must have a maintenance history card. The
card should give details of when the maintenance of the equipment happened, who
maintained, who checked, what problem or issue was identified and what corrective
and preventive actions were taken. The trending of observations of maintenance
history card at the end of the year can determine health of an equipment. Based on
the trend data, companies decide to replace equipment which might create a major
break down issue in future. Unless the pharmaceutical company is very small, an
average size company will have multiple equipment. At times it is difficult to manage
the preventive maintenance programme efficiently by manual process. Increasingly
companies are now a days using Enterprise Resource Planning (ERP) software like
SAP to monitor and manage preventive maintenance programme.

9.3 Purchase Specifications and Maintenance of Stores for Raw

Materials
Once the raw materials reach the stores as input material, it comes under the
organization’s jurisdiction. The organization becomes the custodian of the materials
for its storage and responsible for the quality, quantity and safety of the materials.In
the concept of CGMP, all raw materials are to be procured from an approved vendor.
Pharmaceutical Quality Assurance 73

This means the supplier, or the manufacturer must be evaluated by the quality unit
of the organization and approved before any supply is initiated.
The organization must draw a quality agreement with the approved vendor
mentioning specification,condition and type of the packaging configuration,details
to be mentioned on label and invoices and maintenance/monitoring of storage
condition during transportation.
Raw material storage areas must be of enough capacity to allow orderly storage
of various categories of materials with proper separation and segregation .CGMP
rule specifies to keep raw materials batch wise together with no chance of another
batch number of same material stored with to avoid mix up.Raw Material storage
area should be completely separated from Engineering items and Packaging material
storage areas.
Raw material storage areas are designed with centralized HVAC system to ensure
appropriate storage conditions are maintained. The store should be clean,dry and
sufficiently illuminated. The storage conditions should be monitored on 24/7 basis
and records should be maintained. The storage condition documentation is
considered controlled documents as per CGMP regulations.The design and
construction of raw material store must prevent the goods stored from natural
calamity like flood.
The receiving and dispatch bays should be constructed in such a way that there
is an air lock in between, preventing ingress of outside air, dust and insects entering
the raw material store. All materials received at the receiving bay must be dedusted
and weight checked before allowing entry to main storage area.
When the management of storage is done physically,every raw material store
must have a separate quarantine area labelled identified with UNDER TEST labels,
where materials are to be stored properly till the material is approved by the quality
control unit. Once approved, the material should be moved to approved material
storage area with APPROVED identification labels. All rejected materials should be
labelled REJECTED and promptly moved to rejected area to avoid any mix up with
approved materials. Rejected areas must be secured with lock and access only to the
authorized personnel. As per GMP guideline pharmaceutical companies are to follow
FIFO ( First in -First Out ) procedure while using the approved raw materials unless
justified.
The entry to raw material stores must be controlled through authorized trained
personnel. Specific materials like narcotic drugs,radioactivematerials, hazardous
materials etc. must be stored separately and controlled through applicable statutory
regulations.
74 Pharmaceutical Quality Assurance

Many raw material warehouses create provision of sampling within the stores. If
created, the sampling area must have similar environment control like core process
manufacturing area. Since the raw material container is opened for sampling, care
must be taken that the material does not get exposed to uncontrolled environment.
Normally reverse laminar air flow (LAF)unit is installed in sampling booth. The
personnel involved in sampling should follow similar procedure of garbing and de-
garbing with freshly laundered garments as followed while entering core process area.
Good Warehouse Practice (GWC) is an important component of overall Good
Manufacturing Practices

REVIEW QUESTIONS
➥ Multiple Choice Questions
1. lQ stands for—
(a) Installation Qualification (b) Installed Qualification
(c) Incubation Qualification (d) None of the above
2. In Pharmaceutical Industry DQ stands for—
(a) Design Qualification (b) Documentation Qualification
(c) Detailed Qualification (d) Design Quality
3. SOP of Operating an equipment should be done –
(a) Before Qualification of equipment (b) After Qualification of equipment
(c) At the time of purchasing equipment (d) At the time of FAT
4. Equipment must be—
(a) Installed where the equipment is easily visible
(b) Installed safely to avoid error and risk of contamination
(c) lowest cost to reduce cost of manufacturing
(d) None of the above
5. While dispensing pharmaceutical companies should follow –
(a) First In First Out
(b) Last In First Out
(c) Based on warehouse manager’s decision
(d) None of the above

Keys for Multiple Choice Questions

1 (a), 2 (a), 3 (b), 4 (b)

➥ Long Questions
1. List down the important considerations before finalizing equipment purchasing
2. Write a brief note on preventive maintenance of equipment
3. Write a brief note on the important criteria of a raw material storage area.
4. What are different types of labels are used to identify status of raw materials?
5. Describe the precautions are to be followed while sampling of raw materials
UNIT–1II
.
 Chapter 10

Quality Control Test for Containers,

Rubber Closures and Secondary
Packing Materials
10.1 Quality Control
Quality Control is a system of maintaining standards in input materials (raw&
packaging materials), in process materials or manufactured products by testing
against a specification. Quality Control can be defined as part of total quality
management focused on fulfilling quality requirements by evaluation in a laboratory.
While Quality Assurance relates to how a process is performed or how a product is
made,Quality Control is more the inspection aspect of Quality Management.

10.2 Quality Control Laboratory

Pharmaceutical companies are required to establish a quality control laboratory
having facilities for testing of physical, chemical, microbiological or biological
parameters, as required, of all APIs,excipients, packaging materials and finished
products as per approved specification. However, regulatory authorities also allow
companies to take support of approved analytical testing laboratories if the facility
is not available in house. Quality Control department must also have adequately
trained personnel who can carry out testing of the materials as per approved
specification.

10.3 Responsibility of Quality Control

Quality Control department must be responsible for following activities–
1. To prepare specifications and standard test procedures of all input materials,in
process materials, finished products.
2. To approve or reject, input materials, in process materials and finished products.
3. To ensure all required testing are carried out as per approved specifications
4. To approve sampling procedures.

77
78 Pharmaceutical Quality Assurance

5. To ensure that all validations including analytical procedures and calibrations

of analytical equipment are carried out and documented.
6. To carry out regular self-inspections.
7. To ensure that all personnel involved in qualitycontrol function are trained
8. To write standard operating procedures specific to the functioning of quality
control
9. To carry out stability studies of finished products as per approved protocol
10. To maintain retain samples of input materials and finished products and
11. To maintain all control documents with primary and final data securely for
audit purposes.

10.4 Sampling
Quality Control department must have scientifically written sampling procedures
for sampling of materials. The procedure is established in such a way that the
sample taken for testing in quality control laboratory must represent the entire
consignment received or batch manufactured.

10.5 Retention Samples

Samples of raw materials (APIs and excipients),primary packaging materials and
finished products must be retained at least one year beyond expiry date.The quantity
to be retained should be at least twice the quantity required for analysis.

10.6 Types of packaging materials used in Pharmaceuticals

Type of Materials Used for
Glass Bottles, Ampoules, Vials, Cartridges, Syringes
HDPE Bottles, Closures,
Metal Collapsible tubes, foil, containers
Rubber Closures
Paper Cartons, Labels, leaflets, Shippers

10.7 Classification of Packaging Materials

The packaging materials are classified in three categories –
(a) Primary – The packaging materials which comes in direct contact with the
product. Example – Aluminum foil used for packing tablets, Glass Bottle holding
a liquid product.
Pharmaceutical Quality Assurance 79

(b) Secondary – The packaging materials in contact with primary packaging

materials. Example – Labels on a bottle, Cartons holding Aluminum Strips
(c) Tertiary – Final packaging of products. Example – Shipper or cardboard box
holding bottles, cartons of finished products

10.8 Function of Packaging Materials

The main functions of packaging materials are to protect the product from adverse
environment condition, insect or extraneous materials and breakages during
transportation. Convenience in carrying, stocking and ease while consuming also
important factor. Beside packaging of products convey unique identification of
products.
In pharmaceutical industry food grade high density polyethylene (HDPE)
(generally used for solid products)or glass containers (generally used for Liquid
products) are recommended to use for product packing.

10.8.1 HDPE Containers

HDPEcontainers are checked for following tests in compliance to the specifications.

10.8.1.1 Physical Tests

(a) Description –Visual description of the bottle. The description should match
with the description mentioned in the specification
(b) Weight of the bottle – weight of the bottles is checked and compared with the
specification.
(c) Dimension – total height, neck diameter, internal bore diameter, body diameter
and wall thickness of the bottle is checked as per specification
(d) Overflow capacity – filling the bottle up to brim with water and measure the
volume of water in a measuring cylinder.
(e) Visual inspection – checking bottles visually for any defect.

10.8.1.2 Instrumental Tests.

2.1 Spectral Transmission
Procedure – Cut a portion of the bottle of HDPE like the shape of UV cuvette
holder. Wash and dry the piece taking care to avoid scratching the surfaces. Place
the test piece in the spectrophotometer with the cylindrical axis parallel to the plane
of the slit and approximately centered with respect to the slit. Measure the
transmittance of the section at wavelength 290 to 450 nm.
80 Pharmaceutical Quality Assurance

Acceptance Criteria- The transmittance should not be more than 10%.

2.2 Identification by IR
Procedure –Cut a flat section of HDPE bottle and trim the same to mount on an
ATR assembly of IR spectrophotometer. Determine the IR spectrum from 3500 to
600 cm¹. Determine the IR spectrum of reference standard (USP HDPE standard) in
the same manner.
Acceptance Criteria– The IR spectra of the sample should match with that of
reference standard.
2.3 Identification by Thermal Analysis (DSC)
Procedure –Cut a section weighing about 12mg and place it in the sample pan
and determine the thermogram under nitrogen using the heating and cooling
condition as specified below
(i) Hold the specimen for 1 minute at 40 °C.
(ii) Heat from 40°C to 200°C at 10°C per minute.
(iii) Hold the specimen for 1 minute at 200°C
(iv) Cool from 200°C to 40°C at 10°C per minute
Compare the DSC thermograph of the sample with that of reference spectrum(USP
HDPE standard).
Acceptance Criteria-The DSC thermogram of the test sample should be like the
thermogram of reference standard and the temperature of the endotherm (melt) in
the thermogram of the test sample does not differ from that of reference standard
by 6.0°.

10.8.1.3 Physicochemical Tests–

3.1 Appearance of the solution:
Preparation of sample (Solution C1) – Fill the container up to its normal capacity
with purified water and close the container. Heat in an autoclave at 121°C ±2°C for
30 minutes. Use solution C1 within 4 hours of preparation. Prepare a blank by
heating purified water in a borosilicate glass flask closed with aluminum foil at the
same temperature and time used for the preparation of solution C1. After autoclaving
note down the appearances of the solution.
Acceptance Criteria – Solution C1 is clear and colorless, comparable with blank
solution
3.2 Absorbance – Determine the spectrum of solution C1 between 230 and 360
nm using solution C1, comparing with the blank solution.
Acceptance Criteria–The absorbance value should not be more than 0.2.
Pharmaceutical Quality Assurance 81

3.3 Total Organic Carbon (TOC)– Measure the TOC of solution C1 in TOC
analyzer comparing with blank.
Acceptance Criteria–The difference of TOC between solution C1 and the blank
should not be more than 8 mg/L.
4.0 Moisture Vapour Transmission – Select 12 bottles and add desiccant
(anhydrous calcium chloride) to 10 bottles within 13 mm of the closure if bottle
volume is 20 ml or more. If the bottle volume is less than 20 ml, fill up to two third
capacity. Close the bottle immediately after adding desiccant. The remaining two (2)
bottles are used as control. Add enough glass beads in the control bottles so that the
weight of the bottles is approximately equal to the each of the test containers. Close
the bottles and note individual weights. Keep the bottles in a chamber at 75% ±3%RH
and temperature of 23±2°C for 14 days. After 14 days, record the weight of the
bottles individually and calculate the rate of moisture permeability in mg per day
per L by using the formula
Permeability – (1000/14V) [(Tf –Ti) – (Cf -Ci)]
Where
V –Volume of the container
Tf – Final weight of each containers in mg
Ti – Initial weight of each containers in mg
Cf – Average final weight of two control bottles in mg
Ci – Average initial weight of two control bottles in mg
Acceptance Criteria – Not more than one of the ten test containers exceed 100 mg
per day per liter in moisture permeability and none exceeds 200 mg per day per liter.

10.8.2 Glass Containers

Different types of Glasses are used in glass containers used in Pharmaceutical
Industries-
Type of Glass Composition Used for
Type 1 Borosilicate Injectable product (acidic, alkaline or neutral pH )
Type II Soda lime glass Injectable product (acidic or
with inner neutral pH)
surface coated
with protective
layer.
Type III Soda lime glass Oral products, powder for injection
Type IV General purpose Topical, Oral products
Soda lime
Glass Containers are checked for following tests in compliance to the
specifications
82 Pharmaceutical Quality Assurance

10.8.2.1 Description
The glass containers are checked as per description specified in specification
especially paying attention of any cracks on surface or broken pieces within the
container.

10.8.2.2 Physical Tests

(a) Dimensions – Each container type should have specification of dimensions.
The height,body diameter and bore diameter are checked as per specification.
(b) Weight – The weight of the bottle should comply with the specification.
(c) Overflow capacity - Filling the bottle up to brim with water and measure the
volume of water in a measuring cylinder. The overflow capacity must meet the
specification.

10.8.2.3 Instrumental Tests

3.1 Spectral transmission test–Take a portionof the container, wash and dry taking
care avoiding scratching the surfaces. Place the section in the spectrophotometer
with its cylindrical axis parallel to the plane of the slit and approximately centered
with respect to the slit. Measure the transmittance of the section at wavelength 290
to 450nm.
Acceptance criteria -The transmission should not be more than 10%.
3.2 Glass Grain Test (Alkalinity of glass)– Rinse and crush the a container and
transfer the samples through stacked sieves numbers 25 , 40 and 50. Collect the
samples retained over sieve number 25 , 40 & 60 in a beaker , washed with acetone
and dry at oven at 140°C for 20 minutes. Transfer the dried glass into separate
weighing bottles and cool in a desiccator. In a separate weighing bottle take 50 ml
of purified water as control or blank. Autoclave both at 121°C for 30 minutes. After
autoclaving cool, add 0.05 ml methyl red solution and titrate with 0.02M HCL.
Subtract the titration volume of blank or control from test solution. Calculate the
mean value of the results in ml of 0.02 M HCL per gm of the sample.
Acceptance criteria– NMT 0.85 ml of 0.02 M HCL consumed per gm of test glass.
3.3 Surface Glass Test (Surface alkalinity of the glass) – Select 6 containers and
fill with Purified water to about the rim avoiding overflow. Close the containers and
autoclave at 121°C for 60 minutes. After autoclaving cool the containers. combine
the liquids obtained from the containers and mix. Take the volume as per container
capacity in a conical flask for titration. Take the same volume of purified water in
another conical flask as blank. Add 0.05 ml methyl red solution in each flask for
each 25ml of liquid. Titrate both blank and test solution with 0.01 M HCL to end
point. Subtract the volume found in blank solution from test solution and express
the result in ml of 0.01M HCL per 100ml.
Pharmaceutical Quality Assurance 83

Acceptance criteria – NMT 4.8 ml of 0.01 M HCL consumed per 100ml of test
liquid.
If the HDPE/Glass containers are supplied by an approved vendor, for routine
quality control, generally description of containers and physical tests are enough to
approve the consignments. However, whenever a new vendor supplies the containers
for the first time, regulator’s expectation would be to carry out all the tests of
physical, instrumental and physicochemical tests.

10.8.3 Quality Control Tests for Rubber Closures

Following are the tests normally carried out on rubber closures
1.0 Description – Observe the samples visually for the conformance of description
as per specification.
2.0 Dimensions – Using a calibrated vernier caliper measure the height, outer
diameter, neck diameter and rim thickness of rubber closures as per specification
3.0 Fragmentation Test – Fill 12 clean glass vials with purified water to 4 ml less
than the nominal capacity. Fit the closures to be examined, secure with aluminum
cap and allow to stand for 16 hours.
Using a hypodermic needle fitted with a syringe inject into each vial 1ml of water
while removing 1ml of air.Repeat this procedure four times for each closure tested,
piercing each time at a different site. Use a new needle for each closure tested,
checking that it is not blunted during the test. Filter the total volume of liquid in all
the vials tested through a filter having pore size 0.5 micron. Count the number of
rubber fragments on the surface of the filter visible to the naked eyes.
Acceptable Criteria – Not more than 5 fragments should be visible on filter surface
for 12 rubber closures.

10.8.3.1 Acidity and Alkalinity

Bromothymol blue solution - Dissolve 50 mg of bromothymol blue indicator in a
mixture of 4ml of 0.02M sodium hydroxide and 20 ml of alcohol. Dilute with water
to 100ml.
Preparation of solution S – Place whole, uncut closures corresponding to a surface
area of 100±10 cm²into a suitable glass container. Cover the closures with 200 ml of
purified water. If it is not possible to achieve the prescribed closure surface area (
100±10 cm² ) using uncut closures , select the number of closures that will most
closely approximate 100 cm² , and adjust the volume of water used to the equivalent
of 2ml per each 1 cm² of actual closure surface area used. Boil for 5 minutes and
rinse five times with cold purified water.
84 Pharmaceutical Quality Assurance

Place the washed closures into a type 1 wide necked glass (borosilicateglass)
flask. Add the same quantity of purified water initially added to the closures and
weigh. Cover the mouth of the flask. Heat in an autoclave at 121 ±2°C for 30 minutes.
Cool and add purified water to bring up to the original mass. Shake and immediately
decant and collect the solution. Note – The collected solution must be shaken
before use in each of the tests.
Procedure – To 20ml of Solution S, add 0.1 ml of Bromothymol blue solution. If
the solution is yellow, titrate with 0.01 N sodium hydroxide until a blue end point
is reached. If the solution is blue initially, titrate with 0.01 N HCL until a yellow
endpoint is reached. If the solution is green, it is neutral, and no titration is required.
Blank correction - Titrate 20 ml of blank (purified water) similarly. Correct the
results obtained for solution S by subtracting or adding the volume of titrant required
for the blank, as appropriate.
Acceptance Criteria –Not more than 0.3ml of 0.01N NaOH or not more than 0.8
ml of 0.01N HCL is required to change the colour to blue or yellow respectively

10.8.3.2 Ammonium –
Procedure :
Alkaline Potassium Tetraiodomercurate Solution -Prepare a 100 ml solution
containing 11 gm of potassium iodide and 15 gm of mercuric iodide in water.
Immediately before use, mix 1 volume of the solution with an equal volume of a 250
gm per liter solution of sodium hydroxide.
Test Solution – Dilute 5 ml of Solution S to 14 ml with purified water. Make
alkaline if necessary, by adding 1 N sodium hydroxide and dilute with water to 15
ml. Add 0.3 ml of alkaline potassium Tetraiodomercurate solution and close the
container.
Ammonium Standard Solution – Prepare a solution of ammonium chloride in
water (1 ppm NH4). Mix 10 ml of the 1 ppm ammonium chloride solution with 5
ml water and 0.3ml of alkaline potassium Tetraiodomercurate solution and close the
container.
Acceptance Criteria – After 5 mins any yellow colour in the test solution is no
more than the standard ammonium standard solution (NMT 2 ppm of NH4 in
solution S)

10.8.3.3 Self-Sealing
Procedure - Fill 10 suitable glass vials for the rubber closures with purified
water to the nominal volume. Close the vials with the rubber closures to be examined
and cap with aluminum seals.Using a hypodermic syringe, pierce each rubber
closures 10 times – piercing each time at a different place. Take a desiccator filled
Pharmaceutical Quality Assurance 85

with solution of 0.1% (1 gm per liter) methylene blue in purified water and immerse
10 vials. Apply vacuum of 27 kPa for 10 minutes. Bring back to normal atmospheric
pressure and leave the vials immersed in 0.1% methylene blue solution for 30
minutes. Remove the vials from desiccator and rinse the outside of the vials and
check for methylene blue colour stain.
Acceptance criteria –Inside of none of the vials should contain any traces of
methylene blue solution.

10.8.3.4 Absorbance between 220 to 360 nm

Procedure – Pass solution S (previously prepared under test of acidity and
alkalinity) through 0.45-micron filter, discarding first few ml of filtrate. Measure the
absorbance of the filtrate at wavelengths between 220 and 360 nm in a 1 cm cell
using purified water as blank in a matched cell with reference beam.
NOTE – This test should be performed within 5 hours of preparing solution S
Acceptance Criteria - The absorbance should not be more than 0.2.

10.8.3.5 Reducing Substances –

Procedure –To 20 ml of solution S add 1 ml of diluted sulfuric acid and 20 ml of
0.002 M potassium permanganate solution. Boil for 3 minutes. Cool and add 1 gm
of potassium iodide and titrate immediately with 0.01 M sodium thiosulfate, using
0.25 ml of starch solution as indicator. Perform titration using 20 ml of purified
water as blank and note the difference in volume of 0.01M sodium thiosulfate
required.
NOTE –Perform the test within 5 hours of preparing solution S
Acceptance Criteria –The difference between titration volume should not be more
than 3.0 ml.

10.8.3.6 Extractable Zinc

Test solution – Prepare test solution by diluting 10 ml of solution S to 100ml
with 0.1 N HCL. Prepare blank using purified water similarly.
Zinc standard solution – Prepare a solution (10 ppm zinc) by dissolving zinc
sulfate in 0.1N HCL
Reference solution - Prepare three reference standard solution by diluting zinc
standard solution with 0.1 N HCL. The reference standard solutions should have
concentration covering expected limit of test solution.
Procedure – Use a suitable atomic absorption spectrophotometer equipped with
a zinc hollow cathode lamp and air acetylene flame. Test each of the reference
standard solution at the zinc emission line of 213.9 nm at least three times. Record
the readings.Rinse the apparatus with the test blank solution each time to ensure
that the reading returns to initial blank value. Prepare a calibration curve from the
mean of the three readings obtained for each reference solution. Record the
86 Pharmaceutical Quality Assurance

absorbance of the test solution. Determine the ppm of zinc concentration in test
solution using the calibration curve.
Acceptance Criteria - Not more than 5 ppm of extractable zinc.

10.8.3.7 Volatile Sulfides –

Procedure – Place closures (cut if necessary) with a total surface area of
approximately 20 cm ² in a 100ml conical flask and add 50 ml of 20 gm per liter citric
acid solution. In the same manner and at the same time, prepare a control solution
in a separate 100 ml conical flask by dissolving 0.154 mg of sodium sulfide in 50ml
of 20gm per liter citric acid solution. Place a piece of lead acetate paper over the
mouth of each conical flask. Hold the paper in position by placing over it an inverted
weighing bottle. Heat the flask in an autoclave at 121 ±2°C for 30 minutes.
Acceptance Criteria – Black stain on lead acetate paper produced by test solution
should not be intense as compared to stain produced by control substances.

10.9 Secondary Packing Materials

The secondary packing materials do not come in direct contact with the product
but used to pack primary packing materials. Primary packing materials are bottles,
aluminum foil , ointment tubes etc. which come in direct contact with the product.
The secondary packing materials in pharmaceutical industry are labels and cartons
or show boxes. Following tests are normally carried out on secondary packing
materials –
1. Description – Every label or carton must have specification detailing the
description, which specifies printed text matters and colours shade. The text
matter on labels and cartons are finalized while developing the artwork for the
printed packing material. All artworks must be approved by authorized
personnel before allowing for printing. Pharmaceutical companies use labels
and cartons with various combination of colours. It is important to maintain the
actual colour shades of printed packing materials to retain brand identification
and value. Normally, a standard sample with approved colour shade is used to
compare with the test sample before approval.
2. Dimension – The dimensions like length, width and height of the carton or
length and width of label is measured and must comply with the approved
specification.
3. GSM – The grammage of the paper used to manufacture secondary packing
material is expressed in gram per square meter (GSM). The specification should
specify the grammage of paper which the printer should be using for printing.
4. Rub Resistance Test – The printed surface of the packing materials is rubbed
on a surface and checked for fasting of colours. The colour should not fade after
rubbing and retain original colour.
Pharmaceutical Quality Assurance 87

5. Pasting Quality – Synthetic adhesives are used in cartons for pasting. The
adhesive must be strong enough to hold the carton in original shape during
transportation and use.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. Raw Material testing can be performed in—
(a) Warehouse (b) Quality Control Laboratory
(c) Quality Assurance Department (d) None of the above
2. Fragmentation Test is related to—
(a) Glass Containers (b) HDPE Containers
(c) Rubber Stoppers (d) Collapsible Tubes
3. Borosilicate Glass is used in—
(a) Ampoules (b) Oral products
(c) Topical Products (d) Powder for Injection
4. Surface Alkalinity Test is carried out on—
(a) HDPE containers (b) Glass Containers
(c) Aluminium Collapsible Tube (d) None of the above
5. Rub resistance Test is carried out on—
(a) Printed Packaging Materials (b) Shippers
(c) Ampoules (d) Collapsible Tubes
6. Extractable Zinc Test is carried out on—
(a) Rubber Stoppers (b) HDPE containers
(c) Ampoules (d) None of the above

Keys for Multiple Choice Questions

1 (b), 2 (c), 3 (a), 4 (b), 5 (a), 6 (a),

➥ Long Questions
1. Define Quality Control and differentiate from Quality Assurance.
2. What are the functions of Quality Control?
3. What are the different typesof packaging materials used in pharmaceuticals?
4. What are the different tests performed in HDPE containers?
5. What are the different types of glasses are used in pharmaceuticals?
6. What are the different tests performed in glass containers?
7. Describe tests performed on rubber closures.
8. What are different tests performed on secondary packaging materials.
 Chapter 11

Good Laboratory Practices

11.1 General Provisions

People are often confused between Good Laboratory Practices (GLP) with practices
in a quality control laboratory of a pharmaceutical industry. The practices in a
quality control laboratory falls under Good Manufacturing Practices (GMP) because
it is associated with lot or batch release of finished products. Whereas GLP is
applicable to non-clinical laboratory studies to assure the quality and integrity of
data of research for marketing permits of products regulated by govt. agencies like
USFDA, EU, WHO etc.
GMP and GLP regulations serve testing of two different purposes. The GLPs are
designed to protect integrity of scientific data and provide the regulatory authorities
with auditable record of research studies. In contrast, the GMPs are to demonstrate
to regulatory authorities whether individual batches of a regulated product are
manufactured according to pre- defined manufacturing criteria.Since functioning of
quality control laboratory is an integral part of helping to manufacture a product
and ultimately testing for batch release, its activity comes under GMP and not
under GLP.
All regulatory authorities have framed guidelines for carrying out research
activities under non-clinical studies meant for submitting data for marketing
authorization.GLP became part of regulatory requirements in late 1970s, when
massive malpractices of R&D functions of pharmaceutical laboratories in USA were
detected by USFDA.
The provision in GLP guideline is to promote safety,consistency, quality and
reliability of data in a non-clinical laboratory testing. GLP is not limited to
pharmaceuticals but also applies to medical devises, food packaging, and other non-
pharmaceutical products or ingredients.

88
Pharmaceutical Quality Assurance 89

11.2 Organization and Personnel –

The GLP regulations require that the structure of the testing laboratory
organizations and job responsibilities of personnel are defined and authorized.
Qualified, experienced and trained personnel are key factor for the success of
compliance to GLP regulations. There should be an organization chart clearly
depicting the areas of operation and relationship with each other within the
organization. Each study carrying out in a non-clinical laboratory should have
following activities defined–
1. Management Responsibilities –Top management takes complete accountability
for the integrity and accuracy of data generated.
2. Sponsor Responsibilities – The sponsor whose behalf the laboratory is carrying
out the study must take responsibility that they have evaluated the competence
and integrity of the functioning of the laboratory.
3. Study Director Responsibilities – Each study must be identified with a study
director, who would be primarily responsible to overview and evaluate the
data generated.
4. Principal Investigator –Principal Investigator is normally identified with a
specific project,whereas a study director can overview multiple studies at the
same time.
5. Study Personnel Responsibilities – Each study can have multiple persons
involved in research work.Against each project all the personnel involved should
be named and their job responsibilities authorized.
All the personnel involved in non-clinical laboratory activities must have their
written job responsibilities available and authorized by their supervisors. GLP
regulation also mentions that there should be enough personnel to perform the task.

11.3 Testing Facilities Operation

The regulation emphasizes the need for testing laboratory having following
facilities :
(a) The laboratory should be of adequate size and design that prevents
contamination and mix up. There should be adequate lighting and well
ventilated.
(b) Laboratory activities should be carried out within their defined areas. There
should be demarcated areas for conducting sampling, testing, approval and
rejection of materials.
90 Pharmaceutical Quality Assurance

(c) Safety rules should be maintained in the lab. The laboratory should be provided
with emergency eye wash/ shower. Fume hoods should be used for handling
highly volatile and inflammable solvents.
(d) The documentation areas within the laboratory should be demarcated from the
working areas.
(e) There should be provision to retain samples as per storage condition for
traceability and review.
(f) If animals are used for testing, they must be housed in appropriate conditions
with compliance to all statutory rules and regulations.

11.4 Equipment
The laboratory should be provided with adequate number and types of equipment
to carry out a sponsored programme. All equipment must follow a strict schedule
of qualification, calibration and maintenance to ensure that the equipment is
functioning as per their intended purpose. Qualification, calibration and maintenance
documentations must be retained for audit purpose.

11.5 Test and Control of Articles

It is essential that the laboratory understands as much as possible about the
materials used during the study. The process is called characterization. It is
prerequisite for any study to evaluate the properties of pharmaceutical compounds
during non-clinical studies about test items and test system (sometimes animal or
plant) to which the test item is to be administered.Quality Assurance Unit must
inspect critical phases of each study and inform management about the integrity of
the studies and compliance to GLPs. The quality assurance unit should be separate
and independent from the personnel engaged in the study. It is an oversight function
only and not involved in any testing or recording of data.

11.6 Protocol for Conduct of a Nonclinical Laboratory Study

Protocols are agreements or plans between participating parties clearly specifying
objectives for carrying out studies following GLPs. The regulation has set out a rule
for good laboratory practices and help researchers perform their work in compliance
with their pre-established plans and standardized procedures. The regulation is not
concerned about the scientific content or value of the studies. Protocol defines the
main steps of the research studies, with experimental design and time frame for the
study. However, it does not give technical details necessary for the studies which
are covered in the respective standard operating procedures (SOPs). The laboratory
Pharmaceutical Quality Assurance 91

must have all their activities written in detail in SOPs covering all the activities of
day to day operation and proposed study. With the protocol and SOPs, it should be
possible to repeat the study with reproducible results if necessary.
The protocol should have following details :
1. Objective of the test
2. Tests performed
3. A brief description of the test methods, including sample size, equipment used
for testing and any consensus standard utilized
4. Pre-defined pass or fail criteria (when applicable)
5. Results summary
6. Discussion and Conclusions
7. Name of the study director and principal investigator

11.7 Records and Reports

All studies generate raw data. the raw data must be recorded contemporaneously
and preserved. Raw data are outcome of research and form the basis for establishing
scientific interpretations and arriving at the conclusions.
The study report should contain an account of the way the study was performed.
The report should incorporate raw data with scientific interpretations including
statistical analysis. The report is submitted to regulatory authorities as part of the
submission for registration and marketing approval.
The raw data and reports should be archived in fire and flood proof location for
many years and should have the provision of prompt retrieval.

11.8 Disqualification of Testing Facilities

If the regulatory authorities during their audit of the testing laboratories find
noncompliance to GLPs, they might announce disqualification. When disqualification
is declared by official announcement, the testing laboratory is not allowed to carry
out any more studies for regulatory submission. The disqualification can draw civil/
criminal proceedings with fines and imprisonment of study director and principal
investigator.If a testing facility is disqualified, any studies done before or after the
disqualification must be evaluated for acceptance or rejection.
A facility once disqualified by regulatory authorities must go through re audit by
the same authority once all the corrective and preventive actions are implemented.
If the regulatory authorities during re audit find the testing laboratory is now in
92 Pharmaceutical Quality Assurance

compliance to GLP, an official communication is sent announcing the withdrawal of

the disqualification notification. Once the disqualification notice of the laboratory is
withdrawn, the laboratory can re-start carrying out studies for submission of data
for regulatory approval.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. Quality Control Activity in a pharmaceutical company is governed by—
(a) GLP (b) GMP
(c) GCP (d) GWP
2. Study Director ‘s role is—
(a) Carry out the actual study (b) Management responsibility
(c) Principal Investigator (d) Link between Sponsor and Management
3. The role of Quality Assurance Dept. In a Non –clinical laboratory is—
(a) Testing (b) Checking integrity of testing
(c) Finalising Study Director (d) Finalising Report
4. Disqualification of testing Facilities is done, when—
(a) Non Compliance to GLP (b) Incomplete Testing
(c) Non Compliance to GCP (d) None of the above

Keys for Multiple Choice Questions

1 (b), 2 (b), 3 (b), 4 (a),

➥ Long Questions
1. What is GLP and discuss its scope?
2. Describe the organizational structure and responsibilities in a laboratory.
3. What are the salient features of a studyprotocol?
4. How can disqualification of a laboratory happen and what is the procedure of
requalification?
UNIT–IV
.
 Chapter 12

Complaints
12.1 Complaints and Evaluation of Complaints
In pharmaceutical Industry immediate response of any market complaint is critical
because any untoward reaction in patients after administration of a defective product
can have serious life-threatening consequences. Once the product gets into the market,
the origin of the complaints can be anything like production,packing,or
transportation. The critical steps in a pharmaceutical company is to address product
complaint expediously right from receiving the complaint to the closure. If the
complaint is genuine, then a root cause analysis should be performed, and a corrective
and preventive action initiated to avoid similar complaints in future.Every company
should have a person authorized and responsible for handling market complaints.
The investigation of market complaint essentially should focus to address
followingfour areas—
1. Time bound investigation – it is expected to complete the investigation within
30 working days. In case of product complaints having life threatening
consequences, the investigation should be completed within a week.
2. Finding the root cause of the complaint – all out efforts should be made to find
the exact root cause for the complaint
3. Risk analysis of all batches of the product already in the market – while doing
risk analysis other products and batches are also to be evaluated if it has any
impact of the specific market complaint received.
4. Corrective and Preventive Actions (CAPA) – based on root cause analysis a
CAPA should be implemented to avoid receiving similar complaints in future.
The regulatory authorities have clear expectation on handling of market
complaints. For example, USFDA defines handling of complaints under Current
Good Manufacturing Practice for Finished Pharmaceuticals 21CFR 211.198. EU
defines handling of complaints in Annex 8 of their GMP guidelines.

95
96 Pharmaceutical Quality Assurance

Flow chart of handling market complaints

Step 1 : receiving By e mail, toll free

Complainant
complaints number, verbal etc.

Quality Assurance l Document the

(Person responsible for Handling of complaint
Complaints) l Revert to complainant
if any details are
missing like complaint
sample, batch number

Step 2 : l Classify the complaint

Investigation (critical,major,minor)
l Review Batch Documentation
including Retention samples
l Check past trends on similar
complaints
l Based on criticality file FAR
(only in US)
l Conclude the investigation,
decide on recall l Conclude
l Risk Assessment on other Investigation within 30
batches of same product or working days
other products in the l If Investigation takes
market.Decide Recall, if more than 30 days,
necessary justify
l If the complaint is Adverse
Drug Effect (ADE), do a safety
evaluation through
Pharmacovigilance group
l Conclude whether the
complaint is genuine

Step 3-Feedback l Reply to Complainant with

and Corrective Investigation result with CAPA
Preventive Action l Close the Investigation
(CAPA)
Pharmaceutical Quality Assurance 97

If the product is found to be defective or have any adverse impact on patients,

immediate recall decisions should be taken
Each manufacturing facility should have a written Standard Operating Procedure
(SOP) in handling Market Complaints. The SOP should include following
1. Review by quality control unit (QCU) of any complaint.
2. Evaluation of possible failure of a drug product to meet any of its specifications
3. Determination whether the complaint represents a serious and unexpected
adverse drug experience that is required to be reported to regulatory authorities.
Based on the SOP, a complaint file should be maintained with written records of
complaints received with following details
1. Name and strength of product
2. Lot or batch number
3. Complainant information
4. Nature of complaint and
5. Reply to complainant
Market complaints are serious issues which can cost a pharmaceutical company’s
reputation. Continuous improvement and advancement of pharmaceutical
manufacturing are now a paramount part of all regulatory authorities’ mission to
safeguard and encourage public health. It is expected that a pharmaceutical company
reviews and analyses its market complaints and make necessary improvements in
manufacturing to enhance customer’s expectation.
The types of complaints received in a year should be trended to evaluate the risk
involved in keeping product in the market. The trend analysis and corrective and
preventive actions implemented should be part of company’s Annual Product
Review.

12.2 Handling of Return Goods

Pharmaceutical products can be returned from market for various reasons.
Following could be some of the major reasons for return of goods –
1. Product expired while in the market
2. Product having very short expiry period available. Many customers expect the
product to have a minimum available expiry period
3. Defective product and based on the recall decision products are returned
98 Pharmaceutical Quality Assurance

4. Product requires redressing or repacking due to some external damage during

transportation which has no impact on product quality, efficacy and safety.
5. Product damaged during transportation and not salvable
All return goods are to be segregated and properly labelled and stored to avoid
any mix up. Quality department should take prompt decision on the disposal of the
returned goods based on scientific rationale and good manufacturing practices. All
the returned goods are to be accounted and documented and reconciled with the
quantity of goods originally sent to market.

12.3 Recall
Recall is an integral part of pharmaceutical business. All over the
world,pharmaceutical manufacturing is highly regulated in view of direct health
impact on consumers because of any defective product is introduced in supply
chain. Regulatory authorities expect ethical behavior from pharmaceutical
manufacturer to recall voluntarily defective products even if the defects are
considered minor if it is anyway unacceptable by consumer.However,on critical
impact of product quality on consumer’s health,regulatory authorities can force
recalling of products.
All pharmaceutical manufacturers must have a standard operating procedure
(SOP) detailing the decision process, execution and coordination of recall of products.
In the advanced countries like USA,EU, Japan etc. there is clear process defined
to recall a product.
For example, in USA, if a market complaint is received which can have potential
for recall, companies are expected to file a Field Alert Report (FAR) in form FDA3500
within 3 working days of receipt of complaint. In FAR a company must state the
product details like Name, Batch number, Pack details with the nature of complaints
and investigation report or at least the status of investigations if not completed. A
follow up FAR with complete investigation report must be filed within a reasonable
timeline along with the decision of recall if necessary.In USA, the recalls are classified
into three categories
Class 1 – The defect in the product can have serious consequence in a patient and
can also be irreversible. For example, sterility failure in an injection product or
higher potency than label claim etc. The class 1 recalls are executed up to consumer
or patient level.
Pharmaceutical Quality Assurance 99

Class II – The defect in the product can have some impact on the health of a
patient but the impact is reversible. For example, a product failed in impurities and
the impurities are not genotoxic. The class II recalls are executed up to retailer level.
Class III – The defect in the product does not have any impact on health of a
patient. Like complaints of broken tablets, failure in dissolution rate, change in color
of product with no impact on quality or efficacy of product etc. Class III recalls are
executed up to wholesaler level
Once a recall decision is made,competent regulatory authorities must be intimated
in writing about the recall decision. The progress of recall process should be closely
monitored.
The quantity of product received back after recall should be reconciled with the
quantity originally delivered to market. Normally, a recall is decided closed when
in three consecutive months, no further quantity of defective product is received
back from market.A final report should be issued with the reconciliation record of
delivered and returned quantities of products.The recalled products must be secured
and quarantined so that the returned stock does not get mixed up with good stock.
All recalled products must be destroyed by following environment friendly
procedures.
The regulatory guidelines stipulate to carry out yearly Mock Recalls of products
to test the effectiveness of the procedure for recall. The result of mock recall must
be documented and retained by Quality Department.

12.4 Waste disposal

It is expected from all pharmaceutical companies to behave responsibly and
dispose the wastes as per the Government’s Environment Department’s directive.
The impact on the general population and on environment must be considered
before any waste disposal decision is taken.In a pharmaceutical company generally
Environment, Health and Safety (EHS) department handles the hazardous waste
disposal.Pharmaceutical companies handle many toxic and hazardous materials in
their process. Every pharmaceutical company should have standard operating
procedures explaining in detail the procedure of disposal of waste materials.
Following are different types of wastes handled in a pharmaceutical company –
1. Hazardous Wastes–Hazardous wastes are the wastes which can create
irreversible damage to humans and environments. Every country through their
Environment and Health Policies have classified the type of wastes considered
hazardous and enforced through Environmental department. Chemicals and
100 Pharmaceutical Quality Assurance

solvents, product wastes are generally considered hazardous materials and must
be disposed off as per the guideline stipulated by the environment regulatory
authorities.
2. Non- hazardous Wastes – Non -hazardous wastes are generally not harmful to
humans and environment. Example – Paper wastes from a pharmaceutical
company.
3. Biomedical Wastes –Biological wastes are waste generated while carrying out
biological tests, microbiological tests or diagnostic tests. Biomedical wastes
should be treated as extremely critical and special agencies handle the disposal
as per authorization of environmental regulatory authorities.
Pharmaceutical companies are required to install Effluent Treatment Plant to
treat liquid wastes before allowed to dispose. Increasingly environmental agencies
are insisting companies to install zero discharge effluent treatment plants to avoid
any discharge of liquid effluent out of the facility and mandatorily recycled for use.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. The investigation of market complaint must be concluded in—
(a) A year (b) Within 30 working days
(c) Within 3 months (d) None of the above
2. USFDA defines handling of market complaints in 21CFR under—
(a) 211.198 (b) 210.198
(c) 211.112 (d) 211.190
3. CAPA should be implemented—
(a) Immediately after receiving complaint
(b) After conclusive investigation
(c) After receiving acknowledgement from complainant
(d) Once regulatory authorities instruct
4. USFDA Form 3500 is used for—
(a) Intimate a potential recall (b) handling of return goods
(c) All complaints (d) Product approval
5. Field Alert Report ( FAR) should be filed within—
(a) 3 working days (b) 7 days’
(c) 30 working days (d) Not mandatory to file
Pharmaceutical Quality Assurance 101

6. Class III recalls are done when—

(a) Serious product complaint (b) Irreversible effect on patients’
(c) Directive from USFDA (d) None of the above
7. Non –hazardous wastes are—
(a) Paper wastes (b) Waste from microbiological laboratory
(c) Solvents (d) Biomedical wastes

Keys for Multiple Choice Questions

1 (b), 2 (a), 3 (b), 4 (a), 5 (a), 6 (d), 7 (a)

➥ Long Questions
1. Draw a flow chart on handling of market complaints.
2. What are details should be recorded in a complaint register?
3. How the recalls are classified?
4. When a product needs to be recalled?
5. What are the main reasons for a product returned from market?
6. What are the different types of wastes in a pharmaceutical company?
102 Pharmaceutical Quality Assurance

Chapter 13

Document Maintenance in
Pharmaceutical Industry

13.1 Introduction
Documentation is very important aspect in Pharmaceutical Industry. All
Pharmaceutical activities are covered under Current Good Manufacturing Practices
(CGMP) and in CGMP all the instructions and the decisions taken must be written
documents and nothing should be left for verbal interpretation. Documentations are
the written proof of any activity in pharmaceutical manufacturing. This minimizes
the risk of inherent misinterpretation from oral instructions or communications.
Regulatory authorities expect unambiguous written procedures for confirmation of
actual procedure followed, performance of doer and checker for each critical step,
and traceability of all the activities performed.
Good Documentation Practice (commonly abbreviated as GDP, however
recommended to abbreviate GDocP to distinguish from Good Distribution Practice)
is extensively used in Pharmaceutical Industries to define and describe systematic
procedure of preparation, checking, verifying, issuing, usage and permanent or
reasonable time period maintenance of documents for traceability.
“If you have not documented an activity, you have not done it”– USFDA’s
interpretation.

Document all the activities as performed. If it is not documented, it is concluded

that the activity is not performed by regulatory authorities.

13.2 Salient features of good documentation-

1. Define Specifications and Testing Procedures for all materials and procedures
of manufacturing and controls.
Pharmaceutical Quality Assurance 103

2. Ensure training of all personnel involved to know what to do, when to do and
how to record.
3. Ensure authorized personnel have all information to take an informed decision
in release of products at various stages of manufacturing and distribution.
4. Ensure original documented evidence of traceability of records and audit trail
for investigation and storage
5. Ensure availability of data for any review and statistical analysis.

13.3 The documentations in Pharmaceutical Industry should cover

following areas-
1. Organization and Personnel
2. Buildings and Facilities
3. Instrument and Equipment
4. Handling of input raw materials and packing materials
5. Production and Process Controls
6. Packaging and Labelling Controls
7. Storage of Input Materials,in process Materials, Finished Products and
Distribution.
8. Laboratory Controls and
9. Return of Finished Products
The principle of Good Documentation Practices (GDocP) defined by USFDA
guidance is commonly called ALCOA:
A – ATTRIBUTABLE : Data should clearly demonstrate who observed and
recorded it, when it was observed and recorded and what it was about
L – LEGIBLE : Data should be easy to read and understand, recorded permanently
and original entries should be preserved.
C – CONTEMPOREOUS : Data should be recorded as it was observed and at the
time it was executed
O – ORIGINAL : Source data should be accessible and preserved in its original
form
A-ACCURATE : Data should be free from errors and conform with the written
instructions
104 Pharmaceutical Quality Assurance

13.4 The Principles of Good Documentation Practices –

1. A document with original signatures should never be destroyed
2. Never falsify information
3. Never use white out to correct or obliterate any mistake in documentation
4. Critical entries must be independently checked and verified by a second person.
5. Always use indelible ink for writing
6. Never leave any space, lines or fields blank in documentation. All should be
appropriately marked and commented.
7. Never overwrite a record. Errors are corrected by striking off earlier data by a
single line, corrected the record with specifying reason for correction along
with signature and date.
8. Never use symbols e.g. ditto marks or arrows to indicate repetitive or consecutive
entries and
9. Always document contemporaneously as the data is collected and decisions are
made.

13.5 Master Formula Record (MFR)

Master Formula Record is a set of documents specifying the starting materials
with their specifications and quantities including packaging materials, together with
a description of the procedures and precautions required to produce a specified
quantity of a finished product as well as the processing instructions, yields at various
stages of manufacturing with in-process controls.Master Formula Records are usually
prepared by the R&D of the organization.
Each product of a pharmaceutical company should have MFR appropriately
authorized by competent and responsible people. For routine manufacturing of a
product, batch manufacturing record and batchpackaging record are derived from
MFR.

n Details in Master Formula Record –

1. Product name (both generic and brand, if any)
2. Product strength
3. Product code – Pharmaceutical companies today use Enterprise Resource
Planning (ERP) software like SAP to monitor and control material movement.
Product code helps identifying the product in the ERP system.
Pharmaceutical Quality Assurance 105

4. Label claim of all ingredients used in the product

5. Product Description
6. Batch Size
7. Shelf Life
8. Storage Conditions for in process and finished products
9. Packing configuration and pack size.
10. MFR number and date
11. Superseded MFR number and date
12. Authorized signature and date of competent authorities
13. Flow Chart of manufacturing steps to be monitored including movement of
materials from Dispensing to Finished Product storage
14. List of equipment to be used in manufacturing including capacity and
identification number.
15. Calculations of active materials to be used to target 100% of label claim
16. Manufacturing instructions specifying all stages of manufacturing. All process
steps like sifting or screening,milling,mixing,granulation,compression, coating
etc. should be written in detail including the process time and yield. The
manufacturing steps also should mention temperature and humidity conditions
for every step. If the process requires any special precaution or instructions,the
MFR should mention in unambiguous language.
17. Packing process specifying quantity, specification of packaging materials with
identification code of printed packaging materials. And
18. Yield including theoretical yield, actual yield and acceptance criteria

13.6 Batch Manufacturing Record (BMR)

Batch Manufacturing Record is a written documentation of a specific batch
manufactured by following the process described in Master Formula Record. The
record contains actual data and step by step description of each manufacturing
process of every batch. It is a written documentary proof that the product batch was
manufactured as per laid down procedure, checked and approved by Quality
personnel.
As per Good Manufacturing Practice(GMP) each manufacturing process of a batch
product should be documented properly to establish evidence that the process
operated within pre-established validated parameters and meets pre-established
106 Pharmaceutical Quality Assurance

specifications and quality attributes. Batch Manufacturing Record is a proof that

batches were properly manufactured, applicable standard operating procedures were
followed and ensures uniformity in finished product of each batch.
Batch Manufacturing Record is designed based on Master Formula Record received
for a product. It describes all the stages included in the batch manufacturing of a
product right from issuance of the raw materials to the final packaging. BMR is the
historical documentation of a batch when manufactured and released to market.
One should be able to reconstruct all the happenings while manufacturing the batch
by retrospectively reviewing the BMR if any market complaint is received.

13.7 Details in Batch Manufacturing Records -

1. General instructions for manufacturing – Health and safety instructions to the
operating personnel to be followed during the manufacturing process and
equipment handling. Especially important is the instructions on hygiene to avoid
introduction of contaminations
2. Equipment Cleaning Records- All equipment should have latest approved
Standard Operating Procedures (SOP) with detailed cleaning check list. The
check list should specify previous product, batch number and date of
cleaning.Cleaned equipment should be approved by Quality personnel.
3. The BMR should mention batch number, batch size, composition, reference of
MFR, storage condition specifying temperature and RH, manufacturing date
and expiry date
4. Bill of Material – Complete list of raw materials with specification reference
needed to manufacture the finished product with required quantity.
5. Line Clearance Procedure – SOPs to be followed for line clearance should be
mentioned in BMR. Line clearance after every manufacturing steps is very
important to avoid any unintended mix up or adulteration of product.
6. Manufacturing Procedure – Manufacturing process should be written step by
step in easy unambiguous language with each step mentioning specific time
period for completion. After completion of each step, quality checks should be
performed before allowing the next step to commence.
7. Yield – At the end of every step yield should be calculated and compared with
the expected yield to evaluate process loss.
8. History of Changes–The BMR should have a list of changes since first
implemented with the revision number and date of change.
9. Abbreviations – List of abbreviations used in the documentation should be
made to understand easily the terminology.
Pharmaceutical Quality Assurance 107

13.8 Standard Operating Procedures (SOPs)

Standard Operating Procedures (SOP) are at the heart of Good Manufacturing
Practices. SOPs are detailed step by step instructions given by an organization to its
employees to follow a routine operation. SOPs bring uniformity of performance of
a task while reducing confusion and miscommunication bringing efficiency.
In pharmaceutical industry all activities in connection with quality, efficacy and
safety of a product are governed through SOP. International Council of
Harmonization (ICH) defines SOP as “detailed,written instructions to achieve
uniformity of the performance of a specific function”.SOPs are written in clear
unambiguous languages for an average employee to follow easily. All regulatory
authorities expect the employees responsible for carrying out a task are adequately
trained on the specific SOP.

13.9 Details in Standard Operating Procedures -

1. SOP Number and Revision Number

2. Title of the SOP
3. Effective and Expiry date of SOP
4. Scope or Purpose of SOP- : Briefly write the scope or areas, the SOP would be
dealing with
5. Responsiblity : Mention the position who would be responble to follow SOP
6. Accountability : Mention the position, who would be accountable if the SOP is not
followed
7. Definitions : Explain all the abbreviations used in the SOP. Example-RM-Raw Materials,
PM- Packaging Materials
8. Procedure : Write in un- ambiguous language the procedure so that it is easy to follow
or perform as per defined procedure
9. History of Changes : Mention all the changes that have taken place in the SOP since
the 1st version to the present revision
10. Flow Chart : Wherever possible, include a flowchart to explain the procedure. It is
easy to follow and train the people with the help of flow chart
11. Preparation review and approval of SOP- : Write the names of the people who have
prepared, reviewed and approved the SOP. All persons named should be signing
against their names.
108 Pharmaceutical Quality Assurance

1. SOP number and revision number – Each SOP should have a unique number
and revision number
2. Title of SOP– Each SOP should have a title clearly indicating the area where
the SOP is applicable. For example, SOP titled ”Handling of Market Complaints“
clearly indicates that the SOP deals specifically how to handle complaints once
received.
3. Effective date and validity period – Each SOP should have an effective date -
the date when the SOP was put in use. The validity period of a SOP is normally
three (3) years. The SOP must be revised mandatorily after 3 years with new
revision number.
4. Scope or purpose of the SOP–The SOP should briefly describe the scope of the
SOP clearly limiting area to avoid any further interpretation. For example, the
scope of SOP “Handling of Market Complaints can be ‘‘receiving, investigating,
corrective and preventive actions and responding to complainants’’.
5. Responsibility and Accountability – Each SOP should specify the position
responsible to follow the SOP and in case of noncompliance who would be
accountable.
6. Definitions – The complete list of all abbreviations with full name should be
listed down. For example, PO – Purchase Order, RM – Raw Materials, PM –
Packaging Materials etc.
7. Procedure–Each SOP should specify every step which must be followed along
the way while completing the task. This should be done by taking inputs and
discussion across the team responsible and finalize the steps as suggested. The
procedure also should include any sub task if it is also carried out. The procedure
should be in detail with very clear understandable language which can be easily
followed by the operating personnel.
8. History of Changes – SOP can undergo changes over a period due to
improvement in the process or due to regulatory requirements. As the SOP is
revised, the version number would get changed keeping the original SOP number
same. A list of changes have taken place since the introduction of the SOP
should be part of the SOP.
9. Flow Chart – As far as possible, SOP should have a flow chart explaining the
procedure. The Flow chart is especially important while training the operating
personnel
10. Preparation, review and approval of SOP – All SOPs must be prepared,
reviewed and approved by the competent people by signing with date of
signature. As per GMP guidelines, all SOPs having any impact on quality,
efficacy and safety of products must be approved by the Quality department.
Pharmaceutical Quality Assurance 109

13.10 Quality Audit and Self Inspection

Quality audit is a process of systematic evaluation of a quality system carried out
by external quality auditors like regulatory authorities or customers. The outcome of
quality audit is an important parameter of management to gauge the health of its
quality management system.
Self-Inspection is on the other hand is an objective evaluation of one's own quality
system by an internal team of subject matter experts. If the design and implementation
of Self inspection is done adequately, usually it helps the organization in facing
external audits successfully.All regulatory authorities and guidelines, like ISO 9000,
21CFR 213 of USFDA, EU etc. strongly recommend self-inspection to maintain and
improve quality system in an organization.
Audits are an important tool for verifying objective evidence of processes, to
assess how successfully processes have been implemented and usually identifies the
weak areas to take necessary corrective and preventive actions with the aim to
improve quality system in an organization.
In Self inspection programme, a team of competent technical people are mandated
by the management to carefully study every point in the quality system to ensure
good manufacturing practices are followed during manufacturing of products keeping
in mind quality, efficacy and safety of the product. A self-inspection team is usually
drawn from the members of Quality, Manufacturing, Engineering and R&D personnel
and conducted at least once in a year.
The periodicity of Quality audit by external authorities are determined by the
respective regulatory authorities or customers.

13.11 Quality Review and Quality Documentation

As explained in the earlier text that in pharmaceutical industry documentation is
paramount important to keep records of each activity carried out while developing
and manufacturing of products. While documents are created and data recorded, it
is also very important to review the data for its authenticity and accuracy. Regulatory
authorities expect quality department of the organization should carefully review
and approve documentation of each steps as the activity progresses. All reviews and
approvals should be contemporaneous. Any review of control documents related to
good manufacturing practices carried out later, however back dated to show the
activity contemporaneous is considered a serious fraud and raises the issue of data
integrity.
110 Pharmaceutical Quality Assurance

As per GMP guidelines all documents related to manufacturing of product should

be carefully reviewed and approved by quality department before the product can
go out for sale.
The quality department should also review and approve, all SOPs, Validation
documents, Analytical specifications and procedures, Manufacturing records,
Packaging records, deviations and investigations.
All documents should be stored in a secured room protected from fire and flood
hazard with entry restrictions only by authorized persons. A suitable system should
be designed to achieve document retrieve easily when required. Some documents
like Validation documents, Qualification reports of equipment,Water system, and
Heating ventilation and air conditioning system, Master Batch Records etc. are to be
stored perpetually. Batch specific documents, Batch manufacturing records, Batch
packaging records, Batch specific analytical records etc. are generally discarded one
year after expiry date.

13.12 Reports and Documents

Records must provide the history of each batch of drug product manufactured by
the organization. A good record keeping practice helps personnel with information
that happened during manufacturing operation in any pharmaceutical company.
Appropriate record keeping helps to maintain the audit trail for subsequent
investigations and tracking of drug product batches. Following reports and documents
should be preserved in a pharmaceutical company
1. Specifications
2. Procedure and test methods
3. Records and reports of analysis
4. Master Product Record
5. Batch Manufacturing Record
6. Materials/Component control record
7. Personnel record
8. Training record
9. Cleaning logbooks
10. Equipment logbooks
Pharmaceutical Quality Assurance 111

13.13 Distribution records

The primary purpose of Distribution record is to ensure that the details are
available with the organization to access trade customers should a recall of the
product is initiated.
Distribution record should have following details -
1. Name, strength and batch number of the product
2. Description of the shipping packs
3. Name and address of the consignee
4. Quantity shipped and
5. Date of shipping

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. What is C stands for in ALCOA?
(a) Continuous (b) Contemporeous
(c) Current (d) Conclusive
2. Master Formula Record (MFR) should mention—
(a) Product name (b) Batch Size
(c) Shelf life (d) All of the above
3. Batch Manufacturing Record (BMR) is designed based on—
(a) Master Formula Record (b) Expertise of manufacturing
(c) Expertise of QC (d) None of the above
4. Line clearance should be followed after—
(a) After every batch manufacturing
(b) After completion of campaign manufacturing
(c) At the end of the day when manufacturing completed
(d) At the beginning of the week
5. Each SOP should have effective date and ________
(a) Validity period (b) Training date
(c) Both a & b (d) Name of QC manager
6. Distribution record should have—
(a) Name of the product (b) Name of the QC manager
(c) Date of dispensing (d) Date of analysis
112 Pharmaceutical Quality Assurance

7. Self Inspection is a requirement of—

(a) USFDA (b) ISO 9000
(c) WHO (d) All of the above

Keys for Multiple Choice Questions

1 (c), 2 (d), 3 (a), 4 (a), 5 (a), 6 (a), 7 (d)

➥ Long Questions
1. Why documentation is important to pharmaceutical industry and write down the salient
features of documentation.
2. What is full form of ALCOA? What are the 9 principles of Good Documentation?
3. What is Master Batch Record?
4. What are the details a Batch Manufacturing Record should have?
5. What is Standard Operating Procedure? What are the essential components in a Standard
Operating Procedure?
6. What is Quality Audit and Self Inspection? What is the difference between them?
7. List down the Documents a Pharmaceutical Company must preserve.
8. What are the details Distribution Record must have?
UNIT–V
.
 Chapter 14

Calibration, Qualification
and Validation
14.1 Calibration
Calibration is a process that demonstrates an instrument or equipment, or device
produces results within limits as specified during qualification or as compared to
those produced by a traceable standard over an appropriate range of measurements.
Calibrations should be performed by only trained technical people following
approved SOP.
In pharmaceutical industry calibration is a regular periodic activity determined
by the nature of use of the instrument, equipment or device. For example, a weighing
balance is regularly calibrated since its use is frequent and critical. Once in a year
weighing balances should also be calibrated by an accredited agency with standard
weights traceable as mentioned in weights and measures act. Quality control
equipment like UV spectrophotometer, HPLC, Dissolution apparatus etc. are
generally calibrated quarterly or half yearly. Manufacturing equipment like Tableting
machine, Capsuling machine, Granulators etc. are recommended to be calibrated at
least once in a year. Normally companies start periodicity of calibration quarterly or
half yearly and over a period based on trend data of calibration decide to space out
calibration periodicity.

14.2 Qualification
Qualification is an activity of providing and documenting that the instrument,
equipment or ancillary systems like water system or HVACs are properly installed,
work correctly as per design and comply with specified requirements. All instrument,
equipment, ancillary systems etc. must be qualified before putting into use.
Qualification is an integral part of overall validation process.

115
116 Pharmaceutical Quality Assurance

The qualification process in pharmaceutical industry, broadly follows four steps–

1. Design Qualification (DQ) – In DQ, Pharmaceutical companies with the help
of technical people or consultants determine the expected requirement or
performance of proposed equipment or ancillary systems. For example, based
on the volume and quality of water required in manufacturing, design of a
water system can be done and based on the agreed design, purchase order is
released to the vendor for supplying water system.There could be many
equipment where DQ is not required to be carried out. For example, a tableting
machine can be procured based on the already available model, if it is suitable
for the manufacturing. If DQ is not carried out, specific comments in
documentation should be made to explain why DQ was not carried out.
2. Installation Qualification (IQ) – In IQ, Pharmaceutical companies compare
the inventory of the equipment or ancillary systems supplied with the purchase
order. This is systematic documented exercise to list down all the details
including spare parts matches with the ordered equipment in quantity and
quality. Any discrepancy between order and receipt items must be
documented and communicated to the vendor. At this stage of qualification,
the system or the ancillary systems are installed as per directive of vendor.
3. Operational Qualification (OQ) – In OQ,the equipment or ancillary systems
are checked after installation to ensure that the installation qualification has
been done correctly and would function appropriately as designed. For
example, a tableting machine is installed and electrical connections given and
run to ensure that the machine runs smoothly. A HVAC system is run for
some days to ensure the system working fine without any teething trouble.
4. Performance Qualification (PQ)- PQ is the qualification of manufacturing
equipment or ancillary system to confirm they can operate during commercial
sustained manufacturing. This is done in actual manufacturing condition over
a specific period.
In PQ of water system, water samples are collected regularly (usually 30 days)
and tested to specification including microbial test. Once all tests conform to
specifications, the system is released for use of water in regular manufacturing. In
a tableting machine, many companies run placebo tablets during PQ stage for
evaluation of performance, mimicking actual manufacturing. After successful
completion of PQ, the qualification documents are compiled(DQ, IQ, OQ & PQ) and
certified that the qualification process is completed. Among the approving authorities,
Quality function must be one of the signatories while approving the document.
Before any equipment is delivered by the vendor, Factory Acceptance Test (FAT)
is carried out at the vendor’s place. This is an opportunity for the purchasing
Pharmaceutical Quality Assurance 117

company to involve their technical people and operators to run the equipment at
vendor’s place with active supervision and satisfy about the performance of the
equipment.Normally companies use FAT to initially train their technical people and
operators in running a newly acquired equipment.
In today’s pharmaceutical manufacturing, computer systems and software aided
equipment are extensively used. All software’s and computer systems used,must be
qualified and validated as per 21CFR Part 11 guideline as per regulatory authorities.
Companies usually put up a procedure for requalification of equipment once in
five years.

14.3 VALIDATION
Validation is a documented objective evidence that provides a high degree of
assurance that a process will consistently produce a product meeting its agreed
specifications. While carrying validation of manufacturing process, a company needs
1) trained people 2) qualified equipment 3) qualified systems or software’s and 4)
well defined procedures. The basic difference between qualification and validation
is validation is directly related to process and qualification is directly related to
equipment and software. However, many times validation and qualification are
interchangeably used in pharmaceutical industry.

14.4 VALIDATION MASTER PLAN (VMP)

Validation Master Plan (VMP) is a document holistically describes the principle
a company is following encompassing facility and processes to ensure that all
activities are carried out in a qualified and validated state.This is a document which
gives an overall picture of how the company has integrated CGMP in day to day
activities.VMP need not go into specific details but should give an overall picture
of the company’s approach in process validation, facility and utility qualification,
equipment qualification, cleaning validation and computer validation.The Validation
Master Plan (VMP) must be authorized by competent technical personnel including
quality function.

14.5 IMPORTANCE AND SCOPE OF VALIDATION

Regulatory authorities around the world is not merely satisfied with the product
meeting the specifications but also require the entire process of manufacturing like
procedures , intermediate stages of inspection, and testing carried out during
manufacturing are designed in such a way that it produces consistently reproducible
results which meets the quality standard of the product being manufactured.
118 Pharmaceutical Quality Assurance

“A properly designed system will provide a high degree of assurance that

every step, process and change has been properly evaluated before its
implementation. Testing a sample of a final product is not considered sufficient
evidence that every product within a batch meets the required specification”
- Guide on General Principles of Process Validation by USFDA
The scope of validation should cover all aspects of pharmaceutical manufacturing
including facilities, equipment, utility system, process, cleaning, analytical testing
and computer system used .

14.6 Types of Validation

Following are the types of validation carried out in a pharmaceutical company
1. FacilityValidation –Facilities are designed and validated to ensure movement
of people and materials are made unidirectional to avoid any cross movement
leading to contamination or adulteration of product. All rooms in the facility
should have identification number and name. The pre- requisite of facility
validation is to ensure that the design and environment is such that a product
can be manufactured in full CGMP compliance.
2. Equipment Validation- All equipment used in the manufacturing and testing
of a product must be qualified for the purported use. Once qualified, each
equipment must be governed by SOP with clear instructions for carrying out
periodic calibration.
3. Water System Validation - Water is important component in pharmaceutical
manufacturing. Water is used extensively not only in the product but also for
cleaning of facility and equipment. As per CGMP, purified water is used in
manufacturing and final cleaning of equipment. The water system should be
designed and validated appropriately to ensure the water always meet the
specification both chemically and microbiologically.
4. HVAC System Validation – Heating Ventilation Airconditioning (HVAC)
System is the backbone of maintaining atmospheric conditions within a
manufacturing facility. Based on the requirement of the product manufacturing,
various filters and volume of air (air changes per hour) is used to maintain
temperature / humidity and confine the dust generated within the specific
areas. The HVAC is designed in such a way that approx. 80-90% of air is recycled
with only 10-20% replenishment of fresh air. This type of design helps in
reducing the cost of running the manufacturing facility. Mostly core process
areas, where product gets exposed during manufacturing are provided with
HEPA filtered air.
Pharmaceutical Quality Assurance 119

5. Cleaning Validation – If the facility is not dedicated to a product, multiple

products of various compositions can be manufactured at a time. So, it is
important that the equipment and the facility used for manufacturing is free of
traces of previous product. Cleaning Validation establishes that the SOPs
followed for cleaning various equipment and facility are reproducible and
capable of removing remnants of previous product manufactured using the
same equipment and facility.
6. Process Validation- Process validation should always be carried out
prospectively i.e, before introduction of the product into the market by following
process validation protocol. No regulatory authority now accepts retrospective
or concurrent process validation. Prospective process validation is the
documentary evidence demonstrating that the manufacturing of the product
will always maintain desired level of CGMP compliance and meet the expected
specification.
7. Analytical Method Validation – The testing method and procedure followed in
testing a product must be validated. Normally, analytical method validation is
carried out at R&D while developing the product and subsequently transferred
to manufacturing for regular use. Analytical method validation must address
(a) System Suitability
(b) Specificity
(c) Linearity
(d) Precision
(e) Accuracy
(f) Limit of Detection (LOD)
(g) Limit of Quantification (LOQ)
(h) Robustness and
(i) Ruggedness
8. Computer System Validation– Now a day’s computer systems are increasingly
getting used in pharmaceutical industry.USFDA defines computer system
validation as “confirmation by examination and provision of objective
evidence that the software specifications conform to user needs and intended
uses , and that the particular requirements implemented through software
can be consistently fulfilled” – 21CFR Part 11 Rules on the use of Electronic
Records , Electronic Signatures.
Normally, companies take help of qualified vendors to carry out computer system
validations at the time of installations. The computer system validation should be
120 Pharmaceutical Quality Assurance

repeated once in 3-5 years and specifically whenever any change is made in the
system.
As per ICH Q12 Guideline, companies are expected to take risk-based product
life cycle approach in validation. This means development of a drug product
commencing with research, rationale for adapting a best fit formula which represents
the relationship between inputs and outputs and the procedure for manufacturing.
Each step is required to be justified and monitored to achieve manufacturing of
quality drug product.

14.7 Calibration of pH meter

pH is the hydronium ion concentration of an aqueous solution expressed between
1 to 14. The value of pH is measured in pH meter using a suitable properly calibrated,
potentiometric sensor and measuring system. When pH value of a solution falls
between 1 to less than 7, the solution is acidic and pH value above 7 to 14 alkaline
and pH 7 of a solution is neutral. The pH meter is calibrated by comparing pH
reading in the meter with known pH of buffer solutions.

n Procedure :
1. Wash the electrode 2-3 times with purified water & wipe gently with tissue
paper.
2. Prepare standard solution of pH 1.68, 4.01, 6.86, 9.18, & 12.45 using commercially
available pH standard tablet or alternatively use standard pH buffer solution
available commercially with certificate of quality traceable to NIST (National
Institute of Standard Testing)
3. Always verify the temperature of buffer solution. The temperature should be as
per standard referenced value of buffer solution.
Commercially available pH meters have the inbuilt provision of calibration.
Following is the procedure for calibration using inbuilt calibration provision.
Press calibration button, previous calibration slope will be displayed on the screen,
Press ‘Enter’ key to start the new calibration.
1. ‘Enter Buffer 1’ from menu and the display will be shown on the screen. Type
standard buffer value as 1.68 and dip both Electrode and RTD Sensor in standard
buffer 1.68, then press ‘Enter’ key.
(i) Wait for stabilization; allowing the instrument to read the standard buffer.
After stabilization press ‘Enter’ key.
(ii) ‘Enter Buffer2’ and the display will be shown on screen. Type standard
buffer value as 4.01 and dip both Electrode and RTD Sensor in standard
buffer 4.01 than press ‘Enter’ key.
Pharmaceutical Quality Assurance 121

(iii) Wait for stabilization allowing the instrument to read the standard buffer.
After stabilization press ‘Enter’ key.
(iv) Similarly perform the calibration with standard buffer solution of 6.86, 9.18
and 12.45.
(v) After completion of calibration, the instrument prints the calibration data
with the help of an inbuilt printer.
(vi) The slope is also read automatically by pressing calibration of slope key of
the instrument. After completion of calibration, remove the electrode from
solution, wash the electrode 2-3 times with purified water & wipe with
tissue paper. Discard all the used buffer solutions.

n Acceptance criteria :
1. Slope of calibration should be 90% to 105%.
2. The observed pH value of standard buffer solution should be within ± 0.02 of
labelled value.
Frequency of calibration : Daily or before starting the instrument.
Note : When the electrode is not in use keep the electrode dipped in 3M KCL
Solution.
Temperature Sensor Calibration : Carried out once in a year through an external
calibration agency.

14.8 Qualification of UV – Visible Spectrophotometer

Ultraviolet-Visible Spectrophotometer is an optical system capable of producing
monochromatic radiation in the range 200–780 nm and is capable of detecting the
optical transmittance, usually expressed in absorbance (A), whose primary function
is to measure the stated absorbance / transmittance at defined wavelength(s). The
absorbance value is proportional to the concentration of analyte within the validated
range of linearity.
The qualification and acceptance criteria are to ensure that the instrument is
suitable for its intended purpose, and that it will continue to function as expected
over extended time period as part of the qualification.

14.9.1 QUALIFICATION :
l Frequency of Qualification : Normally UV-Vis Spectrophotometer is qualified
once in 6 months.
UV-Visible spectrophotometer is qualified for the following parameters.
A. Control of wavelength
B. Wavelength Calibration
122 Pharmaceutical Quality Assurance

C. Control of absorbance
D. Photometric Accuracy
E. Limit of Stray light and
F. Resolution

14.9.2 Control of Wavelength

Reagent solutions are prepared as per the below procedure or alternatively
certified commercially available solutions can also be used.

l Preparation of 1.4 M per chloric Acid solution :

Dilute 11.5 ml of perchloric acid (70% w/w) to 100 ml with Purified Water.

l Preparation of 4% w/v Holmium per chlorate solution :

Dissolve 0.4 g of Holmium oxide in 5 ml of 1.4 M per chloric acid with the aid
of heating on water bath, cool and dilute to 10 ml with 1.4 M perchloric acid.
1. Scan the solution in the range of 200 to 400 nm for ultraviolet and 400 to 600
nm for visible range using 1.4 M perchloric acid as a blank. Record the maxima
observed. The permitted tolerance is ±1 for the ultraviolet range (200-400 nm)
and ±3 for the visible range (400-600nm).
2. Acceptance criteria for the control of wavelength should be as below.

Wavelength Maximum Tolerance

241.15 nm 240.15 to 242.15 nm
287.15 nm 286.15 to 288.15 nm
361.50 nm 360.50 to 362.50 nm
536.30 nm 533.30 to 539.30 nm

14.9.3 Wavelength Calibration

1. First scan in the range of 660 nm - 650 nm of wavelengths
2. Select scan speed medium, & press ‘Start’ key of spectrophotometer. Check and
record the wavelength of maximum absorbance.
3. Then, scan in the range of 490 nm - 480 nm
4. Select scan speed medium & press ‘Start’ key. Check and record wavelength of
maximum absorbance.
5. Acceptance Criteria: Peak absorbance should occur at
(a) 656.1 ± 1.0 nm (655.1 to 657.1nm) when scanned between 660 nm ~ 650 nm.
(b) 486.0 ± 1.0 nm (485.0 to 487.0nm) when scanned between 490 nm ~ 480 nm.
Pharmaceutical Quality Assurance 123

14.9.4 Control of Absorbance :

l Preparation of solution A : Add 5.4 ml of Sulphuric acid in 500 ml Purified
water and dilute to 1000 ml with Purified water. Take 100 ml of this solution and
dilute to 2000 ml with Purified water to achieve 0.005 M Sulphuric acid solution.
(Blank)
[Alternatively, commercially available certified solution also can be used.]
l Preparation of solution B : Dry Potassium dichromate (Analytical. Reagent
Grade) at 130°C to constant weight and weigh a quantity accurately between 57.0
mg and 63.0 mg into a 1000.0 ml volumetric flask.
Check the absorbance of solution B at wavelengths (nm): 235, 257, 313, and 350
using 0.005M Sulphuric acid as blank.
l Preparation of solution C : Dry Potassium dichromate (Analytical Reagent
Grade) at 130°C to constant weight and weigh a quantity accurately between 57.0
mg and 63.0 mg into a 100.0 ml volumetric flask. Add 0.005 M Sulphuric acid to
dissolve and dilute to the mark. (Solution C).
1. Check the absorbance of solution C at 430 wavelength (nm) using 0.005 M
Sulphuric acid as blank.
2. Record the absorbance
3. Calculate the value A (1%, 1 cm) as per the following formula :
Absorbance × Dilution of K2Cr2O7_
A (1 %, 1 cm) = ————————————————————
Weight of K2Cr2O7 in gm x 100
4. Check the value of A at each wavelength against the acceptance criteria given
below.
l Acceptance criteria :

Wavelength (nm) Specific Maximum Tolerance

absorbance A (1%,1 cm)

235 124.5 122.9 to 126.2

257 144.5 142.8 to 146.2

313 48.6 47.0 to 50.3

350 107.3 105.6 to 109.0

430 15.9 15.7 to 16.1

124 Pharmaceutical Quality Assurance

14.9.5 Photometric Accuracy :

1. Prepare a solution of 14.20 % w/v Potassium Nitrate (AR grade) in Purified
water (stock solution).
2. Dilute above stock solution in triplicate to achieve solutions with concentrations
of 1.065%, 0.710 % and 0.355 % w/v as per below.

Solution 1A Solution 2A Solution 3A

Solution 1B Solution 2B Solution 3B
Solution 1C Solution 2C Solution 3C
Dilute 15 ml of Stock solution Dilute 10 ml of Stock solution Dilute 5 ml of Stock solution to
to three separate 200ml to three separate 200ml three separate 200ml
volumetric flasks with Purified volumetric flask with Purified volumetric flasks with Purified
Water to get 1.065 % w/v Water to get a 0.710% w/v Water to get 0.355 % w/v
solution. solution. solution.

3. Check the absorbance of the above solutions at 302 nm using Purified Water as
blank and calculate corrected absorbance by following formula :
14.2 x Absorbance at 302 nm
= ———————————————————
Weight of Potassium Nitrate (g)
4. Record the absorbance of each solution at 302 nm.Each solution of respective
concentration should meet the acceptance criteria as given below.
Expected Absorbanceat 302 Acceptance Criteria
Solutions% w/v nm (± 0.010)

1.065 0.751 0.741 to 0.761

0.710 0.500 0.490 to 0.510
0.355 0.250 0.240 to 0.260

5. Calculate correlation coefficient using mean of the triplicate absorbance value

and the correlation coefficient should be NLT 0.999.

14.9.6 Limit of Stray Light :

Measure absorbance of a 1.2 % w/v solution of potassium chloride (12 gm of
potassium chloride in 1000 ml of Purified Water), at a path length of 1 cm cell
between 220 nm and 200 nm. The absorbance is noted at wavelength at 198 & 200nm
taking purified water as reference.
l Acceptance Criteria : Absorbance should be greater than 2 at 198 & 200 nm.
Pharmaceutical Quality Assurance 125

14.10 Resolution
1. Prepare a solution of 0.02 % v/v Toluene in Hexane:
Dilute 2 ml of Toluene to 200 ml with Hexane. Further dilute 2 ml of above
solution to 100 ml with Hexane. (Note: Use only spectroscopy grade Toluene
and Hexane).
2. Record the spectrum in the range 260 to 275 nm of 0.020 % v/v Toluene in
Hexane using Hexane in the reference cell.
3. Calculate the ratio of the absorbance between the maximum at about 269 nm
(A) and minimum at about 266 nm (B).
l Acceptance Criteria : Ratio (A/B) is not less than 1.5
All qualification records should be preserved for regulatory audit. After
qualification the spectrophotometer should be labelled with qualification date,
next qualification due date and the name signature of the person who qualified
the instrument.

14.11 General Principles of Analytical Method Validations

Analytical method validation is a process of documenting and proving that an
analytical method provides data which are acceptable for the intended use. A drug
substance or product must meet all its specifications during its entire shelf life. The
method of analysis should be discretionary enough to indicate and identify any
possible degradation or noncompliance in the drug substance or product while using
the analytical method.All methods used in analysis including microbiological
methods must be validated before using in routine testing of the product.
The approach to analytical method validation should be as follows
1. Optimization or pre-validation activities –At this stage, based on scientific
judgement and technical reference data, determination of tentative method is
done. The tentative method decides, sample preparation, experimental
conditions, parameters and acceptance criteria.
2. Qualification of method –Based on an experimental protocol,this stage
demonstrates that an accepted method will provide meaningful data at the
specific condition decided upon. The qualification of method merely verifies
the suitability of the experimental protocol under actual conditions.
3. Validation of method –This is the final procedure of validation where
comprehensive experiments, evaluation of data and documentation determines
the quantitative performance of the method. The experiments should include
126 Pharmaceutical Quality Assurance

specificity, sensitivity, accuracy, precision, limits of detection and limits of

quantitation. The method must also establish inter laboratory robustness.The
validation is carried out based on final approved protocol and documentation
of data in the report.
There are nine (9) parameters usually checked during analytical method validation
1. System suitability - System suitability must be carried out before starting
analysis especially in HPLC analysis. This establishes the equipment,
environment, reagents and analyst are in complete sync before starting any
analysis. In HPLC analysis, replicate injection of standard with RSD less than
2%, resolution factor, tailing factor etc. are some of the parameters checked in
system suitability.
2. Specificity – Specificity of an analytical method is its ability to differentiate
unequivocally the analyte in presence of other similar compounds present in
the matrix.
3. Accuracy – This is the closeness of the analytical result with the expected true
value. The accuracy of an analytical method should be established over a range
of its concentration. Usually it is established with the comparison with the
reference standard.
4. Precision – Precision is the reproducibility of the result from replicate analysis
using same sample solution. During precision study the focus is on scatter of
data rather than exact value of the analysis. Normally it is established in a
range of concentration of between 80-120%
5. Linearity – Linearity is the ability of the method to report result that are directly
proportional to the concentration of the target analyte within a range in the
sample.
For example, if the limit of assay of a product is 90-110% of label claim, linearity
will be established between 80-120% of label claim to ensure that the method
will be able to detect sub potent or supra potent product.
6. Limit of Detection (LOD) – Detection limit is the lowest amount of analyte
which can be detected by a method. In HPLC analysis, this is the concentration
which is distinguishable from background noise but is not sufficiently precise
or accurate to be quantitated.
7. Limit of Quantitation (LOQ) – Limit of quantitation is the lowest concentration
of an analyte in a sample which can be quantitatively determined with enough
precision and accuracy. In HPLC analysis, many times LOQ is established at
0.05 ppm level especially for method of impurity analysis.
Pharmaceutical Quality Assurance 127

8. Ruggedness – Ruggedness is also called intermediate precision. The ruggedness

of an analytical method is the ability of reproducibility of results of the same
sample under a variety of conditions, like different laboratories, different
instrument, different analysts, different analysis day etc. Ruggedness is the
measure of reproducibility of test results under the variations in conditions
normally expected from laboratory to laboratory and from analyst to analyst.
9. Robustness – It is the reliability measurement of deliberate variations in method
parameters. For example, the robustness of an HPLC analysis is even variation
of 10-15% in composition of mobile phase, the method can detect the analyte
with enough precision and accuracy.
Before initiating analytical validation study, a well-planned protocol should be
written and reviewed for scientific justification and completeness by qualified
analytical experts. The protocol should describe the procedure in detail and include
pre-determined acceptance criteria and pre-defined statistical methods. After
approval by the competent authorities, the protocol should be executed in timely
manner.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. PQ in pharmaceutical company stands for—
(a) Perfect Qualification (b) Performance Qualification
(c) Production Qualification (d) Perfect Quality
2. While Qualification of water system, sampling should be done—
(a) Daily (b) Weekly
(c) Monthly (d) Bi weekly
3. Guideline of USFDA stipulates computer system validation in 21CFR........
(a) Part 11 (b) 211.190
(c) 210.180 (d) None of the above
4. In pharmaceutical industry DQ stands for—
(a) Document Qualification (b) Detailed Qualification
(c) Design Qualification (d) Detailed Quality
5. Linearity is checked in validation of—
(a) Computers (b) Analytical
(c) Water system (d) Cleaning
128 Pharmaceutical Quality Assurance

6. Cleaning validation must be carried out in a —

(a) Dedicated facility (b) Multi product facility
(c) QC laboratory (d) Warehouse
7. pH 7 is ________ in nature
(a) Neutral (b) Basic
(c) Acidic (d) None of the above
8. pH Meter should be calibrated—
(a) Daily (b) Weekly
(c) Monthly (d) Not required
9. UV –Visible Spectrophotometer operates between –
(a) 200 – 780 nm (b) 460 -780 nm
(c) 200 – 460 nm (d) None of the above
10. VMP in pharmaceutical industry is—
(a) Validity Master Plan (b) Validation Master Plan
(c) Validation Maximum Production (d) Validity Minimum Plan
11. Robustness is studied while validating—
(a) HVAC (b) Water system
(c) Analytical method (d) Process

Keys for Multiple Choice Questions

1 (b), 2 (a), 3 (a), 4 (c), 5 (b), 6 (b), 7 (a), 8 (a)

➥ Long Questions

1. Define Calibration and why it is important?

2. What are the different types of qualifications?
3. What is validation? What are different types of validations?
4. What are the different parameters studied during analytical method of validation?
5. Describe how a pH is calibrated?
6. Describe how a UV-Visible spectrophotometer is calibrated?
 Chapter 15

Warehousing and
Material Management

15.1 Introduction
Warehousing in pharmaceutical industry is very important function and falls
within the scope of overall quality management and good manufacturing practices.
Good Warehousing Practices (GWP) is crucial in determining the quality, efficacy
and safety of products. Pharmaceutical warehousing is a controlled operation,
governed by stipulated SOPs and must be managed by qualified and trained
personnel.

15.2 Basic functions of Warehouse –

1. Receipt and storage of materials as per agreed procedure to prevent the material
from exposure to adverse temperature and humidity.
2. Protect the materials from damage during storage and transportation
3. Avoid mix up and contaminations with other materials
4. Maintain product identity,approval status and traceability
5. Prevent expired, damaged and rejected materials from being used in
manufacturing

15.3 Classification of Pharmaceutical Warehouse–

1. Finished Product Warehouse – holds finished products before sending to market
2. Engineering Warehouse -holds engineering items and change parts of equipment
3. Input Materials Warehouse – holds all starting materials directly or indirectly
required for manufacturing.
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15.4 Types of materials stored in Warehouse -

1. Non production consumables – like tissue papers, hand gloves, face masks etc.
2. Production materials consumables – like filters, polythene bags, papers etc.
3. Laboratory chemicals and reagents
4. Manufacturing starting materials – like active ingredients, excipients, solvents
etc.
5. Packaging materials – like shippers, bottles, caps etc.
6. Printed packaging materials – like printed labels, cartons, printed foils etc.

15.5 Typical Design of Warehouse

Warehouse is designed based on the materials it holds. So, a typical warehouse
can have some areas having temperature and humidity controlled,whereas some
areas without any atmospheric controls. For example, where active substances and
excipients are stored, the warehouse will have temperature and humidity control
based on the label claim. However, for storing bottles or shippers,there is no need
to have temperature-controlled warehouse. Warehouses can have physical controls
or through ERP system administrative controlled. In a typical physically controlled
warehouse, the warehouse is divided in to three zones – undertest, approved and
rejected. The materials are stored based on the status at the segregated storage
areas.With the advent of modern Enterprise Resource Planning (ERP) software’s like
SAP system, more and more companies are opting for administrative controls in
warehouse with the advantage of minimal material handling and complete controls
of materials through electronic system. In administrative controlled warehouse only
rejected and damaged materials are physically separated under lock and key.
Otherwise undertest and approved materials are stored together with electronic
control of its movements. Many materials require storage in sub zero or between 2-
8°C storage conditions.So, warehouse can have freezer or cold room based on the
requirement.
In drug substance manufacturing companies, additionally hazardous substance
storage area and solvent yards are recommended

15.6 Procedure of receiving materials in Warehouse

Receiving of materials in warehouse must be governed by an approved SOP.
When materials reach a pharmaceutical warehouse, it is considered controlled activity
and should follow GMP. The following are the essential procedure by warehouse
personnel while receiving the materials –
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1. The material is supplied by an approved supplier or vendor.

2. There is no physical damage or visual contamination in the material
3. The containers or packaging are appropriately sealed by the vendor and no
apparent mark of pilferage
4. The material is correctly labelled with the vendor’s name, address, lot number
and where applicable storage conditions
5. Temperature probes for materials require specific temperature for storage and
during transportation identifying that the material was transported in
appropriate temperature condition.
6. The containers or packages of material must be cleaned and/or mopped before
allowing entry to warehouse.
7. The material is given a unique in-house lot number for traceability in future. In
today’s warehouse management, the unique lot number is randomly generated
through ERP system like SAP.
8. The material is included in inventory. If the warehouse is managed by physical
control, then each container or package must have an “under test” label and
physically separated in quarantine area. For administratively controlled
warehouse, separate physical quarantine is not required.
9. The Quality Control (QC) is informed for sampling of the material.
The materials used to manufacture a product must have approved specification
and testing procedure and QC must approve before the material is used in
manufacturing. However, other materials like consumables (face mask, hand gloves),
engineering materials including change parts may have different procedure for
approval other than the involvement of QC

15.7 Storage of material in warehouse

To prevent possible deterioration, material must be stored at the appropriate
storage condition. All containers or packages should be in sealed condition and if
any container or package is opened for sampling, extra precaution must be taken to
ensure hermetically closed to avoid deterioration and contamination.
A routine pest control service must be used to ensure the warehouse is free from
ingress of rodents and insects. Any spillage of material must be handled
appropriately to protect other materials and personnel.All entry and exit doors of
warehouse should have airlocks to prevent entry of dirt or insects.
In pharmaceutical warehouse First in – First Out (FIFO) procedure is followed
while dispensing and use of material in products. This means, the material first
received and approved must be used before stocks of any subsequent receipt of the
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same material.The warehouse personnel should also ensure that all stored materials
are always appropriately labelled. Any unlabeled container or package must not be
used in manufacturing and moved away to rejected area.

15.8 Pest Control in Warehouse

Pest control in warehouse is a major focus area for regulatory authorities. Every
pharmaceutical company must have a designated person responsible for pest control.
The responsibilities of the person for pest control are –
1. Enter with a pest control service agency for periodic pest control services and
ensure that the contractual agreements are renewed timely.
2. Keep maps showing bait locations within and outside of warehouse.
3. Documentation of all pest control treatments
4. Keeping records of any sightings of pests between visit of pest control service
agency.
5. Ensure using only approved pesticides by the pest control service agency

15.9 Training of warehouse personnel

All warehouse personnel must be trained in SOPs applicable for warehouse
operation. The training should cover at least following areas –
1. Monitoring of temperature and humidity within the warehouse.
2. Appropriate safe handling of materials during movement like use of pallet
trucks
3. Ensure material is stored at their correct storage condition
4. Safe handling procedure of materials according to its Material Safety Data Sheet
(MSDS)
5. Periodic stock taking to ensure correct inventory stock is maintained.
6. Accurately locate and pick up right stock for dispensing following FIFO.
7. Training to use computer system especially use of ERP like SAP.
8. Routine calibration of weighing scales used in warehouse.

15.10 Material Management

Material Management in Pharmaceutical company comprises of purchasing,
receiving, inventory control, storing, production scheduling, manufacturing and
shipping of finished products. Hence material management is an integrated operation
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between purchasing, production, quality, marketing and sales team. Material

management effectively controls the inventory to maximize the use of working
capital.
Often computer systems like Enterprise Resource Planning (ERP) software is used
to monitor material management effectively. These systems are validated and
institute a strict procedure to maintain security level. Well managed material
management always improve efficiency by bringing down inventory level and reduce
product cost.

REVIEW QUESTIONS

➥ Multiple Choice Questions

1. In administrative controlled warehouse only __________________ are kept separately
(a) Under test materials (b) Approved materials
(c) Rejected materials (d) All of the above
2. Sampling of raw materials are done by—
(a) Warehouse personnel (b) QC personnel
(c) manufacturing personnel (d) Any of the above
3. Pest control of warehouse is done by—
(a) Warehouse (b) QC
(c) Housekeeping (d) Pest control agency
4. Weighing scales in warehouse are calibrated –
(a) Daily (b) Monthly
(c) Bi weekly (d) Yearly
5. Monitoring of temperature & humidity at warehouse is monitored by –
(a) Engineering (b) QC
(C) QA (d) Warehouse
6. The material received in Warehouse must be from —
(a) Approved vendor (b) At the discretion of purchase manager
(c) As per decision of QC manager (d) Any of the above

Keys for Multiple Choice Questions

1 (c), 2 (b), 3 (d), 4 (a), 5 (d), 6 (a)

➥ Long Questions
1. What are basic functions of a Pharmaceutical Warehouse?
2. What are the different types of materials stored in Pharmaceutical Warehouse?
3. Describe the procedure of receiving materials in Pharmaceutical Warehouse?
4. What are the different points for Pest Control in Warehouse?
5. What are the different areas a warehouse person should have training?