UNIT - I

Chapter … 1
QUALITY ASSURANCE AND
QUALITY MANAGEMENT
CONCEPT
Objectives:
Upon completion of this section, the student should be able to
• Describe the major events that led to the development of quality concepts in the
pharmaceutical industry.
• List the important pharmaceutical regulatory bodies across the world.
• Understand the drug approval process.
• Define the terms ‘Quality Assurance’ and ‘Quality Control’ and their objectives.
• Differentiate between Quality Assurance and Quality Control.
• Define the term Good Manufacturing Practices (GMPs).
• Explain the areas covered under current Good Manufacturing Practices (cGMPs).

Introduction
Quality is an important requirement for products in any industry because it directly
determines the profits realized from their sale. However, in the pharmaceutical industry, there
is yet another important reason why quality products are necessary. In fact, this is one of the
major reasons why this industry is so highly regulated – because any errors in the
manufacturing process can lead to dangerous and even fatal results for the patients
consuming the products. Therefore, it is vital that pharmaceutical products must be
manufactured to meet stringent regulatory standards.
1.1 HISTORY OF DRUG REGULATIONS
In the field of drug products, it is the United States of America that has always been at
the forefront of developing the necessary regulatory guidelines, and the trend continues to
this day. Much of the history of drug regulations therefore cover events in the US.
In the olden days, medicines were prepared mainly in the form of elixirs, ointments and
pills, and sold by the person making them. These medicine containers were labeled with
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nothing much beyond the name of the product they contained, and the troubles they
promised to cure. Later, as science and technology advanced, some small family businesses
began manufacturing other products like vaccines and anti-toxins too, but there was almost
no control over these operations.
In 1902, a mishap occurred to focus attention on the dangers of such manufacturing.
Twelve children died after being administered an antitoxin for diphtheria and it was found
that the product had been contaminated with live tetanus bacilli. In response to strong
protests from the public, the United States Congress passed the Biologics Control Act. Under
this Act, the manufacturers and sellers of such biological products had to test their products
for strength and purity; they also had to undergo regular inspections by the health
authorities.
In 1906, the US Congress passed the Pure Food and Drug Act. This made it illegal for
people to sell adulterated/contaminated food or meat. Medicines were now required to have
labels that stated the true facts about their contents, without any false information or
promising magical cures. Out of this Act was born one of the world’s first government
regulatory bodies, which we now known as the United States Food and Drug Administration
(USFDA).
This body was conferred the authority to seize illegal drugs and foods. Any dangerous
ingredients in medicines now had to be labeled, and the labeling had to be true and
accurate.
In 1935, 107 people, a majority of them children, died after consuming oral sulfanilamide
elixir. An investigation showed that this product had been made using a solvent called
diethylene glycol which is a poisonous solvent! The public was incensed and demanded
stricter laws.
In response, the US Congress passed the Federal Food, Drug and Cosmetic Act of 1938.
For the first time in the history of drug manufacturing, it became necessary for companies to
prove that the products made by them were safe, before allowing them into the market. This
Act also made factory inspections mandatory, set down standards for food products, and
made penalties and criminal proceedings more stringent.
In 1941, yet another tragedy occurred in which close to 300 people died. The cause was
Sulfathiazole tablets had got contaminated with a sedative Phenobarbital. This led to
significant changes in the regulations controlling manufacturing and quality control
requirements for drugs. The Public Health Services (PHS) Act that was passed in 1944 further
expanded the scope of regulations to biological products.
The process of certification of batches by the FDA began during the time of World War II.
Manufacturers of insulin, penicillin and other antibiotics would submit samples to the FDA
from each lot they made and get permission for the release of these products.
In 1955, days after a mass polio vaccination drive began using the newly developed Salk
polio vaccine, it had to be abandoned. The reason was children who received the vaccine
(from batches made by Cutter Laboratories) were found to have developed the disease.
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An investigation showed that there had been a failure in the process of inactivating the live
polio virus, and this had gone undetected! This incident was widely discussed internationally
and brought home the need for even more control over the safety standards of vaccines. The
worst was yet to come, though.
In 1957, a pharmaceutical company in Germany called Chemie Grunenthal GmbH
developed the world’s first non-barbiturate anti-convulsant drug called as Thalidomide.
It was found to also have a sedative effect and doctors began prescribing it as a tranquilizer.
Thalidomide was sold over-the-counter based only on the claims of its manufacturer.
Laboratory studies on animals showed it was practically impossible to reach a LD50 dose.
(LD50 is the lethal dose which causes death in 50% of the animals tested.) So the company
advertised it as totally safe even for mother-and-child. This “wonder drug” became hugely
popular and was marketed to 46 countries across the world.
Around 1960, an Australian obstetrician McBride noticed that the drug also helped to
reduce the morning sickness associated with pregnancy. He began recommending it to his
pregnant patients, and through word-of-mouth reports in the medical fraternity, this
practice, too spread across the world. Only in the USA, the drug had not been approved for
use by the FDA’s drug examiner named Frances Kelsey. (Years later, she was conferred with
awards for the service she had rendered to the American public through this act.)
However, by 1961, McBride began noticing a severe birth defect called phocomelia in
babies delivered by his patients who had taken Thalidomide. Phocomelia is the condition
where a baby has no limbs, or shortened or flipper-like limbs. A newspaper in Germany
reported that close to 161 babies had been thus adversely affected by the drug, and the
distribution of Thalidomide in Germany was stopped, with other countries following suit. By
1962, after at least 10,000 cases of deformed infants had been born, Thalidomide was finally
completely banned.
This shocking tragedy was the catalyst for putting in place a more rigorous drug approval
and quality monitoring system developed by the USFDA. Companies were now required to
test both efficacy and safety of their drugs. Drugs had to be tested on animals before they
could be tried on humans. Clinical trial regulations became more stringent and the drug
investigators were made responsible for supervising the drugs being studied. In other words,
companies now had to obtain consent from the regulatory authorities before testing a drug
and had to prove the drug’s safety and efficacy before manufacturing it and taking it to the
market.
It was only in 1963 that the USFDA published the first ever set of Good
Manufacturing Practices (GMP) for finished pharmaceuticals.
Today, GMP or current Good Manufacturing Practices (cGMP), as it is now known, is the
very backbone of ensuring the quality, safety and efficacy of drug products. Every country
has regulatory bodies to oversee the drug development, manufacturing and distribution
process. These bodies lay down cGMP guidelines that ensure all processes right from
procuring materials to drug manufacturing to their distribution occurs under the most
stringent of controls.
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Global Regulatory Bodies

Country Regulatory body
USA Food & Drug Administration (FDA)
Japan Ministry of Health Labour and Welfare
Australia Therapeutic Goods Administration (TGA)
UK Medicines and Healthcare products Regulatory Agency (MHRA)
South Africa Medicine Control Council (MCC)
India Central Drugs Standard Control Organization (CDSCO)
China State Food and Drug Administration

1.2 THE REGULATORY DRUG APPROVAL PROCESS

Drug development is a complex process and the transition of a molecule from the
laboratory bench to the patient’s bedside is a long and arduous journey that can take
anywhere from 10 – 15 years at the very least.
A drug company first chooses a biochemical mechanism that is the basis of some
disease, and begins screening molecules to overcome that condition. Through the use of
proteomics, functional genomics and other screening methods, a few lead molecules that
show promise are chosen for characterization.
Characterization involves the study of the molecule’s shape, size, strengths, bioactivity,
weaknesses, toxicity, bioavailability and the possible mechanism of its action. Next, work
commences on formulating the molecule into a suitable dosage form for administration. This
involves a study of the drug’s stability to heat, light, and within the formulation itself.
This stage is followed by an investigation of the pharmacokinetics of the drug and ADME
(Absorption/Distribution/Metabolism/Excretion) studies to get information that also helps to
improve the formulation.
Next come the pre-clinical toxicology tests for acute toxicity, repeated dose toxicity, and
genetic and, reproductive toxicity, carcinogenicity etc. Armed with results from all these tests,
the company files an Investigative New Drug Application (INDA) with the FDA, who
scrutinizes the application and if satisfied, gives the green signal for the clinical trials to
begin.
Clinical research trials are held in three phases – the first is to test the safety of the drug
in healthy human volunteers; the second phase is run with 100 – 250 patients who suffer
from the disease, and the third phase is performed on even larger groups of patients in
multi-center trials. By this stage, if the molecule still proves to be safe and effective, the
company files the New Drug Application with the FDA. Following a regulatory review of this,
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the FDA takes the decision about approving or not approving the drug for manufacture.
Approved drugs then enter into the fourth phase of clinical research which is the post-
marketing surveillance study that is closely monitored by the FDA.
From a study of this entire process, it is quite clear that drug development is a time-
consuming and costly affair. For every 5000 molecules that enter the process, only about 5
make it to the stage of clinical testing and probably just 1 out of those 5 gets FDA approval.
1.3 QUALITY ASSURANCE
Getting FDA approval is however only the start of yet another equally tough journey. The
drug formulation has to transit from the laboratory to the manufacturing floor, which has its
own challenges. As obvious from the history of how cGMP came into being, there are many
things that can go wrong and it is vital to have sufficient control over all the factors that can
influence the quality of the final drug product.
For several years, pharmaceutical companies relied a lot on Quality Control (QC) for
adequate testing of the quality of their products. With time, however, as processing
operations grew more complex, the realization grew that testing often misses detecting
problems because tests are run on randomly selected samples. One cannot hope to “test
quality into” products that do not have the quality inherent in them.
This realization led to the development of the concept of Quality Assurance (QA) which
seeks to build quality into the products from the very beginning of the process of drug
manufacture. By careful planning, training and monitoring QA is a means to control
processes right from choosing the right vendor for the starting and packing materials, to the
manner in which distribution of finished product takes place. The aim is to cover all the
aspects that individually and collectively impact the quality of products.
The World Health Organization (WHO) defines QA as, “The totality of arrangements
made with the object of ensuring that pharmaceutical products are of the quality required for
their intended use.”
1.3.1 Objectives of Quality Assurance
The objectives of QA system in a pharmaceutical industry are to ensure that:
• Product design and development is in accordance with requirements of cGMP, Good
Laboratory Practices (for non-clinical developmental studies) and Good Clinical
Practices (for clinical studies).
• All operations in production and control steps are specified clearly in writing.
• Managerial responsibility is specified clearly in each job description.
• Correct starting materials and packaging materials are used to manufacture drug
products.
• Appropriate controls – such as in-process checks, calibrations and validations – exist
to ensure quality of raw materials, intermediate products and finished products.
• Finished products are appropriately checked in accordance with pre-determined
procedures.
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• Every production batch is certified by authorized persons before it is released for sale
and supply.
• There are satisfactory measures adopted to ensure quality of the product which is
maintained throughout its shelf life.
• Procedures exist for regular self-inspection or quality audits to assess the
effectiveness of the QA system.
• Deviations of any nature are reported, adequately investigated and the results are
recorded.
• Changes having an impact on product quality are adopted through a system that
calls for approval from management.
• Quality of products is regularly evaluated in order to verify that the process is
consistently providing quality products.
1.4 CURRENT GOOD MANUFACTURING PRACTICES (cGMP)
cGMP is the aspect of QA that ensures the consistent production and control of products
to meet pre-determined quality standards. The primary aim of cGMP is to reduce two
inherent risks involved in pharmaceutical production – mix-ups and cross-contamination.
Mix-up refers to the confusion caused by interchange of materials, whereas cross-
contamination is unexpected contamination of one batch of product by another product.
cGMP guidelines are prescribed by every country’s drug regulatory authority and
according to WHO, cGMP requires that :
(a) All manufacturing processes are clearly defined, systematically reviewed in the light
of experience, and shown to be capable of consistently manufacturing
pharmaceutical products of the required quality that comply with their specifications;
(b) Qualification and validation are performed;
(c) All necessary resources are provided, including:
(i) Appropriately qualified and trained personnel;
(ii) Adequate premises and space;
(iii) Suitable equipment and services;
(iv) Appropriate materials, containers and labels;
(v) Approved procedures and instructions;
(vi) Suitable storage and transport;
(vii) Adequate personnel, laboratories and equipment for in-process controls;
(d) Instructions and procedures are written in clear and unambiguous language,
specifically applicable to the facilities provided;
(e) Operators are trained to carry out procedures correctly;
(f) Records are made (manually and/or by recording instruments) during manufacture to
show that all the steps required by the defined procedures and instructions have in
fact been taken and that the quantity and quality of the product are as expected; any
significant deviations are fully recorded and investigated;
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(g) Records covering manufacture and distribution, which enable the complete history of
a batch to be traced, are retained in a comprehensible and accessible form;
(h) The proper storage and distribution of the products minimizes any risk to their
quality;
(i) A system is available to recall any batch of product from sale or supply;
(j) Complaints about marketed products are examined; the causes of quality defects are
investigated, and appropriate measures taken in respect of the defective products to
prevent recurrence.
1.5 QUALITY CONTROL
As per ISO 9000, Quality Control (QC) is defined as, “A part of quality management
focused on fulfilling quality requirements.”
WHO defines QC as, “The sum of all procedures undertaken to ensure the identity and
purity of a particular pharmaceutical.”
QC is the part of GMP that deals with developing specifications, sampling input materials,
intermediates and finished products; testing them, documenting results, and setting up
release procedures to ensure that all relevant testing has been performed and only products
with ascertained quality are released for use.
1.5.1 Objectives of Quality Control
The objectives of QC department in a pharmaceutical industry are to ensure that:
• There is a day-to-day control maintained over the quality aspects of drug products.
• Incoming raw materials, in-process goods and finished products are all tested for
compliance with predetermined quality specifications.
• Environmental monitoring is performed to make sure products are manufactured,
packed and stored under prescribed conditions.
• Instruments are calibrated and working as expected.
• Analytical methods are developed and validated to assure they stay capable of
providing results that are accurate and predictable.
Differences between QA and QC
Attribute QA QC
Goal Preventing defects. Identifying defects.
Focus Building quality into product from Testing if quality exists in product
design stage itself. after its manufacture.
Work flow Establish quality management Find source of problems in quality.
system, continuous monitoring of
processes.
Type of tool Managerial. Corrective.

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Given the rapid pace at which the pharmaceutical environment is changing today,
companies must adapt to the quality requirements needed to consistently manufacture and
deliver products with zero-defects. There can be no compromise on the efficacy, quality and
safety attributes of drug products. Developing, manufacturing and selling a quality product is
a collective responsibility of everyone in an organization. This calls for an integrated
approach that includes building quality into a product by design, development of quality
management systems that are strictly monitored and focusing on continual improvement to
meet consumers’ health requirements.

REVIEW QUESTIONS
1. Name the important regulatory bodies that govern the pharmaceutical industry.
2. Discuss how the cGMPs were developed by the USFDA.
3. Explain the steps involved in developing a drug from initial discovery to final
marketing of the formulation.
4. Define the terms QA and QC and explain the differences between them.
5. Describe the functions of QA and QC in a pharmaceutical company.
6. What is cGMP? Highlight the important areas covered under cGMP guidelines.

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