This document discusses quality control and quality assurance for veterinary dosage forms. It begins by defining Good Manufacturing Practices (GMP) which outline the production and testing aspects that can impact a product's quality. GMP guidelines ensure manufacturing processes are clearly defined, critical processes are validated, changes are evaluated, documentation is clear, operators are trained, records are made, distribution minimizes risks, and recalls can be done. The guidelines are enforced by regulatory agencies and aim to produce safe, effective medicines and medical products.

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1-Introduction:
1.1-Good Manufacturing Practices:
"Good manufacturing practice" or "GMP" is part of a quality system covering the manufacture
and testing of pharmaceutical dosage forms or drugs and active pharmaceutical ingredients,
diagnostics, foods, pharmaceutical products, and medical devices. GMPs are guidelines that
outline the aspects of production and testing that can impact the quality of a product. Many
countries have legislated that pharmaceutical and medical device companies must follow GMP
procedures, and have created their own GMP guidelines that correspond with their legislation,
basic concepts of all these guidelines remains more or less similar that is ultimate goal to
produce a good quality medicine or medical devices or active pharmaceutical products.
Although there are a number of them, all guidelines follow a few basic principles.
Manufacturing processes are clearly defined and controlled. All critical processes are validated
to ensure consistency and compliance with specifications.
Manufacturing processes are controlled, and any changes to the process are evaluated. Changes
that have an impact on the quality of the drug are validated as necessary.
Instructions and procedures are written in clear and unambiguous language. (Good
Documentation Practices)
Operators are trained to carry out and document procedures.
Records are made, manually or by instruments, during manufacture that demonstrate that all the
steps required by the defined procedures and instructions were in fact taken and that the quantity
and quality of the drug was as expected. Deviations are investigated and documented.
Records of manufacture (including distribution) that enable the complete history of a batch to be
traced are retained in a comprehensible and accessible form.
The distribution of the drugs minimizes any risk to their quality.
A system is available for recalling any batch of drug from sale or supply.
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Complaints about marketed drugs are examined, the causes of quality defects are investigated,
and appropriate measures are taken with respect to the defective drugs and to prevent recurrence.
GMP guidelines are not prescriptive instructions on how to manufacture products. They are a
series of general principles that must be observed during manufacturing. When a company is
setting up its quality program and manufacturing process, there may be many ways it can fulfill
GMP requirements. It is the company's responsibility to determine the most effective and
efficient quality process.
1.2-Guideline versions
GMPs are enforced in the United States by the US FDA, under Section 501(B) of the 1938 Food,
Drug, and Cosmetic Act (21USC351). The regulations use the phrase "current good
manufacturing practices" (cGMP) to describe these guidelines. Courts may theoretically hold
that a drug product is adulterated even if there is no specific regulatory requirement that was
violated as long as the process was not performed according to industry standards.[citation needed] As
of June 2010, the same CGMP requirements apply to all manufacturers of dietary supplements.[1]
The World Health Organization (WHO) version of GMP is used by pharmaceutical regulators
and the pharmaceutical industry in over one hundred countries worldwide, primarily in the
developing world. The European Union's GMP (EU-GMP) enforces similar requirements to
WHO GMP, as does the Food and Drug Administration's version in the US. Similar GMPs are
used in other countries, with Australia,Canada, Japan, Singapore and others having highly
developed/sophisticated GMP requirements. In the United Kingdom, the Medicines Act (1968)
covers most aspects of GMP in what is commonly referred to as "The Orange Guide", which is
named so because of the color of its cover; it is officially known as Rules and Guidance for
Pharmaceutical Manufacturers and Distributors.[2]
Since the 1999 publication of GMPs for Active Pharmaceutical Ingredients, by the International
Conference on Harmonization (ICH), GMPs now apply in those countries and trade groupings
that are signatories to ICH (the EU, Japan and the U.S.), and applies in other countries (e.g.,
Australia, Canada, Singapore) which adopt ICH guidelines for the manufacture and testing of
active raw materials.
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1.3-Enforcement:
Within the European Union, GMP inspections are performed by National Regulatory Agencies
(e.g., GMP inspections are performed in the United Kingdom by the Medicines and Healthcare
products Regulatory Agency (MHRA)); in the Republic of Korea (South Korea) by the Korea
Food & Drug Administration (KFDA); in Australia by the Therapeutical Goods Administration
(TGA); in South Africa by the Medicines Control Council (MCC); in Brazil by the Agência
Nacional de Vigilância Sanitária (National Health Surveillance Agency Brazil) (ANVISA);
in Iran, in India gmp inspections are carried out by state FDA and these FDA report to Central
Drugs Standard Control Organization [3]and Pakistan by the Ministry of Health;[4] and by similar
national organisations worldwide. Each of the inspectoratescarry out routine GMP inspections to
ensure that drug products are produced safely and correctly; additionally, many countries
perform pre-approval inspections (PAI) for GMP compliance prior to the approval of a new drug
for marketing.
Regulatory agencies (including the FDA in the U.S. and regulatory agencies in many European
nations) are authorized to conduct unannounced inspections, though some are scheduled. FDA
routine domestic inspections are usually unannounced, but must be conducted according to
704(A) of the FD&C Act (21USC374), which requires that they are performed at a "reasonable
time". Courts have held that any time the firm is open for business is a reasonable time for an
inspection.
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Figure 1. Steps involved in GMP
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1.4-Other good manufacturing practices:
Good laboratory practice (GLP), for laboratories conducting non-clinical
studies (toxicology and pharmacology studies in animals);
Good clinical practice (GCP), for hospitals and clinicians conducting clinical studies on new
drugs in humans;
Good regulatory practice (GRP), for the management of regulatory commitments, procedures
and documentation.
Collectively, these and other good-practice requirements are referred to as "GxP" requirements,
all of which follow similar philosophies. (Other examples include good agriculture practices,
good guidance practices, and good tissue practices.) In the U.S., medical device manufacturers
must follow what are called "quality system regulations" which are deliberately harmonized
with ISO requirements, not cGMPs.
1.5-What is GMP?
REGULATION OF THE PHARMACEUTICAL /
BIOTECHNOLOGY INDUSTRY AND GOOD
MANUFACTURING PRACTICES
This introductory text briefly discusses how the pharmaceutical industry is regulated and the
relationship between that industry and the Food and Drug Administration. The legislation that
authorized the current Good Manufacturing Practices that guide the production of
pharmaceuticals is introduced.
• INTRODUCTION
• THE LIFE CYCLE OF A PHARMACEUTICAL PRODUCT
1.5A-INTRODUCTION
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• The production of pharmaceutical and other medical products is stringently regulated by
the federal government and these regulations also have a profound effect many
biotechnology companies. The r honesty (as in labeling), effectiveness and reliability.
• While we take for granted that the government regulates the production of drugs, this was
not always the case, as is illustrated dramatically in the history of drug and food
regulation in the U.S. Much of this history involves tragedies and abuses that led to
increasingly stringent regulation of drug and food production. A few important incidents
and enactments are:
• Upton Sinclair recorded filthy conditions and unacceptable practices in the food industry
in his novelThe Jungle. As a result, the original Food Drug and Cosmetic Act (FDCA)
was passed in 1906 to prevent the commerce of unacceptable food and drugs. The 1906
FDCA authorized regulations to ensure that pharmaceutical manufacturers did not
adulterate or mislabel their products but did not deal with the safety or effectiveness of
drugs.
• In 1927 a separate law enforcement agency was formed, first known as the Food, Drug
and Insecticide Administration, and then, in 1930, as the Food and Drug Administration
(FDA) to enforce legislation relating to food and drugs.
• In 1937, a batch of sulfanilamide was dissolved in the industrial solvent, diethylene
glycol. There were 358 poisonings and 107 deaths, mostly children. As a result of this
incident, the revised Food, Drug and Cosmetic Act was passed in 1938 which required
drugs to be tested for safety before release.
• In 1955 some children vaccinated with polio vaccine contracted paralytic polio. Fifty one
people were paralyzed and ten died. The problem was traced to one manufacturer who
apparently did not properly inactivate the virus used to make the vaccine. This incident
egulated characteristics of such products relate to safety, and others like it led to
increased factory inspections and testing of the safety of products before their release to
the public.
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• One of the great successes of the FDA occurred in the early 1960s. At that time the drug
thalidomide was commonly prescribed for insomnia and nausea in pregnant women in
Europe. Unfortunately, this drug led to the birth of thousands of children without arms or
legs. Thalidomide was not used commercially in the U.S. because Dr. Frances Kelsy of
the FDA refused to accept it in the U.S. until it was proven safe. News of the thalidomide
tragedy influenced the U.S. congress in 1962 to pass the Kefauver-Harris Amendments
which required that drugs be proven to be both safe and effective before release.
• In 1963 the first set of Good Manufacturing Practices, GMP, regulations were published.
These regulations guide companies in the production of safe and effective drugs.
• A number of injuries and deaths in the 1960s and 1970s caused by contaminated products
led to the revised GMPs in the late 1970s. These regulations included requirements for
standard operating procedures, validated systems, and extensive documentation.
• Inspections of pharmaceutical animal testing laboratories revealed that toxicology studies
supporting new drug applications were poorly conceived and improperly conducted.
These inadequacies led to the promulgation of the Good Laboratory Practices
Regulations in 1976, whose goal is to assure the quality of data submitted to FDA in
support of the safety of new products.
• In 1982 insulin produced by recombinant DNA methods became the first such "modern
biotechnology" product to be approved for market and sale.
• This brief historical summary illustrates that the regulation of food and medical products
is generally driven by a tragedy, a problem, or an advance in science and technology. The
public and their elected officials respond by enacting a law(s) that is intended to reduce
risks while maximizing benefits. A governmental regulatory agency is empowered to
interpret and enforce the law through a system of regulations
Congress enacted the Food, Drug and Cosmetics Act,
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FDCA which states that food and drugs should not be
"adulterated" and empowers the FDA to enforce food
and drug laws.
One of the key clauses in the FDCA is "[a] drug is adulterated...if
the methods used in...its manufacture...do not conform to...current
good manufacturing practice..."
The FDA devises regulations which outline in more
detail the meaning of "good manufacturing practices"
(GMP). These are published in The Code of Federal
Regulations (CFR), a document published annually,
which contains all federal regulations.
The FDA periodically publishes Guidelines to more
fully interpret technical details relevant to GMP
practices. The Guidelines do not have the force of law,
but a company should follow them or be prepared to
justify any deviation. "Points to Consider" are FDA
documents that discuss issues relating to innovative
technologies.
1.5B-THE LIFE CYCLE OF A PHARMACEUTICAL PRODUCT
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Pharmaceuticals have a long life cycle involving extensive development, testing, an approval
process, marketing and post-marketing surveillance. Only about 1 in 10 potential drugs performs
successfully during testing and is actually marketed.
The idea for a product is researched in the laboratory during the early stages of research and
development (R&D). Until recently, FDA was not involved in the early R&D phases of a
product. However, FDA is beginning to inquire about the results, documentation, and
experiments that were performed during R&D because the ultimate quality of a product depends
on the foundation built during development.
If a potential product shows promise in the laboratory, toxicity tests are performed in animals to
determine whether the substance is safe for human testing. Before the mid-1970s, the conduct of
animal testing was not scrutinized by the FDA. However, in 1975, FDA inspections of several
pharmaceutical testing laboratories revealed poorly conceived and carelessly executed
experiments, inaccurate record-keeping, poorly maintained animal facilities, and a variety of
other problems. These deficiencies led the FDA to institute theGood Laboratory
Practice2 regulations (GLPs) to govern animal studies of pharmaceutical products. GLPs
require that testing laboratories follow written protocols and standard operating
procedures (SOPs), have adequate facilities and equipment, provide proper animal care, properly
record data, have well-trained and competent personnel, and conduct high quality, valid toxicity
tests.
If a potential new product appears safe in animal studies, then scientists prepare a plan to
investigate the product in human volunteers. The company submits their plan to the FDA,
including a description of the product, the results of animal tests, and the plans for further
testing. The FDA then decides whether or not the company's materials are sufficiently complete
that the company can begin testing the product in humans.
Good Clinical Practices (GCPs) relate to the performance of clinical trials of drug safety and
efficacy in human subjects. GCPs aim to protect the rights and safety of human subjects and to
ensure the scientific quality of the studies. Clinical trials are conducted in stages, each of which
must be successful before continuing to the next phase.
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Phase I clinical trials are the first introduction of the proposed drug into humans. During Phase
I trials, the safety of the drug is carefully evaluated and its metabolic and pharmacologic
properties in healthy humans are determined. If a drug meets the safety requirements at this
phase and appears to have the desired properties, then it enters Phase II clinical trials. Phase II
trials are performed on a small number of diseased patients to determine the drug's efficacy. If
the drug continues to meet safety requirements and demonstrates efficacy at Phase II, it
progresses to a broaderPhase III trial involving hundreds or thousands of patients. At this point,
the safety and efficacy of the drug continue to be evaluated, dosages are determined, a risk
versus benefit analysis is performed, drug interactions are explored, and other data are collected.
If a drug passes all three phases of testing, the company may submit to the FDA an application
which provides convincing evidence that the new drug or biologic is safe, reliable and effective.
Note that FDA itself does not actually test each drug product. Rather, FDA expert reviewers
examine test results and information submitted by the company to determine whether a product
is acceptable. If the review team decides the evidence is sufficient, the new product is approved
by FDA and can be manufactured for commercial sale.
As a therapeutic agent progresses through these various phases, the requirements for its
manufacture become more and more stringent. Once in commercial production, the manufacture,
labeling, packaging, shipping, storing, quality control, and marketing of the product must meet
all GMP and other relevant requirements.
An important part of the enforcement of GMP is unannounced inspections of pharmaceutical
facilities by FDA inspectors. Inspectors note practices that violate GMP requirements on a form
called a "483". Generally, companies are able to correct deficiencies noted by inspectors.
Occasionally the FDA seizes and destroys products that it believes were not properly
manufactured, or levies fines against a company. In more extreme cases, where individuals or
companies act deceitfully or refuse to comply with regulations, individuals may be charged as
criminals and may be imprisoned if convicted.
FDA thus plays many roles in the development of a pharmaceutical product. These regulatory
functions include:
• Establishing rules that ensure consumer protection
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• Communicating the rules to industry and educating the public
• Monitoring industry compliance with the rules
• Performing scientific review and providing information and support to ensure that the
rules are up-to-date
• Enforcing applicable laws and regulations
1.6-Validation:
Validation is defined as the establishing of documented evidence which provides a high degree
of assurance that a planned process will consistently perform according to the intended specified
outcomes. Validation studies are performed for analytical tests,equipment, facility systems such
as air, water, steam, and for processes such as the manufacturing processes, cleaning,
sterilization, sterile filling, lyophilization, etc.
There will be a separate validation for the lyophilizer as an equipment item and for the
lyophilization process; for the cleaning of glassware and the cleaning of the facility; and for the
sterilization process and for the sterility test. Every step of the process of manufacture of a drug
product must be shown to perform as intended.
Validation studies verify the system under test under the extremes expected during the process to
prove that the system remains in control.Once the system or process has been validated, it is
expected that it remains in control, provided no changes are made. In the event that
modifications are made, or problems occur, or equipment is replaced or relocated, revalidation is
performed. Critical equipment and processes are routinely revalidated at appropriate intervals to
demonstrate that the process remains in control.
The validity of systems/equipment/tests/processes can be established by prospective,concurrent
or retrospective studies. Prospective validation is data collected based on a pre-planned protocol.
This is the most controlled method and is the validation approach presented in this Guide.
1.7-Master validation plan:
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The Master Validation Plan is a document pertaining to the whole facility that describes which
equipment, systems, methods and processes will be validated and when they will be validated.
The document should provide the format required for each particular validation document
(Installation Qualification, Operational Qualification and Performance Qualification for
equipment and systems; Process Validation; Analytical Assay Validation), and indicate what
information is to be contained within each document. Some equipment requires only installation
and operational qualifications,and various analytical tests need to establish only some
performance parameters – this must be explained in the master protocol along with some
principles of how to determine which of the qualifications are required by each, and who will
decide what validations will be performed.
The Master Validation Plan should also indicate why and when revalidations will be performed,
either after changes or relocation of equipment or systems; changes to processes or equipment
used for processing; or for changes in assay methods or inequipment used in tests.
If a new process or system is implemented, a Design Qualification (DQ) may be necessary.
Guidelines for such cases should be included in the Master Validation Plan. A Design
Qualification would be necessary when planning and choosing equipment or systems to ensure
that components selected will have adequate capacity to function for the intended purpose, and
will adequately serve the operations or functions of another piece of equipment or operation.
For example:
• a water system must produce sufficient water of specified quality to serve the
requirements of the facility including production, testing, and as a source for steam or for
a second system producing higher quality water;
• ii) a steam generator must produce sufficient steam of the correct quality to fulfill all the
autoclaving needs and Steam-in-Place (SIP) cleaning procedures of the facility; or iii)
the equipment chosen for a particular operation must have sufficient space and access for
proper cleaning operations and maintenance.
The order in which each part of the facility is validated must be addressed in the Master
Validation Plan. For example the water system should be validated before validating a piece of
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equipment that uses this water system. The IQ, OQ and PQ must be performed in order: the
master validation plan should indicate how to deal with any deviations from these qualifications,
and state the time interval permitted between each validation.
1.8-Process validation:
Good manufacturing requirements -- Part 2: Validation ranges, etc. The controls and tests and
their specifications must be defined.The purity profiles for production processes must be defined
for each step. To be considered validated, the process must consistently meet all specifications at
all steps throughout the procedure at least three times consecutively.
It is very important that the specifications for a process undergoing validation be pre-determined.
It is also important that for all critical processing parameters for which specifications have been
set, there must be equipment to measure all of those parameters during the validation study.
Process Validation studies examine a process under normal operating conditions to prove that the
process is in control. Once the process has been validated, it is expected that it remains in
control, provided no changes are made. In the event that
modifications to the process are made, or problems occur, or equipment or systems involved in
the process are changed, a re-validation of the process would be required.Very often validation
studies require that more measurements are made than are required for the routine process.
The validation must prove the consistency of the process and therefore must assess the efficiency
and effectiveness of each step to produce its intended outcome.The following format outlines the
requirements for a protocol for Process Validation. (In essence, this form is an SOP titled “How
to Write a Process Validation Protocol”)
1.9-Quality Control:
Quality control is a process by which entities review the quality of all factors involved in
production. This approach places an emphasis on three aspects:
Elements such as controls, job management, defined and well managed processes[1][2],
performance and integrity criteria, and identification of records
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Competence, such as knowledge, skills, experience, and qualifications
Soft elements, such as personnel integrity, confidence, organizational culture, motivation, team
spirit, and quality relationships.
The quality of the outputs is at risk if any of these three aspects is deficient in any way.
Quality control emphasizes testing of products to uncover defects, and reporting to management
who make the decision to allow or deny the release, whereas quality assurance attempts to
improve and stabilize production, and associated processes, to avoid, or at least minimize, issues
that led to the defects in the first place.[citation needed] For contract work, particularly work awarded
by government agencies, quality control issues are among the top reasons for not renewing a
contract.
1.10-Total Quality Control:
• "Total quality control" is a measure used in cases where sales decrease despite
implementation of statistical quality control techniques or quality improvements. If the
original specification does not reflect the correct quality requirements, quality cannot be
inspected or manufactured into the product. For instance, the parameters for a pressure
vessel should include not only the material and dimensions, but also operating,
environmental, safety, reliability and maintainability requirements.
• Quality control in project management
• In project management, quality control requires the project manager and the project team to
inspect the accomplished work to ensure it's alignment with the project scope[4]. In practice,
projects typically have a dedicated quality control team which focuses on this area.
1.11-Quality Assurance:
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Quality assurance is the process of verifying or determining whether products or services meet
or exceed customer expectations. Qualityassurance is a process-driven approach with specific
steps to help define and attain goals. This process considers design, development, production,
and service.The most popular tool used to determine quality assurance is the Shewhart Cycle,
developed by Dr. W. Edwards Deming. This cycle forquality assurance consists of four
steps: Plan, Do, Check, and Act. These steps are commonly abbreviated as PDCA.
The four quality assurance steps within the PDCA model stand for:
• Plan: Establish objectives and processes required to deliver the desired results.
• Do: Implement the process developed.
• Check: Monitor and evaluate the implemented process by testing the results against the
predetermined objectives
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