QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS

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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