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  1. 1. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS1-Introduction:1.1-Good Manufacturing Practices:"Good manufacturing practice" or "GMP" is part of a quality system covering the manufactureand testing of pharmaceutical dosage forms or drugs and active pharmaceutical ingredients,diagnostics, foods, pharmaceutical products, and medical devices. GMPs are guidelines thatoutline the aspects of production and testing that can impact the quality of a product. Manycountries have legislated that pharmaceutical and medical device companies must follow GMPprocedures, 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 toproduce 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 validatedto ensure consistency and compliance with specifications.Manufacturing processes are controlled, and any changes to the process are evaluated. Changesthat have an impact on the quality of the drug are validated as necessary.Instructions and procedures are written in clear and unambiguous language. (GoodDocumentation Practices)Operators are trained to carry out and document procedures.Records are made, manually or by instruments, during manufacture that demonstrate that all thesteps required by the defined procedures and instructions were in fact taken and that the quantityand 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 betraced 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.N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 1
  2. 2. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSComplaints 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 aseries of general principles that must be observed during manufacturing. When a company issetting up its quality program and manufacturing process, there may be many ways it can fulfillGMP requirements. It is the companys responsibility to determine the most effective andefficient quality process.1.2-Guideline versionsGMPs 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 goodmanufacturing practices" (cGMP) to describe these guidelines. Courts may theoretically holdthat a drug product is adulterated even if there is no specific regulatory requirement that wasviolated as long as the process was not performed according to industry standards.[citation needed] Asof 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 regulatorsand the pharmaceutical industry in over one hundred countries worldwide, primarily in thedeveloping world. The European Unions GMP (EU-GMP) enforces similar requirements toWHO GMP, as does the Food and Drug Administrations version in the US. Similar GMPs areused in other countries, with Australia,Canada, Japan, Singapore and others having highlydeveloped/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 isnamed so because of the color of its cover; it is officially known as Rules and Guidance forPharmaceutical Manufacturers and Distributors.[2]Since the 1999 publication of GMPs for Active Pharmaceutical Ingredients, by the InternationalConference on Harmonization (ICH), GMPs now apply in those countries and trade groupingsthat 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 ofactive raw materials.N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 2
  3. 3. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS1.3-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 Healthcareproducts Regulatory Agency (MHRA)); in the Republic of Korea (South Korea) by the KoreaFood & Drug Administration (KFDA); in Australia by the Therapeutical Goods Administration(TGA); in South Africa by the Medicines Control Council (MCC); in Brazil by the AgênciaNacional 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 CentralDrugs Standard Control Organization [3]and Pakistan by the Ministry of Health;[4] and by similarnational organisations worldwide. Each of the inspectoratescarry out routine GMP inspections toensure that drug products are produced safely and correctly; additionally, many countriesperform pre-approval inspections (PAI) for GMP compliance prior to the approval of a new drugfor marketing.Regulatory agencies (including the FDA in the U.S. and regulatory agencies in many Europeannations) are authorized to conduct unannounced inspections, though some are scheduled. FDAroutine domestic inspections are usually unannounced, but must be conducted according to704(A) of the FD&C Act (21USC374), which requires that they are performed at a "reasonabletime". Courts have held that any time the firm is open for business is a reasonable time for aninspection.N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 3
  4. 4. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS Figure 1. Steps involved in GMPN K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 4
  5. 5. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS1.4-Other good manufacturing practices:Good laboratory practice (GLP), for laboratories conducting non-clinicalstudies (toxicology and pharmacology studies in animals);Good clinical practice (GCP), for hospitals and clinicians conducting clinical studies on newdrugs in humans;Good regulatory practice (GRP), for the management of regulatory commitments, proceduresand 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 manufacturersmust follow what are called "quality system regulations" which are deliberately harmonizedwith ISO requirements, not cGMPs. 1.5-What is GMP? REGULATION OF THE PHARMACEUTICAL / BIOTECHNOLOGY INDUSTRY AND GOOD MANUFACTURING PRACTICESThis introductory text briefly discusses how the pharmaceutical industry is regulated and therelationship between that industry and the Food and Drug Administration. The legislation thatauthorized the current Good Manufacturing Practices that guide the production ofpharmaceuticals is introduced. • INTRODUCTION • THE LIFE CYCLE OF A PHARMACEUTICAL PRODUCT 1.5A-INTRODUCTIONN K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 5
  6. 6. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS • 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.N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 6
  7. 7. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS • 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 regulationsCongress enacted the Food, Drug and Cosmetics Act,N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 7
  8. 8. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSFDCA which states that food and drugs should not be"adulterated" and empowers the FDA to enforce foodand drug laws.One of the key clauses in the FDCA is "[a] drug is adulterated...ifthe 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 GMPpractices. 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 PRODUCTN K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 8
  9. 9. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSPharmaceuticals have a long life cycle involving extensive development, testing, an approvalprocess, marketing and post-marketing surveillance. Only about 1 in 10 potential drugs performssuccessfully during testing and is actually marketed.The idea for a product is researched in the laboratory during the early stages of research anddevelopment (R&D). Until recently, FDA was not involved in the early R&D phases of aproduct. However, FDA is beginning to inquire about the results, documentation, andexperiments that were performed during R&D because the ultimate quality of a product dependson the foundation built during development.If a potential product shows promise in the laboratory, toxicity tests are performed in animals todetermine whether the substance is safe for human testing. Before the mid-1970s, the conduct ofanimal testing was not scrutinized by the FDA. However, in 1975, FDA inspections of severalpharmaceutical testing laboratories revealed poorly conceived and carelessly executedexperiments, inaccurate record-keeping, poorly maintained animal facilities, and a variety ofother problems. These deficiencies led the FDA to institute theGood LaboratoryPractice2 regulations (GLPs) to govern animal studies of pharmaceutical products. GLPsrequire that testing laboratories follow written protocols and standard operatingprocedures (SOPs), have adequate facilities and equipment, provide proper animal care, properlyrecord data, have well-trained and competent personnel, and conduct high quality, valid toxicitytests.If a potential new product appears safe in animal studies, then scientists prepare a plan toinvestigate 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 furthertesting. The FDA then decides whether or not the companys materials are sufficiently completethat the company can begin testing the product in humans.Good Clinical Practices (GCPs) relate to the performance of clinical trials of drug safety andefficacy in human subjects. GCPs aim to protect the rights and safety of human subjects and toensure the scientific quality of the studies. Clinical trials are conducted in stages, each of whichmust be successful before continuing to the next phase.N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 9
  10. 10. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSPhase I clinical trials are the first introduction of the proposed drug into humans. During PhaseI trials, the safety of the drug is carefully evaluated and its metabolic and pharmacologicproperties in healthy humans are determined. If a drug meets the safety requirements at thisphase and appears to have the desired properties, then it enters Phase II clinical trials. Phase IItrials are performed on a small number of diseased patients to determine the drugs efficacy. Ifthe drug continues to meet safety requirements and demonstrates efficacy at Phase II, itprogresses 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 riskversus 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 applicationwhich 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 reviewersexamine test results and information submitted by the company to determine whether a productis acceptable. If the review team decides the evidence is sufficient, the new product is approvedby FDA and can be manufactured for commercial sale.As a therapeutic agent progresses through these various phases, the requirements for itsmanufacture become more and more stringent. Once in commercial production, the manufacture,labeling, packaging, shipping, storing, quality control, and marketing of the product must meetall GMP and other relevant requirements.An important part of the enforcement of GMP is unannounced inspections of pharmaceuticalfacilities by FDA inspectors. Inspectors note practices that violate GMP requirements on a formcalled a "483". Generally, companies are able to correct deficiencies noted by inspectors.Occasionally the FDA seizes and destroys products that it believes were not properlymanufactured, or levies fines against a company. In more extreme cases, where individuals orcompanies act deceitfully or refuse to comply with regulations, individuals may be charged ascriminals and may be imprisoned if convicted.FDA thus plays many roles in the development of a pharmaceutical product. These regulatoryfunctions include: • Establishing rules that ensure consumer protectionN K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 10
  11. 11. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMS • 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 regulations1.6-Validation:Validation is defined as the establishing of documented evidence which provides a high degreeof assurance that a planned process will consistently perform according to the intended specifiedoutcomes. Validation studies are performed for analytical tests,equipment, facility systems suchas 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 thelyophilization process; for the cleaning of glassware and the cleaning of the facility; and for thesterilization process and for the sterility test. Every step of the process of manufacture of a drugproduct must be shown to perform as intended.Validation studies verify the system under test under the extremes expected during the process toprove that the system remains in control.Once the system or process has been validated, it isexpected that it remains in control, provided no changes are made. In the event thatmodifications are made, or problems occur, or equipment is replaced or relocated, revalidation isperformed. Critical equipment and processes are routinely revalidated at appropriate intervals todemonstrate that the process remains in control.The validity of systems/equipment/tests/processes can be established by prospective,concurrentor 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:N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 11
  12. 12. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSThe Master Validation Plan is a document pertaining to the whole facility that describes whichequipment, 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 forequipment and systems; Process Validation; Analytical Assay Validation), and indicate whatinformation is to be contained within each document. Some equipment requires only installationand operational qualifications,and various analytical tests need to establish only someperformance parameters – this must be explained in the master protocol along with someprinciples of how to determine which of the qualifications are required by each, and who willdecide 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 equipmentused 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 DesignQualification would be necessary when planning and choosing equipment or systems to ensurethat components selected will have adequate capacity to function for the intended purpose, andwill 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 MasterValidation Plan. For example the water system should be validated before validating a piece ofN K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 12
  13. 13. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSequipment that uses this water system. The IQ, OQ and PQ must be performed in order: themaster 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 andtheir specifications must be defined.The purity profiles for production processes must be definedfor each step. To be considered validated, the process must consistently meet all specifications atall 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 beenset, 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 theprocess is in control. Once the process has been validated, it is expected that it remains incontrol, provided no changes are made. In the event thatmodifications to the process are made, or problems occur, or equipment or systems involved inthe process are changed, a re-validation of the process would be required.Very often validationstudies 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 efficiencyand effectiveness of each step to produce its intended outcome.The following format outlines therequirements for a protocol for Process Validation. (In essence, this form is an SOP titled “Howto Write a Process Validation Protocol”)1.9-Quality Control:Quality control is a process by which entities review the quality of all factors involved inproduction. 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 recordsN K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 13
  14. 14. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSCompetence, such as knowledge, skills, experience, and qualificationsSoft elements, such as personnel integrity, confidence, organizational culture, motivation, teamspirit, 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 managementwho make the decision to allow or deny the release, whereas quality assurance attempts toimprove and stabilize production, and associated processes, to avoid, or at least minimize, issuesthat led to the defects in the first place.[citation needed] For contract work, particularly work awardedby government agencies, quality control issues are among the top reasons for not renewing acontract.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 its 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:N K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 14
  15. 15. QUALITY CONTROL AND QUALITY ASSURANCE OF VETERNERY DOSAGE FORMSQuality assurance is the process of verifying or determining whether products or services meetor exceed customer expectations. Qualityassurance is a process-driven approach with specificsteps 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 foursteps: 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 objectivesN K B R COLLEGE OF PHARMACY AND RESEACH CENTRE,MEERUT Page 15

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