Quality Assurance Of Pharmaceuticals
QAPPR 12/16/06 12:10 PM Page iQuality assurance ofpharmaceuticalsA compendium of guidelinesand related materialsVolume 2, 2nd updated editionGood manufacturing practicesand inspection
QAPPR 12/16/06 12:10 PM Page iiWHO Library Cataloguing-in-Publication DataQuality assurance of pharmaceuticals : a compendium of guidelines and related materials.Vol. 2, Good manufacturing practices and inspection. – 2nd ed.1.Drug and narcotic control – standards 2.Drug industry – standards3.Pharmaceutical preparations – standards 4.Biological products – standards5.Quality control 6.Guidelines I.World Health OrganizationII.Title: Good manufacturing practices and inspectionISBN 92 4 154708 1ISBN 978 92 4 154708 6(NLM classification: QV 33) World Health Organization 2007All rights reserved. Publications of the World Health Organization can be obtained fromWHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland(tel.: 41 22 791 3264; fax: 41 22 791 4857; e-mail: bookorders@who.int). Requests forpermission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: 4122 791 4806; e-mail: permissions@who.int).The designations employed and the presentation of the material in this publication do notimply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, orconcerning the delimitation of its frontiers or boundaries. Dotted lines on maps representapproximate border lines for which there may not yet be full agreement.The mention of specific companies or of certain manufacturers’ products does not implythat they are endorsed or recommended by the World Health Organization in preference toothers of a similar nature that are not mentioned. Errors and omissions excepted, the namesof proprietary products are distinguished by initial capital letters.All reasonable precautions have been taken by the World Health Organization to verify theinformation contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for theinterpretation and use of the material lies with the reader. In no event shall the World HealthOrganization be liable for damages arising from its use.Printed in India
QAPPR 12/16/06 12:10 PM Page iiiContents1Introduction1. WHO good manufacturing practices: main principles forpharmaceutical products7Quality management in the drug industry: philosophy andessential elements (update on sampling) (new)7Heating Ventilation and air-conditioning systems for non-sterilepharmaceutical dosage forms (new)58Validation (new)101Water for pharmaceutical use (new)1702. WHO good manufacturing practices: starting materialsActive pharmaceutical ingredients (bulk drug substances)Pharmaceutical excipients3. WHO good manufacturing practices: specificpharmaceutical productsSterile pharmaceutical productsBiological productsInvestigational pharmaceutical products for clinical trialsin humansThe manufacture of herbal medicines (updated)Radiopharmaceutical products4. InspectionPre-approval inspectionsInspection of pharmaceutical manufacturersInspection of drug distribution channelsQuality systems requirements for national goodmanufacturing practice inspectoratesGuidance on good manufacturing practices:inspection reportModel certificate of good manufacturing 3322338347
QAPPR 12/16/06 12:10 PM Page ivQUALITY ASSURANCE OF PHARMACEUTICALS5. Hazard and risk analysis in pharmaceutical productsApplication of hazard analysis and critical control point(HACCP) methodology to pharmaceuticals3466. Sampling operations (new)Sampling of pharmaceutical products and relatedmaterials (new)359Index389iv346359
QAPIN 12/16/06 12:17 PM Page 1IntroductionThe quality of pharmaceuticals has been a concern of the World HealthOrganization (WHO) since its inception. The setting of global standards isrequested in Article 2 of the WHO Constitution, which cites as one of theOrganization’s functions that it should “develop, establish and promote international standards with respect to food, biological, pharmaceutical and similarproducts.”Every government allocates a substantial proportion of its total healthbudget to medicines. This proportion tends to be greatest in developingcountries, where it may exceed 40%.Without assurance that these medicines are relevant to priority health needsand that they meet acceptable standards of quality, safety and efficacy, any healthservice is evidently compromised. In developing countries considerable administrative and technical effort is directed to ensuring that patients receive effectivemedicines of good quality. It is crucial to the objective of health for all that a reliable system of medicines control be brought within the reach of every country.The supply of essential medicines of good quality was identified as one ofthe prerequisites for the delivery of health care at the International Conferenceon Primary Health Care in Alma-Ata in 1978. Similarly, the Conference ofExperts on the Rational Use of Drugs, held in Nairobi in 1985, and WHO’sRevised Drug Strategy, adopted by the World Health Assembly in May 1986,identified the effective functioning of national drug regulation and controlsystems as the only means to assure safety and quality of medicines. Yet theWorld Health Assembly continues to express great concern about the quality,safety and efficacy of medicines, particularly those products or active pharmaceutical substances imported into, or produced in, developing countries. Inrecent years counterfeit products have infiltrated certain markets in disquietingproportions. Since the founding of WHO, the World Health Assembly hasadopted many resolutions requesting the Organization to develop internationalstandards, recommendations and instruments to assure the quality of medicines,whether produced and traded nationally or internationally.In response to these resolutions, the WHO Expert Committee onSpecifications for Pharmaceutical Preparations, which was originally created toprepare The International Pharmacopoeia, has made numerous recommendations relevant to quality assurance and control. Most of these recommendations,1
QAPIN 12/16/06 12:17 PM Page 2QUALITY ASSURANCE OF PHARMACEUTICALSeven though they were made several years ago, are still valid. Thus far, however,most have been available only as separate sets of recommendations containedin annexes to various WHO Technical Reports. The recommendations are essential to all concerned with the quality assurance of medicines, but separatepublications over a period of years has made it difficult to recognize them ascomplementary parts of a comprehensive system of quality assurance.To provide easy access to this information, the appropriate annexes andupdates are reproduced in the volumes of this publication. They are supplemented with other material relevant to the quality assurance of pharmaceuticals, some already issued in the form of WHO documents. The information ispresented in logical sequence as a series of administrative instruments and technical elements of an overall quality assurance system. Readers should bear inmind that, in certain previously published texts, reference is made to WHOguidelines and other documents that have since been updated. Some of theseupdated texts are themselves included in the compendium.Volume 1 of Quality assurance of pharmaceuticals: a compendium of guidelines and related materials was published by WHO in 1997. Material relating tonational drug regulations, product assessment and registration, The InternationalPharmacopoeia and related activities, quality control laboratories, internationaltrade in pharmaceuticals and their distribution, counterfeit products, basic testsfor pharmaceutical products and training of technical personnel is collected andreproduced in Volume 1. Volume 2, first published by WHO in 1999, reproduces guidelines related to good manufacturing practices (GMP) and to theinspection of pharmaceutical manufacturers and drug distribution channels.This volume was updated in 2004, and the current version constitutes thesecond updated edition of Volume 2 including new texts and revisions adoptedto date as WHO guidelines.Both for manufacturers and at national level, GMP are an important partof a comprehensive system of quality assurance. They also represent the technical standard upon which is based the WHO Certification Scheme on theQuality of Pharmaceutical Products Moving in International Commerce. Thefirst GMP text published by WHO was developed during 1967–69 uponrequest by WHO’s Member States and was revised in 1975. In the 1980s andearly 1990s, several national and regional drug regulatory authorities issued orrevised guidelines reflecting the ongoing elaboration of the concept of GMP. Inaddition, the WHO Certification Scheme on the Quality of PharmaceuticalProducts Moving in International Commerce was extended in 1988. Together,these developments necessitated an update of the existing guidelines on GMPpublished by WHO.Revised and expanded GMP guidelines were prepared during 1989–90,approved by the WHO Expert Committee on Specifications for Pharmaceutical Preparations in late 1990 and subsequently published by WHO. At thattime, Part One of these revised and expanded guidelines set out the philosophyand essential elements of GMP; Part Two dealt with good practices in produc2
QAPIN 12/16/06 12:17 PM Page 3INTRODUCTIONtion and quality control. These two parts together represented the “core” of theGMP guidelines published by WHO.Their provisions were and still are fully consonant with those of other internationally recognized texts on GMP. GMP guidelines published by WHO areto be regarded as advisory in nature and may need to be adapted to addressspecific conditions in individual countries. However, if any departures fromrecommended practices are introduced, the equivalence of such alternativeapproaches should be validated.In 1996, GMP guidelines were published by WHO for the validation ofmanufacturing processes. These guidelines were prepared to explain andpromote the concept of validation embedded in the core GMP texts, and toassist in establishing priorities and selecting approaches when a validation programme is being developed. In 1997, the WHO Expert Committee on Specifications for Pharmaceutical Preparations approved an explanatory text on therole and functions of the “authorized person” at manufacturing establishmentsin the medicines industry. The core GMP guidelines define the authorizedperson as the person responsible for the release of batches of finished productsfor sale. The explanatory text is intended to assist manufacturers wishing tostrengthen their quality assurance systems. These concepts were integrated inits revised text in 2003. The guidance on validation has been extensively revisedand expanded. The new text has been adopted in 2005 and is now included inits revised form.GMP guidelines published by WHO in 1992–2006 constitute in the firstinstalment an ongoing series of applications of the principles of GMP to variousspecialized areas. The series of the “main” GMP texts on the manufacture ofpharmaceutical active substances and excipients, were approved by the WHOExpert Committee on Specifications for Pharmaceutical Preparations in 1992,1997, and therafter.Chapter 1 (“Main principles for pharmaceutical products”) includes thecore GMP guidelines, as well as GMP guidance texts for the heating, ventilation and air-conditioning systems; validation; and water for pharmaceutical usein their updated forms.The two texts in Chapter 2 constitute the existing body of GMP guidancefor pharmaceutical starting materials. As strict application of full GMP is notalways practical or necessary for such materials, these texts outline the procedures and practices that manufacturers should employ to ensure that themethods, facilities and controls used for their production are operated ormanaged so that pharmaceutical starting materials have the quality and purityappropriate for use in finished pharmaceutical products.On the other hand, certain specific kinds of pharmaceutical productsdemand practices or procedures not described in the core GMP guidelines. Forexample, section 17 in Part Three of the 1992 guidelines, updated in 2002 (tobe found in Chapter 3) stresses additional points necessary to minimize the risksof microbiological, particulate and pyrogen contamination in sterile pharma3
QAPIN 12/16/06 12:17 PM Page 4QUALITY ASSURANCE OF PHARMACEUTICALSceutical products. Other specialized GMP guidelines were subsequentlypublished by WHO for biological products, investigational pharmaceuticalproducts, herbal medicinal products, radiopharmaceuticals, etc.The GMP guidelines for biological products have been approved by boththe WHO Expert Committee on Biological Standardization and the WHOExpert Committee on Specifications for Pharmaceutical Preparations. Unlikeconventional pharmaceutical products which are normally produced and controlled by means of reproducible chemical and physical techniques, biologicalproducts are manufactured with biological materials and processes, such as thecultivation of cells or the extraction of materials from living organisms. As suchmaterials and processes display inherent variability, the range and nature of manufacturing by-products in biological products are likewise variable. For suchproducts, including allergens, antigens, vaccines, hormones, cytokines, enzymes,human whole-blood and plasma derivatives, immune sera, immunoglobulins,products of fermentation and diagnostic agents for in vitro use, full adherenceto the GMP guidelines for biological products is recommended for all production steps, including those from which active ingredients are produced.The GMP guidelines for the manufacture of investigational pharmaceuticalproducts for clinical trials in humans supplement both the core GMP guidelines for pharmaceutical products and “Guidelines for good clinical practice(GCP) for trials on pharmaceutical products” (WHO Technical Report Series,No. 850, 1995, pp. 97–137). These specialized GMP guidelines specificallyaddress those manufacturing practices that may be different for investigationalproducts (which are not usually manufactured in accordance with a set routine),and which may be incompletely characterized during the initial stages ofclinical development.The specialized GMP guidelines for the manufacture of herbal medicinalproducts address the manufacture of products from material of plant origin,which may be subject to contamination and deterioration and vary in its composition and properties. Furthermore, in the manufacture and quality controlof herbal medicinal products, procedures and techniques are often used that aresubstantially different from those employed for conventional pharmaceuticalproducts. The newly revised text was adopted by the Expert Committee in 2005(WHO Technical Report Series, No. 937, 2006, pp. 85–116).The text on radiopharmaceuticals has been developed in close collaboration with the International Atomic Energy Agency (IAEA). The text coversradiopharmaceutical products that are prepared in hospital radiopharmacies,centralized radiopharmacies, nuclear centres and insititutes or by industrialmanufacturers, as well as in positron emission tomography (PET) centres.These five sets of specialized guidelines—for sterile, biological, investigational and herbal products and for radiopharmaceuticals—are reproduced inChapter 3 (Specific pharmaceutical products).Inspection is closely related to other elements of the overall medicinesquality assurance system: GMP, licensing of manufacturing facilities, product4
QAPIN 12/16/06 12:17 PM Page 5INTRODUCTIONregistration, etc. Without a competent inspectorate operating to high professional standards, neither GMP compliance nor licensing provisions can be effectively enforced. In addition, inspection of manufacturing facilities is pivotal tothe operation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce, which provides for theissuance of an attestation that a given product is manufactured under GMP conditions as established by periodic inspections.A text on pre-approval inspections was developed to complement the texton inspections, described below. These guidelines apply to the inspection ofmanufacturing and quality control facilities prior to the issuing of a marketingauthorization for a pharmaceutical product.A text entitled “Provisional guidelines on the inspection of pharmaceuticalmanufacturers” was published by WHO in 1992 along with the core GMPguidelines on pharmaceutical products. The provisional guidelines wereintended to promote the harmonization of inspection practices among WHOMember States, and the Expert Committee noted that they would be of particular value to government inspectors operating within small national regulatoryauthorities.In general, the objective of inspecting pharmaceutical manufacturing facilities is either to enforce general GMP compliance or to provide authorizationfor the manufacture of specific pharmaceutical products, usually in relation toan application for registration. The provisional guidelines are applicable mostlyto inspections of the first type, whether performed before a manufacturingauthorization is issued, or on a periodic, routine basis.A further aspect of pharmaceutical inspection is monitoring the quality ofpharmaceutical products in distribution channels, that is, from the point of manufacture to delivery to the recipient. In recent years the hazard posed by theinfiltration of counterfeit products has been identified in addition to problemsrelated to the inadequate stability of drug products and their improper handlingand storage. The text “Guidelines for inspection of drug distribution channels”,part of the Thirty-fifth report of the WHO Expert Committee on Specificationsfor Pharmaceutical Preparations, is included in this volume and providesdetailed advice to national drug regulatory authorities on the inspection ofdistribution channels.The provisional guidelines on the inspection of pharmaceutical manufacturers and the guidelines for inspection of drug distribution channels arereproduced in Chapter 4 (“Inspections”).With the worldwide acceptance of the ISO 9000-series standards addressing quality management and quality systems, a trend has emerged in someMember States for non-commercial institutions such as certification bodies,testing laboratories and the like to introduce principles of quality systems intotheir internal operations. The same principles have begun to be applied togovernmental pharmaceutical inspectorates and medicines control laboratories.The WHO Expert Committee on Specifications for Pharmaceutical Preparations5
QAPIN 12/16/06 12:17 PM Page 6QUALITY ASSURANCE OF PHARMACEUTICALSrecently recommended that further guidance in this area should address theintroduction of quality systems principles in the practice of pharmaceuticalinspections.Following the publication of the guidance texts on inspections, additionalguidelines dealing with the quality system requirements for national good manufacturing practice inspectorates were adopted by the Expert Committee. Thisguidance is one important tool when implementing GMP. The establishmentand operation of a quality system is an essential element in the mutual recognition among inspectorates. The quality system should include all activitiesinvolved in the inspection.To complement the set of guidance texts in this area, the Expert Committeeadopted a model layout for an inspection report, as well as a model certificateof GMP for a manufacturing site.H
Vol. 2, Good manufacturing practices and inspection. – 2nd ed. 1.Drug and narcotic control – standards 2.Drug industry – standards 3.Pharmaceutical preparations – standards 4.Biological products – standards 5.Quality control 6.Guidelines I.World Health Organization II.Title: Good manufacturing practices and inspection
critical issues the University has established a Quality Assurance Directorate, which is mandated to develop a Quality Assurance Framework and a Quality Assurance Policy. The Quality Assurance Framework would clearly spell out the Principles, Guidelines and Procedures for implementing institutional quality assurance processes.
In order to ensure the safe and swift provision of pharmaceuticals, medical devices, etc., necessary . Responsibility pertaining to the assurance, etc., of the quality, efficacy and safety of pharmaceuticals etc. is imposed on relevant parties. (3) Marketers of pharmaceuticals etc. are to prepare package inserts based on the latest findings .
Quality Assurance and Improvement Framework Guidance 2 Contents Section 1: Quality Assurance and Improvement Framework 1.1 Overview 1.1.1 Quality Assurance (QA) 1.1.2 Quality Improvement (QI) 1.1.3 Access 1.2 Funding Section 2: Quality Assurance 2.1 General information on indicators 2.1.1 Disease registers 2.1.2 Verification
Software Quality Assurance Plan (SQAP) for the SRR-CWDA-2010-00080 H-Area Tank Farm (HTF) Performance Revision 0 Assessment (PA) Probabilistic Model August 2010 Page 5 of 15 1.0 SCOPE This Software Quality Assurance Plan (SQAP) was developed in accordance with the 1Q Quality Assurance Manual, Quality Assurance Procedure (QAP) 20-1, Rev. 11.
This quality assurance manual specifies the methods to prepare and submit Quality Assurance Process Design Diagram for products and parts to be supplied to NSK by suppliers. 2. Purpose Each supplier should prepare quality assurance process design diagram clearly showing the quality assurance methods used in each products and parts production .
Quality Assurance Representative. The Site Manager will appoint a member of the Project Office to control all Quality Assurance issues including - Assisting the Site Manager to co-ordinate and develop the Quality Assurance Plan. Advise Engineers, General Foremen, Foremen and Chargehands in all matters of Quality Assurance.
Quality assurance or software quality assurance is an integral part of the development process and is used in the IT industry by quality assurance professionals as well as testers. Quality assurance is associated with the concept of dependability. Dependability is, first, a guarantee of increased cybersecurity, reliability and
Quality Assurance and Quality Control (QA/QC) policy. Quality assurance/quality control measures for water treatment utilities refer to a set of activities that are to be undertaken to ensure compliance and above all, ensure that the water is safe for public consumption in a sustainable manner. In general, quality assurance (QA) refers to the
