WHO GOOD PRACTICES FOR PHARMACEUTICAL MICROBIOLOGY .
Working document QAS/09.297/Rev.2July 2010RESTRICTEDWHO GOOD PRACTICES FORPHARMACEUTICAL MICROBIOLOGY LABORATORIESDRAFT FOR COMMENTPlease address comments on this proposal, by 1 October 2010, to Dr A.J. van Zyl,Head of Inspections, Prequalification Programme, Quality Assurance and Safety:Medicines, World Health Organization, 1211 Geneva 27, Switzerland, e-mail:vanzyla@who.int with a copy to Mrs M. Gaspard (gaspardm@who.int).During the past few years we have moved more towards an electronic systemfor sending out our working documents for comment, for convenience and inorder to speed up the process. If you do not already receive our documentselectronically, please let us have your e-mail address (to bonnyw@who.int)and we will add it to our electronic mailing list. World Health Organization 2010All rights reserved.This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. Thedraft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole,in any form or by any means outside these individuals and organizations (including the organizations' concerned staff andmember organizations) without the permission of the World Health Organization. The draft should not be displayed on anyweb site.Please send any request for permission to:Dr A.J. van Zyl, Head of Inspections, Prequalification Programme, Quality Assurance and Safety: Medicines, Department ofEssential Medicines and Pharmaceutical Policies, World Health Organization, CH-1211 Geneva 27, Switzerland;e-mail: vanzyla@who.int.The designations employed and the presentation of the material in this draft do not imply the expression of any opinionwhatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area orof its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximateborder lines for which there may not yet be full agreement.The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed orrecommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errorsand omissions excepted, the names of proprietary products are distinguished by initial capital letters.All reasonable precautions have been taken by the World Health Organization to verify the information contained in thisdraft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. Theresponsibility for the interpretation and use of the material lies with the reader. In no event shall the World HealthOrganization be liable for damages arising from its use.This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
Working document QAS/09.297/Rev.2page 2SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENTQAS/09.297/Rev.2:WHO GOOD PRACTICES FORPHARMACEUTICAL MICROBIOLOGY LABORATORIESTopic identified by prequalification inspectors4-5 April 2007Proposal discussed in informal consultation on new approaches andrisk evaluation for manufacture of medicines and subsequentlyrecommended to next meeting of the WHO Expert Committee onSpecifications for Pharmaceutical Preparations30 May-1 June 200742nd WHO Expert Committee on Specifications for PharmaceuticalPreparations adopted a recommendation to prepare new guidance15-19 October 2007Identification of resource person and preparation of first draft text byDr Deus Mubangizi (WHO Prequalification Inspection Programme)December 2007March 20092-3 April 2009Presentation of first draft to inspectors assisting in the WHOPrequalification Programme at meeting on good manufacturing practice(GMP) and inspections, Geneva, SwitzerlandCirculation for feedback among specialistsApril-June 2009Discussion during informal consultation on WHO guidelines formedicines quality assurance, quality control laboratories and transferof technology of feedback received27-31 July 2009Mailing (wide distribution) of document for commentsAugust 2009Review of comments receivedSeptember-October 2009Revision drafted by Mr Neil Raw, GMP Inspector, London, UnitedKingdomOctober 2009Presentation as a draft document to 44th WHO Expert Committee onSpecifications for Pharmaceutical Preparations12-16 October 2009Circulation of revised draft for commentsNovember 2009Collation of comments receivedFebruary-March 2010Discussion during the information consultation on quality assurancesystems, medicines and risk analysis4-6 May 2010
Working document QAS/09.297/Rev.2page 3Revision 2 of document mailed out for commentsAugust 2010Presentation to WHO Expert Committee on Specifications forPharmaceutical Preparations18-22 October 2010Further follow-up as necessaryBACKGROUNDThe WHO Expert Committee on Specifications for Pharmaceutical Preparations adopted in2009 a revised version of the Good practices for pharmaceutical quality controllaboratories (1).During the inspections carried out when prequalifying laboratories, the inspectors hadnoticed that some of the texts of these guidelines might benefit from additional guidance,with a special focus on microbiology.In light of the above, the Expert Committee recommended that the WHO Secretariat initiatethe process of developing a new text on good practices for pharmaceutical microbiologylaboratories.On the basis of the above, the following text is proposed to cover this specific type oflaboratory.
Working document QAS/09.297/Rev.2page 4CONTENTSpageIntroduction and scope of document. 5Glossary . 61. Personnel. 72. Environment. 82.1Premises . 92.2Environmental monitoring in the laboratory. 82.3Cleaning, disinfection and hygiene. 92.4Sterility test facilities . 103. Validation of test methods . 114. Equipment . 124.1Maintenance of equipment. 124.2Qualification . 124.3Calibration and monitoring . 125. Reagents and culture media . 155.1Reagents. 155.2Media . 155.3Labelling . 165.4Media resuscitation . 166. Reference materials and reference cultures . 176.1International standards and pharmacopoeial reference standards. 176.2Reference cultures. 177. Sampling . 178. Sample handling and identification . 189. Disposal of contaminated waste. 1910. Quality assurance of results/quality control of performance . . 1910.1 Internal quality control. 1911. Testing procedures . 1911.1 Sterility testing . 1912. Test reports. 19References. 20Appendix A: General use of reference cultures . 22Appendix B: Examples of calibration and calibration checks . 23Appendix C: Examples of equipment qualification and monitoring . 24Appendix D: Examples of maintenance of equipment . 26Appendix E: Examples of zones in which operations could be carried out. 26
Working document QAS/09.297/Rev.2page 5INTRODUCTION AND SCOPE OF DOCUMENTPharmaceutical microbiology laboratories may be involved in:– sterility testing;– detection, isolation, enumeration and identification of microorganisms (bacteria, yest,and moulds) and their metabolites (including endotoxins) in different materials (e.g.starting materials, water, air), products, surfaces, garments and the environment;– assay using microorganisms as part of the test system.This guideline relates to all microbiology laboratories involved in the above outlined testingactivities, whether they are independent or a department/unit of a pharmaceutical manufacturingfacility.This guideline is based on and supplements the requirements described in Good practicesfor pharmaceutical quality control laboratories (1); General guidelines for theestablishment, maintenance and distribution of chemical reference substances. Revision.(2); The International Pharmacopoeia. Fourth edition (3); First Supplement to TheInternational Pharmacopoeia. Fourth Edition (4); and General requirements for thecompetence of testing and calibration laboratories (5).GLOSSARYCalibrationThe set of operations that establish, under specified conditions, the relationship betweenvalues indicated by an instrument or system for measuring (especially weighing),recording and controlling, or the values represented by a material measure, and thecorresponding known values of a reference standard. Limits for acceptance of the resultsof measuring should be established (WHO).Certified reference materialReference material, characterized by a metrologically valid procedure for one or morespecified properties, accompanied by a certificate that provides the value of the specifiedproperty, its associated uncertainty and a statement of metrological traceability (WHO).False negative resultOccurs when the alternative method gives a positive result without confirmation when thereference method gives a negative result. This deviation becomes a false positive result whenthe true result can be proved as being negative.False positive resultOccurs when the alternative method gives a negative result without confirmation when thereference method gives a positive result. This deviation becomes a false negative result whenthe true result can be proved as being positive.
Working document QAS/09.297/Rev.2page 6Limit of detectionApplied to qualitative microbiological tests. The lowest number of microorganisms that can bedetected, but in numbers that cannot be estimated accurately.Limit of determinationApplied to quantitative microbiological tests. The lowest number of microorganisms within adefined variability that may be determined under the experimental conditions of the methodunder evaluation.Quantitation limit (limit of quantitation)The lowest concentration of an analyte in a sample that may be determined with acceptableaccuracy and precision (WHO).PrecisionThe degree of agreement among individual results (WHO).Reference culturesCollective term for reference strain and reference stocks.Reference materialMaterial sufficiently homogeneous and stable with respect to one or more specified properties, whas been established to be fit for its intended use in a measurement process (WHO).Reference methodA method which has been validated as being fit for purpose, with which an alternative methodmay be compared.Reference stocksA set of separate identical cultures obtained by a single subculture from the reference strain(ISO 11133-1:2000).Reference strainsMicroorganisms defined at least to the genus and species level, catalogued and describedaccording to its characteristics and preferably stating its origin (ISO 11133-1:2000). Normallyobtained from a recognized national or international collection.RepeatabilityCloseness of the agreement between the results of successive measurements of the samemeasure and under the same conditions of measurement (adjusted from ISO).ReproducibilityReproducibility expresses precision between laboratories (WHO)Robustness (or ruggedness)The ability of the procedure to provide analytical results of acceptable accuracy and precisionunder a variety of conditions (WHO).
Working document QAS/09.297/Rev.2page 7SensitivityThe fraction of the total number of positive cultures or colonies correctly assigned in thepresumptive inspection (ISO 13843:2000).Specificity (selectivity)The ability to measure unequivocally the desired analyte in the presence of components such asexcipients and impurities that may also be expected to be present (WHO).ValidationAction of proving, in accordance with the principles of GXP, that any procedure, process,equipment (including the software or hardware used), material, activity or system actually andconsistently leads to the expected results (WHO).VerificationThe application of methods, procedures, tests and other evaluations, in addition to monitoring,to determine compliance with GXP principles (WHO.)Working cultureA primary subculture from a reference stock (ISO 11133-1:2000).1.PERSONNEL1.1Microbiological testing should be performed and supervised by an experienced person,qualified in microbiology or equivalent. Staff should have basic training in microbiology andrelevant practical experience before being allowed to perform work covered by the scope oftesting.1.2The laboratory should maintain current job descriptions for all personnel involved intests and/or calibrations, validations and verifications. The laboratory should also maintainrecords of all technical personnel, describing their qualifications, training and experience.1.3If the laboratory includes opinions and interpretations of test results in reports, thisshould be done by authorized personnel with suitable experience and relevant knowledge of thespecific application including, for example, legislative and technological requirements andacceptability criteria.1.4The laboratory management should ensure that all personnel have received adequatetraining for the competent performance of tests and operation of equipment. This shouldinclude training in basic techniques, e.g. plate pouring, counting of colonies, aseptic technique,etc., with acceptability determined using objective criteria where relevant. Personnel may onlyperform tests on samples if they are either recognized as competent to do so, or if they do sounder adequate supervision. Ongoing competence should be monitored objectively withprovision for retraining where necessary. Where a method or technique is not in regular use,verification of personnel performance before testing is undertaken may be necessary. In some
Working document QAS/09.297/Rev.2page 8cases it is acceptable to relate competence to a general technique or instrument used rather thanto particular methods.1.5Personnel should be trained in necessarymicroorganisms within the laboratory facility.procedures1.6Personnel should be trained in safe handling of entof2.1.1 Microbiology laboratories and certain support equipment (e.g. autoclaves,glassware) should be dedicated and separated from other areas.2.1.2 Microbiology laboratories should be designed to suit the operations to be carriedout in them. There should be sufficient space for all activities to avoid mix-ups, Thereshould be adequate suitable space for samples, reference organisms, media (if necessary,with cooling), testing and records. Due to the nature of some materials, separate storagelocations may be necessary, e.g. biological indicators, reference organisms and media.2.1.3 Laboratories should be appropriately designed and should take into account thesuitability of construction materials to enable appropriate cleaning, disinfection andminimize the risks of contamination.2.1.4 There should be separate air supply to laboratories and production areas. Separateair-handling units and other provisions, including temperature and humidity whererequired, are needed for microbiological laboratories. The quality of the air supplied tothe laboratory should be appropriate to the tests being carried out and their quality shouldnot be a source of contamination.2.1.5 Access to the microbiological laboratory should be restricted to authorized personnel.Personnel should be made aware of:– the appropriate entry and exit procedures including gowning;– the intended use of a particular area;– the restrictions imposed on working within such areas;– the reasons for imposing such restrictions; and– the appropriate containment levels.2.1.6 Laboratory activities, such as sample preparation, media and equipment preparation andenumeration of microorganisms, should be segregated by space or at least time, so as tominimize risks of cross-contamination and false positives. Where non-dedicated arras are used,risk management principles should be applied. Sterility testing should always be performed in adedicated area.
Working document QAS/09.297/Rev.2page 92.1.7 Operations should be carried out preferably in the following zones:ZoneSample receiptMedia prepAutoclave loadingAutoclave unloadingSterility testing – UDAFSterility testing – llationgradeUnclassifiedGrade DGrade DGrade BGrade AGrade BGrade DGrade DGrade DProposedUnclassifiedISO 8 & 200 cfu1/m2ISO 8 & 200 cfu/m2ISO 5 (turbulent) & 50 cfu/m2ISO 5 (UDAF) & 1 cfu/m2ISO 5 (turbulent) & 50 cfu/m2ISO 8 & 200 cfu/m2ISO 8 & 200 cfu/m2ISO 8 & 200 cfu/m2Note from Secretariat:Feedback on the usefulness of this table either within the text or as Annex E is requested.2.1.8 In general laboratory equipment should not routinely be moved between areas to avoidaccidental cross-contamination. Laboratory equipment used in the microbiology laboratoryshould not be used outside the microbiology area, unless there are specific precautions in placeto prevent cross-contamination.2.2Environmental monitoring in the laboratory2.2.1 Where appropriate an environmental monitoring programme should be in place whichcovers, for example, use of air settlement plates and surface swabbing, temperature andpressure differentials. Alert and action limits should be defined. Trending of environmentalmonitoring results shall be carried out.2.3Cleaning, disinfection and hygiene2.3.1 There should be a documented cleaning and disinfection programme. Results
noticed that some of the texts of these guidelines might benefit from additional guidance, with a special focus on microbiology. In light of the above, the Expert Committee recommended that the WHO Secretariat initiate the process of developing a new text on good practices for pharmaceutical microbiology laboratories. On the basis of the above, the following text is proposed to cover this .
Bruksanvisning för bilstereo . Bruksanvisning for bilstereo . Instrukcja obsługi samochodowego odtwarzacza stereo . Operating Instructions for Car Stereo . 610-104 . SV . Bruksanvisning i original
10 tips och tricks för att lyckas med ert sap-projekt 20 SAPSANYTT 2/2015 De flesta projektledare känner säkert till Cobb’s paradox. Martin Cobb verkade som CIO för sekretariatet för Treasury Board of Canada 1995 då han ställde frågan
service i Norge och Finland drivs inom ramen för ett enskilt företag (NRK. 1 och Yleisradio), fin ns det i Sverige tre: Ett för tv (Sveriges Television , SVT ), ett för radio (Sveriges Radio , SR ) och ett för utbildnings program (Sveriges Utbildningsradio, UR, vilket till följd av sin begränsade storlek inte återfinns bland de 25 största
Hotell För hotell anges de tre klasserna A/B, C och D. Det betyder att den "normala" standarden C är acceptabel men att motiven för en högre standard är starka. Ljudklass C motsvarar de tidigare normkraven för hotell, ljudklass A/B motsvarar kraven för moderna hotell med hög standard och ljudklass D kan användas vid
LÄS NOGGRANT FÖLJANDE VILLKOR FÖR APPLE DEVELOPER PROGRAM LICENCE . Apple Developer Program License Agreement Syfte Du vill använda Apple-mjukvara (enligt definitionen nedan) för att utveckla en eller flera Applikationer (enligt definitionen nedan) för Apple-märkta produkter. . Applikationer som utvecklas för iOS-produkter, Apple .
och krav. Maskinerna skriver ut upp till fyra tum breda etiketter med direkt termoteknik och termotransferteknik och är lämpliga för en lång rad användningsområden på vertikala marknader. TD-seriens professionella etikettskrivare för . skrivbordet. Brothers nya avancerade 4-tums etikettskrivare för skrivbordet är effektiva och enkla att
Den kanadensiska språkvetaren Jim Cummins har visat i sin forskning från år 1979 att det kan ta 1 till 3 år för att lära sig ett vardagsspråk och mellan 5 till 7 år för att behärska ett akademiskt språk.4 Han införde två begrepp för att beskriva elevernas språkliga kompetens: BI
**Godkänd av MAN för upp till 120 000 km och Mercedes Benz, Volvo och Renault för upp till 100 000 km i enlighet med deras specifikationer. Faktiskt oljebyte beror på motortyp, körförhållanden, servicehistorik, OBD och bränslekvalitet. Se alltid tillverkarens instruktionsbok. Art.Nr. 159CAC Art.Nr. 159CAA Art.Nr. 159CAB Art.Nr. 217B1B
