Presentation on theme: "QC | Slide 1 of 83 August 2006 Good Practices for Quality Control Laboratories WHO Training material amended by Dr. AJ van Zyl for the training workshop."— Presentation transcript:
QC | Slide 1 of 83 August 2006 Good Practices for Quality Control Laboratories WHO Training material amended by Dr. AJ van Zyl for the training workshop in Dar Es Salaam, Tanzania, August 2006 Supplementary Training Modules on Good Manufacturing Practice WHO Technical Report Series, No. 902, 2002. Annex 3
QC | Slide 2 of 83 August 2006 Introduction This QC training module consists of 4 parts: Part 1: Management and organization Part 2: Materials, equipment, instruments and devices Part 3: Working procedures and documents, and safety in the laboratory Part 4: Inspecting the laboratory Part One. Quality Control
QC | Slide 3 of 83 August 2006 Objectives To discuss Good Practices for Quality Control laboratories including quality systems and infrastructure To understand the role and importance of the Quality Control laboratory in: –Sampling and testing –Materials, equipment and systems To discuss approaches in inspecting a Quality Control laboratory Part One Quality Control
QC | Slide 4 of 83 August 2006 Quality Control Part One. Management and infrastructure 1. Organization and management 2. Quality system 3. Control of documentation 4. Records 5. Data processing equipment 6. Personnel 7. Premises 8. Equipment, instruments and other devices
QC | Slide 5 of 83 August 2006 Quality Control Part Two. Materials and set-up of equipment, instruments and other devices 9. Specifications archive 10. Reagents 11. Reference materials 12. Calibration, validation and verification of equipment, instruments and other devices 13. Traceability
QC | Slide 6 of 83 August 2006 Quality Control Part Three. Working procedures 14. Incoming sample 15. Analytical worksheet 16. Testing 17. Evaluation of test results 18. Retained samples Part Four. Safety in pharmaceutical control laboratories 19. General rules
QC | Slide 7 of 83 August 2006 Background Recommendations relevant to quality control testing at the site of the pharmaceutical manufacturer Laboratory provides a service - like a manufacturing unit “ products ” include test results, advice and investigations Needs –buildings, personnel, resources –equipment, raw materials –quality assurance program Part One. Quality Control
QC | Slide 8 of 83 August 2006 When starting to review compliance e.g. during inspection: Preparation with background information Materials and products SMF Product dossier (e.g. specifications, tests) Quality Control
QC | Slide 9 of 83 August 2006 Assess implementation and compliance with all the recommendations GMP GP NCL Different approaches (systematic, material or product flow) Quality Control
QC | Slide 10 of 83 August 2006 Start at laboratory, walk through and assessing Organization and management: Suitable size, construction and location - safety requirements considered in the design Adequate degree of separation of the activities Sufficient number of rooms or areas to assure the isolation of test systems. Suitable testing and safety equipment –E.g. voltage stabilizers should be installed where needed Storage rooms or areas for supplies and materials with protection against infestation, contamination, and/or deterioration. Quality Control Part One. 7.1. – 7.5.
QC | Slide 11 of 83 August 2006 Premises (2) Separate areas for receipt, storage and sample preparation to prevent contamination or mix-ups Ensure maintaining identity, concentration, purity, and stability Safe storage of hazardous substances Fire regulations Flammable reagents, fuming and concentrated acids, bases, volatile amines – safe storage separately Quality Control Part One. 7.6. – 7.7.
QC | Slide 12 of 83 August 2006 Storage areas and central store Separate for secure storage of samples, retained samples, reagents, laboratory accessories, reference materials Appropriate storage conditions e.g. refrigeration where necessary Restricted access to designated personnel Organized to accommodate incoming and outgoing samples, reagents, equipment, instruments and other devices Quality Control Part One. 188.8.131.52. – 184.108.40.206
QC | Slide 13 of 83 August 2006 Appropriate storage conditions. Storage area with clean bottles, vials, spoons, funnels, and labels required for dispensing reagents from larger to smaller containers Store keeper responsibilities: Store and inventory, expiry dates Areas for flammable substances, for fuming and concentrated acids etc Self-igniting materials, such as metallic sodium stored separately. Part Two. 10.7.1. – 10.7.3. Quality Control
QC | Slide 14 of 83 August 2006 Central store (2) Safety instructions if toxic or flammable reagents are stored or used. Poison, narcotic and psychotropic substances –Marked as "Poison", kept separately, in locked cabinets –Register maintained Archive facilities –documents, samples and specimens –Conditions to protect from deterioration, and access restricted Handling and disposal of wastes –Facilities for collection, storage and disposal –Decontamination, where applicable, and transportation. Quality Control Part One. 220.127.116.11. – 7.10.
QC | Slide 15 of 83 August 2006 Personnel Sufficient number, with necessary education, training, technical knowledge and experience No conflict of interest or other pressure Competence ensured for activities, performing tests and/or calibrations, validations or verifications, evaluation of results and signing test reports and calibration certificates Staff undergoing training - supervised, with formal assessment after training Personnel must be qualified on the basis of appropriate education, training, experience and/or demonstrated skills Quality Control Part One. 6.1 – 6.3.
QC | Slide 16 of 83 August 2006 Personnel (2) Permanently employed, or under contract Contracted personnel to be supervised and sufficiently competent, motivated – work complying good practice of the laboratory. Current job descriptions for managerial, technical and key support personnel Records of competence, educational and professional qualifications, training, skills and experience –Readily available, and include date of confirmation of competence, plus criteria for confirmation and name of the confirming authority. Quality Control Part One. 6.4 – 6.5
QC | Slide 17 of 83 August 2006 Managerial and technical personnel: Head of laboratory (supervisor) Head of central registry Analysts Technical staff Head of central store Quality Manager Quality Control Part One. 6.6
QC | Slide 18 of 83 August 2006 Quality system: Management to establish, implement and maintain quality system that covers policies, systems, programmes, procedures and instructions Communicated, available, understood and implemented Documented in a quality manual –available to the laboratory personnel –maintained and updated by a responsible person Quality Control Part One. 2.1.
QC | Slide 19 of 83 August 2006 The quality manual should contain at least: Organizational chart; operational and functional activities; General and specific quality assurance procedures; Proficiency testing schemes; Use of reference materials; Feedback and corrective action (for testing discrepancies) Procedure for dealing with complaints; A flow chart for samples; Details of audit and quality system review; Qualification of personnel; Training and maintaining competence of staff; and A quality policy statement. Quality Control Part One. 2.1.
QC | Slide 20 of 83 August 2006 The quality policy should include at least: A statement of the standard of service it will provide The purpose of the quality system Management's commitment to: –Good professional practice and quality of testing, calibration, validation and verification, as a service to its clients –Compliance with Good Practices All personnel to familiarize themselves with the documentation concerning quality, implementation of the policies and procedures Quality Control Part One. 2.1.
QC | Slide 21 of 83 August 2006 The quality system must be reviewed systematically and periodically –E.g. internal and external audits with reports and details of any corrective action taken. Laboratory quality manager appointed with: –Defined responsibilities and authority for ensuring that the quality system is implemented and followed at all times. –Direct access to the highest level of management at which decisions are taken on laboratory policies or resources Quality Control Part One. 2.2. - 2.3.
QC | Slide 22 of 83 August 2006 Control of documents Documentation (essential part of QA) Procedures to control and review all documents The laboratory must establish and maintain procedures for: –identification, collection, indexing, access, storage, maintenance and disposal of quality documentation and technical records. Quality Control Part One. 3.1.
QC | Slide 23 of 83 August 2006 SOPs: Written and authorized For administrative and technical operations, such as: Purchase and receipt of consignment of materials –e.g. samples, reference material, reagents Internal labelling, quarantine, and storage of materials Appropriate installation of each instrument and equipment Sampling and inspection Testing materials, describing the methods and equipment used Quality Control Part One. 4.4.
QC | Slide 24 of 83 August 2006 Other SOPs... Qualification, analytical apparatus Calibration, maintenance, cleaning, sanitation Safety measures Personnel matters including –qualification, training, clothing, and hygiene Environmental monitoring Preparation and control of reference materials. Quality Control Part One. 4.4.
QC | Slide 25 of 83 August 2006 Verify compliance (in practice) From register, select a batch of API, excipient and finished product Request specifications and test methods Retention samples Verify information in register against sampling sheet, PO, delivery note, incoming goods register, analytical report, sampling SOP etc Quality Control
QC | Slide 26 of 83 August 2006 Specifications archive Current versions of all specifications Pharmacopoeia compendia or in manufacturers' registration documents. Archive must contain: List of all pharmacopoeias in the laboratory – all updates and corrections must be noted; – adequate numbers of supplements and addenda. File of non-pharmacopoeia quality specifications – numbered and dated, latest version; – information relevant to the status of the quality specifications; – corrections or changes appropriately handled, including producing a revised document as soon as possible. Part Two. 9.1. – 9.2. Quality Control
QC | Slide 27 of 83 August 2006 Specifications archive Use of the master copy – photocopies accounted for and controlled for use Confidentiality of specifications Responsibility defined for: Updating all pharmacopoeias - including supplements, addenda, and corrective measures used in the laboratory; Maintaining a specifications file Part Two. 9.3. – 9.5. Quality Control
QC | Slide 28 of 83 August 2006 E.g. Artesunate What should you look for initially? Quality Control
QC | Slide 29 of 83 August 2006 Incoming samples (Sampling plan and procedures) Sample size sufficient for: – the tests to be performed – replicate tests – retained / retention sample The laboratory must have a sampling plan and internal procedure for sampling, available to all analysts and technicians within the laboratory Part Three. 14.1.1. – 14.4.3. Quality Control
QC | Slide 30 of 83 August 2006 Test request can be filled out during sampling - accompany each sample submitted to the laboratory, and should contain the following information e.g.: source of the material full description including its International Nonproprietary Name, concentration or strength, manufacturer, and batch number (if available), size of the sample reason for requesting the analysis date on which the sample was collected Part Three. 14.2.1. – 18.104.22.168. Quality Control
QC | Slide 31 of 83 August 2006 (cont): size of the consignment from which it was taken, when appropriate expiry date (pharmaceutical product) retest date, (starting material, pharmaceutical excipients) pharmacopoeia specifications or other official specifications to be used for testing record of further comments (e.g. discrepancies found) required storage conditions Part Three. 14.2.1. – 22.214.171.124. Quality Control
QC | Slide 32 of 83 August 2006 Registration and labelling All samples should be assigned a registration number Separate registration numbers - different batches A label with appropriate information on each container of the sample Part Three. 14.3.1. – 14.3.2. Quality Control
QC | Slide 33 of 83 August 2006 Central register The following information should be recorded: registration number date of receipt specific unit to which the sample was forwarded. Sample received should be inspected: the findings must be recorded, dated and initialled discrepancies and damage recorded queries referred back to the provider of the sample Part Three. 14.4.1. – 14.5.1. Quality Control
QC | Slide 34 of 83 August 2006 Storage The sample prior to testing, the retained sample and any remaining portions of the sample after performance of all required tests must be stored safely (storage conditions) Analysis is determined by the head The sample must be stored until all relevant documentation has been received Request for analysis may be accepted verbally only in case of emergencies Data recorded on the analytical worksheet Copies or duplicates of all documentation must accompany each numbered sample when sent to the specific unit. Part Three. 14.6.1. -14.9. Quality Control
QC | Slide 35 of 83 August 2006 Specification as per dossier Version and reference number Reference to test methods/procedures Test parameters and acceptance limits Verify tests done Quality Control
QC | Slide 36 of 83 August 2006 Identification on sample from each container Verify spectrum and or chromatogram (number of containers) Traceability to instrument used, reference standard used, analyst, date, source data (preparation of sample e.g. logbook or worksheets) Refer to the test method for materials required Quality Control
QC | Slide 37 of 83 August 2006 4. Records All original observations, calculations and derived data, calibration, validation and verification records etc. and final results must be retained on record for an appropriate period of time e.g. – whole length of time the drug is on the market Records to contain sufficient information to permit repetition of tests and include e.g.: –identity of the personnel involved in sampling, preparation and testing of the samples –Instruments, equipment etc. Quality Control Part One. 4.1 – 4.2.
QC | Slide 38 of 83 August 2006 Records must be: Legible and readily retrievable Stored and retained in a manner that prevents modification, damage or deterioration and/or loss Held secure and in confidence Includes reports from internal audits and management reviews and records from possible corrective and preventive actions Quality Control Part One. 4.3.
QC | Slide 39 of 83 August 2006 Analytical worksheet An internal document in a printed form for recording information Complemented by the raw data obtained in the analysis One used for each numbered sample A further set of analytical worksheets in duplicate can be used for a collaborating unit (after testing, all results are assembled in one analytical worksheet, using the data from all collaborating units). Part Three. 15.1. – 15.3.2. Quality Control
QC | Slide 40 of 83 August 2006 The analytical worksheet must provide or leave space for the following information: registration number of the sample page numbering including total number of pages (including annexes) date of the test request date of analysis performed name and signature of analyst description of the sample received reference to the specifications to which the sample was tested including limits (adding any or special methods employed) - reference number of the specifications, if available (e.g. pharmacopoeia monograph) Part Three. 15.4.1. Quality Control
QC | Slide 41 of 83 August 2006 The analytical worksheet must provide or leave space for the following information (cont): results obtained of tested sample the interpretation of the results and the final conclusions, signed by each of the analysts involved and initialled by the supervisor the identity of the test equipment used further comments, for example, for internal information Part Three. 15.4.1. Quality Control
QC | Slide 42 of 83 August 2006 The above information may be complemented by: detailed notes on the specifications selected and the methods of assessment used whether and when portions of the sample were forwarded to other units for special tests (for example, mass spectrometry, x- ray diffraction), and the date when the results were received identification number of any reference material if applicable, data to be attached of an instrument verification if applicable, data to be attached of a reagent verification. Part Three. 15.4.1. Quality Control
QC | Slide 43 of 83 August 2006 The completed analytical worksheet must be signed by the responsible analyst/s and initialled by the supervisor. Specifications necessary to assess the sample: Particular pharmacopoeia monograph Manufacturer’s specifications National pharmacopoeia to be used Specifications contained in the product licence, and should be the current version Part Three. 15.4.2. – 15.5.2. Quality Control
QC | Slide 44 of 83 August 2006 Verification of data: Reference standard (library?), batch number Primary/official standard or working standard Procedure for preparation (who, how, where, container, labelling, records, tests, expiry date, storage condition) Use log – and information file Quality Control
QC | Slide 45 of 83 August 2006 Reference materials have assigned values of a quantity. Hierarchy for reference materials: Primary chemical substance – has appropriate qualities within a specified context, and whose value is accepted without requiring comparison to another chemical substance Secondary chemical reference substance –- characteristics are assigned and/or calibrated by comparison with a primary chemical reference substance. The extent of characterization and testing of a secondary chemical reference substance may be less than for a primary chemical reference substance. This definition may apply inter alia to some substances termed “working standards. International Biological Standards –a category of biological reference material having World Health Organisation (WHO) status Part Two. 13.5.1. – 13.5.3. Quality Control
QC | Slide 46 of 83 August 2006 Reference materials Used for testing and/or calibration, validation or verification of a sample or equipment, instruments or other devices Responsibility must be assigned to a specific person Registration and labelling with an identification number assigned –A new identification number to each new batch –Number marked on each vial –Quoted on the analytical worksheet at every use Part Two. 11.1. – 11.2.4. Quality Control
QC | Slide 47 of 83 August 2006 Central register for reference materials containing information: identification number of the material precise description of the material source date of receipt batch designation or other identification code intended use of the material (e.g. as an infrared reference material, as an impurity reference material for thin-layer chromatography, etc.) location of storage in the laboratory, and any special storage conditions further indications (e.g. results of inspections). Part Two. 11.3.1 – 11.3.2. Quality Control
QC | Slide 48 of 83 August 2006 Information file for reference materials containing information: In addition to the central register - a file containing information on the properties of each reference material Working standards - include the results of all tests and verifications Inspection Inspected at regular intervals, no deterioration, appropriate storage conditions Inspections must be recorded in the central register and/or the information file See also "The general guideline on the establishment, maintenance and distribution of reference materials" Part Two. 11.4.1. – 11.6. Quality Control
QC | Slide 49 of 83 August 2006 5. Data processing equipment Includes computers, automated tests or calibration equipment; used for collection, processing, recording, reporting, storage or retrieval of test- and/or calibration-data Where used, requires systematic verifications of calculations and data transfers For computer software developed by the user: – this documented in detail – validated or verified as being adequate for use Quality Control Part One. 5.1.
QC | Slide 50 of 83 August 2006 5. Data processing equipment Located in suitable environmental supporting operating conditions Maintenance of computers and automated equipment Procedures established and implemented for protecting data integrity – Include e.g. integrity and confidentiality of data entry or collection, data storage, transmission and processing Procedures in place to describe how: – Changes are made, documented, and controlled for information maintained – To protect and keep back-up data at all times – To prevent unauthorized access or amendments to the data. Quality Control Part One. 5.1.
QC | Slide 51 of 83 August 2006 Reagents Reagents, chemicals, including solvents and materials used in tests and assays - of appropriate quality and supplied with COA List of pre-qualified suppliers Clear responsibility in job descriptions for the preparation of reagents in the laboratory SOPs according to pharmacopoeia or other standards Records for the preparation, and standardization of volumetric solutions Quality Control Part Two. 10.1. – 10.3.
QC | Slide 52 of 83 August 2006 Reagent labels must clearly specify: – the contents, the manufacturer, the date received, and as appropriate, the concentration, standardization factor, shelf-life and storage conditions (purchased) – date of preparation, name and initials of person (if prepared in the laboratory) Volumetric solutions: – the name of the manufacturer of the original reagent (where diluted), the date of preparation, the date of standardization and factor, and identify the responsible technician Reagents must not be moved unnecessarily from unit to unit Whenever possible, transportation in original containers Subdivided in scrupulously clean, fully labelled containers Part Two. 10.4-10.5.3. Quality Control
QC | Slide 53 of 83 August 2006 Inspect reagent containers when delivered (e.g. seals intact) Inspection recorded on the label giving the date, name and initials If tampered with, rejected, unless identity and purity can be confirmed Distilled water and deionized water Water should be considered as a reagent. Precautions to avoid contamination during: –supply, storage and distribution. To comply with pharmacopoeia and other official requirements for quality. Part Two. 10.6.1. - 10.6.4.3 Quality Control
QC | Slide 54 of 83 August 2006 Calibration, validation and verification of equipment, instruments and other devices Regular calibration, validation and verification of all equipment, instruments and other devices used to measure the physical properties of substances must be performed Specific procedures for each type of equipment, instrument and other devices must be established, having regard to the extent of which they are used, verified and calibrated at regular intervals according to SOP Part Two. 12 -12.2. Quality Control
QC | Slide 55 of 83 August 2006 The records must include at least the following: name of equipment, instrument and other devices manufacturer's name, type identification, serial number or other unique identification verification/calibration to comply with the specifications current location, where appropriate the manufacturer's instructions, if available, or reference to their location Part Two. 12.5. Quality Control
QC | Slide 56 of 83 August 2006 The records must include at least the following (2): dates, results and copies of reports, verifications and certificates of all calibrations, adjustments, acceptance criteria, and due date of next verification/calibration maintenance carried out to date and the maintenance plan history of any damage, malfunction, modification or repair. It is also recommended to keep records and additional observations of the time, the equipment, instruments or devices were used Part Two. 12.5. Quality Control
QC | Slide 57 of 83 August 2006 Maintenance procedures and records Prevent contamination or deterioration - perform systematic verifications Defective instruments - taken out of service, and clearly labelled or marked Status of calibration and the date when recalibration is due, indicated Instruments to be satisfactory before being returned to service Part Two. 12.6. – 12.10. Quality Control
QC | Slide 58 of 83 August 2006 Performing the tests Official pharmacopoeia requirements - see general notices and the specific monographs of the pharmacopoeia System suitability done as relevant All values obtained from each test, including blank results, must immediately be entered on the worksheet, and all graphical data, whether obtained from recording instruments or hand-plotted must be attached to the analytical worksheet Part Three. 16.3.1. – 16.4. Quality Control
QC | Slide 59 of 83 August 2006 Evaluation of test results Results must be reviewed and evaluated – do they meet specifications Consider the results of all tests Doubtful results should be investigated (Internal quality system, OOS investigation etc) Doubtful results can be rejected only if they are clearly due to error, which has been identified. All conclusions entered on the analytical worksheet by the analyst and initialled by the supervisor Part Three. 17.1. – 17.2. Quality Control
QC | Slide 60 of 83 August 2006 Analytical test report must provide the following information: registration number name and address of laboratory testing the sample name and address of originator requesting analysis name and description and batch number of the sample, where appropriate reference to the specification(s) used for testing the sample including limits results of all tests performed, numerical results of all tests performed (if applicable) conclusion whether or not the sample was found to meet the limits of specifications Part Three. 17.3.2. Quality Control
QC | Slide 61 of 83 August 2006 Analytical test report must provide the following information (cont): date of test performed signature of the head of the laboratory or authorized person name and address of repacker/trader, if applicable name and address of original manufacturer compliance to requirements date received expiry date. Part Three. 17.3.2. Quality Control
QC | Slide 62 of 83 August 2006 Traceability Analytical specificities of each measurement procedure and reference material that is used to ascertain traceability, must be known. Traceability chain, including measurement procedures and reference materials at all levels, must be prepared Laboratory investigations - applies to measurement procedures as well as to reference materials used Part Two. 13.1. – 13.3. Quality Control
QC | Slide 63 of 83 August 2006 Filing Analytical worksheet filed for safe keeping together with any attachments, including calculations and tracings of instrumental analyses Analytical test report must be prepared on the basis of the worksheet Mistakes, amended data or text - old information may be deleted by a single line (not erased nor made illegible) and the new information added alongside, initialled or signed, and an explanation for the change given Part Three. 15.6. – 15.8. Quality Control
QC | Slide 64 of 83 August 2006 Other checks Water system Compressed air Steam Environmental monitoring Waste Inspecting the QC laboratory
QC | Slide 65 of 83 August 2006 Safety in the laboratory –General aspects to consider... Part Four. Quality Control
QC | Slide 66 of 83 August 2006 General and specific safety instructions must be: available to each staff member and supplemented regularly as appropriate (e.g. written material, poster displays, audio-visual material, and occasional seminars) General rules and SOPs should include: availability of safety data sheets to staff prior to testing being carried out prohibition of smoking, eating, and drinking in the laboratory familiarity with the use of fire-fighting equipment, including fire extinguishers, fire blankets, and gas masks the use of laboratory coats or other protective clothing including eye protection Part Four. 19.1. – 19.2. Quality Control
QC | Slide 67 of 83 August 2006 special handling as required for example for highly potent, infectious, or volatile substances full labelling of all containers of chemicals, including prominent warnings (e.g. "Poison", "Flammable", "Radiation", etc.) whenever appropriate adequate insulation and spark-proofing of electrical wiring and equipment, including refrigerators observation of safety rules in handling cylinders of compressed gases and familiarity with their colour identification codes awareness of avoiding solitary work in the laboratory provision of first-aid materials and instruction in first-aid techniques, emergency care, and use of antidotes Part Four. 19.2. Quality Control
QC | Slide 68 of 83 August 2006 Protective clothing must be available, including eye protection, masks and gloves Water showers should be installed Rubber suction bulbs used on manual pipettes and siphons Staff must be instructed in the safe handling of glassware, corrosive reagents, and solvents, and particularly in the use of safety containers or baskets to avoid spillage from containers Warnings, precautions and instructions must be given Safe disposal of unwanted corrosive or dangerous products by neutralization or deactivation Safe and complete disposal of mercury and its salts Part Four. 19.3. Quality Control
QC | Slide 69 of 83 August 2006 Poisonous or hazardous products Singled out and labelled appropriately Unnecessary contacts with reagents, especially solvents and their vapours, must be avoided The use of known carcinogens and mutagens must be limited or totally excluded if required by local regulations Replacement of toxic solvents and reagents by less toxic materials or reduction of their use Part Four. 19.4 Quality Control
QC | Slide 70 of 83 August 2006 Thank you Group sessions Inspecting the QC laboratory