Good Practices for Quality Control Laboratories WHO Training material amended by Dr. AJ van Zyl for the training works

1. Supplementary Training Modules on Good Manufacturing Practice 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 WHO Technical Report Series, No. 902, 2002. Annex 3

2. Quality Control 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.

3. Quality Control 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

4. 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

5. 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

6. 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

7. Quality Control 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.

8. Quality Control When starting to review compliance e.g. during inspection: • Preparation with background information • Materials and products • SMF • Product dossier (e.g. specifications, tests)

9. Quality Control Assess implementation and compliance with all the recommendations • GMP • GP NCL • Different approaches (systematic, material or product flow)

10. Quality Control 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. Part One. 7.1. – 7.5.

11. Quality Control 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 Part One. 7.6. – 7.7.

12. Quality Control 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 Part One. 7.7.1.1. – 7.7.1.4

13. Quality Control • 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.

14. Quality Control 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. Part One. 7.7.1.4. – 7.10.

15. Quality Control 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 Part One. 6.1 – 6.3.

16. Quality Control 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. Part One. 6.4 – 6.5

17. Quality Control Managerial and technical personnel: • Head of laboratory (supervisor) • Head of central registry • Analysts • Technical staff • Head of central store • Quality Manager Part One. 6.6

18. Quality Control 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 Part One. 2.1.

19. Quality Control 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. Part One. 2.1.

20. Quality Control 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 Part One. 2.1.

21. Quality Control • 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 Part One. 2.2. - 2.3.

22. Quality Control 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. Part One. 3.1.

23. Quality Control 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 Part One. 4.4.

24. Quality Control 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. Part One. 4.4.

25. Quality Control 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

26. Quality Control 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.

27. Quality Control 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.

28. Quality Control E.g. Artesunate • What should you look for initially?

29. Quality Control 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.

30. Quality Control 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. – 14.4.2.2.

31. Quality Control (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. – 14.4.2.2.

32. Quality Control 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.

33. Quality Control 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.

34. Quality Control 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.

35. Quality Control • Specification as per dossier • Version and reference number • Reference to test methods/procedures • Test parameters and acceptance limits • Verify tests done

36. Quality Control • 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

37. Quality Control 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. Part One. 4.1 – 4.2.

38. Quality Control 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 Part One. 4.3.

39. Quality Control 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.

40. Quality Control 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.

41. Quality Control 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.

42. Quality Control 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.

43. Quality Control 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.

44. Quality Control 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

45. Quality Control 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.

46. Quality Control 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.

47. Quality Control 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.

48. Quality Control 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.

49. Quality Control 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 Part One. 5.1.

50. Quality Control 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. Part One. 5.1.