1. Quality Control Rutendo Kuwana Technical Officer, WHO, Geneva Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

2. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 2 |2 | Good Practices for Quality Control Laboratories Supplementary Training Modules on Good Manufacturing Practice WHO Technical Report Series, No. 902, 2002. Annex 3

3. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 3 |3 | 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

4. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 4 |4 | Management and infrastructure: Organization and management Quality systems Control of documentation and records Data processing equipment Personnel Premises, equipment, instruments and other devices Part One. Quality Control

5. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 5 |5 | Organization and management: Function in accordance with national legislation Operate in accordance with the guideline –WHO Technical Report Series, No. 902, 2002, Annex 3 See also general texts on Good Manufacturing Practices and Good Practices in Quality control –WHO Technical Report Series, No. 908, 2003, Annex 4 Part One 1.1– 1.2 Quality Control

6. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 6 |6 | Organization and management (2): Personnel –Managerial and technical positions to ensure operation in accordance with quality systems –No conflict of interest Organizational chart and job descriptions Supervision and training Part One. 1.3 Quality Control

7. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 7 |7 | Organization and management (3): Large laboratories may have subunits A central registry responsible for: – receipt and distribution of samples – keeping records and documents of incoming samples – allocation of work and responsibilities – maintaining specifications "up to date" (specifications "archive") Quality Control Part One. 1.4

8. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 8 |8 | Quality system: Management to establish, implement and maintain quality system –It should cover 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

9. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 9 |9 | 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) Quality Control Part One. 2.1

10. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 10 | The quality manual should contain at least (continued): Procedure for dealing with complaints A flow chart for samples – QA is responsible for reviewing and approving sampling procedures. Sampling may be conducted by other persons provided they have been appropriately trained Details of audit and quality system review Qualification of personnel Training and maintaining competence of staff A quality policy statement Quality Control Part One. 2.1

11. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 11 | Control of documents Documentation is essential 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

12. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 12 | 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

13. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 13 | 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

14. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 14 | Use of Notebooks Bound and pre-numbered Loose sheets – pre-numbered, printing controlled and should be stored as control records Electronic data collection system Raw data should be recorded at the time of production

15. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 15 | 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

16. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 16 | Testing Methods and Results Analytical methods and test procedures should be cross referenced (e.g. pharmacopoeia) or detailed to be understood by the local analyst. Formulae – with explanations and simplifications. This makes easy review by a second person

17. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 17 | Out of Specification Results Must be handled based on a written procedure, that includes: Checklist of potential defects (e.g. calculations, methods, visual appearance, test procedure modified, experience of analyst during test, calibration of equipment …) Similar checklist for potential deviations in production Checking sampling and sampling devices Guidance on when re-sampling and re-testing may be required and documented justification in each instance Inclusion of known control sample in any testing

18. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 18 | Approval and Rejection of Results Before approval or rejection – criteria to be used and results to be averaged should be specified in SOP(s) Criteria to include - averaging and/or rounding results and comparing results against specifications Control charts can be used to detect trends and atypical results (see www.ivthome.com)www.ivthome.com Rounding results should be according to pharmacopoeial requirements (see also ICH Q3A) NB: take care when averaging results from atypical values e.g. outliers, or single result out of specification limits

19. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 19 | 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

20. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 20 | 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

21. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 21 | 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

22. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 22 | 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

23. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 23 | 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

24. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 24 | Premises - 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. 7.7.1.1 – 7.7.1.4

25. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 25 | Equipment, instruments and other devices Designed, constructed, adapted, located, calibrated, qualified, verified and maintained Purchased from approved suppliers – can give technical support, maintenance Documentation in the language employed in the laboratory Appropriate test equipment, instruments or other devices in the laboratory Suitable for correct performance of tests and/or calibrations, validations and verifications Meet laboratory's requirements, and comply with the relevant standard specifications, as well as be verified and/or calibrated Quality Control Part One. 8.1 – 8.3

26. Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda 26 | Use of Primary and Secondary Standards SOP required on – use, records, acquisition, identification and storage For Pharmacopoeial methods – reference standards should be acquired from that pharmacopoeia. Secondary standards to be routinely tested against the primary standard When a non-Pharmacopoeial standard is used as a reference for assay the mean and standard deviation of the assigned assay value should be known. Retest/expiration date should be assigned