Quality Control

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. Supplementary Training Modules on Good Manufacturing Practice Good Practices for Quality Control Laboratories WHO Technical Report Series, No. 902, 2002. Annex 3

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 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.

5. Quality Control 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

6. Quality Control 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

7. Quality Control 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") Part One. 1.4

8. Quality Control 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 Part One. 2.1

9. 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) Part One. 2.1

10. Quality Control 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 Part One. 2.1

11. Quality Control 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 Part One. 3.1

12. Quality Control 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

13. 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

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. 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

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. 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. 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) • 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. 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

20. Quality Control 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

21. Quality Control 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

22. 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

23. 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

24. Quality Control 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 Part One. 7.7.1.1 – 7.7.1.4

25. Quality Control 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 Part One. 8.1 – 8.3

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