World Health Organization

World Health Organization
5 April, 2017 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 This 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 WHO Technical Report Series, No. 902, Annex 3

Quality Control 5 April, 2017 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 5 April, 2017 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 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 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

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

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

Quality Control 5 April, 2017 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 5 April, 2017 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 5 April, 2017 Assess implementation and compliance with all the recommendations GMP GP NCL Different approaches (systematic, material or product flow)

Quality Control 5 April, 2017 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. 7. Premises 7.1 The laboratory should be of a suitable size, construction and location. Safety requirements should be taken into the design consideration (see Part Four). 7.2 The design of the laboratory should provide an adequate degree of separation of the activities, which may interfere with the proper conduct of each study. 7.3 The laboratory should have a sufficient number of rooms or areas to assure the isolation of test systems. 7.4 The premises must have suitable testing and safety equipment. For example, the needed energy sources and where the line voltage is variable, suitable voltage stabilizers should be installed. 7.5 Storage rooms or areas should be available as needed for supplies and materials and should be conveniently located. These rooms should be separated from those areas housing the test systems and should provide adequate protection against infestation, contamination, and/or deterioration. Part One – 7.5.

Quality Control 5 April, 2017 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 7.6 To prevent contamination or mix-ups, separate rooms or areas for receipt and storage of test and reference items should be available, as well as for the mixing of test items with a vehicle. 7.7 Storage rooms or areas for test items should be separate from rooms or areas containing the test systems. They should be built adequately to preserve identity, concentration, purity, and stability, and ensure safe storage of hazardous substances. All storage areas must be located and equipped in accordance with fire regulations. For safety reasons and to reduce contamination of the laboratory environment, storage of flammable reagents, fuming and concentrated acids, bases, volatile amines and others must never be kept in the laboratory without good reasons. Part One – 7.7.

Quality Control 5 April, 2017 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 7.7.1 Central store Separate central storage facilities must be maintained for the secure storage of samples, retained samples (see Part Three. 18), and reagents, laboratory accessories (see Part Two. 10.7) and reference materials (see Part Two. 11). Storage facilities must provide the possibility to store material, if necessary, under refrigeration and securely locked-up. Access to be restricted to designated personnel. The central store should be organized in such a way to accommodate incoming and outgoing samples, reagents, equipment, instruments and other devices. Appropriate safety regulations must be drawn up and rigorously implemented wherever toxic or flammable reagents are stored or used. Reagents subject to poison regulations or to the controls applied for narcotic and psychotropic substances must be clearly marked as "Poison". They must be kept separately from other reagents in locked cabinets. Part One –

Quality Control 5 April, 2017 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. 10.7 Storage Stocks of reagents must be maintained in a central store taking into account the storage conditions. The store must contain a supply of clean bottles, vials, spoons, funnels, and labels required for dispensing reagents from larger to smaller containers. Special equipment may be needed for the transfer of larger volumes of corrosive liquids. The function of a store keeper must be defined. The responsibility of the person is to look after and tend the central store and its inventory. The expiry date of chemicals and reagents should be observed. Training may be needed in handling chemicals with the necessary care and safety. The laboratory must provide for the purpose of storage separate rooms or areas for flammable substances, for fuming and concentrated acids, bases, volatile amines and others, such as hydrochloric acid, nitric acid, ammonia, and bromine. Self-igniting materials, such as metallic sodium and potassium, must also be stored separately. Part Two –

Quality Control 5 April, 2017 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. The designated responsible member of staff must maintain a register of these substances. The head of each unit must accept personal responsibility for the safekeeping of any of these reagents kept in the workplace (see Part One ). 7.8 Archive facilities should be provided for the secure storage and retrieval of all documents (internally generated or from external sources), samples of test items and specimens. Archive design and archive conditions should protect contents from untimely deterioration. Access to be restricted to designated personnel. 7.9 Handling and disposal of wastes should be carried out as not to jeopardize the integrity of studies and environment. Provision of appropriate facilities for collection, storage and disposal should be available, as well as means of decontamination, where applicable, and transportation. 7.10 The environment in which the tests are undertaken must not invalidate the test results or adversely affect the required accuracy of measurements. This particularly applies to sites other than the permanent laboratory premises. Testing premises must be protected as required from excessive conditions, such as heat, cold, dust, moisture, steam, noise, vibration and electromagnetic disturbance or interference. Devices to monitor the environmental conditions must be installed if required by the nature of testing. Access to and use of all test areas must be controlled and limited to their designated purpose. For persons external to the laboratory the conditions of entry must be defined. Adequate measures must be taken to ensure good housekeeping in the test laboratory. Part One – 7.10.

Quality Control 5 April, 2017 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 6. Personnel 6.1 The laboratory must have sufficient personnel with the necessary education, training, technical knowledge and experience for their assigned function. The personnel should be free from any conflict of interest and pressure that will interfere with the quality of the results. 6.2 The laboratory management must ensure the competence of all persons operating specific equipment, instruments or other devices, who are performing tests and/or calibrations, validations or verifications. Their duties also involve the evaluation of results as well as signing test reports (Appendix 1) and calibration certificates. 6.3 Staff undergoing training must be appropriately supervised, and a formal assessment after training is recommended. Personnel performing specific tasks must be qualified on the basis of appropriate education, training, experience and/or demonstrated skills, as required. Part One. 6.1 – 6.3.

Quality Control 5 April, 2017 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. 6.4 The laboratory must use permanently employed personnel, or who are under contract. The laboratory must ensure that contracted, additional technical and key support personnel are supervised and sufficiently competent, motivated, and that their work is in accordance with the good practice of the laboratory. 6.5 The laboratory must maintain current job descriptions for managerial, technical and key support personnel involved in tests and/or calibrations, validations and verifications. Part One. 6.4 – 6.5

Quality Control 5 April, 2017 Managerial and technical personnel: Head of laboratory (supervisor) Head of central registry Analysts Technical staff Head of central store Quality Manager 6.5.1 The laboratory must maintain records of all technical personnel, contracted personnel included, concerning the relevant competence, educational and professional qualifications, training, skills and experience. This information must be readily available and must include the date on which authorization and/or competence has been confirmed. The criteria on which the authorization is based must also be given and the name of the confirming authority. 6.6 The laboratory must have the following managerial and technical personnel: 6.6.1 Head of laboratory (supervisor) The person must be of high professional standing with extensive experience in drug analysis and laboratory management in a pharmaceutical control laboratory in the regulatory sector or in the industry. The person’s function is to ensure that (a) all key members of the laboratory staff have the requisite competence and are given levels of grades matching their responsibilities (b) standard samples are analysed periodically (c) the adequacy of existing staffing, management, and training procedures is reviewed periodically (d) "self-checking" procedures for instrument operators are devised (e) regular in-service training programmes to update and extend the skills of both professionals and technicians are arranged (f) the safe-keeping of any narcotics (see Part One ) kept in the workplace is under the supervision of an authorized person (g) ultimate responsibility for recommending any regulatory action in the event of non-compliance of a tested sample is taken. Part One. 6.6

Quality Control 5 April, 2017 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 2. Quality system 2.1 The laboratory management establishes, implements and maintains a quality system appropriate to the scope of its activities, including the type, range and volume of testing and/or calibration, validation and verification activities it undertakes. The laboratory management describes its policies, systems, programmes, procedures and instructions to the extent necessary to enable the laboratory to assure the quality of the test results it generates. Documentation used in this quality system must be communicated and available to, understood and implemented by, the appropriate personnel. The elements of this system must be documented in a quality manual, which is available to the laboratory personnel and must be maintained and updated by a nominated responsible member of the laboratory personnel. The quality manual must contain at minimum: (a) the structure of the laboratory (organizational chart); (b) the operational and functional activities pertaining to quality, so that each person concerned will know the extent and the limits of responsibilities; (c) general internal quality assurance procedures; (d) reference to specific quality assurance procedures for each test; (e) participation in appropriate proficiency testing schemes, use of reference materials. etc.; (f) satisfactory arrangements for feedback and corrective action when testing discrepancies are detected; (g) procedure for dealing with complaints; (h) a flow chart for samples; (i) details of audit and quality system review; (j) appropriate qualification of personnel; (k) training and maintaining competence of staff; and (l) a quality policy statement, including at least the following: i. a statement of the laboratory management's intentions with respect to the standard of service it will provide ii. the purpose of the quality system iii. the laboratory management's commitment to good professional practice and quality of testing, calibration, validation and verification, as a service to its clients iv. the laboratory management's commitment to compliance with the content of this guideline v. a requirement that all personnel concerned with testing and calibration activities within the laboratory familiarize themselves with the documentation concerning quality, implementation of the policies and procedures in their work. Part One. 2.1.

Quality Control 5 April, 2017 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.

Quality Control 5 April, 2017 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.

Quality Control 5 April, 2017 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 2.2 The quality system must be reviewed systematically and periodically (internal and external audits) by, or on behalf of, , the management to ensure continued effectiveness of the arrangements, and apply any necessary corrective measures. Such reviews must be recorded together with details of any corrective action taken. 2.3 The laboratory management must appoint a member of the staff as quality manager, who, irrespective of other duties and responsibilities, should have defined responsibilities and authority for ensuring that the quality system is implemented and followed at all times. The quality manager must have direct access to the highest level of management at which decisions are taken on laboratory policies or resources. Part One

Quality Control 5 April, 2017 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. 3. Control of documentation 3.1 Documentation is an essential part of the quality system. The laboratory must establish and maintain procedures to control and review all documents (internally generated and from external sources) that form part of the quality documentation. Part One. 3.1.

Quality Control 5 April, 2017 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 4.4 Standard operating procedure (SOP). Authorized written procedures are required, but not limited to, giving instructions for administrative and technical operations, such as: (a) purchase and receipt of consignment of materials (e.g. samples, reference material, reagents) (b) internal labelling, quarantine, and storage of materials (c) appropriate installation of each instrument and equipment (d) sampling and inspection (e) testing materials, describing the methods and equipment used (f) equipment qualification (g) analytical apparatus and calibration (h) maintenance, cleaning, sanitation (i) safety measures (j) personnel matters including qualification, training, clothing, and hygiene (k) environmental monitoring (l) preparation and control of reference materials. Part One. 4.4.

Quality Control 5 April, 2017 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.

Quality Control 5 April, 2017 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 5 April, 2017 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. MATERIALS AND SET-UP OF EQUIPMENT, INSTRUMENTS AND OTHER DEVICES 9. Specifications archive 9.1 A specifications archive is recommended for every pharmaceutical control laboratory. Current versions of all specifications necessary should be kept in accordance with the national legislation, as described in pharmacopoeial compendia or in manufacturers' registration documents. 9.2 Content 9.2.1 The specifications archive must contain (a) list of all pharmacopoeias in the laboratory i. all updates and corrections must be noted in the principal volumes to prevent the use of obsolete sections. Additional or replacement pages for loose-leaf publications must be inserted immediately after receipt; pages no longer valid must be removed; ii. adequate numbers of supplements and addenda must be ensured. (b) file of non-pharmacopoeial quality specifications for drugs tested to specifications, established either by the manufacturer or by the laboratory itself and approved by the Authority i. each entry must be numbered and dated as to easily recognize the latest version; ii. the version in the archive file (master copy) must bear the date of approval by the national registration authority or the specific unit and contain any other information relevant to the status of the quality specifications; iii. all subsequent corrections or changes must be entered in the master copy and endorsed with the persons' name, signature and the date. A revised document should be produced as soon as possible. Part Two – 9.2.

Quality Control 5 April, 2017 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 9.3 Forwarding of documents from the specifications archive. The master copy should not be released from the archive; photocopies must be accounted for and controlled for laboratory use. 9.4 Confidentiality of manufacturers’ specifications. Manufacturers' specifications are the property of the company. Often they are made available to governments strictly for the purpose of assessing application for marketing authorization. The pharmaceutical control laboratory may need to negotiate their release with manufacturers or even, in some cases, to develop independent specifications. National laboratories may be asked routinely to give their opinion on the specifications for each newly introduced pharmaceutical product before being authorized for marketing by the drug regulatory authority. 9.5 In a large laboratory the specifications archive supervisor provides a documentation service and has the responsibility for (a) updating all pharmacopoeias - including supplements, addenda, and corrective measures used in the laboratory; (b) maintaining a specifications file for all drugs authorized for marketing within the country. Part Two – 9.5.

Quality Control 5 April, 2017 E.g. Artesunate What should you look for initially?

Quality Control 5 April, 2017 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 14. Incoming samples 14.1 Sampling (plan and procedures) (11) Samples provided to the laboratory may reflect either routine samples for control, suspected samples and samples submitted in connection with a marketing authorization process. Close collaboration with those providing the samples is important. Pharmaceutical inspectors in particular, frequently submitting samples, must take into account that the sample size must be large enough to provide an adequate reserve to cover, if required, a number of replicate tests (see Part Three.16.3) and for the preparation of a retained sample (see Part Three.18). Often the number of samples taken is three, sealed and documented; where non-compliance is suspected, the number retained in the laboratory is two and the third sample is retained by the manufacturer. The first sample is tested in accordance with the specification. If the latter is non-compliant and the manufacturer objects to the results, the third sample is analyzed in the presence of the specialist of the manufacturer. The second sample is analyzed in case of dispute. The laboratory must have a sampling plan and internal procedure for sampling, available to all analysts and technicians within the laboratory. Part Three –

Quality Control 5 April, 2017 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 14.2 Test request A standard test request form must be filled out during sampling and must accompany each sample submitted to the laboratory. The test request must provide or leave space for the following information: (a) name of the institution or inspector that supplied the sample (b) source of the material (c) full description of the drug, including its composition, International Nonproprietary Name (INN) (if available), brand name, dosage form, concentration or strength, manufacturer, and batch number (if available), the marketing authorization number (d) size of the sample (e) reason for requesting the analysis (f) date on which the sample was collected (g) size of the consignment from which it was taken, when appropriate (h) expiry date (pharmaceutical product) retest date, (starting material, pharmaceutical excipients) (i) pharmacopoeial specifications or other official specifications to be used for testing (j) record of further comments (e.g. discrepancies found) (k) required storage conditions. Part Three –

Quality Control 5 April, 2017 (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 14.2 Test request A standard test request form must be filled out during sampling and must accompany each sample submitted to the laboratory. The test request must provide or leave space for the following information: (a) name of the institution or inspector that supplied the sample (b) source of the material (c) full description of the drug, including its composition, International Nonproprietary Name (INN) (if available), brand name, dosage form, concentration or strength, manufacturer, and batch number (if available), the marketing authorization number (d) size of the sample (e) reason for requesting the analysis (f) date on which the sample was collected (g) size of the consignment from which it was taken, when appropriate (h) expiry date (pharmaceutical product) retest date, (starting material, pharmaceutical excipients) (i) pharmacopoeial specifications or other official specifications to be used for testing (j) record of further comments (e.g. discrepancies found) (k) required storage conditions. Part Three –

Quality Control 5 April, 2017 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 14.3 Registration and labelling All newly delivered samples and the accompanying documents (e.g. test request) must be assigned a registration number. Separate registration numbers must be assigned to requests referring to two or more drugs, different dosage forms, or different batches of the same drug. If applicable (see Part Three.18), a registration number to any incoming retained sample must also be assigned. A label bearing the registration number must be affixed to each container of the sample avoiding obliteration of other markings or inscriptions. Part Three –

Quality Control 5 April, 2017 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 14.4 Central register A central register must be kept, which may be a record book, a card file, or data processing equipment, where the following information is recorded: (a) registration number (b) date of receipt (c) specific unit to which the sample was forwarded. 14.5 Inspection of the submitted sample The sample received must immediately be inspected to ensure that the labelling is in conformity with the information contained in the test request: (a) the findings must be recorded, dated and initialled (b) if discrepancies are found, or if the sample is obviously damaged, the fact must be recorded without delay on the test request form (c) any queries must be immediately referred back to the provider of the sample. Part Three –

Quality Control 5 April, 2017 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. The sample prior to testing (see Part Three.16.1), the retained sample (see Part Three.18) and any remaining portions of the sample after performance of all required tests must be stored safely taking into account, if necessary, the storage conditions (12) specified for the sample. 14.7 Forwarding to testing The specific unit to which the sample is sent to for testing is determined by the head of the central registry. The examination of a sample must not be started before the relevant test request has been received. The sample must be stored adequately until all relevant documentation has been received. A request for analysis may be accepted verbally only in case of emergencies. All details must immediately be placed on record pending the receipt of written confirmation. 14.8 Data must be recorded on the analytical worksheet (see Part Three.15). 14.9 Copies or duplicates of all documentation must accompany each numbered sample when sent to the specific unit. Part Three

Quality Control 5 April, 2017 Specification as per dossier Version and reference number Reference to test methods/procedures Test parameters and acceptance limits Verify tests done

Quality Control 5 April, 2017 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 5 April, 2017 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. 4. Records 4.1 The laboratory must establish and maintain procedures for identification, collection, indexing, access, storage, maintenance and disposal of quality documentation and technical records. 4.2 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 in accordance to national regulations. Ideally, they should be kept for the whole length of time the drug is on the market. The records for each test must contain sufficient information to permit repetition of tests. The records must include the identity of the personnel involved in sampling, preparation and testing of the samples. The records of samples for legal proceedings should be kept according to legal requirements. Part One. 4.1 – 4.2.

Quality Control 5 April, 2017 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 4.3 All records must be legible, readily retrievable, stored and retained, using facilities that provide a suitable environment to prevent modification, damage or deterioration and/or loss. All original records must be held secure and in confidence. Quality records must include reports from internal audits and management reviews including records from possible corrective and preventive actions. Part One. 4.3.

Quality Control 5 April, 2017 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). 15. Analytical worksheet 15.1 The analytical worksheet is an internal document in a printed form for recording information about the sample, test procedure and results of testing. It may be complemented by the raw data obtained in the analysis. 15.2 Purpose The analytical worksheet contains the (a) confirmation that the sample being examined is in accordance with the requirements (b) documentary evidence to support regulatory action, if necessary. 15.3 Use For each numbered sample a separate analytical worksheet must be used. If necessary, 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 –

Quality Control 5 April, 2017 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) 15.4 Content The analytical worksheet must provide or leave space for the following information: (a) registration number of the sample (see Part Three ) (b) page numbering including total number of pages (including annexes) (c) date of the test request (see Part Three.14.2) (d) date of analysis performed (e) name and signature of analyst (f) description of the sample received (g) reference to the specifications to which the sample was tested including limits (adding any or special methods employed) (see Part Three ) - reference number of the specifications, if available (e.g. pharmacopoeial monograph) (h) results obtained of tested sample (see Part Three.16.4) (i) the interpretation of the results and the final conclusions (whether or not the sample was found to comply with specifications), signed by each of the analysts involved and initialled by the supervisor (j) the identity of the test equipment used (see Part Two. 12. (k) further comments, for example, for internal information (see Part Three.16.11). The above information may be complemented by: (a) detailed notes on the specifications selected and the methods of assessment used (see Part Three.15.5) (b) 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 (c) identification number of any reference material (see Part Two ) (d) if applicable, data to be attached of an instrument verification (e) if applicable, data to be attached of a reagent verification. Part Three

Quality Control 5 April, 2017 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 15.4 Content The analytical worksheet must provide or leave space for the following information: (a) registration number of the sample (see Part Three ) (b) page numbering including total number of pages (including annexes) (c) date of the test request (see Part Three.14.2) (d) date of analysis performed (e) name and signature of analyst (f) description of the sample received (g) reference to the specifications to which the sample was tested including limits (adding any or special methods employed) (see Part Three ) - reference number of the specifications, if available (e.g. pharmacopoeial monograph) (h) results obtained of tested sample (see Part Three.16.4) (i) the interpretation of the results and the final conclusions (whether or not the sample was found to comply with specifications), signed by each of the analysts involved and initialled by the supervisor (j) the identity of the test equipment used (see Part Two. 12. (k) further comments, for example, for internal information (see Part Three.16.11). The above information may be complemented by: (a) detailed notes on the specifications selected and the methods of assessment used (see Part Three.15.5) (b) 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 (c) identification number of any reference material (see Part Two ) (d) if applicable, data to be attached of an instrument verification (e) if applicable, data to be attached of a reagent verification. Part Three

Quality Control 5 April, 2017 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

Quality Control 5 April, 2017 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 The completed analytical worksheet must be signed by the responsible analyst/s and initialled by the supervisor. 15.5 Selection of the specifications to be used. Specifications necessary to assess the sample are selected according to: (a) Specifications given in the test request, usually an existing i. particular pharmacopoeial monograph, or ii. manufacturer’s specifications. (b) No precise instruction given i. specifications in the officially recognized national pharmacopoeia to be used or, failing that ii. the manufacturer's officially approved or other nationally recognized specifications. (c) No suitable method available i. specifications contained in the product licence may be requested from the manufacturer and validated, if the general policy of the laboratory permits this action (see Part Two 9.3.1) ii. the requirements are drafted in the laboratory itself on the basis of published information and any other relevant documentation and should be validated by the testing laboratory before including it as a SOP (1, 2). For official specifications, the current version must be available (see Part Two.9.1). Part Three –

Quality Control 5 April, 2017 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 5 April, 2017 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 A designated primary chemical substance is one that is widely acknowledged to have the appropriate qualities within a specified context, and whose value is accepted without requiring comparison to another chemical substance. (7) A secondary chemical reference substance is a substance whose 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 are a category of biological reference material having World Health Organisation (WHO) status which have been exhaustively studied and which meet with demanding international (WHO) requirements for accuracy, consistency and stability and which are established by the WHO Expert Committee on Biological Standardization (ECBS). International Biological Standards are generally assigned potency values expressed in terms of International Units (IU) of biological activity, on the basis of an extensive international collaborative study. Part Two –

Quality Control 5 April, 2017 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 11. Reference materials 11.1 Reference materials (7, 8) (for example, official reference substances and reference preparations, secondary reference materials and non-official materials prepared in the laboratory as working standards) are necessary for the testing and/or calibration, validation or verification of a sample or equipment, instruments or other devices. 11.2 Registration and labelling An identification number must be assigned to all reference materials, whether newly delivered or prepared. A new identification number must be assigned to each new batch. The number must be marked on each vial of the material. The identification number must be quoted on the analytical worksheet at every use of the material (see Part Three. 15.4). Part Two –

Quality Control 5 April, 2017 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). 11.3 Central register Details concerning all reference materials required are compiled in a central register, which may be a record book, a card file, or data processing equipment. The central register must provide the following information: (a) identification number of the material (b) precise description of the material (c) source (d) date of receipt (e) batch designation or other identification code (f) intended use of the material (e.g. as an infrared reference material, as an impurity reference material for thin-layer chromatography, etc.) (g) location of storage in the laboratory, and any special storage conditions (h) further indications (e.g. results of inspections). Part Two –

Quality Control 5 April, 2017 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" 11.4 Information file In addition to the central register, a file must be kept containing all information on the properties of each reference material. For working standards prepared in the laboratory, the file must include the results of all tests and verifications used to establish the standard, and initialled by the responsible analyst. 11.5 Inspection All reference materials must be inspected at regular intervals to assure deterioration has not occurred and appropriate storage conditions are being observed. The results of these inspections must be recorded in the central register and/or the information file, and initialled by the responsible analyst. 11.6 Further guidance. The general guideline on the establishment, maintenance and distribution of reference materials gives further details on the handling and storage of reference materials (7). A compilation of national, regional and international reference substances is also kept up-to-date at the Secretariat and is available (8). Part Two – 11.6.

Quality Control 5 April, 2017 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 5. Data processing equipment 5.1 For computers, automated tests or calibration equipment the collection, processing, recording, reporting, storage or retrieval of test- and/or calibration-data, the laboratory must ensure that: (a) calculations and data transfers be subject to appropriate verifications in a systematic manner; (b) computer software developed by the user is documented in sufficient detail and suitably validated or verified as being adequate for use; (c) procedures are established and implemented for protecting the integrity of data. Such procedures must include, but are not limited to, integrity and confidentiality of data entry or collection, their storage, transmission and processing; (d) computers and automated equipment are maintained to function properly. They are provided with environmental and operating conditions necessary to ensure integrity of test- and calibration-data; (e) procedures are established to describe how changes are made, documented, and controlled for information maintained in computerized systems; and (f) procedures exist to protect and keep back-up data on computers or other means at all times, and prevents unauthorized access or amendments to the data. Part One. 5.1.

Quality Control 5 April, 2017 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. 5. Data processing equipment 5.1 For computers, automated tests or calibration equipment the collection, processing, recording, reporting, storage or retrieval of test- and/or calibration-data, the laboratory must ensure that: (a) calculations and data transfers be subject to appropriate verifications in a systematic manner; (b) computer software developed by the user is documented in sufficient detail and suitably validated or verified as being adequate for use; (c) procedures are established and implemented for protecting the integrity of data. Such procedures must include, but are not limited to, integrity and confidentiality of data entry or collection, their storage, transmission and processing; (d) computers and automated equipment are maintained to function properly. They are provided with environmental and operating conditions necessary to ensure integrity of test- and calibration-data; (e) procedures are established to describe how changes are made, documented, and controlled for information maintained in computerized systems; and (f) procedures exist to protect and keep back-up data on computers or other means at all times, and prevents unauthorized access or amendments to the data. Part One. 5.1.

Quality Control 5 April, 2017 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 10. Reagents 10.1 All reagents, chemicals, including solvents and materials used in tests and assays must be of appropriate quality. 10.2 Purchase. Reagents must be purchased from reputable manufacturers or dealers, accompanied with the certificate of analysis. In some cases, a list of pre-qualified suppliers has to be established. 10.3 Preparation of reagents in the laboratory Clear responsibility must be given within the job description of the person assigned for the preparation of reagents in the laboratory. Prescribed procedures must be used and, when available, according to published pharmacopoeial or other standards. Records should be maintained for the preparation, and standardization of volumetric solutions. Part Two – 10.3.

Quality Control 5 April, 2017 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 10.4 Labels. The label must clearly specify (a) the contents, the manufacturer, the date received, and as appropriate, the concentration, standardization factor, shelf-life and storage conditions. Reagents prepared in the laboratory, must state the date of preparation, and give the name and initials of the responsible technician; (b) for volumetric solutions prepared by dilution, the name of the manufacturer of the original reagent, the date of preparation, the date of standardization and factor, and identify the responsible technician. 10.5 Transportation and subdivision Reagents must not be moved unnecessarily from unit to unit. Whenever possible, transportation must be done in the original containers. When subdivided, the transfer must always be done in scrupulously clean, fully labelled containers. Part Two

Quality Control 5 April, 2017 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. 10.6 Inspection All reagent containers must be inspected to ensure that seals are intact both when delivered to the central store and when distributed to the units. These inspections must be recorded on the label giving the date, name and initials. Reagents appearing to have been tampered with should be rejected, which could exceptionally be waived if the identity and purity can be confirmed by testing. Distilled water and deionized water Water should be considered as a reagent. Precautions must be taken to avoid contamination during its supply, storage and distribution. Stocks must be verified regularly to ensure pharmacopoeial and other official requirements for quality. Part Two

Quality Control 5 April, 2017 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 12. Calibration, validation and verification of equipment, instruments and other devices 12.1 Regular calibration, validation and verification of all equipment, instruments and other devices used to measure the physical properties of substances must be performed. 12.2 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

Quality Control 5 April, 2017 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 12.5 Records must be maintained of each item of equipment, instrument and other devices significant to the tests and/or verification/calibration performed. The records must include at least the following: (a) name of equipment, instrument and other devices (b) manufacturer's name, type identification, serial number or other unique identification (c) verification/calibration to comply with the specifications (d) current location, where appropriate (e) the manufacturer's instructions, if available, or reference to their location (f) dates, results and copies of reports, verifications and certificates of all calibrations, adjustments, acceptance criteria, and due date of next verification/calibration (g) maintenance carried out to date and the maintenance plan (h) 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

Quality Control 5 April, 2017 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

Quality Control 5 April, 2017 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 12.6 To prevent contamination or deterioration, the laboratory must perform systematic verifications, have procedures and an established plan for safe handling, transport, storage, use and maintenance of measuring equipment to ensure proper functioning. 12.7 Maintenance procedures must be established (regular servicing must be arranged by a team of maintenance specialists, internal or external, whenever possible). 12.8 Equipment, instruments and other devices, either subjected to overloading, mishandling, giving suspect results, shown to be defective or outside specified limits, must be taken out of service, and clearly labelled or marked. Wherever possible they must be kept until repaired and shown by calibration or test to perform correctly. 12.9 All equipment, instruments and other devices under the control of the laboratory and requiring calibration must be labelled, coded or otherwise identified to indicate the status of calibration and the date when recalibration is due. 12.10 When the equipment, instruments and other devices are outside the direct control of the laboratory for a certain period of time, the laboratory must ensure that their function and calibration status are verified and shown to be satisfactory before being returned to service. Part Two –

Quality Control 5 April, 2017 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 16.3 Guidance for performing test methods Official pharmacopoeial requirements usually give detailed guidance in the general notices and the specific monographs of the pharmacopoeia. Where system suitability criteria are defined in the method they should be fulfilled. 16.4 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 (see Part Three.15). Part Three – 16.4.

Quality Control 5 April, 2017 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 17. Evaluation of test results 17.1 Results must be reviewed and, where appropriate, evaluated statistically after completion of all tests to determine whether they are mutually consistent and if they meet specifications. The evaluation should take into consideration the results of all tests. Whenever doubtful results are obtained they should be investigated. The complete testing procedure needs to be checked according to the internal quality system (see also Part One.2). Doubtful results can be rejected only if they are clearly due to error, which has been identified. 17.2 All conclusions must be entered on the analytical worksheet (see Part Three.15) by the analyst and initialled by the supervisor. Part Three – 17.2.

Quality Control 5 April, 2017 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 Content of the analytical test report The canalytical test report must provide the following information (see Appendix 1): (a) registration number (b) name and address of laboratory testing the sample (c) name and address of originator requesting analysis (d) name and description and batch number of the sample, where appropriate (e) reference to the specification(s) used for testing the sample including limits (f) results of all tests performed, numerical results of all tests performed (if applicable) (g) conclusion whether or not the sample was found to meet the limits of specifications (h) date of test performed (i) signature of the head of the laboratory or authorized person (j) name and address of repacker/trader, if applicable (k) name and address of original manufacturer (l) compliance to requirements (m) date received (n) expiry date. Part Three

Quality Control 5 April, 2017 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. Content of the analytical test report The canalytical test report must provide the following information (see Appendix 1): (a) registration number (b) name and address of laboratory testing the sample (c) name and address of originator requesting analysis (d) name and description and batch number of the sample, where appropriate (e) reference to the specification(s) used for testing the sample including limits (f) results of all tests performed, numerical results of all tests performed (if applicable) (g) conclusion whether or not the sample was found to meet the limits of specifications (h) date of test performed (i) signature of the head of the laboratory or authorized person (j) name and address of repacker/trader, if applicable (k) name and address of original manufacturer (l) compliance to requirements (m) date received (n) expiry date. Part Three

Quality Control 5 April, 2017 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 13. Traceability 13.1 Traceability aims at ensuring that results of laboratory measurements using procedures of lower metrological order are reproducible and scientifically acceptable by referring to an internationally agreed denominator by means of a reference procedure of highest metrological order and/or a primary reference material. Therefore, the analytical specificities of each measurement procedure and reference material that is used to ascertain traceability, must be known. A transfer protocol with a detailed description of the traceability chain, including measurement procedures and reference materials at all levels, must be prepared. The protocol must be meticulously followed to ensure the reproducibility of results. 13.2 Traceability takes into account that the validity of laboratory investigations is limited by uncertainties. Traceability applies to measurement procedures as well as to reference materials used for the calibration of measurement procedures. 13.3 For the majority of quantities a variety of measurement procedures have been developed to meet the requirements of the intended purpose of analysis. Part Two – 13.3.

Quality Control 5 April, 2017 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 15.6 Filing The analytical worksheet must be placed on file for safe keeping together with any attachments, including calculations and tracings of instrumental analyses. If the analytical worksheet is stored in a central archive a copy should be retained in the specific unit for easy reference. 15.7 The analytical test report (see Part Three.17.3) must be prepared on the basis of the worksheet. See Appendix 1 and Annex 10. 15.8 Amendments or additions. When mistakes occur in worksheets or when data or text need to be amended, the old information should be deleted by a single line (not erased nor made illegible) and the new information added alongside. All such alterations should be initialled or signed by the person making the correction and the date of the change inserted. An explanation for the change should also be given on the worksheet. Part Three – 15.8.

Inspecting the QC laboratory
World Health Organization 5 April, 2017 Other checks Water system Compressed air Steam Environmental monitoring Waste Other checks: Utilities, waste and environmental monitoring The inspection should also include utilities like the water system, compressed air, steam and other media. What is the quality of the water used in the lab? As water is considered to be a reagent, the quality should be specified and tested in regular intervals (e.g. chemical, microbiological specifications, endotoxins). The water quality can strongly influence the outcome of the testing. The water treatment, distribution and staorage system therefore should be validated. Compressed air and other gases that may influence the outcome of testing results should also be controlled properly. The quality should be specified and tested. Check for the procedures for testing and the records. The distribution systems should be validated. The quality of the steam should be specified and monitored. Especially when the steam is used for the autoclave. Procedures and records should be available also. Have a look at the environmental monitoring. Are there specifications for temperature and humidity? Are there procedures and records for the monitoring? Is there a procedure on the actions taken if temperature and humidity are out of limits? The specifications for temperature and humidity, in the case of sterility testing specifications for particles and microbes should be appropriate. Look at the handling of waste. Is the handling of waste, treatment of waste e.g. waste from the micro lab, described in procedures? Waste handling should not put personnel at any risk nor influence the results of the analytical testing.

Quality Control 5 April, 2017 Safety in the laboratory General aspects to consider. . . Part 4 deals with general aspects and safety in the laboratory Part Four.

Quality Control 5 April, 2017 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 19.1 General and specific safety instructions must be (a) available to each staff member and (b) supplemented regularly as appropriate (e.g. written material, poster displays, audio-visual material, and occasional seminars). 19.2 General rules for safe working in accordance with the national regulation and SOPs include normally (a) availability of safety data sheets to staff prior to testing being carried out (b) prohibition of smoking, eating, and drinking in the laboratory (c) familiarity with the use of fire-fighting equipment, including fire extinguishers, fire blankets, and gas masks (d) the use of laboratory coats or other protective clothing including eye protection (e) special handling as required for example for highly potent, infectious, or volatile substances (f) full labelling of all containers of chemicals, including prominent warnings (e.g. "Poison", "Flammable", "Radiation", etc.) whenever appropriate (g) adequate insulation and spark-proofing of electrical wiring and equipment, including refrigerators (h) observation of safety rules in handling cylinders of compressed gases and familiarity with their colour identification codes (i) awareness of avoiding solitary work in the laboratory (j) provision of first-aid materials and instruction in first-aid techniques, emergency care, and use of antidotes Part Four – 19.2.

Quality Control 5 April, 2017 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 19.1 General and specific safety instructions must be (a) available to each staff member and (b) supplemented regularly as appropriate (e.g. written material, poster displays, audio-visual material, and occasional seminars). 19.2 General rules for safe working in accordance with the national regulation and SOPs include normally (a) availability of safety data sheets to staff prior to testing being carried out (b) prohibition of smoking, eating, and drinking in the laboratory (c) familiarity with the use of fire-fighting equipment, including fire extinguishers, fire blankets, and gas masks (d) the use of laboratory coats or other protective clothing including eye protection (e) special handling as required for example for highly potent, infectious, or volatile substances (f) full labelling of all containers of chemicals, including prominent warnings (e.g. "Poison", "Flammable", "Radiation", etc.) whenever appropriate (g) adequate insulation and spark-proofing of electrical wiring and equipment, including refrigerators (h) observation of safety rules in handling cylinders of compressed gases and familiarity with their colour identification codes (i) awareness of avoiding solitary work in the laboratory (j) provision of first-aid materials and instruction in first-aid techniques, emergency care, and use of antidotes Part Four

Quality Control 5 April, 2017 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 19.3 Protective clothing must be available, including eye protection, masks and gloves. Water showers should be installed. Rubber suction bulbs must be 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 for work with violent, uncontrollable or dangerous reactions when mixing specific reagents, such as mixing water and acids, acetone-chloroform and ammonia, or flammable products, oxidizing and radioactive agents, especially biologicals such as infectious agents. Peroxide-free solvents should be used. Knowledge is required for safe disposal of unwanted corrosive or dangerous products by neutralization or deactivation and of the need for safe and complete disposal of mercury and its salts (see also Part One.7.9 and 7.10). Part Four

Quality Control 5 April, 2017 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 19.4 Poisonous or hazardous products must particularly be singled out and labelled appropriately. All other chemicals and biologicals must not be taken for granted to be safe. 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 must always be the aim, particularly when new techniques are developed. Part Four. 19.4

Inspecting the QC laboratory
World Health Organization 5 April, 2017 Thank you Group sessions Other checks: Utilities, waste and environmental monitoring The inspection should also include utilities like the water system, compressed air, steam and other media. What is the quality of the water used in the lab? As water is considered to be a reagent, the quality should be specified and tested in regular intervals (e.g. chemical, microbiological specifications, endotoxins). The water quality can strongly influence the outcome of the testing. The water treatment, distribution and staorage system therefore should be validated. Compressed air and other gases that may influence the outcome of testing results should also be controlled properly. The quality should be specified and tested. Check for the procedures for testing and the records. The distribution systems should be validated. The quality of the steam should be specified and monitored. Especially when the steam is used for the autoclave. Procedures and records should be available also. Have a look at the environmental monitoring. Are there specifications for temperature and humidity? Are there procedures and records for the monitoring? Is there a procedure on the actions taken if temperature and humidity are out of limits? The specifications for temperature and humidity, in the case of sterility testing specifications for particles and microbes should be appropriate. Look at the handling of waste. Is the handling of waste, treatment of waste e.g. waste from the micro lab, described in procedures? Waste handling should not put personnel at any risk nor influence the results of the analytical testing.

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