WHO PUBLIC INSPECTION REPORT (WHOPIR) Quality Control Laboratory. Uganda (NDQCL-NDA) Mulago Hill, P.O. Box 23096, Kampala, Uganda. NDA,

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1 SOP Annex D 20, avenue Appia CH-1211 Geneva 27 Switzerland Tel central Fax central WHO PUBLIC INSPECTION REPORT (WHOPIR) Quality Control Laboratory Part 1: General information Name of QC Laboratory Physical address Contact person and address. National Drug Quality Control Laboratory of NDA Uganda () Mulago Hill, P.O. Box 23096, Kampala, Uganda. Mr. Gordon. K. Sematiko-Executive Secretary/Registrar NDA, esr@nda.or.ug Date of inspection 4-5 September 2014 Type of inspection Type(s) of testing included in the inspection Summary of the testing activities performed by the QC Laboratory Ms. Annette Bukirwa Ssenkindu, Acting Head of the Quality Control Department/, absenkindu@nda.or.ug Mr. Peter Ssali, NDA Quality Manager, pssali@nda.or.ug Initial Chemical, physical Type of analysis Physical/Chemic al analysis Identification Assay, impurities and related substances, degradation Finished products ph, water content loss on drying, friability, dissolution, density IR, HPLC (UV- Vis detection), UV-vis spectrophotomet ry and basic tests HPLC (UV Vis detection), UVvis spectrophotomet ry, volumetric Active pharmaceutical ingredients ph, loss on drying, water content, density, melting point FTIR, HPLC (UV-Vis detection), UV- Vis spectrophotomet ry HPLC (UV Vis detection), UVvis spectrophotomet ry, volumetric 1 of 8

2 products. titrations, Polarimetry, titrations, Polarimetry, Part 2: Summary General information about the laboratory and site The Quality Control department also referred to as the National Drug Quality control laboratory ( NDQCL) was divided into three units; the medicine unit, medical device and public health products unit, as well as the quality management unit. The head of each unit reported to the head of the quality control department, who in turn reported to the Executive Secretary/Registrar of the NDA. The functions and roles were to coordinate and carry-out testing of all medicine samples, medical devices and public health products. The department also participated in cgmp inspections of local and foreign drug manufacturing facilities. It performed reviews of batch manufacturing records (BMRs) and validation records from local manufacturers. Routine analysis was performed on samples from ports of entry and the market. It was responsible for testing the initial 3 batches of new formulations for local manufacturers before marketing. There were 5 high performance liquid chromatography (HPLC) systems, 2 UV- Visible spectrophotometers (UV-Vis), 2 gas chromatography (GC) systems, 2 Autotitrimeters, 5 dissolution testing apparatus, 1 Fourier-transform infrared spectrophotometer (FTIR), 3 analytical balances, 2 ph-meters. Anti-malarial, antiretroviral and anti-tuberculosis medicines were tested among others. National Drug Authority inspectors collected samples and forwarded them to the laboratory. The laboratory was also responsible for testing male latex condoms, medical gloves and insecticides found in Long Lasting Insecticide treated nets ( LLINs ) for the country. It was in process of building a microbiology laboratory the heating, ventilation and air conditioning system (HVAC) and related equipment had been received and was pending installation. These areas were outside of the scope of this inspection. History of WHO and/or regulatory agency inspections This was the first WHO inspection of this site. Technical assistance had been provided in the past by WHO and USP. The inspection focussed on the quality management system (QMS) and on the main areas of quality control testing being requested for prequalification by the WHO. Inspected Areas 2 of 8

3 On Day 1, inspectors reviewed QMS documentation, briefly inspected all the laboratory facilities and equipment at the laboratory. Incoming samples, reagents and flammable liquids, reference standard management, qualification of equipment and analytical worksheets were also reviewed. On Day 2, inspectors inspected the equipment in detail, as well as method validation/verification, subcontracted tests, evaluation of test results, computerized systems, data processing equipment and data integrity, evaluation of suppliers. 2.1 Organization and management The organization of the laboratory was defined in the Organogram for the Quality Control Department. The organogram named the technical and quality assurance staff under each of their functions. The organizational and managerial structure in place was adequate to ensure that the laboratory would fulfil its responsibilities. However, several positions were vacant or filled by interim staff. The was in the process of recruiting for these positions and a short-list of candidates was expected in the near future. 2.2 Quality management system The laboratory had an up-to-date master list of standard operating procedures (SOPs) for equipment and for the quality management system which listed all SOPs by number along with their version, effective date and expiry date as well. However, this list was not signed and dated hence it was not clear when it was issued. Various SOPs were reviewed. They were easily retrievable and version control appeared to be appropriate. The following SOPs were reviewed: Laboratory document control SOP. It stated that when a document is superseded, the copies distributed are retrieved. Every analyst could read SOPs from the server. Obsolete documents were stamped as obsolete. After approval, training was given before the SOP was made effective. Laboratory change control SOP: it covered changes to documents. Handling of laboratory complaints SOP. Receipt, storage and handling of laboratory chemicals and reagents, SOP: It contained the necessary elements requiring verification of the reagents upon receipt and issuance of Good Receipt Notes. It specified how the reagents and chemicals should be labelled with date of receipt, expiry date, etc. It stated that the environmental conditions of storage should be controlled. This was seen to be applied in practice. Handling of deviations in the laboratory SOP: It described the documentation, investigation, evaluation and approval of the deviation from any approved procedure. There was no instructions on how recurring deviations should be handled. Laboratory management reviews SOP: The meetings were conducted at the end of the management year in September or in October latest. These included a review of major changes, subcontractor audits, internal audits, review of complaint records, infrastructure and work environment, proposed quality systems, budget performance, et cetera. 3 of 8

4 Handling of out-of-specification (OOS) test results: Trending of OOSs is to be performed. A register of OOS was requested and was reviewed. Several OOS examples were reviewed as well. Internal audits for the laboratory SOP. The example of an audit plan was reviewed and was found to be acceptable overall. Corrective action and preventive action SOP: It included evaluation of risk and criticality. The 5 W s (Who? What? When? Where? Why?) were stated to be used although not specified in writing. A CAPA register tracking form was set in place to provide effective means of tracking CAPA close-out. An implementation correction plan report was also drafted further to audit reports. This was acceptable. 2.3 Control of documents It was stated that obsolete documents were collected from the end-users once declared obsolete. This area was considered to be acceptable in general after CAPAs. 2.4 Records Electronic and paper records were kept for 7 years as per national regulations and the SOP for record handling and management. The laboratory maintained two types of electronic records: -Test reports -Data on equipment (HPLC, GC, Auto-titrimeters and spectrophotometer) The current SOP Data Handling and Management was reviewed. Test reports were scanned and stored on the server as well as on a hard drive. The equipment data was on stand-alone systems with individual logon. Back-ups were to be performed on a regular basis as per SOP. The laboratory was maintaining 2 copies of the sample database, one manual and one electronic Microsoft Access database. The SOP on Data Handling and Management detailed the procedure on how to make entries in the database and how to generate reports. Quality decisions were being made on the database. The database was locked (read-only) and editing rights were appropriately granted. The SOP specified the path year folder/month folder/qc data file number for major testing equipment such as HPLC, GC, auto-titrimeters as well as the path for excel calculation sheets. 2.5 Data-processing equipment The HPLC systems, GC system, ultra-violet spectroscopy and infrared spectroscopy equipment were linked to the computers operated by their respective software. An SOP was established on qualification of equipment. Equipment qualification protocols were available and qualification was performed. 4 of 8

5 In general, if changes were requested or required, they would consult the supplier and then re-qualify. In the event of system crash, they would have to be re-installed by supplier and re-qualified. There was a log for maintenance. The Equipment Fault reporting form was reviewed. This form was completed by the analyst, reviewed by the technician and then the maintenance/equipment service report was completed to fix the problem. The Equipment Fault reporting forms should be numbered, logged and stored by equipment maintenance technician. In general, the data processing equipment was found to be adequate. The procedure on creation, validation and use of Excel calculation sheets, was reviewed. The cells were appropriately locked. Users could only print and save a copy of the Excel sheet. Printouts of the cells with formulae were attached to the validation report. It was noted that there was no space for signature and date on the form. Section of the SOP stated that verification of the "last modified date" shall be done every 6 months. The validation of Excel calculation sheet forms was reviewed. All formula cells were locked. Spreadsheets were copied to a folder for the generic name/brand name/sample identification number which was then completed by analysts and saved. The formula cells remained locked. In general, the validation and use of Excel calculation sheets was found to be well documented, validated and in control. 2.6 Personnel The responsibilities of personnel were clearly defined in job descriptions which were signed off by the corresponding staff and the Quality Manager. The job descriptions for Laboratory Technician and Equipment Maintenance Technician were reviewed and found to be complete. The SOP on Training of Laboratory Personnel and its associated training forms, were reviewed as well as randomly selected training files. Analysts are to be evaluated after training and before use, regarding use of equipment. In general, the training, skills, experience and qualification of staff were adequate and well documented. 2.7 Premises Premises were generally appropriate for the work being done. Sufficient space was available for adequate conduct of analytical tests and related activities. It is noted that the laboratory was in process of creating a new microbiology laboratory. 2.8 Equipment, instruments and other devices There were 5 high performance liquid chromatography (HPLC) systems, 2 UV- Visible spectrophotometers (UV-Vis), 2 gas chromatography (GC) systems, 2 Autotitrimeters, 5 dissolution testing apparatus, 1 Fourier-transform infrared 5 of 8

6 spectrophotometer (FTIR), 3 analytical balances, 2 ph-meters. Equipment that was out of maintenance was clearly marked as such. 2.9 Contracts Contracts are established with certain suppliers. Some of the chemicals pose challenges when they have to be imported from outside the country. Basic technical evaluations were done and documented in the table for grade and quantities required. Manufacturer s authorizations for the sale and distribution of chemicals are obtained. For new manufacturers, evidence of compliance with ISO, for instance, are requested but no evidence of this was available. Recommendations from other recipients for chemicals and reagents are obtained in some instances. The laboratory performs their own verification once they receive chemicals. A recent incident was mentioned where chemicals from India were rejected. A rejected items list was shown. Documentation of these processes should be specified in a procedure and done in a systematic manner Reagents Reagents and flammable liquids were appropriately stored. Reagents were stored under controlled temperature in an area equipped with air extraction. The labels did not indicate expiry date or date of receipt and date of opening. Date of receipt was already part of the label template but was not yet filled since this was a new system in place that had just recently been implemented Reference substances and reference materials Most of the reference standards in use were primary pharmacopoeial standards. These were kept either under refrigerated or room temperature conditions in temperature and humidity monitored storage areas. The refrigerators used for the storage of the reference standards were attached to a calibrated external temperature monitoring device with limits of 2 to 8 o C. Outside these limits an alarm would be triggered. These alarms were not logged however the refrigerators were linked to a generator with a 30 second delay which ensured constant power. There was no storage area for standards that would require freezing. The checks performed to ensure that reference standards were not expired need better documentation of the date and thoroughness of the check performed Calibration, verification of performance and qualification of equipment, instruments and other devices FTIR calibration was performed when the equipment was used. Recent issues had been noted with the lamp. The laboratory was in process of communicating with their service provider on the potential impact of this issue. Performance verification of balances was seen to be performed using an adequate set of standardized weights which were traceable to their respective calibration certificates. This was acceptable. Performance verification of the dissolution testing apparatus was performed using a mechanical calibration kit and prednisone tablets from the current USP lot. The complete test kit was accompanied by the necessary calibration certificates (for the 6 of 8

7 shaft, gauge, spirit level, tachometer, etc.). There were 6 dissolution apparatus. There was one that was not under use because of issues with the operating software. The SOP for calibration of dissolution testers and related form were acceptable Traceability Traceability was generally found to be acceptable to the equipment number used, reference standard numbers, etc Incoming samples Incoming samples were received and logged the same day. The room in which they were received was not temperature controlled, but this was not a significant concern as they would be quickly moved to a temperature-controlled area. Incoming samples were registered along with brand name, generic name, customer number, QC number, quantity received,dosage form, batch number, manufacturing date, expiry date, name and address of manufacturer, analysed by, disposition, release date and remarks in both a paper logbook and an electronic database. Entries will be verified by a second person. The samples were then transferred to the samples store medicines room which was a temperature controlled room. The temperature and humidity were monitored and noted on the form Temperature and relative humidity monitoring at NDQCL. After testing, the samples were returned to this room and placed in passed, failed or quarantined areas as appropriate and retained for one year after expiry. Overall, the samples were considered to be appropriately stored Analytical sheet Worksheets were issued as per the SOP for preparation and issuance of analytical worksheets. Analytical worksheets specified the following: -Method file name -Sequence file name -Tests to be done (assay/dissolution) -Name of HPLC/GC, model number, Lab ID No, detector type, calibration status, name of column used, type of stationary phase, length x diameter, particle size, serial number of column, guard column used, column oven temperature, mobile phase/carrier gas composition and ratio, flow rate, run time, injection volume, detector wavelength, system suitability requirements, individual injection data and % RSD. Relative standard deviation of retention time RT. % RSD limits for area NMT 2.0%. HPLCs would also generate statistical reports automatically. -Other tests covered by the worksheet include assay by titration, manual titration, auto titration equipment setup and sample measurement, ph determination, melting point determination, dissolution apparatus set-up, sampling and preparation of dissolution solution, set-up and sampling. These were considered to be very thorough in general. Dissolution worksheets include information about whether filtration was done and which filters were used. Results were calculated using Excel spreadsheets by a dedicated person, not by the analyst Validation of analytical procedures 7 of 8

8 Method verification and validation was verified for selected analytical procedures in use at the laboratory. The SOP on analytical method validation/method transfer was reviewed Testing The SOP on operation of the Agilent HPLC was reviewed. It provided instructions on creating sequences. The procedures for data handling and management indicates how integrations should be done Evaluation of results A revised SOP for review, release and reporting of test results is in place and supplemented with a review check list Certificate of analysis The laboratory did not issue certificates of analysis. Instead, they issued test reports for the medicines that were tested, since these were for the purposes of the NDA only. An example of a certificate of analysis was shown for condoms. The laboratory stated that this format could be adapted to medicines should this be required. This is acceptable Retained samples Samples were retained for 1 year past shelf life Safety No issues of concern were noted. Part 3: Conclusion Based on the areas inspected, the people met and the documents reviewed, and considering the findings of the inspection, including the observations listed in the Inspection Report, as well as the corrective actions taken and planned, the National Drug Quality Control Laboratory of NDA Uganda () was considered to be operating at an acceptable level of compliance with in compliance with WHO Good Practices for Pharmaceutical Quality Control Laboratories. All the non-compliances observed during the inspection that were listed in the full report as well as those reflected in the WHOPIR, were addressed by the laboratory, to a satisfactory level, prior to the publication of the WHOPIR. This WHOPIR will remain valid for 3 years, provided that the outcome of any inspection conducted during this period is positive. 8 of 8