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SOP 404 Annex D

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Prequalification of Medicines Programme

WHO PUBLIC INSPECTION REPORT (WHOPIR) Quality Control Laboratory

Part 1: General information Name of QC Laboratory Laboratorio de control de calidad de medicamentos y

toxicologa/ Laboratory for the Quality Control of Drugs and Toxicology (CONCAMYT)

Physical address Calle Rafael Zubieta, n 1889, Zona de Miraflores, La Paz, Bolivia

Contact person and email address Cecilia Garnica Lopez Director of CONCAMYT [email protected]

Date of inspection 13-14 August 2013

Type of inspection Routine

Type(s) of testing included in the inspection

Physical, chemical, microbiological testing

Summary of the testing activities performed by the QC Laboratory

Type of analysis Finished products Active pharma-ceutical ingredients

Physical/ Chemical analysis

pH, water content, loss on drying, density, conductivity, refractometry, dimensions, disintegration, dissolution, uniformity of dosage units (mass, content)

NA

Identification HPLC (UV-VIS, PDA, fluorescence detection), TLC, spectroscopy (UV-VIS, IR), basic tests

NA

Assay, impurities and related substances

HPLC (UV-VIS, PDA, fluorescence detection), spectroscopy (UV-VIS, IR), volumetric titrations, polarimetry

NA

Microbiological tests

Sterility test, microbial purity, microbial assay of antibiotics

NA

This inspection report is the property of the WHO Contact: [email protected]

WHO Public Inspection Report CONCAMYT, La Paz, Bolivia 13-14 August 2013 Page 1 of 12


Part 2: Summary General information about the company and site The Laboratorio de control de calidad de medicamentos y toxicologa/ Laboratory for the Quality Control of Drugs and Toxicology (hereafter referred to as CONCAMYT) is the official laboratory of Bolivia in charge of the quality control of medicines manufactured and sold in the country. The CONCAMYT is one of the laboratories under the National Institute of Health Laboratories (hereafter referred to as INLASA), which is dealing with general activities such as human resources management, purchasing of materials, equipment and services for CONCAMYT. The CONCAMYT coordinates with the Medicines and Health Technology Unit (hereafter referred to as UNIMED), the regulatory body for the country. The Ministry of Health and Sports of Bolivia is the governing body for both UNIMED and INLASA. There were 21 staff members in the laboratory, 3 of them working in the microbiology laboratory (MB). From March 2012 until March 2013, the laboratory performed 848 analyses. The laboratory participated in proficiency testing; samples were received from CNCC Peru. History of WHO and/or regulatory agency inspections The CONCAMYT expressed its interest in prequalification in October 2009 and the first inspection was performed by the WHO inspection team within the Prequalification procedure on 22-23 March 2010. This is the second inspection performed by the WHO inspection team. The CONCAMYT was audited and certified by the Bureau Veritas Certification Argentina, German and according to ISO 9001:2000 and had a certificate valid until December 2010 which had not been renewed. The microbiology laboratory was inspected in March 2012 by the Peruvian regulatory authority. Focus of the inspection The inspection focussed on the inspection covered the following sections of the WHO good practices for pharmaceutical quality control laboratories (GPPQCL).

Inspected Areas The inspection covered the following sections of the WHO GPPQCL text Organization and management Quality management system Control of documentation Records Data-processing equipment Personnel

WHO Public Inspection Report CONCAMYT, La Paz, Bolivia, 13-14 August 2013 Page 2 of 12


Premises Equipment, instruments and other devices Contract Reagents Reference substances and reference materials Calibration, verification of performance and qualification of equipment, instruments and

other devices Traceability Incoming samples Analytical worksheet Validation of analytical procedures Testing Evaluation of test results Certificate of analysis Retained samples Safety

2.1 Organization and management CONCAMYT was legally authorized to perform the tests mentioned above. The CONCAMYT had managerial and technical personnel with the authority and resources needed to carry out their duties. The organization and management structure of the laboratory was defined although lacked a detailed organization chart specifying the names of the staff occupying key functions at the laboratory. 2.2 Quality system The quality management system (QMS) covered all the departments of CONCAMYT. The QMS was based on the ISO 9001 requirements. In addition, it followed the requirements of the WHO Good Practices for Pharmaceutical Control Laboratories. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth Report. Geneva, World Health Organization, 2010 (WHO Technical Report Series, No. 957), Annex 1. CONCAMYT was evaluating the possibility of applying for ISO/IEC 17025 accreditation in the near future. The Quality Management System (QMS) of CONCAMYT comprised 4 management sections (processes): Strategic and Quality Management Service Management Logistics Management Human Resources Management The processes were clearly described and well documented, as well as their interactions, through policies, procedures, instructions, plans, programmes and records. The Quality Manual (QM) was a high level general document covering all activities and processes. It contained the Quality Policy. The QM was composed of independent sections,



each of them with its own tracking of versions. There existed 2 controlled copies, one in the Microbiology section and one in the Chemical section. The QM presented the structure of the QMS documentation. The roles and responsibilities of the different positions within CONCAMYT were described in the Manual of Functions. Customer service: the main customer was UNIMED, which brought to CONCAMYT the samples to be analysed (coming from market surveillance department) together with the testing specifications and method to be applied. There was the SOP dealing with the communication with customers and evaluation of their satisfaction which was compiled via a questionnaire and discussed during management review meetings. Complaints: Complaints received at CONCAMYT were dealt with in the same manner as during the last WHO inspection according to the SOP. Complaints received through telephone, mail, fax, etc., were reported in a specific form. The implementation and follow up of the necessary corrective/preventive actions was done via the same process as for internal audits. Internal audits: The internal audit procedure dealt with the planning, performance and follow up of internal audits. The procedure described that the audit plan was prepared and approved by the Quality Committee. Internal audit plans were approved by the Head of the laboratory. Internal audits were performed according to the check lists and audit plan for different QMS topics. Reports of audits performed on 4-5 October 2012 and 11-12 July 2013 were reviewed. The audit reports were approved by the head of the laboratory. CAPAs were evaluated by the head of the laboratory and responsible person in charge of QA Audit findings were reported in a specific form. Non-conformities detected during internal audits were reported in a specific form, with a link to the audit date. The corrective/preventive actions identified after the audit were reported in a specific form, and their follow up was reported in a specific form. Non-conforming (NC) work/Corrective and preventive actions (CAPA): Corrective and preventive actions taken further to management reviews and further to the last WHO inspection were reviewed. This area was found to be acceptable in general and no changes were made since the last inspection. Management review: The last management review was performed 15 January 2013 and was spanning the entire year 2012. This was performed annually. It was based mainly on the perception and satisfaction of the client questionnaires and hence the timing of the management review was based on that. The management review also included an evaluation of the performance of CONCAMYT in inter-laboratory assays.



2.3 Control of documentation During the previous WHO inspection, an observation had been raised with regard to the SOP on elaboration of procedures and instructions. This was satisfactorily addressed, as the SOP on control of documentation was revised to specify the annexes and ensure traceability of the annexes to the main SOP. Furthermore, the relevant annexes were generally stapled to the relevant procedures. Another observation was given with regards to the fact that laboratory notebooks were found not to be paginated during the last inspection. A new procedure was created entitled instructions for the filling of the work books and training given as to how laboratory books should be created and maintained. This procedure was found to be appropriately implemented through the random verification of laboratory notebooks. A master list of QMS documents (procedures, instructions, manuals, records, plans, processes and registers) was available and generally up to date. SOPs were reviewed every 2 years, while instructions and forms were reviewed every 4 years. Changes in documents were tracked in a separate document containing the history of changes, annexed to each quality document. Staff signed for acknowledgement of the issue of an updated/new document. A list of external documents was available and they were kept in the library. Retrieval of documents from the library was documented. Changes in documents were tracked and a history of changes was available with each 2.4 Records Management of records was described in the SOP. Retention time for the different types of quality and laboratory records was defined (5 years). Issues that were raised during the last WHO inspection were found to have been resolved in general. 2.5 Data-processing equipment Electronic backups were stored at a different location, as part of the CAPAs related to the last WHO inspection. 2.6 Personnel The Human Resources Department of INLASA was in charge of the selection of new staff according to pre-defined criteria, also for staff working at CONCAMYT. Training was carried out according to a training plan. The training plan for 2013 was presented to inspectors. Training files were available for each analyst. The staffs occupying the positions in the laboratory were not identified in the organization chart or in the job descriptions. The job descriptions were not signed or dated. Instead, the staff was notified by a memorandum that they were assigned to a particular position.



Training effectiveness was verified in practice by determining the relative standard deviation (RSD) in a titration assay sample. The percentage of difference obtained in the preparation of standards, percentage RSD and acceptable percentage difference were assessed and recorded in induction training notebooks. The training plan for one of the analysts was seen as an example. Although it was stated that the verification of the performance of the analyst was done once per year, this was done through the standard deviation of each analyst. There was no overview or confirmation available that this had indeed been done for all of the tests that the analyst was authorized to perform. Analysts were claimed to be re-qualified along with the validation and verification of methods however there were no names available in the reports to confirm this. 2.7 Premises Wet chemistry and physico-chemical testing: The chemical laboratory facilities were considered to be acceptable in size and suitable for storage and performing of the analyses. All the surfaces and finishing were suitable for easy maintenance. Premises were kept clean and tidy to ensure safe work. Temperature was routinely controlled and recorded in the different areas. Microbiology: Microbiological laboratory facilities were of a suitable size, construction and location. These facilities were designed to suit the functions and operations to be conducted in them. The microbiological laboratory was divided in 6 areas in total but the pressure cascades were not shown. There were 3 separate (similar design) sterile areas used for: Microbiological strains preparation and growth promotion tests Sterility tests Microbiological limit and antibiotic potency tests. Entrances to those sterile rooms were via 3 change rooms. Materials were brought to those rooms via double material pass boxes. A single air handling unit (AHU), equipped with HEPA filters, was installed to supply the air to the entire microbiology laboratory. The area was recently re-qualified and improvements were made as per the laboratorys CAPAs. 2.8 Equipment, instruments and other devices The maintenance and cleaning plan for equipment was described in the SOP. The calibration/verification plan was laid down in the specific document. There was also a plan for the maintenance of sterile areas. These plans were detailed and contained all necessary information to ensure a good performance of equipment in both laboratories. Equipment, instruments and other devices were designed, adapted, located, calibrated, qualified, verified and maintained as required by the operations carried out in both WHO Public Inspection Report CONCAMYT, La Paz, Bolivia, 13-14 August 2013 Page 6 of 12


laboratories. Both laboratories had the required test equipment, instruments and other devices for the correct performance of the tests, calibrations, validations and verifications. 2.9 Contracts Services such as metrology, qualification and equipment maintenance were sub-contracted. The laboratory did not subcontract any of the routine analyses forwarded to them. 2.10 Reagents Purchases CONCAMYT made a list of needed materials and services, together with the required specifications and this list was sent to INLASA, which performed the purchases. At reception, delivered products were verified against specifications. There was 1 person responsible to verify reagents at arrival. Evaluation of suppliers CONCAMYT made a yearly evaluation of suppliers according to the SOP. A list of approved suppliers was available on a specific record. The process in place for the evaluation of suppliers was exhaustively documented and traceable. Criteria were pre-defined and a score was given to the suppliers with detailed explanations. Solvents The quality standard for commercial solvents was defined as per USP. Reagents Stocks of reagents were maintained under controlled conditions. Reagents storage was found to be in good order. Consumption of the reagents was recorded on stock cards and in general was traceable and adequately organized. Water Distilled water Water was sourced internally using distiller and resin interchange connected in-line. Distillation equipment was mechanically cleaned on daily basis and sanitized once per month using 10% acetic acid solution. Daily cleaning and monthly sanitization were adequately recorded. Water conductivity was checked and recorded daily, chemical analysis was carried out and results recorded twice per month. Purified water Purified water was obtained by ultrafiltration and complied with requirements for water for HPLC. Reagent solutions prepared in the laboratory The corresponding procedures were prepared in accordance to compendial standards where available. Volumetric solutions were prepared following instruction. Volumetric solutions were listed in a specific form. The preparation and standardization of volumetric solutions were recorded. The information provided in the labels of reagents



(commercial), reagents solutions (in house) and volumetric solutions (in house) included the information required. Reagents were not subdivided. Culture Media In the Microbiology sector, dehydrated culture media were used to prepare ready-to-use media. Dehydrated culture media were adequately stored under controlled conditions, according to the supplier information. All culture media were registered and a code number was assigned to each one. The growth promotion tests were performed for every batch of dehydrated culture media and after preparation/sterilization of soluble culture media. Positive and negative controls were performed and adequately recorded. Culture media prepared by the laboratory were clearly labelled but were missing dates of expiry. There was a procedure for culture media preparation and sterilization and the issues raised during the last WHO inspection (e.g. growth promotion test not performed) were found to be resolved. 2.11 Reference substances and reference materials SOP for management of reference standards valid for Chemistry and Microbiology sectors was available. Reference standards were stored in safe and controlled conditions. Storage temperature was routinely controlled and recorded. Chemistry sector USP and secondary reference standards were routinely used. The central register of reference materials consisted of a record book. This information was updated by the corresponding responsible staff member, however some of the reference standards that had been disposed of, were still listed as being present. The corresponding reference to standard used (including batch) was recorded in the analytical worksheet. Microbiology sector All of the strains required for sterility tests and microbiological enumeration test were available. The register for all strains included all of the required information. The strains were adequately stored under safe and controlled conditions. 2.12 Calibration, validation and verification of equipment, instruments and other

devices Equipments, instruments and other devices used were regularly calibrated, validated and verified according to a calibration and verification plan. Most calibrations/ verifications were properly recorded. Records for calibrations/verifications included all the required information. Chemistry sector The lists of equipment calibration/verification for 2012 and 2013 were seen.



All the equipment, instrument and other devices used for testing were verified and calibrated following the corresponding plans and SOPs. There was a person responsible for each item of equipment, instrument or other device. The equipment and instruments were calibrated and verified at the prescribed times the calibration/verification status was clearly visible on the corresponding labels. Ultraviolet spectrophotometers were internally verified every 3 months using holmium oxide filter, holmium solution in perchloric acid, potassium dichromate solution and potassium chloride solution. Verification was found to be adequately carried out and recorded. However there were observations regarding traceability and expiry dates of standards. Polarimeter verification was carried out internally every 4 months. Different concentrations of sucrose solutions were used for verification purposes. Verification was found to be adequately carried out and recorded. The laboratory used Class A and Class B volumetric glassware for quantitative analysis however at the time of the inspection; the glassware was undergoing a verification process. The laboratory did not have potentiometric titration equipment other than Karl Fisher USP apparatus. It was stated that equipment was in process of being purchased and that alternate methods were being used for analysis. Excel datasheets Although an observation was made during the last WHO inspection that there was no procedure to validate, verify and maintain Excel datasheets, this was not found to be an issue during the current inspection as Excel spread sheets were no longer being used, all calculations being done manually with a calculator. Calculations were being verified through a 2nd check by QA. Microbiology sector Each item of equipment, instrument or other device used for testing was uniquely identified and accompanied by registers when necessary. Most equipments, instruments and other devices requiring calibration were properly labelled in order to identify the status of calibration and the date for recalibration. SOPs for the use, maintenance, verification, qualification and calibration of equipments, instruments and other devices were available for laboratory personnel. Volumetric material such as burettes, pipettes, pycnometers, etc. was calibrated every two years either externally by IBMETRO or internally by the assigned CONCAMYT personnel. 2.13 Traceability The reference material(s), equipment(s), reagent(s), culture media, analyst(s), calculation(s) were suitably recorded in the analytical report and therefore traceability was deemed suitable and sufficient.



2.14 Incoming samples The laboratory was not responsible for sampling as samples were sent to them by the Medicines and Health Technology Unit of Bolivia (UNIMED). The majority of samples were obtained by the post commercialization vigilance which obtains the samples from the wholesalers, manufacturers, importers and pharmacies. Incoming samples were assigned 2 unique numbers upon receipt: 1 sample number and 1 marketing authorization dossier number in black and blue colours respectively. These were tracked using an Excel spread sheet. Incoming samples were verified to be of sufficient size to enable, if required, replicate analysis as well as to retain sample. Incoming samples were accompanied by the corresponding test request containing all the required information. Each sector (chemistry and microbiology) received its own samples. Therefore a test request was provided for each laboratory accompanying the corresponding sample. Samples and related documents were stored for 5 years. 2.15 Analytical worksheet Laboratory notebooks were used in lieu of separate worksheets. These contained an adequate amount of details, such as calculations of preparation concentrations, lot numbers of reagents, etc. Traceability from a certificate of analysis to laboratory notebooks or from a notebook to the raw data was found acceptable in general. The analytical worksheets were signed by the analyst and verified, approved and signed by the supervisor. Once approved and signed by the supervisor, analytical worksheets were filed with the corresponding attachment safely. 2.16 Validation of analytical procedures A new SOP verification of analytical methods was set in place further to the last inspection. It was reviewed along with a randomly selected example to verify whether it was consistently applied. Pharmacopoeial methods were verified using statistical analyses of variation coefficients and linearity of a total of 9 repeats (3 replicates and 3 repeats of each replicate). Linearity and coefficient of determination were used as acceptance criteria. Repeatability and accuracy also included 3 concentration levels spanning 80 to 120 % in duplicate. This was adequately performed in the examples that were seen during the inspection. 2.17 Testing Samples were tested in accordance with the work plan of the laboratory. Test procedures were described in sufficient detail. Any deviation from the test procedure was approved and documented.



Specifications The laboratory maintained a specifications archive, which included: Pharmacopoeias: USP, Farmacopea Espaola, British Pharmacopoeia, Japanese

Pharmacopoeia and European Pharmacopoeia Manufacturers specifications. Chemistry sector System suitability requirements (RSD, peak symmetry, resolution) were completed, when relevant. The calculation of the different system suitability parameters were was also included in the analytical workbook along with the corresponding acceptance criteria. The issues noted during the previous WHO inspection with regards to system suitability criteria and policy for handling results from analyses, were found to be correctly addressed by the laboratorys revised procedure on HPLC testing. Microbiology sector The SOP on verification of antibiotics was reviewed during the inspection and contained the necessary criteria. During the previous WHO inspection, observations were raised with regards to procedures not including the methods performed for the microbiological examination of non-sterile product, procedures not being based on the harmonized pharmacopoeial monographs and not including the requirement for negative and positive controls. Corrective action to the last WHO inspections observations were deemed acceptable in that test procedures were now based on the harmonized monographs for USP, Ph. Eur. 2.18 Evaluation of test results Test results were reviewed by the quality assurance unit. Further to the last WHO inspection, a new SOP was established for the investigation of out of specification results (OOS). OOS investigation flowchart was shown. The flowchart showed how the investigation proceeded from the 3 initial determinations. A separate SOP was created for OOS investigations in microbiology. 2.19 Certificate of Analysis (CoA) File folders containing the test requisition form, were reviewed together with the laboratory notebooks by QA. An example was shown for amoxicilline trihydrate 500 mg capsules, along with the information from the sample box. A draft CoA was printed by the analyst. The reviewer from QA verified that the conditions of the analysis and that the test method used was identical to that specified in the pharmacopeia or manufacturers method. This included a review of the calibration status of the equipment, the standard used. It is only after this step that the final certificate was issued. The laboratory head did the ultimate verification of the certificates.



2.20 Retained samples Samples were retained for 5 years. Retained samples were stored safely under controlled conditions. The laboratory kept a register of retained samples. 2.21 Safety The safety manual of INLASA was available to all staff and contained an adequate level of detail. INLASA had a Department dedicated to the Biosecurity and they wrote the manual with the collaboration of CONCAMYT. Equipment for individual protection and safety instructions were available and used as well as poster displays on the walls and doors. Fire extinguishers were periodically revised and refilled and were accessible in all areas. All staff was trained on the use of fire extinguishers as well as on risks linked to the use and storage of reagents and disposal of waste. All staff was trained on first aid measures. Safety showers were available but there were no eye showers. Chemical fume hoods were re-qualified each year. 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 Laboratorio de control de calidad de medicamentos y toxicologa/ Laboratory for the Quality Control of Drugs and Toxicology (CONCAMYT) ) was considered to be operating at an acceptable level of compliance with in compliance with WHO Good Practices for Pharmaceutical Quality Control Laboratories for the scope activities listed below: Physical/Chemical and microbiological analysis of finished pharmaceutical products and

active pharmaceutical ingredients All the non-compliances observed during the inspection that were listed in the full report 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.


Part 2: SummaryThe CONCAMYT expressed its interest in prequalification in October 2009 and the first inspection was performed by the WHO inspection team within the Prequalification procedure on 22-23 March 2010. This is the second inspection performed by the WHO ins...The CONCAMYT was audited and certified by the Bureau Veritas Certification Argentina, German and according to ISO 9001:2000 and had a certificate valid until December 2010 which had not been renewed. The microbiology laboratory was inspected in March ...Part 3: Conclusion Physical/Chemical and microbiological analysis of finished pharmaceutical products and active pharmaceutical ingredients

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