20, avenue Appia CH-1211 Geneva 27 Switzerland Tel central Fax central

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1 SOP Annex C 20, avenue Appia CH-1211 Geneva 27 Switzerland Tel central Fax central WHO PUBLIC INSPECTION REPORT (WHOPIR) Contract Research Organization Part 1: General information WHO product numbers covered by the inspection Study number Title of the study Clinical Part of the study: Name and address of the organization Bio-analytical laboratory: Name and address TB263 (moxifloxacin 400 mg tablets) Study # NCS CS Date of inspection January 2014 Part 2: Summary A randomized, open label, balanced, single center, two treatment, two period, two sequence, single dose, crossover bioequivalence study of MOXIFLOXACIN TABLETS 400 mg of Micro Labs Ltd., India and Avelox 400 mg filmomhulde tabletten moxifloxacin, of Bayer B.V., Energieweg 1, RT Mijdrecht, in normal, healthy, adult, human subjects under fasting conditions. Pvt Ltd (Sahakara Nagar site), 43/2, 3rd floor, Cauvery Medical Center, NH-7, Bellary Road, Sahakara Nagar, Bangalore , India Pvt Ltd (Koramangala site), #147/F, 8th Main, 3rd Block, Koramangala, Bangalore , India General information about the site(s) Pvt Ltd ("Norwich") was formed as a partnership between Alvogen and the Lotus clinical Research academy Pvt Ltd(LCRA). The Koramangala office housed most of the company s activities except for clinical. LCRA had offices in the same building under their own name and housed a M.Sc. program in pharmaceutical research run in collaboration with the Birla Institute of Technology (BIT), Ranchi. Norwich started their operations in 2010 with pharmacovigilance, which represented over 50 % of their activities at the time of the inspection. The clinical unit was commissioned in 2012 with 72 beds. The bioanalytical unit started their operations in The bioanalytical area had 3 liquid chromatography-tandem mass spectrometry (LC-MS/MS) systems currently in operation, all API 4000 models. The API of 6

2 used for study under review (Study No. NCS CS) was still available but was decommissioned in May There were 119 members of staff, with 24 in pharmacovigilance, 26 for clinical, 16 in the bioanalytical laboratory, 4 in the information technology (IT) department, 3 in validation and good laboratory practices (GLP), 10 in quality assurance (QA). A presentation giving a summary of changes made to Norwich since the study was performed was given: -A new archive was created in the Koramangala facility. -Key person changes included a new unit head, new executive nurses, clinical research coordinators, 1 person for documentation and 2 wardens. -In the bioanalytical laboratory, 3 members of staff were added. -Analyst and were introduced. -A system called SDMS was used for the on-line review of chromatographic data. SMDS reporter software was used for the transfer of bioanalytical data from the laboratory to the pharmacokinetics unit. -A data-logger management system had been set in place. -The number of standard operating procedures (SOPs) had more than doubled since History of WHO and/or regulatory agency inspections This was the first inspection by the WHO. The site had not yet been inspected by any stringent regulatory authorities (SRAs). It was approved on 19 January 2012 by the DCGI of India. It obtained ANVISA(Brazil) approval on 6 December 2012 and on 10 June 2013, it obtained MOH Turkey approval for conducting biostudies. According to the opening meeting presentation, studies have been conducted for the USFDA, ANVISA, WHO and Turkey, for a total of 69 studies, 30% pivotal. Focus of the inspection The inspection focused on the clinical and bioanalytical portions of the bioequivalence study conducted for the product TB263. The pharmacokinetic and statistical calculations were also checked. Inspected Areas Day 1 After the opening meeting presentation, Inspectors proceeded to the following activities: Inspection of the clinical areas 1. Subject registration and entertainment room 2. Informed consent room and monitor office 3. Washroom facilities 4. Clinical beds 5. Emergency treatment room as well as emergency medicines, resuscitation devices, etc. 6. Phlebotomy room 2 of 6

3 Documentation review: A number of different SOPs and forms were reviewed. Day 2 Inspectors proceeded with a tour of the pharmacy and reviewed remaining clinical documentation. At the end of the afternoon, inspectors headed to the bioanalytical and archive facilities. The different items inspected included: -ultra deep freezers -preparation areas -LC-MS/MS rooms -Computerized systems -restricted area -basement archive -ground floor archive -closets used as archives for LCRA documentation. Day 3 Method validation, preparations, bioanalytical data, audit trails were reviewed. Sample preparation forms were reviewed for all subjects. No issues of significance were found. All of the calibration curve standards (CCs) and quality control standards (QCs) passed, all of the integrations were automatically performed and were the best possible using the selected automatic integration algorithms. Smoothing factor was found to be excessively high at 10 but no instances of its use to hide poor chromatography were found. Freezer temperature records were reviewed and showed no abnormalities. Daily and monthly checks of the balance were reviewed. Day 4 Method validation: the sample preparation forms of all runs and the electronic chromatograms of matrix effects, selectivity, precision and accuracy (3 runs) and long-term stability in plasma were reviewed. The documents on the quarterly checks of 3 pipettes were reviewed. Back up policy, computerised system validation and management of user access rights were discussed with IT personnel. The process for the generation of randomisation lists and their management was investigated. Transfer of data to the pharmacokineticist and statistician were discussed. I. CLINICAL 2.1. PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL All of the prerequisites were considered to be met THE PROTOCOL For the study that was seen, the protocol was considered to be acceptable overall. 3 of 6

4 2.3. PROTECTION OF TRIAL SUBJECTS Informed consent forms were checked for all subjects. The signatures were compared with those on the informed consent distribution form RESPONSIBILITIES OF THE INVESTIGATOR The responsibilities of the investigator were considered to be adequately addressed in general RESPONSIBILITIES OF THE SPONSOR Sponsor responsibilities were fulfilled in their most part. Issues were nevertheless raised and pursued directly with the sponsor RESPONSIBILITIES OF THE MONITOR Monitor responsibilities were fulfilled in their most part MONITORING OF SAFETY Subjects were assessed before being enrolled as per the selection criteria stated in the protocol. The vital signs and clinical examination were conducted as per the protocol. Also, the protocol required handling and reporting of adverse events and serious adverse events. In general, this area was found satisfactory RECORD-KEEPING AND HANDLING OF DATA The official archives were in good order STATISTICS AND CALCULATIONS A data review meeting was convened before the randomisation list was released and the statistical analysis was performed HANDLING OF AND ACCOUNTABILITY FOR PHARMACEUTICAL PRODUCTS The company received 500 tablets of the test product from the sponsor, according to the forms that were shown. For the reference product, 585 tablets were received from Micro Labs. The batch numbers of the products received matched those reported in the trial report. The SOPs and associated forms on dispensing were reviewed. The notion of stepwise performance of documentation of line clearance and labelling was not reflected in the documentation that was seen ROLE OF THE DRUG REGULATORY AUTHORITY According to the information provided by the company, the site was licensed by the DCGI for its operations QUALITY ASSURANCE FOR THE CONDUCT OF A CLINICAL TRIAL QA project activities were managed through SOP No. QA , effective 6 December The procedure on QA project activities in Bioanalytical lab was reviewed. 4 of 6

5 2.13. SHIPPING AND HANDLING OF SAMPLES Double aliquots were taken. Shipment was performed using boxes equipped with dry ice and temperature was recorded throughout the entire process via data loggers GENERAL INFO ABOUT THE STUDY Analyst version 1.4.1, was used for the acquisition and integration of chromatograms and to calculate concentrations. The internal standard was gatifloxacin samples were received and all were analyzed. LC-MS/MS No. 3 (API3000) was used. Incurred sample reanalysis (ISR) was initiated on 15 May There was 1 repeat sample due to internal standard not added. Sample storage was for a maximum of 26 days. Method validation took place between 10 April 2012 and 14 April The demonstration of the long-term stability of moxifloxacin in plasma was finalised on 18 May SAS 9.2 for Windows was used on 16 May 2012, in association with WinNonlin version COMPUTERIZED SYSTEMS AND DATA INTEGRITY For Analyst and databases, backups were performed twice a day. Backup of data acquired on the hard drives of local computers was performed twice a day by automatic transfer to a backup server. The subject database used at the clinical site was also backed up twice a day. Further backups on tapes were performed daily, weekly and monthly. Daily tapes got re-used after a week and were overwritten when full. The same thing happened for weekly and monthly tapes, which were re-used after one month and one year respectively. It was said that they had a capacity of approximately 4 backup cycles. Duplicate copies of the weekly and monthly tapes were generated and kept at the clinical site. HPLC-MS/MS data was archived on duplicate CD-Roms or DVDs at the end of each project, from the hard drive of the work station. The CDs or DVDs were checked for the number of files transferred, but the data on the disks was not checked for integrity. Servers were validated in No changes were made since. All 3 version of Analyst were claimed to have been validated. However the set-up of the Windows access rights was found to be inadequate during the visit of the laboratory, as users had the possibility to delete or rename files, resulting in a possible loss or corruption of data although no such instances were observed. The company has a retrieval logbook where one was able to find the dates of retrival of DVDs of data shown to inspectors. 5 of 6

6 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 study # NCS CS for TB263, 400 mg Moxifloxacin tablets, was considered to have been conducted at an acceptable level of compliance with WHO GCP and GLP at, at the Sahakara Nagar site, 43/2, 3rd floor, Cauvery Medical Center, NH-7, Bellary Road, Sahakara Nagar, Bangalore , India for the clinical part of the study and at the Koromangala site, #147/F, 8th Main, 3rd Block, Koramangala, Bangalore , India, for the bioanalytical part of the study. 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 CRO, 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. 6 of 6