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Medicīniskās aprūpes un darbaspējas ekspertīzes kvalitātes kontroles inspekcijai

20, AVENUE APPIA – CH-1211 GENEVA 27 – SWITZERLAND – TEL CENTRAL +41 22 791 2111 – FAX CENTRAL +41 22 791 3111 WHO PUBLIC INSPECTION REPORT
(WHOPIR)
Contract Research Organization
Part 1: General information

WHO product numbers covered TB 199 Ethambutol/Isoniazid/Rifampicin 275/75/150mg by the inspection S-IO-103

Title of the study A randomized, open label, balanced, single center, two treatment, two period, two sequence, single dose, crossover oral bioequivalence study of test product (Four tablets of fixed dose combination of Rifampin 150 mg , Isoniazid 75 mg and Ethambutol Hydrochloride 275 mg) with that of reference product [two capsules of Rifamate® (containing Rifampin 300 mg and Isoniazid 150 mg) of Sanofi A ventis, USA and three tablets of Myambutol® (Ethambutol Hydrochloride) 400 mg of Riemser Arzneimittel, Germany] in healthy human adult male subjects, under fasting conditions. Clinical facility: Semler Research Center Pvt. Ltd. Name and address Sharon Hospital Campus, 18, Tanmag Road, Vinayagampatti, Salem - 636 008, India Telephone: 0427-2404612, 2404614. Fax: 0427-2404611 Bio-analytical laboratory: Semler Research Center Pvt. Ltd. Name and address 75 A, 15th Cross, I Phase J.P. Nagar, Bangalore - 560078, India Telephone: 080-42627200 Fax: 080-26640683 Date of inspection 11- 15 July 2011 This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report Part 2: Summary
The purpose of the inspection was to inspect the bio-equivalence study performed at Semler Research Center Pvt. Ltd (hereafter referred to as "Semler"), to assess compliance with GCP, GMP and GLP (as appropriate) and to verify the related source data for the above mentioned study. General information about the site
Semler was located in the following three different locations:

Clinical facility
Semler Research Center Pvt. Ltd.
Sharon Hospital Campus,
18, Tanmag Road, Vinayagampatti,
Salem - 636 008.
Screening Facility
Semler Research Center Pvt. Ltd.
C/O SKS Hospital
3rd floor, 23 SKS Hospital Road
Alagapuram
Salem -636004.
Bioanalytical and statistical facility
Semler Research Center Pvt. Ltd.
75 A, 15th Cross, I Phase J.P. Nagar,
Bangalore - 560078.
Semler bioanalytical facility was inspected on 11-12 July 2011, clinical facility on
13-14 July 2011 and screening Facility on 15 July, 2011.

History of WHO and/or regulatory agency inspections
This site was preciously inspected by the WHO team 12, 14, 15 and 16 July 2010 Focus of the inspection
This inspection focused on the bio-equivalence study performed on behalf of the sponsor
for the above mentioned product (TB 199). The inspection covered the relevant sections
of the WHO GCP, GLP and related texts, including the WHO guidance for organizations
performing in vivo bioequivalence studies.
General information

Protocol issue date was 21 October 2010.
This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report IEC approval date was 26 October 2010. The study clinic start date period I was 27.10.2010. End date period I was 29.10.2010. The study clinic start date period II was 10.11.2010. End date period II was 12.11.2010. The study BA part start and end dates were the following: Isoniazid 15.11.2010. (start) 10.12.2010. (end) 18.11.2010. (start) 16.12.2010. (end) Ethambutol 15.11.2011. (start) 20.12.2010. (end) Summary of an audited PK status results was dated  Rifampicin 24 December, 2010.  DecAcetyl Rifampicin 21 December 2010.  Isonoazid 15 December, 2010  Ethambutol 24 December, 2010. Number of subjects Subject dosed in Period 1 Subject dosed in Period 2 No. of subjects withdrawn No. of subjects dropped out Adverse drug events Deviations from the protocol
Blood withdrawal
A total of 23 (1x6 ml) blood samples were collected from each subject in each study
period.
The pre-dose and post-dose samples up to 24 hours were collected via an indwelling cannula placed in an ante-cubital vein or one of the forearm veins. Heparin-lock technique was used to prevent clotting of the blood in the indwelling cannula. The collected blood was transferred immediately after collection in vacuum tubes containing anticoagulant (K2EDTA) in each period. The total volume of blood drawn including the volume necessary for the laboratory tests and the volume of heparinized blood discarded before each blood draw was about 310 ml for each subject for the entire study. Blood sample collection and processing was done under yellow monochromatic light as Rifampicin and ascorbic acid solution used as the antioxidant are both light sensitive. This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report Subject monitoring
Subjects were monitored at 4, 6, 12 and 24 hours post dose in each period. In addition,
vitals were recorded at the end of the study.
The subjects were asked regarding their well-being at regular intervals. Hematology and serum biochemistry investigations (except blood grouping and Rh typing) done at screening were repeated at the end of study. Adverse event monitoring was done throughout the study. For all dosed subjects ECG was recorded at the end of study and documented in ECG recording form (appendix 10). Immediately prior to check-in of each period, all subjects were tested for alcohol in breath and for the presence of drugs of abuse in urine. Inspected Areas and documents reviewed
On the first day inspectors visited:  BA laboratory  Sample preparation  LSMS room  Balance room  Deep freezers room  Archive On the first and second day the inspectors reviewed various documents which included SOPs such as:  SOP "Sample transfer to Bioanalytical laboratory"  Freezer print outs from 10.11.2010 till 17.12.2010.  Data Logger memory  Qualification report of freezer .Qualification was carried out for loaded freezer and unloaded freezer. Report was audited and approved by QA  SOP "Receipt, storage and usage of reference standards"  Alarm log book deep-freezer  SOP"Chain of Custody of Biological samples"  Performance qualification for temperature maintenance using dry ice. Conclusion was made that samples can be maintained at a temperature below - 50 C for approximately 42 hours  SOP "Operation, maintenance and Qualification of Ultra Low Temperature Freezer" Freezer Maintenance records were presented and reviewed  SOP "Operation; maintenance and qualification of Micropipettes". Micropipettes Performance Qualification was carried out on weekly basis and three month basis. Micropipettes Performance Qualification weekly and tree monthly performance Qualification reports were presented and reviewed  SOP "Chromatographic Acceptance Criteria and Reintegration criteria"  SOP "Preparation of Calibration Curve and Quality Control Samples and Batch acceptance Criteria" This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report  Working standard logbook for ethambutol, isoniazid, rifampicin, desacetyl rifampicin  Maintenance logs of LCMS used for ethambutol, isoniazid, rifampicin and desacetyl  Colum usage logs for LCMS  SOP "Quality assurance department"  SOP "Training and job responsibilities of quality assurance unit clinical personnel"  SOP "Study specific audit report"  Organization chart  Job description and training records of the Study Director  Method validation protocol of Rifampicin and desacetyl rifampicin  SOP "System suitability"  SOP "Re-assay of samples in bioanalytical laboratory for pharmacokinetic reasons"  List of studies performed during 2010.  SOP "Estimation of rifampicin and its metabolite desacetyl rifampicin in LC-MS/MS using rifabutin as internal standard in human plasma"  SOP "Estimation of ethambutol in human plasma using propranolol as an internal  SOP "Estimation of isoniazid in human plasma using lansoprazol as an internal  SOP "Reassay of samples in the bioanalytical laboratory"  Log book for samples in-out to the deep-freezer ULTF  SOP "Obtaining blood samples"  SOP "Sample transfer to bioanalytical laboratory"  SOP "Operation, maintenance and qualification of ultra low temperature freezers"  Records of shipment of samples from clinical to bioanalytical facility  Records of calibration of data-loggers used during shipment  SOP "Operation, maintenance and performance of qualification of wireless data  Temperature records for freezer (clinical facility) for the time period of the study (manual and electronic)  SOP "Line clearance for drug dispensing"  SOP "Line clearance for drug administration"  SOP "Check-in and check out of subjects"  SOP "Study specific training and delegation"  Job description and training records on the specific study for clinical research coordinator, pharmacist, principal investigator, phlebotomist, contracted medical doctor  SOP "Randomization and blinding procedures"  SOP "Clinical study protocol preparation, review and version control"  SOP Adverse event recording and reporting"  Concomitant medication log  Adverse event logs during study  SOP "Lebeling of vacutainers and vials" This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report  SOP "Operation, maintenance, and qualification of micropipettes" The method validation protocols and final reports for all of the four substances (Ethambutol/Isoniazid/Rifampicin/Desacetyl Rifampicin), as well as protocol and report for the study S-IO-103, were signed by the study director and included a QA statement. Minor comments were made referred to the latter, listed in the report below. Method validation for rifampicin was reviewed and verified, including specificity, reinjection, dilution, precision, and carry over, accuracy, recovery, matrix effect, stability (bench top, auto-sampler, freeze-thaw, long-term, stock solution). Relevant dates regarding study S-IO-103 were the following:  Experimental starting date: 15/Nov/2010  Experimental completion date: 20/Dec/2010  Date when samples where collected: 27 – 29/Oct/2010 (period 1) 10-12/Nov/2010  Date when samples where received: 12/Nov/2010  Study completion date: 28/Dec/2010 Usage, maintenance and calibration logs for relevant study equipment were reviewed (LCMS, micropipettes, scales, deep-freezers). The inspectors also checked test item and internal standards weights, preparation of working standards and spiked calibration curve and QC samples records, certificates of analysis and chain of custody was reconstructed. Records generated during the receipt of samples were reviewed, as well as sample accountability and crosschecking versus study raw data. Back calculation of around 1/3 of the subjects (13 out of 36) was performed; for all of the subjects recalculated, acceptance criteria for 100% of the calibration standards and QC samples, internal standard variation, run times of the analytical sequences and time spent by the samples at room temperature (time from retrieval from the deep-freezer until placement into the auto-injector) were verified. Calculated concentrations were checked against concentrations indicated on chromatograms and the reported tabulated data and dossier report. Repeated analysis and missing samples were verified as well as the audit trail for their respective runs. Raw chromatograms of repeated analysis as well as from a number of subjects were checked. On the third day inspectors visited Clinical facility and screening facility. The Clinical facility was separated from the functional hospital. The following activities and services were provided at the Clinical facility:  Checking of volunteers for the studies  Drug administration  Blood sampling There were 8 phlebotomy stations and 8 phlebotomists available  Sample storage There were three housing areas in total 48 beds were provided for the studies: This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report Housing area I had 12 beds Housing area II had 12 beds Housing area III had 24 beds  Subject pantry area  Two Intensive Care Units (ICU) with the following equipment were available for the  Pulso-meter  Suction equipment  Oxygen generator  Nebulizer  Cardio-monitor  Intubation bags  Essential medicines. On spot checks all medicines were within their shelf lives. Medicines inventory showing expiry dates was available and was kept up-dated. Till the date of inspection there were no subjects moved to the ICUs.  One mobile ambulance  Check out of volunteers  Pharmacy, dispensing Dieticians' service, preparation of food was outsourced; canteen was audited and approved by the Semler staff. Volunteer recruitment and enrollment:
Volunteer recruitment was done through advertising and by word-of-mouth and recall
from the data base. There were about 2463 volunteers in the "volunteer bank". In case
advertising was done via newspaper, the IEC had to be informed and approval should be
obtained
General screening:
Volunteers were sent for screening at the SKS hospital in Salem. The rooms provided for
screening were separated from the hospital and entrance was controlled. The following
activities and services were provided at the Screening facility:
 Screening-enrolment. Volunteers were assigned 6 digits identification number
which will last for the entire subject "volunteer life". Volunteers had to sign written consent for enrolment, if necessary witness was present and also signed the form. Upon arrival volunteers had to register and they were given a token number. Upon arrival volunteer photo was taken and compared with photo (saved in the system) and ID number. Volunteers' data were stored on excel sheet, which was not validated. Only cross checks of date was carried out. CRO was in progress of introducing fingerprint identifications. Volunteers' last participation (data of last blood withdrawal) in the study was extracted from the excel sheet where it was entered manually. Excel sheet was passport protected. This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report  Screening consent form. Screening consent forms were given to the volunteers. If
required, a witness was present. The following vital parameters were checked:  Weight  Height  Blood pressure  Temperature  Respiration rate  Pulse rate  ECG  Blood analysis (contracted to the hospital)  Urine analysis (contracted to the hospital)  X rays (contracted to the hospital) The validity period was 21 days for tests and 6 moths for the X ray.
On the fourth day inspectors reviewed below listed documents and did some cross checks
as mentioned below.

Ethics Committee (IEC)
The IEC consisted of 9 persons. It was established in 2007. The IEC had an office in
Salem. It operated in accordance with a SOP . SOP specified:
 Training
 Responsibilities  Operations  Meetings  Hierarchy, etc The following documentation was sent to the IEC on 21.10.2010 for review and approval  Study protocol and appendixes'  Declaration of sponsor  Declaration of investigator  Declaration of Helsinki  Table of study meals  Lab reference ranges  Height and weight reference chart  CV of investigators  Restriction and well being questionnaire  Inclusion and exclusion criteria form  ECG recording form  IC documents in English  IC documents in Tamil This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report The following documents also were reviewed:  ICF shipping letter to the ICE, sent 21.10.2010.  Minutes of IEC meeting held on 26.20.2010.  Confidentiality agreement with IEC was presented during inspection.  IEC chairman CV and training  IEC member secretary CV and training  EC member CV and training  Insurance, dated 11.12.2009. - which was valid for one year  Pre screening information Investigators brochure was not available. - Pharmacology section was part of the protocol and included:  Mechanism of action  Indications  Dosing information  Contraindications  Pharmacokinetics  Distribution  Elimination  Warnings and precautions  Drug interactions  Adverse reactions  Parameters.
Protocol:
Protocol was issued on 21.10.2010 and approved by IEC 26.10.2010. The following
documents were reviewed:
 ICF for screening - English and Gujarati languages
 ICF for study - approved by IEC English and Gujarati languages
 ICF for all subjects (signatures were cross checked with subject arrival records - ID)  Enrolment forms were cross checked for all subjects:  VIN (Volunteer Identification Number)  signatures  date of birth was verified as well as identification  Screening consent forms for all subjects were crosschecked with VIN and signature  CRF for all subjects were reviewed and crosschecked with randomization list and drug administration labels:  Screening records were filed separately from CRFs. Screening records for all subjects were reviewed and crosschecked (ECGs and Chest X rays). Also several other subject analysis were cross checked. This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report  Vacutainer labels  Break-up compensation policy approved by IEC on 4.3.2010.  Compensation list and payment slip
 Insurance policy
Other documents reviewed:
 Study specific delegation training and signature log  Study specific training document  QA audits were carried out in accordance with the SOP"Study specific audit in the clinical unit" .Audits were carried out at specific time periods as: o Pre-study o During study o After study Check lists were used for the audits. During the check list review observations had been raised. Responses were given in conservation response sheets. Responses were verified by the QA department staff. After that the QA statement has been issued. Temperature records for the time period of the study (manual and electronic) were reviewed, as well as temperature recorded during the shipment of the samples to the bioanalytical facility were reviewed. Line clearance for drug dispensing for period I and period II, as well as line clearance for drug administration for period I and II were checked. It was also verified the concomitant medication log, and adverse event log for the study; furthermore, job description and training records for the pharmacist, principal investigator, phlebotomist and contracted medical doctor were reviewed. Electronic backups were made on a daily, weekly and monthly basis; at the end of the month, a full copy was sent to an external facility. Integrity of information upon retrieval has been tested during periodic mock-ups.
2.1. PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL
Acceptable
2.2. THE PROTOCOL
The Protocol was found in general to be acceptable. Following deviations were recorded:  Blood sampling deviations  One subjects did not turn up for the end lf study safety analysis  Check in deviations
2.3. PROTECTION OF TRIAL SUBJECTS
Protection of the volunteers was found to be acceptable, Helsinki declaration was followed, and informed consents were within the requirements. This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report 2.4. RESPONSIBILITIES OF THE INVESTIGATOR

Responsibilities of the investigator were defined, selection of subjects were done in
accordance with defined procedures. Subjects were properly informed; ICF's were signed
by the volunteers. Adverse reactions were reported. The study protocol was reviewed and
approved by the ethics committee. The Monitor performed a site audit and monitoring
reports were available.
Pharmaceutical products were handled appropriately. The trial site had adequate
premises.
2.5.
RESPONSIBILITIES OF THE SPONSOR
The activity inspected was found to be in general, acceptable. The trial was performed in
accordance with the protocol. Trial management and handling of data was properly
carried out. Required standard procedures were available. Subjects received
compensation in accordance with the protocol.
2.6.
RESPONSIBILITIES OF THE MONITOR
Responsibilities of the monitor were specified in the contract between sponsor and CRO. Case report forms were appropriate. Although there was one monitoring visit carried out of the study, this required attention (See observations below). Monitor report was dated October 27.2010. Monitor carried out only one visit before the study. Monitor report was available as a check list, covering:  Protocol  Study personnel records  Clinical supplies receipt/dispensing accountability  Dispensing & dosing of clinical supplies  Documentation Standards
 QA
2.7.
MONITORING OF SAFETY
Subjects were monitored for safety and tolerability during the study and until the completion of the study. Safety assessments were done based on clinical observations, laboratory data at the beginning and at the end of the study and evaluation of the AEs observed during the course of the study. Adverse drug events were classified as:  Mild This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report Four Adverse Drug Reactions were reported and classified as mild and unlikely related to
the study.
2.8.
RECORD-KEEPING AND HANDLING OF DATA

Handling of data was considered acceptable. Study records were stored in the CRO
archive.

2.9.
STATISTICS AND CALCULATIONS
Not inspected

2.10. HANDLING OF AND ACCOUNTABILITY FOR PHARMACEUTICAL
PRODUCTS
Supply of products and storage of products as well as labeling and packaging were found in general to be acceptable. Dispensing was done in accordance with an SOP. The following documentation for investigational products was reviewed:  Courier slip for shipment of IMP  Gate pass documents:  Covering letter dated  CoA Rifampicin Isoniazid & Ethambutol HCl tablets 150 mg/75 mg/ 275mg  CoA Rifamate  CoA Myambutol  Data logger print outs  Import license for Myambutol  Purchase invoice for Rifamate Drug product reconciliation was carried out - no deviations were observed.
2.11. ROLE OF THE DRUG REGULATORY AUTHORITY
Acceptable
2.12. QUALITY ASSURANCE FOR THE CONDUCT OF A CLINICAL TRIAL
A quality assurance system was in place. Audits of clinical and bioanalytical parts were
performed, audit reports were available for inspection,
This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report 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, the study S-IO-103 "A randomized, open label, balanced, single
center, two treatment, two period, two sequence, single dose, crossover oral
bioequivalence study of test product (Four tablets of fixed dose combination of Rifampin
150 mg , Isoniazid 75 mg and Ethambutol Hydrochloride 275 mg) with that of reference
product[ two capsules of Rifamate® (containing Rifampin 300 mg and Isoniazid 150 mg)
of Sanofi A ventis, USA and three tablets of Myambutol® (Ethambutol Hydrochloride)
400 mg of Riemser Arzneimittel, Germany] in healthy human adult male subjects, under
fasting conditions conducted at Semler Research Center Pvt. Ltd. Sharon Hospital
Campus, 18, Tanmag Road, Vinayagampatti, Salem - 636 008, Semler Research Center
Pvt. Ltd. C/O SKS Hospital 3rd floor, 23 SKS Hospital Road Alagapuram Salem -636004
and at Semler Research Center Pvt. Ltd. 75 A, 15th Cross, I Phase J.P. Nagar, Bangalore
- 560078 was considered to have been conducted at an acceptable level of compliance
with WHO GCP and GLP.
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. This inspection report is the property of the WHO Contact: [email protected] WHO Public Inspection Report

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