SOP 408.

4
Annex C
20, avenue Appia CH-1211 Geneva 27 Switzerland Tel central +41 22 791 2111 Fax central +41 22 791 3111
www.who.int

WHO PUBLIC INSPECTION REPORT

(WHOPIR)
Contract Research Organization
Part 1: General information
WHO product numbers covered HA497 (Didanosine chewable/dispersible 100mg tablets)
HA509 (Efavirenz 100mg tablet for oral suspension)
by the inspection
937/06 (HA497): A randomized, open label, twotreatment, two-period, two-sequence, single-dose,
crossover bioequivalence study of Didanosine chewable
and buffered tablets of Ranbaxy Laboratories Limited,
India versus the Reference product, in healthy human
adult male subjects under fasting condition.

Study numbers and title

Clinical phase: Period I: 19 July 2006 to 20 July 2006

Period II: 24 July 2006 to 25 July 2006
Bioanalytical phase: 10 August 2006 to October 2006
113_EFAVI_10 (HA509): Open label, balanced,
randomized, two-treatment, two-period, two-sequence,
single-dose, crossover comparative bioavailability study
of two tablets for oral suspension of efavirenz 100 mg
(total dose 200 mg) manufactured by Ranbaxy
Laboratories Limited, India versus the Reference product
in healthy, adult, human male subjects under fasting
condition.
Clinical phase: Period I: 26 May 2010 to 30 May 2010
Period II: 2 July 2010 to 6 July 2010
Bioanalytical phase: Analysis start 28 August 2010 and
completed 8 September 2010
Analytical Report: 21 September 2010
Clinical Part of the study:
Name

and

organization

address

of

Study No. 937/06: Lotus Ltd., St. John's National

Academy of Health Sciences, 141/2, John Nagar, Opp.
the
BDA Complex, Koramangala III Block, Bangalore 560
034, India
Study No. 113_EFAVI_10: Ranbaxy Laboratories Ltd.
Clinical Pharmacology Unit
Majeedia Hospital (2nd floor)
Jamia Hamdard (Hamdard University)

Page WHO Public Inspection Report(WHOPIR)

1 of 3

Hamdard Nagar
New Delhi 110062
India
Bio-analytical laboratory:
Name and address

Study No. 937/06: (Note: this was an older study and the
site is no longer in use) Ranbaxy Laboratories Limited
Clinical Pharmacology & Pharmacokinetics
Sector 18, Plot No. 20, Udyog Vihar Industrial Area,
Gurgaon - 122 015, Haryana,
India.
Study No. 113_EFAVI_10: Ranbaxy Laboratories Ltd.
Clinical Pharmacology & Pharmacokinetics
Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
122 015 Gurgaon, Haryana
India

Date of inspection

8 9 December 2011

Page WHO Public Inspection Report(WHOPIR)

2 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

Part 2: Summary
General information about the site(s)
Ranbaxy currently has 4 R&D locations where clinical studies and bioanalytical
testing is performed. These include:
Clinical Pharmacology Unit 1 (Majeedia Hospital, now named Hakeem Abdul
Hameed Centenary Hospital), Jamia Hamdard, Hamdard Nagar, New Delhi110062.
Clinical Pharmacology Unit 2, Fortis Hospital Complex, Sector 62, Noida
(Uttar Pradesh), India.
Bioavailability/Bioequivalence Department, Terapia SA., 124 Fabricii Street,
400632, Cluj Napoca, Romania.
Bioanalytical, Pharmacokinetics, Biostatistics and Reports Division, as well as
the Clinical Laboratory, Plot No. GP5, Sector 18, HSIDC, Old Delhi, Gurgaon
Road, Gurgaon, 122015, (Haryana) India.
History of WHO and/or regulatory agency inspections
The most recent WHO inspection was performed in August 2009, for a study which
had been performed between 17 August 2007 and 20 October 2007 (clinical and
bioanalytical).
Focus of the inspection
The inspection focused on the bioanalytical portion of the bio-equivalence study
conducted for products HA497 and HA509 and was performed at the Bioanalytical,
Pharmacokinetics, Biostatistics and Reports Division, as well as the Clinical
Laboratory, Plot No. GP5, Sector 18, HSIDC, Old Delhi, Gurgaon Road, Gurgaon,
122015, (Haryana) India. The inspection covered various sections of the WHO GCP
and GLP texts, including the WHO additional guidance for organizations performing
in vivo bioequivalence studies.
Inspected Areas
Days 1 and 2 focussed mostly on the simultaneous verification of the bioanalytical
data for both studies, as well as a verification of the general organization of the site.
The remaining points and closing meeting were given on Day 2.
1. Study 937/06 (HA407):
Study facts and design
The bioanalytical portion of the didanosine study was performed in August 2006, at
the Clinical Pharmacology & Pharmacokinetics, Sector 18, Plot No. 20, which is no
Page WHO Public Inspection Report(WHOPIR)
3 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

longer in use by Ranbaxy and hence could not be inspected. Instead, the inspection
had to be conducted at Plot No.GP 5, at the same address. The clinical portion of the
study was conducted by contract research organization in July 2006, a CRO which has
recently been inspected by the WHO for the study. Study facts were verified to be
correct relative to the information contained in the dossier submitted to the WHO
Prequalification of Medicines Programme.
Repeat analysis
The SOP for repeat analysis which was valid at the time of the study for didanosine,
dated 7 December 2005, was reviewed. Different cases where repeat analysis can be
performed were defined in the SOP. Only 1 subject was repeated (the entire run) for
the study. Observations were raised in this regard which were addressed in the
company CAPAs.
Sample custody chain and mix-up prevention
Adequate records were maintained for sample shipment, shipment temperature
conditions and for sample receipt on 11 August 2006 using data loggers. Data logger
printouts were consulted and showed that temperatures were maintained at around 70oC until storage in the cold room.
Samples were first retrieved by sample custodians who entered the information about
retrieval in the logbooks. The analysts and lab supervisors verified the order and
labelling of the tubes against the sequence. Once transferred to the auto-sampler, this
was once again checked by the supervisors.
There was no documentation of the check which was performed on samples between
removal from the freezer and before and during processing, as well as for placement
on the auto-sampler. This was resolved in the company CAPAs for future studies.
Preparations and sample processing
Sample processing sheets were reviewed. Samples were withdrawn from the freezer
(this was recorded in both the sample processing sheets and freezer logbooks),
thawed, 200 uL was removed and the remnants were placed back in the freezer.
The procedure entitled Procedure for recording of raw data, implemented 26 July
04, valid until 26 July 2007, was reviewed. It defined the different forms to be filled
and the information to be included in each form. Instructions were generally clear.
Forms are assigned a serial number by the laboratory supervisor. Records are
maintained of the issuance of each form.
Reference product
The purchase invoice for chewable didanosine was shown. Since the product was
hand carried, there was no record of temperature during shipment. The product was
transferred in July to the CRO in charge of conducting the clinical study. Records of
storage at Ranbaxy were shown.

Page WHO Public Inspection Report(WHOPIR)

4 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

Preparations
Blank Plasma was screened. It was taken from 10 different source for preparation of
the calibration and QC standards. These were prepared by spiking pooled bulk blank
plasma, were frozen at -15oC, thawed, processed and injected. Fresh CC sets were
processed daily.
Procedure for Mass spectrometry
The MS/MS parameters were optimized because of a change of equipment compared
to the validation which was initially performed on the set method using a different
HPLC MS/MS instrument. The declustering potential was changed from 15 to 30.
Data transfers and statistical analyses
The data was transferred from the bioanalytical input table to area under the curve
calculation for each timepoint (this table also included time deviations and was in
excel format it had been generated by Winonlin), to another excel spreadsheet
where AUC0 t and AUC0 infwere calculated as well as Cmax. The resulting table was
then used as source data for SAS.
The procedures followed were described in the SOP entitled Data handling of
pharmacokinetics analysis dated 18 November 2005 and the SOP entitled Data
handling and verification, dated 13 September 2004.
The SAS program which was used for the study was verified. The data input was
copied and pasted from the data table given by the pharmacokinetics group to the
biostatistics group. The program instructions corresponded to the expected tests. The
data for SAS was first saved on October 4, 2006. A correction was made on October
17, 2006 further to the QA check which detected an error in timepoints which was
described as timepoint deviation. The original SAS outputs were found 90%
confidence interval for AUC of 95.812 and 11.9724, power 99.624. Almost identical
values were found on the rerun dated October 17, 2006.
No outlier tests had been performed for this study. However, the company had a
procedure entitled Statistical Outlier Test. It defined 3 different methods. The
maximized normal residual test (MNR) is one of the proposed methods. The
studentized residuals test is preferred as it is more precise. Another one is the mean
plus or minus 3 SD test which is not recommended according to the procedure since
it is based on general statistical results rather than on individual subject values.
Incurred sample analysis
Not performed at the time of the study hence was not inspected.
Blank Plasma Matrix
The records indicated that CPDA (citrate, phosphate, adenine and dextrose) had been
used for plasma processing at a local hospital. Purchase invoice forms also confirmed
that CPDA plasma had been ordered. Dates of storage and withdrawal were verified.
Each bottle was of 200 mL but the number of freeze thaw cycles was kept within the
validated thresholds.
Page WHO Public Inspection Report(WHOPIR)
5 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

Archives
The archives in the basement and 3rd floor were visited on Day 2. They were
temperature and humidity monitored using a Eurotherm system and were adequately
designed to protect documents from fire hazards.
In-injector stability study
The auto-sampler had a capacity of 350 vials, which is equivalent to 17.5 hours based
on an injection run time of 3 minutes. This was verified to fall within the validation
time threshold.
Chromatographic data verification
Detailed examinations were made of the electronic data for selected subjects.
Simultaneously, the concentration table sheets used by the statistician for importation
into Winonlin were compared to the raw results from Analyst for some of the
subjects. No discrepancies could be found.
2. Study 113_EFAVI_10 (HA509):
Study facts and design
The bioanalytical portion of the efavirenz study was performed in 2010. The clinical
portion of the study was conducted by Ranbaxy at their Clinical Pharmacology
Department in New Delhi. Some of the study facts were verified to be correct relative
to the information contained in the dossier submitted to the WHO Prequalification of
Medicines Programme.
Clinical aspects
The inspection focus was primarily on the analytical part of the study, but a sample of
the clinical data was also reviewed. The CRFs associated with subjects 3, 5, 15, 17
and 20 were reviewed, this included data associated with admission, drug
administration (and randomisation), sampling and adverse event reporting. Note: the
screening records were not reviewed.
Test and Reference Products
The raw data associated with the test and reference product were reviewed. Purchase,
shipment, receipt, storage and accountability records were reviewed. Although there
were some minor temperature excursions with the storage area in the clinic, in general
the documentation was acceptable and provided an adequate level of traceability and
it was possible to reconstruct the study activities. The reported information was also
confirmed to be an accurate reflection of the study data.
The test product (480 tablets of batch number 2141546) was received on 30/04/10 at
Ranbaxy, Gurgaon from Ranbaxy Laboratories Ltd, A-41, Phase UIII-A, Industrial
estate, SAS Nagar IC0071, Punjab, India. On 26/05/10 360 tablets were transferred to
the clinic for the study (113-EFAVI-10). The temperature loggers for the transfer of
the test product demonstrated that the temperature range during shipment was
between 17.95-24.48C, which was in the requirement of <30C. Note: photographs
Page WHO Public Inspection Report(WHOPIR)
6 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

of the test container were reviewed and found to contain the relevant information,
including the name, concentration, batch number, expiry date (03-12), manufacturer
details etc.
The reference product (270 capsules of lot number 7L32764A) was received on
27/04/09. The Investigational Product Accountability Form for Sustiva capsules 200
mg confirms that manufacturer is BMS. The certificate of analysis was received on
25/05/10. Although 8 x 90 capsules were received, only 3 x 90 capsules were sent
from the Formulation department for the clinical trial (113-EFAVI-10). The others
were sent to various locations for example, for analysis or storage (documented
evidence of these activities were briefly reviewed). Note: photographs of the
reference container were reviewed and found to contain the relevant information,
including the name, concentration, lot number, expiry date, storage etc.
Sample custody chain and sample analysis
A selection of samples were traced through from collection at the clinical site through
to analysis and reporting of the data. There appeared to be an adequate level of
documentation to fully reconstruct activities and movement of the samples selected.
Additionally, environmental monitoring conditions, stability periods and equipment
(used during the processing, extraction and analysis steps) calibration documentation
were reviewed and found to be acceptable.
The chromatography (including appropriateness if integrations), internal standard
variation, calibration standard and quality control acceptance, was reviewed online for
subjects 2, 3, 9, 11 and 23.
Data transfer
The results obtained from the analysis were followed through from Analyst into
NuGenesis (including data manipulations by the statistical and PK departments),
through to the report. There was good traceability of the electronic data and an
adequate level of checks had been performed at each stage to ensure that the data
were accurate and complete following each data transfer.
Repeat analysis
The SOP for repeat analysis SOP No. PK-L51-03 (effective 24th April 2009), which
was valid at the time of this study was reviewed. A number of acceptable reasons
were listed for repeating analysis. Each different scenario was assigned a code to be
used within the data. These are:
- Processing related (PR) sample processing/handling problem
- Equipment related (ER) technical error with instrumentation
- Chromatography related (CR) poor chromatography or not meeting
chromatographic acceptance criteria
- Highest calibration standard related (HR) out of range sample concentration
- IS Variation related (IR)
- Repeated by mistake (MR)
- Confirmatory Analysis (CA) for anomalous or aberrant results
Page WHO Public Inspection Report(WHOPIR)
7 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

Following analysis the chromatography is reviewed and where repeat analysis is

deemed necessary (for any of the above reasons) a form is completed and then
authorised by the laboratory manager or study director.
The report details that 1008 blood samples from 24 subjects were to be collected.24
subjects were enrolled, but 21 completed. 1 subject was withdrawn and 2 subjects
dropped out. A total of 944 samples were collected and 881 samples analysed (from
21 subjects who completed both periods).
The only rejected batch was seen for subject 9, PI and PII due to carry over in the
blank samples. This batch, and the subsequent investigation into the batch failure,
was reviewed in detail and found to be comprehensive and appeared to have been
conducted in line with the analytical method and local procedures. The batch was
repeated on 7th September 2010. This batch passed the acceptance criteria and there
was no evidence of carry over in the repeat batch. The report was checked to ensure
an accurate account was presented and found to be acceptable.
The report also details a number of samples that were repeated due to a variety of
reasons. A number of these repeats were selected and found to be correctly described
within the report. For those reviewed, both the original data and the repeat data were
reviewed to ensure that the reason had been assigned and that the correct result was
reported (based on the relevant SOPs).
During the review of these batches, the process for manual integration and altering
integration parameters was discussed and assessed. All manual integration must be
approved. The analyst must print with original integration parameters and the
Chromatographic Review Group will re-integrate the poorly integrated peak and
upload into NuGenesis. The analyst will upload the original, so that both of the
results tables and integrated chromatograms are maintained in NuGenesis.
Incurred sample analysis (ISR)
The chromatography (including appropriateness if integrations), internal standard
variation, calibration standard and quality control acceptance, was reviewed online for
the ISR batches 113-ISR1 and 113-ISR2.
Data associated to 113-ISR2, subject 6 (PII) and subject 18 (PI) were checked against
the report to confirm report accuracy. The data presented within the report was
deemed accurate for these subject samples.
Long Term Stability (LTS)
The spiked matrix QC samples used for the LTS were spiked on 13/08/10 at 20:02.
These were stored in CR-01 (-20C freezer). The matrix was spiked using stock
working solutions AQ-HQC-1308, AQ-MQC-1308, AQ-LOQ-1308 and AQLOQQC-1308. Note: AQ-HQC-1308 and AQ-LOQ-1308 were stored for LTS.
These were prepared from the original stock solution V443-QA1-130810. The stock
and working solutions were prepared 0n 13/08/10, from USP reference standard batch
number FOG376.
Page WHO Public Inspection Report(WHOPIR)
8 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

The Quality Control (QC) samples were then stored until 06/12/10 and were
subsequently analysed against fresh calibration curve and QC samples.
Note: on finalisation of the analytical report only 10 days LTS was available. A
further 115 days LTS was then determined to cover the sample storage, but this was
not available until several months after the finalisation of the report. The 115 day
LTS data were then presented in a partial validation report and submitted to Ranbaxy
Regulatory group on 12/01/11 and to WHO on 31/03/11. A sample of the data from
the report were checked against the Analyst chromatography data and found to be an
accurate representation.
Quality Assurance
During the course of the study a number of audits were performed including inprocess audits for the clinic and the bioanalytical phase of the study. In addition,
there are a number of retrospective audits where document review was undertaken.
Facilities, systems and procedural audits cover the routine activities undertaken within
the facility and the general infrastructure. These audits were generally performed
twice a year.
As the study design of bioanalytical studies performed by Ranbaxy are fairly similar,
the number and nature of the in-process audits performed is determined by the size or
complexity of the studies. It should be noted that in addition to the in-process study
specific audits, a number of process audits, independent of the study, were also
performed on a quarterly basis to cover, for example archiving, equipment calibration,
etc.
The in-process audit in the clinic included review of dosing, post dose restrictions,
blood sampling (3 time points 0.5, 0.75 and 1 hr), sample separation, storage (for the
same time points), vital signs 2 hrs post dose, MSRs and ICFs.
The in-process audit of the bioanalytical phase included review of data associated to
two subjects (17 & 18), labelling of tubes, internal standard records, standard stock
preparation, processing steps, calibration curve and quality control sample preparation
and retrieval and replacement of samples from the deep freezer.
QA have a requirement to issue an audit reports within 21 days for facility audits or in
a few days for in-process and process audits. Note: major or critical observations
identified during an audit would be released immediately. Audit report responses were
required within 30 working days for all audits and QA then have a further 15 working
days for the review of the response. QA will not sign a statement for a final report
until all actions have been completed and closed out. The following timeframes were
noted for the study specific in-process audits:
Clinical Audit performed 27/05/10, reported 28/05/10, response 18/06/09, reviewed
18/06/09.
BA audit performed 22/09/10, reported 24/09/10, response 24/09/10, reviewed and
closed 24/09/10.
Page WHO Public Inspection Report(WHOPIR)
9 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011

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 bioanalytical data of the studies 937/06 (HA497) and
113_EFAVI_10 (HA509) were considered to be of an acceptable level of quality, and
the study thus performed at an acceptable level of compliance with WHO GCP and
GLP at Ranbaxy Laboratories Clinical Pharmacology & Pharmacokinetics, Plot No.
GP-5 - Sector 18, HSIDC, Old Delhi - Gurgaon Road, 122 015 Gurgaon, Haryana,
India.
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.

Page WHO Public Inspection Report(WHOPIR)

10 of Ranbaxy Laboratories Ltd,
10 Plot No. GP-5, Sector 18, HSIDC
Old Delhi-Gurgaon Road
Dec. 8-9, 2011