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WHO Public Inspection Report (WHOPIR) of a

Contract Research Organization
The report is the property of the organization responsible for performing the inspection.
Part 1: General information
Name of organization
Physical address

Macleods Pharmaceuticals Ltd.

R&D Center, G-2, Mahakali Caves Road, Shanti Nagar, Andheri
(East), Mumbai 400093, India

Postal address

Same as above

Telephone number

00 91 22 28306435, 28314611

Fax number
Summary of activities

00 91 22 28304641
Performance of clinical studies, including bioequivalence trials
(clinical and bio-analytical parts)

WHO reference number

Study

TB 134
Study : BEQ-002-ETHA-2005
Study Title: An open label, randomized, two-treatment, twosequence, two period, two-way crossover, single dose
bioequivalence study of Ethambutol tablets (containing
Ethambutol 400 mg) manufactured by Macleods
Pharmaceuticals Ltd., India comparing with Myambutol tablets
(containing Ethambutol 400 mg) manufactured by Reimser
Arzneimittel AG (Wyeth Lederle Germany), in healthy, adult,
male, human subjects under fasting conditions.

Start and stop dates for each Period I: 12-05-2005

phase of the clinical study
Period II: 19-05-2005

Reference Products

Ethambutol Hydrochloride 400 mg, tablets

Manufactured by : Macleods Pharmaceutical Ltd., India
Batch number : EG-402
Myambutol tablet (containing Ethambutol dihydrochloride 400
mg)
Manufacturer bz : Reimser Arzneimittel AG (Wyeth Lederle,
Germany).
Batch number N : 208770

Principal Investigator

Dr. Nathrao Latpate, MD

Sponsor

Macleods Pharmaceuticals Ltd.

Investigational Products

WHOPIR
Macleods, Mumbai, India
25-26 May 2006

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WHO reference number

Study

TB 168
Study : BEQ-005-RIPE(F)-2005
Study Title: An open label, randomised, two treatment, two
sequence, two period, two way, crossover bioequivalence
study of four fixed combination tablets, each containing
rifampicin 150 mg, isoniazid 75 mg, pyrazinamide 400mg,
ethambutol 275 mg manufactured by Macleods Pharmaceutical
Ltd, India comparing with separate formulation of 4 capsules
of Rimactane (150 mg rifampicin) of Novartis South Africa
(Pty) Ltd, 3 tablets of Isozid 100 mg (isoniazid 100 mg) of
Fatol Arzneimittel GmbH, Schiffweiler, Germany, 3 tablets of
Rolab-Pyrazinamide 500 (pyrazinamide 500 mg) of Rolab Pvt
Ltd. (Novartis South Africa), 2 tablets of Myambutol 400 mg
(ethambutol dihydrochloride 400 mg) of Riemser Arzneimittel
AG (Germany) and 3 tablets of Myambutol 100 mg
(ethambutol hydrochloride 100 mg) of Patheon Inc Toronto,
Ontario in healthy adult male human subjects under fasting
conditions.

Investigational Products

Rifampicin Isoniazid Pyrazinamide Ethambutol Hydrochloride

150/75/400/275 mg, tablet
Manufactured by : Macleods Pharmaceutical Ltd., India
Batch number: RF 501
Rimactane 150 mg capsule
Manufactured by : Novartis South Africa (Pyt) Ltd.)
Batch number : 501459
Isozid 100 mg tablet
Manufactured by : Fatol, Arzneimittel GmbH, Schiffweiller,
Germany
Batch number : 004114
Rolab-Pyrazinamide 500 mg tablet
Manufactured by : Rolab Pvt. Ltd. (Novartis South Africa)
Batch number : 135097
Myambutol 400 mg tablets
Manufactured by : Reimser Arzneimittel AG
Batch number : 303350
Myambutol 100 mg tablets
Manufactured by : Patheon Inc. Toronto, Ontario
Batch number : GZ10

Reference Products

Principal Investigator

Dr. Rajendra Jinwal.

Sponsor

Macleods Pharmaceuticals Ltd.

Date of inspection:

25 and 26 May 2006

Project (if any):

Prequalification Programme.

WHOPIR
Macleods, Mumbai, India
25-26 May 2006

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Part 2: Summary
The purpose of the inspection was to assess the bioequivalence study performed at
Macleod Pharmaceuticals Research & Development Centre for the following products:
- TB 134 : Ethambutol Hydrochloride 400 mg, tablet
- TB 168 : Rifampicin Isoniazid Pyrazinamide Ethambutol Hydrochloride
150/75/400/275 mg, tablet
and to evaluate whether the study was conducted in compliance with the protocols, Good
Clinical Practices (GCP) and Good Laboratory Practices (GLP) where applicable.
Macleod Pharmaceuticals, under its R&D centre started clinical and bioanalytical
operations for bioequivalence (BE) studies at this premise on April 2005. There are
currently over 40 staff employed at Macleod BE centre with the following breakdown by
department: 16 in Clinical, 18 in Bioanalytical, 6 in the Quality Assurance, and 2 in
Statistics team.
This Prequalification Programme inspection was the second audit conducted by WHO at
Macleod BE centre.
Documentation reviewed included:
Clinical part

Independent ethics committee review procedures

Screening, and study consent forms

Source data and results

Master lists for subjects

Documentation and SOPs relating to study drugs accountability and dispensing

records, and study drug labels

Randomization schedule

Study drug administration

Blood sample collection

Lists of staff present during the study

Master list of signatures of volunteers

QA audit reports
Bioanalytical part
Various documents were reviewed. This included method validation for rifampicin :
stock solution preparation, weighing, working standards and COA, source data,
calculations, chromatograms (short term, long term, freeze thaw), validation and
qualification. Manual calculations were done for the concentrations (chromatograms) and
checked against the reported tabulated data and dossier report.
Documentation reviewed included for several subjects:

Repeat analysis record

Chromatograms for subjects for different periods

WHOPIR
Macleods, Mumbai, India
25-26 May2006

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Results of calibration curves, and quality controls were reviewed for all runs of the
two studies

2.1. Provisions and prerequisites for a clinical trial

(Including: Ethical principles, supporting data for the investigational product,
Investigator and site(s) of investigation)
In general, besides minor oral observations, acceptable.
2.2.

The protocol

In general acceptable.
2.3. Protection of trial subjects
(Including: Declaration of Helsinki, Ethics committee, Informed consent,
Confidentiality)
The chairman of the ethic committee member approved alone the second version of the
protocol. He was not entitled to do that.
2.4. Responsibilities of the investigator
(Including: Medical care of trial subjects, Qualifications, Selection of trial subjects,
Compliance with the protocol, Information for subjects and informed consent, The
investigational product, The trial site, Notification of the trial or submission to the drug
regulatory authority, Review by an ethics committee, Serious adverse events or
reactions, Financing, monitoring, auditing and inspection, Record-keeping and handling
of data, Handling of and accountability for pharmaceutical products for trial,
Termination of trial, Final report, Trials in which the investigator is the sponsor)
In general, besides minor observations, acceptable.
2.5. Responsibilities of the sponsor
(Including: Selection of the Investigator(s), Delegation of responsibilities, Compliance
with the protocol and procedures, Product information, Safety information,
Investigational product, Trial management and handling of data, Standard operating
procedures, Compensation for subjects and investigators, Monitoring, Quality assurance,
Study reports, Handling of adverse events, Termination of trial)
In general acceptable. Nevertheless, the monitoring of the study was inadequate.
2.6. Responsibilities of the monitor
(Including: Qualifications, Assessment of the trial site, Staff education and compliance,
Data management, Case-report forms, Investigational product, Communication,
Notification of the trial or submission to the regulatory authority, Reports)
WHOPIR
Macleods, Mumbai, India
25-26 May2006

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See observation above.

2.7. Monitoring of safety
(Including: Handling and recording adverse events, Reporting adverse events)
In general acceptable.
2.8. Record-keeping and handling of data
(Including: Responsibilities of the investigator, Responsibilities of the sponsor and the
monitor, Archiving of data)
In general, besides minor observations, acceptable.
2.9. Statistics and calculations
(Including: Experimental design, Randomization and blinding, Statistical analysis)
In general acceptable.
2.10. Handling of and accountability for pharmaceutical products
(Including: Supply and storage, Investigational labelling and packaging, Responsibilities
of the investigator, Responsibilities of the sponsor and the monitor)
In general, besides observations related to the packaging, acceptable. Ten tablets of
Myambutol 100mg (reference) were sent by regulatory affairs to clinical department in a
separate bottle. The bottle was not appropriately labelled and therefore not traceable to
manufacturer.
2.11. Role of the drug regulatory authority
(Including: General responsibilities, On-site inspections)
Not applicable.
2.12. Quality assurance for the conduct of a clinical trial
In general, besides minor observations, acceptable.
2.13

Bioanalytical part of the study

In general, acceptable (nevertheless, some quality controls identified as outlier were not
included in the overall calculation of precision and accuracy. This is considered as a
major deficiency as it can affect the acceptability of the study. Fortunately reintegration
was done during the inspection and the new result found still within the 15% of CV.

WHOPIR
Macleods, Mumbai, India
25-26 May2006

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Part 3: Conclusion
Based on the people met and the documents reviewed, and considering the findings of the
inspection, reflected in the observations listed in the inspection report, the studies,
clinical parts and bioanalytical parts, inspected are considered to have been conducted at
an acceptable level of compliance with WHO Good Clinical Practices (GCP) and Good
Laboratory Practices (GLP), by Bioequivalence dept, Macleods Pharmaceuticals located
in Mumbai, India.

WHOPIR
Macleods, Mumbai, India
25-26 May2006

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