Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 1 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

PART 1 SUMMARY 1. COMPANY AUDITED

M an uf ac tur in g Ad dr es s Ty pe of Au dit N N Plot E-9/3-4 MIDC Tarapur Tal.Palghar Dist. Thane 401506 Maharashtra India

GMP Quality System

For Cause Non GMP

Prospective

Subcontractor: Supplier:

Y Y

API Clinical/R&D Others : Raw Material Distributor-Trader: Y N

Excipient Information System Service Provider:

Packaging Materials Equipment Y N

2.

COMPANY CONTACTS
Q Name: Nasir Y Shaikh Email: nasir@aartidrugs.com C Name: Gala Email: export@aartidrugs.com Tel: +912525271990 Fax: +912525272726 Tel: ???4072249 Fax:

3.

AGREEMENTS / AUDIT HISTORY

Pr ev io us Au dit Date: Ref:

09/15/10

AE_10_AARTI-PORTON-003

This report is confidential to sanofi-aventis Page 1 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 2 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

4.

NATURE OF BUSINESS
MANUFACTURE OF PARACHLOROBENZENESULFOCHLORURE

This report is confidential to sanofi-aventis Page 2 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 3 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

5.

PARTICIPANTS
Jean Saint-Germain IQC Process Development Director Nasir Y Shaikh QA/QC manager Sanjay Patil Works manager Gala Sales manager

6.

PURPOSE / SCOPE OF AUDIT

Pro duc ts/s ervi ce revi ewe d Site (s) req ues ting the aud it PCBSC

Single Site

Multi-site(specify):

7.

SUMMARY OF FINDINGS
6. 1 REGULATORY REQUIREMENTS APPLICABLE: ICH Q7
MAJOR Observations: 4 MINOR Observations: 4

CRITICAL Observations:

This report is confidential to sanofi-aventis Page 3 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 4 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

8.

RECOMMENDATION / DECISION OF THE AUDITORS

The site was found clean and well ordered. Material management was found satisfactory. The major issues result in poor management of change control on site and subsequent information of customers and monitoring of EDC content ( IPC and final release ) in industrial batches. Change Control management should be improve to clearly assess date of implementation of new PCBSC process and validation of EDC method is mandatory before any order of PCBSC material. Use of class 1 solvent should be avoided in manufacturing of reagent and/or starting materials.
Lead Auditor:

This report is confidential to sanofi-aventis Page 4 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 5 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

PART 2 - REPORT

8.

GENERAL ORGANISATION
Aarti Drugs Ltd is part of global group Aarti Industries Aarti has started its operations in the year 1975 in the name of alchemie labs in a small of way with a single product namely Dimentyl sulphate.( DMS ) Today Aarti is one of the leading supplier to global manufacturers of Dyes, Pigments, Agrochemicals, Pharmaceuticals & rubber chemicals. Aarti is one of the largest producers of Benzene based basic and intermediate chemicals in India. It has corporate office in Mumbai & representatives in U.S.A & Europe . Aarti has 16 manufacturing units spread across Gujarat & Maharashtra and a Research & Development unit based in Dombivli. Aarti has customers spread across the globe in 60 countries with major presence in USA, Europe, Japan & India. AartiI has attained a group turnover of US $ 515 million in the year April 2009 March 2010. The site located in Tarapur is dedicated to manufacture of reagents and intermediates. It employs 76 people and certified ISO 9001/2008. it plans to apply for ISO 14001 which is a good initiative. The organisational chart clearly shows independence of QA/QC from production manager which is in accordance with ICH Q7. The people breakdown is 62 for production, 7 for QA/QC and 1 for HSE. The major products manufactured are benzene sulfonyl chloride ( around 100T/year ) and parachlorobenzene sulfonyl chloride ( around 100T/year ). 3 people are dedicated to Process Development for this unit ( 25 people are working in Process Development to support the 8 plants located in the area ).

9.

PROCESS
PCBSC process : the current process performed at site uses monochlorobenzene and chlorosulfonic acid as starting materials in toluene with ammonium chloride as a catalyst. After water washing the crude PCBSC is distilled and then crystallized in toluene to get the finished product of required quality. A new process was developed to avoid the final crystallization step but the solvent used is EDC. Observation ( major ) : a strong practice is to avoid used of class 1 solvent in the process because class 1 solvent must be systematically assessed in the API with stringent specification. Using this new process impurity profile of distilled product is good enough to avoid further crystallisation and the product goes through a flaker system after distillation. 3 pilot batches at 10 Kg scale were manufactured mid 2011 using this new process and samples sent to Sisteron for customer expertise and approval. As EDC content were found above 100 ppm by Siteron people it was decided to review the distillation process and put in place an IPC to control EDC content and start collection if the result was below 5 ppm. ( first distillation crops around 10% rejected and recycled in the next distillation run ) 3 industrial batches, 1 ton each, ( batch numbers 1110/01/DM, 1110/02/DM and 1110/03/DM ) were manufactured according to this modified process. EDC content was checked and found below 2 ppm ( specification set to NMT 5 ppm which is the ICH limit ). The method used is attached in appendix.

This report is confidential to sanofi-aventis Page 5 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 6 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

10. SITE TOUR

Due to time constraints the site tour was focused on critical areas. The room dedicated to the flaker system was inspected and found adequate. The system was acquired in October 2010 and specially designed for this operation. The feeding rate is around 200 to 250 Kg/hour and the operation is performed under nitrogen to avoid potential hydrolysis of the product. The room is regularly cleaned and the flaker cleaned during maintenance shut down ( twice a year ). Observation ( minor ) : SOPs designed to cleaning should be available in the room for potential check ( these procedures were not check during documentation review ). Raw Material warehouse : all the raw materials used are mainly liquids and stored in dedicated and properly labelled tanks. All the goods are delivered by trucks and analyses performed on a sample from the truck and from the tank itself which is a good practice. The remaining stock is checked on a regular basis. The flexibles are dedicated to each product and protected with plastic covers which is a good practice too. Only accepted solid raw materials are stored in the plant because trucks are unloaded only if product is found within specifications. Labelling was found adequate. Finished products warehouse : it was found clean and well organized with identified zones. All the products were clearly labelled. PE bags and liners are stored in a specific area and identified with a batch number which is a good practice ( batches N PM/11/147 and PM/11/141 ). QC tour : main instruments used are 2GC, 1GC/HS and 1 LC, they are quite new. GC calibration are performed in house twice a year using a mixture of benzene, toluene and xylene to test accuracy and linearity. Observation ( minor ) : use of benzene should be limited ( even at lab scale ) for personnel safety. Maintenance is subcontracted and performed once a year, main parameters checked are oven, injector, detector, pressure, maintenance program was found adequate. KF and scales are daily calibrated which is a good practice, full calibration of scales is performed once a year by external company. The method used to determine EDC content in PCBSCl was reviewed, method N E913/AMD/PCBSCL version 1 ( see attachment ) Observation ( major ) : a method used in QC should be signed by QC and authorized by QA Observation ( major ) : a method used to release finished product should be validated. At least validation protocol should include determination of LOD LOQ and recovery checking. QC raw data and consistency between CoA and Quality Control Shift Report was reviewed and found satisfactory. Observation ( minor ) : as several analysts work on shift traceability should be increase by adding the name of the analyst who performed the analysis in the Raw Data report.

11. DOCUMENTATION REVIEW

Several general SOPs were reviewed. Observation ( minor ) : the major SOPs should be reviewed on a regular basis, the accepted periodicity is every 3 years. The SOP to manage Change Control ( SOP QAP/06 ) was reviewed. 2 Change Controls were described in 2011 on the PCBSC process : -15/2/11 CC 11/05 : change from toluene to EDC in the process -17/2/11 CC 11/06 : change from centrifuge to flaker Observation ( major ) : the CC procedure should be reviewed in order to clarify the overall management of the change, ie it should describe initiation, trials, approval or rejection and then implementation of the change. Further more in case of major change a formal approval from the customer should be obtained before implementation.

This report is confidential to sanofi-aventis Page 6 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 7 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

In the case of the preceding changes no date of closure ( approval or rejection ) were indicated neither of formal implementation on site. Management of deviations ( QAP/51 ) and OOS ( QCP/10 ) reviewed and found adequate.

12. APPENDICES
12.1. Audit Team: Appendix 1: Agenda

Auditor 1 J Saint-Germain Lead

Aarti Tarapur site

Opening presentation from Site Management Presentation of the company o Presentation of the plant o Org charts, headcount o Layout of facilities o Flow of material and personnel o Products and their manufacture flow charts Site tour o Warehouse: Incoming materials and Finished products (Receipt, storage, temperature and humidity mapping and monitoring, cold storage, status control, deliveries/distribution) o Manufacturing and packaging areas o Purified Water, WFI, Nitrogen, Compressed Air systems: production/delivery, distribution, and general use within the facility QC Tour - Chemistry o Sampling of raw materials and finished products o Handling of raw data, laboratory documentation, logbooks and/or worksheets o Reagent preparation and recording o Reference standards o Retention samples o Stability chambers, handling of stability samples, qualification, mapping, monitoring, program specifics o Analytical instruments, qualification, calibration

Review of documentation
Auditors could split into 2 teams
This report is confidential to sanofi-aventis Page 7 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 8 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

Aarti Tarapur site

Auditor 1 Systems Review Site Master Plan ( if any ) Documentation (SOP System, Master Records control and approval, Document retention and archiving) Management of deviations Supplier audits (plan, certification, approved suppliers list) Self-inspection program (plan, responsibilities, follow-up) Training System Overview(GMP, on the job, specialist training, Training records, Job descriptions) and selected records Management of complaints Qualification/Validation Program (Overview, and selected equipment and documentation selected earlier) Auditor 2 Systems Review Annual product review ( if any ) Management of Change Control Batch records review Site Quality Management (Roles and Responsibilities, process flow, release of materials ) Environmental Monitoring Data for selected areas (requested during lab tour) Cleaning Validation Technical Agreements between site and suppliers/customers Preventive Maintenance and Calibration Review of process and process validation

Wrap-up
Final Closeout

12.2.

EDC content determination

This report is confidential to sanofi-aventis Page 8 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 9 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

This report is confidential to sanofi-aventis Page 9 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 10 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

This report is confidential to sanofi-aventis Page 10 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 11 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

This report is confidential to sanofi-aventis Page 11 of 12 Audit Report for: 12/08/11 Report Ref: JSG-11Audit-004 Date of Audit:

Supplier / Sub-contractor / Service Provider Audit Report Company / Site

Audit dates: 12/08/11

Page 12 of 12

Aarti Drugs Ltd Tarapur

Report issue date: 02/01/12 Report Reference : JSG-11Audit-004

13. ADDENDUM
OBSERVATIONS NOTED

No 1. 2. 3. 4. 5. 6. 7. 8. 9.

Observations

Observation Level Corrective action proposed

Proposed acceptance from Completion date lead auditor

acceptance Date ok ok ok ok ok ok ok ok ok

This report is confidential to sanofi-aventis Page 12 of 12 Audit Report for: Report Ref: JSG-11Audit-004 Date of Audit: 12/08/11