Prequalification of Medicines Programme. WHO PUBLIC INSPECTION REPORT (WHOPIR) API Manufacturer

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1 Prequalification of Medicines Programme SOP Annex B WHO PUBLIC INSPECTION REPORT API Manufacturer Part 1 General information Name of Manufacturer Unit number WHO PUBLIC INSPECTION REPORT (WHOPIR) API Manufacturer Hetero Laboratories Limited Unit IX Production Block HLL (6 Production Blocks A, B, D, H2, H3, H4 and 2 Pharma sections) HDL (5 Production Blocks A, B, D, H1, H2 and 1 Pharma section) Physical address Contact person and address. Date of inspection Type of inspection Ingredient(s) included in the inspection Summary of the activities performed by the manufacturer Plot No 1 & 2, Hetero Infrastructure LTD, SEZ, N.Narasapuram (Vill), Nakkapally (Mandal), Vishakhapatnam (Dist), Andhra Pradesh. INDIA Dr C. Raghunath Vice President QA & RA (APIs) Hetero Labs Ltd. Telephone Office /24/25, extn 2089 Mobile raghunath.c@heterodrugs.com Routine GMP inspection Hetero Drugs Ltd (HDL) 1. Acyclovir (HDL) APIMF Ritonavir Form I (HDL) APIMF Valganciclovir Hydrochloride (HDL) APIMF 254 Hetero Labs Ltd (HLL) 1. Abacavir Sulfate (HLL) APIMF Efavirenz (HLL) APIMF Emtricitabine (HLL) APIMF Lamivudine (HLL) APIMF Nevirapine Anhydrous (HLL) APIMF Tenofovir Disoproxil Fumarate (HLL) APIMF Zidovudine (HLL) APIMF 124 Production and quality control of active pharmaceutical ingredients (APIs) Page 1 of 7 WHO Public Inspection Report (WHOPIR)

2 Part 2 Summary General information about the company and site The sites inspected were Hetero Labs Limited (HLL) and (HDL), Unit-IX, Plot No 1 & 2, Hetero Infrastructure LTD, SEZ, N.Narasapuram (Vill), Nakkapally (Mandal), Vishakhapatnam (Dist), Andhra Pradesh,, hereafter called HLL Unit IX and HDL Unit IX respectively. Both are owned by Hetero corporate based in Hyderabad. The company corporate office is located at 7-2- A2, Industrial Estates, Sanath Nagar, Hyderabad , Andra Pradesh,. The location is about 84 km away from the Vishakhapatnam Airport. There are 468 employees in HDL and 1125 in HLL. According to the presentation given at the opening meeting, Hetero Labs Limited was established in April 1998, and following details were presented regarding Hetero manufacturing sites Name of the division Location Business unit Hetero Corporate Hetero Foundation Research Unit-IX Hetero Labs Limited Unit-IX Unit-I Unit-VI Hetero Labs Limited Unit-I Hetero Labs Limited Unit-III Sanathnagar, Hyderabad, Balanagar, Hyderabad, Nakkapally Visakhapatnam, Nakkapally Visakhapatnam, Hyderabad, (SEZ) (SEZ) Nakkapally, Visakhapatnam, Gaddapotharam, Hyderabad, Nakkapally, Visakhapatnam, Corporate Office Development of processes for APIs and technical support Ingredients Ingredients Ingredients, Intermediates Ingredients, Intermediates Ingredients Manufacturing Intermediates of It is to be noted that (Unit-IX) has 5 Production blocks and 1 Pharma section whereas Hetero Labs Limited (Unit-IX) has 6 Production blocks and 2 Pharma sections. 2 of 7 WHO Public Inspection Report (WHOPIR)

3 History of WHO and/or regulatory agency inspections Name of the Authority Inspection dates Combined inspections for HDL-IX and HLL-IX WHO Geneva inspection US FDA Inspection Portugal Authority (INFARMED) Inspection 20 th to 23 rd June th to 15 th December th to 15 th March 2013 Name of the Authority HDL-IX other Inspections Inspection dates COFEPRIS Mexican inspection WHO GMP CDSCO Local DCA renewal Inspection Dutch Healthcare Inspectorate (IGZ), The Netherlands inspection 11 th to 20 th July th August th December, th & 12 th March 2014 Name of the Authority HLL-IX other Inspections COFEPRIS (Mexico) Inspection dates 1st to 10th July-2013 WHO GMP CDSCO 28th and 29th April, 2014 Manufacturer licence issued by the state authority, Andhra Pradesh, - HDL dated 4/7/2011 till 19/10/2015 Form 25 48/VP/AP/2010/B/G - HLL dated 20/10/2010 to 19/10/2015 Form 25 47/VP/AP/2010/B/G Focus of the inspection The inspection focused on the production and control of APIs listed under Part 1. 3 of 7 WHO Public Inspection Report (WHOPIR)

4 Inspected Areas The inspection covered most of the sections of WHO GMP for Ingredients (ICH Q7), including Quality Management; Personnel; Buildings and Facilities; Process Equipment; Documentation and Records; Materials Management; Production and In-Process Controls; Packaging and Identification Labelling of APIs and Intermediates; Storage and Distribution; Laboratory Controls; Validation; Change Control; Rejection and Reuse of Materials and Complaints and Recalls. 2.1 QUALITY MANAGEMENT A system for quality assurance was established and covered most of the basic elements of GMP. An organization chart was reviewed. The quality unit was independent of production which fulfils both QA and QC responsibilities. 2.2 PERSONNEL In general, the personnel met and interviewed during the inspection were confident in what they were doing. Job descriptions of key persons were available. 2.3 BUILDINGS AND FACILITIES Overall, buildings were constructed of materials compatible with the activity being conducted. Finishes in Pharma areas were of appropriate design with surfaces easy to clean and with coved joints between walls and floors. 2.4 PROCESS EQUIPMENT The process equipment was designed, and installed satisfactorily. Also, materials used were satisfactory. In general, reactors were equipped with overheads and utilities to allow the normal range of organic reactions to be conducted. Production equipment was cleaned on a scheduled basis as per written SOPs. Cleaning status was shown by a cleaning label. Equipment calibration schedule and planned preventive maintenance (PM) program of equipment and systems was in place. Computerized systems Data capture of QC chromatography data was done electronically. 2.5 DOCUMENTATION AND RECORDS In general, the documentation system was established and maintained. Documents were approved, signed and dated by appropriate responsible persons, regularly reviewed and kept up to date. Specifications and testing procedures were available. Documents related to the batch release were stored one year after the expiry date of the batch. Most of the key quality management system procedures were issued by CQA for both HLL and HDL. In addition, manufacturing sites has site specific procedures for various production and laboratory operations. 4 of 7 WHO Public Inspection Report (WHOPIR)

5 2.6 MATERIALS MANAGEMENT In general, material management was found acceptable. Materials were received according to SOP Receipt, Verification Quarantine and sampling of Raw Materials. Sampling and dispensing booths were installed in the Raw Materials Warehouses. The reception of RM, SM and solvents is conducted according to the requirements of the SOP. SOP on vendor qualification 01/ dated 1/8/2013 provided procedure on qualification of vendors. It has been noted that vendors of API starting materials are qualified based on questionnaire, sample analysis and on-site audit. 2.7 PRODUCTION AND IN-PROCESS CONTROLS At the time of inspection, there was hardly any production running in HDL. Ritonavir Form I Stage I was started for inspection purposes. The synthesis, crystallizer and pharma area was found to be well maintained. At the time of inspection there was no production activity running in Block B and Block D. 2.8 PACKAGING AND IDENTIFICATION LABELLING OF APIs AND INTERMEDIATES There was a written procedure available describing the receipt, identification, quarantine, sampling, examination, testing and release & handling of packaging and labelling materials. While reviewing the batch manufacturing records, it had been noted that there was some ambiguity on the reconciliation of labels issued, used and returned. The existing practice does not allow retaining a printed label as a representative in the batch manufacturing record. 2.9 STORAGE AND DISTRIBUTION Facilities were available for the storage of materials and operated at acceptable level. SOP on approved vendors and storage, handling and retesting of raw materials with storage conditions LABORATORY CONTROLS There was adequate facilities, personnel, approved procedures for testing. Both HDL and HLL laboratories were equipped with modern equipment and instruments. Also, laboratories were found to be spacious and well maintained VALIDATION The Validation Master Plan was available and covered all areas. Revalidation schedule was subject to change controls listed. Process was done and critical process parameters were established. Cleaning validation was in line with daily dose and 10 ppm acceptance criteria. 5 of 7 WHO Public Inspection Report (WHOPIR)

6 2.12 CHANGE CONTROL SOP Change control provided procedure for initiation, handling of changes taken place in plant. The changes are classified into permanent and temporary changes and further divided into minor and major. A flow chart was provided on change process which included impact assessment before implementing any change followed by effectiveness of implemented changes. Product wise change register is maintained which included changes from QC, production, engineering etc REJECTION AND RE-USE OF MATERIALS There is an arrangement for reprocessing and/or reworking of a batch. Upon conducting a thorough investigation, cause for failure and corrective action proposed to reprocess the quality failure, product is determined by conducting the experiments at R&D scale. Batch production records are prepared as per the steps followed at R&D scale, and same shall be approved by QA. It is noted that reprocessed batches will be kept for stability study, and batch release will be done after meeting specification. As per company s policy, there is no reworking done on any failed product COMPLAINTS AND RECALLS Handling of customer complaints provided procedure for handling of complaints for APIs. The complaints are received through marketing and any other source and logged in complaint register. The complaints are acknowledged within 48 hours. The complaints are categorised as critical, major or minor upon receipt. Critical complaints are investigated within 24hours. Send preliminary response within 15days and final response within 30 days to complainants. There was a typo error noted on flow chart (48 hours against 24 hours for investigation of critical complaints). Trending of complaints for the year 2014 (Jan-Jun) was performed. SOP on Product recall provided instruction for recall of API either voluntarily or driven through inspection of regulatory authority. In addition, if any batch put up on stability batches shows deterioration or some quality problem, specific batch of an API can be recalled. The final responsibility to recall API is rest with CQA. Mock recall is performed every two years which is driven through a protocol. Also, a flow chart on recall procedure is available. It is learnt that mock recall is performed for both domestic and markets CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) Not inspected 6 of 7 WHO Public Inspection Report (WHOPIR)

7 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, APIs manufactured at and Hetero labs Ltd, Unit-9 were considered to be manufactured in compliance with WHO GMP for Ingredients. 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 manufacturer, 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. 7 of 7 WHO Public Inspection Report (WHOPIR)

Prequalification of Medicines Programme. WHO PUBLIC INSPECTION REPORT (WHOPIR) API Manufacturer

Prequalification of Medicines Programme SOP 408.4 Annex B WHO PUBLIC INSPECTION REPORT API Manufacturer Part 1: General information Name of Manufacturer Unit number WHO PUBLIC INSPECTION REPORT (WHOPIR)