Inspection Report for WHO · 2010 for HA350 (withdrawn), HA351 (withdrawn) and HA430 (cancelled) ....

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Emcure Pharmaceuticals Limited, MIDC, Hinjawadi, Pune, Maharashtra, India Inspection dates 11-15 Feb 2019 This inspection report is the property of the WHO

Contact: [email protected] of 16

Prequalification Team Inspection services WHO PUBLIC INSPECTION REPORT

(WHOPIR) Finished Product Manufacturer

Part 1 General information Manufacturers details Name of manufacturer

Emcure Pharmaceuticals Limited (Oral Solid Dosage/OSD)

Corporate address of manufacturer

Registered Office T-184, M.I.D.C., Bhosari, Pune - 411 026 Maharashtra, India Tel.: +91-20-30610000

Inspected site Name & address of inspected manufacturing site if different from that given above

Plot No. P-1 & P-2, I.T. B.T. Park, Phase-II MIDC, Hinjawadi, Pune 411 057, Maharashtra, India

Unit / block / workshop number

The OSD facility is comprised of four plants: - Plant I - Plant II - Plant IIA (separate immunosuppressant / hormone manufacturing

facility) - Small Batch Manufacturing (SBM)

The OSD facility is dedicated for manufacturing of oral solid products. Inspection details Dates of inspection 11-15 February 2019 Type of inspection Routine GMP inspection Introduction Brief description of the manufacturing activities

The OSD manufacturing site is located in an industrial zone developed by the Maharashtra Industrial Development Corporation (MIDC). Adjacent to OSD premise, at right hand side is Emcure Sterile Products Division (SPD), on left hand side is an IT industry, Emcure pharmaceutical facility is at the front and High Potent Sterile Manufacturing Facility is situated at the rear end. The size of the plot is 62176 sq. m. The site comprises of an administrative block, raw material warehouse, packaging material warehouse and tablet and capsules manufacturing block. There are independent blocks for API R&D, Formulations Development, Small Batch Manufacturing Facility (SBM), High potent Sterile Manufacturing Facility, Sterile manufacturing facility, utility block, tank farm, drum yard, effluent treatment plant and the security gate. All buildings were constructed between 2002 and 2017.

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General information about the company and site

The company is manufacturing and marketing pharmaceutical formulations since 1983. The Group has manufacturing facilities for non-sterile, sterile formulation and API. The manufacturing facility for non-sterile oral solid dosage is at Hinjawadi, Pune and Jammu with the manufacturing facility for Sterile products and High Potent Sterile products at Hinjawadi, Pune and Sanand. Emcure Pharmaceuticals Ltd based in Hinjawadi, Pune has the following manufacturing units:

- Oral solid dosage form (OSD): dedicated for manufacturing of non-sterile oral solid dosage forms (this was the focus of WHO PQ inspection)

- Sterile product division (SPD): dedicated for manufacturing sterile injectable (except beta-lactam, hormone & cytotoxic)

- Plant III: dedicated for manufacturing sterile cytotoxic and highly potent (hazardous) drug products

- Plant IV: dedicated for manufacturing sterile injectable (terminally sterilized and prefilled syringe except beta-lactam, hormone & cytotoxic)

History The previous WHO PQ inspection at this facility was conducted in March 2010 for HA350 (withdrawn), HA351 (withdrawn) and HA430 (cancelled). Since then, the site had not been not inspected by WHO PQ and products prequalified based on SRA (generic) are continued to be maintained based on SRA’s ongoing inspection program.

Brief report of inspection activities undertaken – Scope and limitations Areas inspected Document Review included but was not limited to:

- Documentation system - Semi-finished & finished product testing and release - Job descriptions - Self-inspection - Change control - Annual product quality review - Deviation control - OOS, OOT and investigation - Handling of laboratory events - Good analytical and review practices - Good chromatographic practices - Process validation and continued process verification - Cleaning validation - Quality risk management - Batch manufacturing records - Specifications and method of analysis - Computer system validation - Stability studies - Validation master plan

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- Electronic data and audit trail Site areas visited:

- Small batch manufacturing (SBM) area - Plant I covering granulation, compression, coating and packing; - QC laboratories including chemical and microbiological; - Sterile product division and microbiology laboratory (with USFDA

investigators on day 1 and day 3) Restrictions The inspection was focussed on the areas in OSD Plant I, II and IIA where

the WHO OSD prequalified products was manufactured and included warehousing, production and packaging. No other activities/areas were inspected during this period.

Out of scope Other than Oral Solid Dosage plant (Plant-I, II, IIA and SBM)

WHO products covered by the inspection

Products under assessment 1. HA701: Dolutegravir (Sodium) Tablet, Film-coated 50mg 2. HA722: Dolutegravir (Sodium)/Lamivudine/Tenofovir disoproxil

fumarate Tablet, Film-coated 50mg/300mg/300mg 3. HA726: Emtricitabine/Tenofovir disoproxil fumarate Tablet, Film-

coated 200mg/300mg 4. HA728: Efavirenz/Lamivudine/Tenofovir disoproxil fumarate

Tablet, Film-coated 600mg/300mg/300mg Products prequalified based on SRA (generic)

1. NDA 205508 USFDA: Atazanavir (sulfate)/Ritonavir Tablet 300mg/100mg

2. ANDA 078785b USFDA: Atazanavir (sulfate) Capsules, hard 200mg

3. ANDA 078958 USFDA: Efavirenz Tablet 600mg 4. ANDA 078887 USFDA: Nevirapine Tablet 200mg 5. ANDA 078785a USFDA: Atazanavir (sulfate) Capsules, hard

100mg 6. ANDA 078785c USFDA: Atazanavir (sulfate) Capsules, hard

150mg 7. ANDA 078929 USFDA: Lamivudine/Zidovudine Tablet

150mg/300mg Abbreviations Meaning AHU Air handling unit ALCOA Attributable, legible, contemporaneous, original and accurate API Active pharmaceutical ingredient APR Annual product review APS Aseptic process simulation BMR Batch manufacturing record BPR Batch production record CC Change control CFU Colony-forming unit

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CIP Cleaning in place CoA Certificate of analysis CpK Process capability DQ Design qualification EDI Electronic deionization EM Environmental monitoring FMEA Failure modes and effects analysis FPP Finished pharmaceutical product FTA Fault tree analysis GMP Good manufacturing practices GPT Growth promotion test HEPA High efficiency particulate air HPLC High performance liquid chromatography (or high-performance liquid

chromatography equipment) HVAC Heating, ventilation and air conditioning IQ Installation qualification LAF Laminar air flow LIMS Laboratory information management system MB Microbiology MBL Microbiology laboratory MF Master formulae MFT Media fill Test MR Management review NC Non-conformity NRA National regulatory agency OQ Operational qualification PHA Process hazard analysis PLC Programmable logic controller PM Preventive maintenance PQ Performance qualification PQR Product quality review PQS Pharmaceutical quality system PW Purified water QA Quality assurance QC Quality control QCL Quality control laboratory QMS Quality management system QRM Quality risk management RA Risk assessment RCA Root cause analysis RO Reverse osmosis SIP Sterilization in place SMF Site master file SOP Standard operating procedure

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https://www.thermofisher.com/us/en/home/life-science/lab-equipment/lab-water-purification/barnstead-water-purification-systems.html?cid=led_purewater_adwords&wt.srch=1&adwordskeyword=genpure




URS User requirements specifications UV Ultraviolet-visible spectrophotometer WFI Water for injection

Part 2 Summary of the findings and comments

1. Pharmaceutical quality system Emcure Pharmaceuticals Ltd. has established a management organization and quality assurance system in accordance with WHO GMP, EU GMP as well as FDA cGMP. The quality Unit and the production departments operate independently under different leadership. Senior Management demonstrated commitment to the QMS by, granting adequate resources to implement, support and manage the QMS. Senior management also participates in the system through the conduct of periodic management review meetings, discussion of PQR`s and the PQS itself. The quality management and quality control functions were supported by IT software, including the following:

Sr. No LIMS Module Site

1 Stability Management

Plant III

SPD

OSD

2 Lot Management SPD

Plant III OSD

3 Environmental Monitoring SPD OSD

Plant III Laboratory Information Management system (LIMS) is the single platform to perform laboratory activities through automated workflows. TrackWise system and LIMS (module for Environmental Monitoring Program) are handled through Corporate Quality SAP. Performance Qualification of Stability Management Module, Environmental Monitoring Module, and Lot Management Module are in progress. Product quality review (PQR) The PQR were performed in accordance with the corporate quality procedure. The procedure applies to products supplied to domestic and export markets. The review included all elements as described in the WHO GMP for main principles. The data were analyzed using the Minitab software. The PQRs of Tenofovir Disoproxil Fumarate 300mg and Emtricitabine 200mg tablets and Dolutegravir Tablet 50mg were reviewed.

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Change control management Change control procedure was discussed. The change controls were handled through the TrackWise system and manually as corporate procedure applied to all Emcure sites. Change control pertaining to the installation of an automatic backup of data and paperless recorders was discussed. Risk assessment was performed as part of the change control. The hazards were identified, and a risk reduction strategy was implemented. Deviation management Corporate procedure for deviation applied to all deviations initiated through TrackWise system and the manual paper-based system. The procedure classified deviations into planned and unplanned deviations with further categorized into minor, moderate and major deviations. Deviation trend analysis was performed on a quarterly basis. Quality risk management QRM procedure was discussed. The procedure was based on the principles of ICH Q9. Risk assessment tools were described in the procedure which included the use of FMEA using the concepts of severity, probability, and detectability. For root cause analysis, a separate procedure “root cause analysis” was in place. This procedure described the use of various tools for the identification of root cause. Risk management report for the OSD area (claimed to be covering Plant I, II and IIA) was discussed. The manufacturing process was mapped, and risk assessment was performed. Batch release Semi-finished & finished product testing and release procedure was discussed. The release was handled through the SAP system. The review of batch manufacturing, packing and analytical records were performed using separate procedures i.e. issuance and review of batch records and analytical data review. Batch release responsibility was limited to two QA personnel and job descriptions of both personnel were found satisfactory. The issues related to this section have been adequately addressed by the manufacturer, and the same shall be verified during future inspections. 2. Good manufacturing practices for pharmaceutical products Basic principles of good manufacturing practices were described and implemented. Manufacturing processes were generally adequately defined and documented in BMRs and BPRs. Required resources were available, including adequate premises, equipment and utilities. Appropriately qualified personnel were employed. The issues related to this section have been adequately addressed by the manufacturer, and the same shall be verified during future inspections.

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3. Sanitation and hygiene Premises and equipment were generally cleaned according to established procedures. Change rooms were well maintained and authorized instructions displayed the steps and dress code. Cleaning records of manufacturing rooms and equipment were in place. 4. Qualification and validation The qualification/validation programs were designed to evaluate the manufacturing process and process equipment to assure quality and cGMP compliance. Qualification programs of area and equipment's were performed periodically to ensure the suitability of area and equipments. Validation programs were established to verify and document the ability to attain reproducible results during manufacturing, packaging, testing and cleaning operations. Validation master plan/VMP was discussed. The document provided a high-level company philosophy on validation activities (processes, methods, equipment, instruments, facility, utilities and personnel). A cross-functional team oversee validation activities. The frequency for the requalification of the HVAC system (every 5 years), equipment (every 3 years), process validation (every 3-year assessment) was part of the VMP. In general, the VMP was found to be adequate. Process validation The SOP on process validation was discussed. The procedure uses the product lifecycle approach with three stages. The production personnel were responsible for compliance of the Stage-II and Stage-III. The SOP on the preparation of a continued process verification report was discussed. It was noted that critical process parameters are accumulated using the SAP system and then transferred to Minitab system for statistical calculation using CpK calculation. Lab scale, scale up and exhibit batches were manufactured prior to commercialization of a product. Cleaning validation and verification procedure was discussed. The approach used for cleaning validation was based on the solubility, strength and therapeutic category, and cumulative score was calculated. If the cumulative score is more than 22, the molecule will be identified as worst case and cleaning validation (3 batches) will be performed. If a molecule does not fall in this category, then cleaning verification (1 batch) will be performed. It was noted that MACO value was calculated using either LD50 data (only in cases where no other data available) or by considering Therapeutic dose (when limited toxicity data available). The procedure described the calculation of MACO using health-based data (ADE/PDE) or using LD50 data or using therapeutic daily dose (TDD). The issues related to this section have been adequately addressed by the manufacturer, and the same shall be verified during future inspections.

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5. Complaints The company had in place a procedure for handling market complaints procedure. The corporate procedure delineated handling process (receiving, recording, assessing, reviewing, investigating, documenting, responding and trending) of complaints at Emcure Pharmaceuticals Limited. A process flow chart was part of the procedure for handling complaints manually and using TrackWise system. In general, the procedure appeared to be adequate. 6. Product recalls Not inspected due to time constraint. 7. Contract production, analysis and other activities Emcure confirmed that no manufacturing activities for WHO PQ products were contracted out. The company uses the services of outside contract laboratories for analysis of few tests. This section was not inspected in detail. 8. Self-inspection, quality audits and suppliers’ audits and approval Corporate procedure for self-inspection reviewed indicated that most of the quality system elements were audited by the site QA once every four months (QA, production, QC, microbiology, central testing laboratory). In addition, corporate quality performs compliance audit twice per year. Self-inspection plan for the year 2018 was reviewed confirming that self-inspection was performed in accordance with the schedule. Corrective action and preventive actions (CAPA) were handled through TrackWise CAPA for self-inspection of the warehouse (October 2018) was reviewed and found satisfactory. 9. Personnel Organization charts were available reflecting an adequate structure. In general personnel met during the inspection appeared aware of the basic principles of GMP. Job descriptions of the QA Managers were compliant and current. Number of employees engaged in production, quality control, warehouse and engineering were as follows:

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10. Training Training was imparted to all employees to ensure awareness about cGMP and the job requirements. Training needs were identified, and training was organized in a scheduled manner as per the SOP. After completion of training, an employee undergoes a test in the e-LMS system. The evaluation of training activities was conducted in the e-LMS and the records of training were maintained by the Human Resource Department. Training programs for employees are planned in the form of:

- Induction training - Orientation training - cGMP Awareness Training - Job related skills' Training - SOP Training - Training by external faculty through seminars / conferences - In-house training program

In general, this section was found adequate. 11. Personal hygiene Personnel gowning procedure was appropriate and was generally followed. Personnel was medically examined before offered a contract and then annually. Human resources were responsible for monitoring the medical examination program and maintain relevant records. 12. Premises Plant I have two floors and a cellar. The ground floor consists of change rooms, tablets and Capsule manufacturing, and packaging facilities. In tablet / capsule manufacturing area, the temperature was maintained between 15°C and 25°C and relative humidity was maintained between 30% and 60% RH. The first floor housed the quality control laboratory (designed and constructed in 2015) with the service floor comprising of AHUs and the Purified Water Plant. The cellar consists of finished product warehouse. Plant II has three floors. The basement consists of change rooms, packaging material store and finished product warehouse. The ground floor consists of a tablet manufacturing facility as well as the packaging material testing area. The Service floor comprises of AHUs and Purified Water Plant. In Tablet and Capsule manufacturing area the temperature was maintained between 15°C and 25°C and relative humidity was maintained between 30% and 60% RH. The small batch manufacturing (SBM) area consisted of a change room, tablets manufacturing and packaging facilities. The first floor consists of a service floor comprising of AHUs and Purified Water Plant. The temperature was maintained between 15~C and 25°C and relative humidity is maintained between 30% and 55% RH.

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Plant IIA has three floors. The basement consists of change rooms, ground and first floor consist of tablet manufacturing facility as well as separate immunosuppressant manufacturing facility. Service floor comprises of AHUs and Purified Water Plant. The building was of suitable size and construction. Manufacturing areas had adequate space for equipment and orderly flow of processes to prevent cross-contamination. In tablet manufacturing area the temperature was maintained between 15°C and 25°C and relative humidity was maintained between 30% and 60% RH. Equipment like steam boilers, air compressors, chillers, diesel generators, transformers, motor control centers (MCC) and power control centers (PCC) were housed in this Plant. Cooling towers, water pumps, and water tanks were located on the terrace. Utilities were common for Plant I, Plant II, Plant IIA, and Small Batch Manufacturing Plant. The issues related to this section have been adequately addressed by the manufacturer, and the same shall be verified during future inspections. 13. Equipment The equipment used in the manufacturing, processing, and packaging was of appropriate design, adequate size, and complying cGMP norms. The equipment was placed in a suitable location to facilitate operations for their use, cleaning, and maintenance. The instruments/equipment used in the Quality Control were of appropriate design, complying cGMP norms. Validation of the laboratory instruments and software was performed. Tasks were identified to be executed for the validation of instrument and software. Lifecycle management for computerized and automated manufacturing systems procedure was discussed. This procedure provided an organized and consistent life cycle approach for the computerized and automated systems installed in the manufacturing/production area across all sites of Emcure group of companies. The IT was responsible for the implementation of this procedure who reported to the corporate QA. The issues related to this section have been adequately addressed by the manufacturer, and the same shall be verified during future inspections. 14. Materials There was a procedure in place describing receipt and storage of raw materials. A checklist was used for receipt of raw materials. A unique material code was assigned to each material in the system. Procedures for material sampling and dispensing were available. Temperature and Relative Humidity were monitored and controlled. Due to time constraint, this section was not inspected in detail. 15. Documentation Site documentation was controlled by the Quality Assurance Department. The users of the individual departments prepare procedures (SOPs) in standard format as per the SOP for SOP Writing. Site documentation control system procedure was in place describing the preparation, checking, authorization, controlling of documents and distribution. Quality Assurance was responsible for controlling and distribution of documents. Master documents were stored in the Documentation room having access control and lock and key.

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The master index of documents from Corporate Quality was obtained. Total of 61 corporate SOPs was in place, in addition, respective plants also have the SOPs. Document design control issuance and numbering procedure described the documents in four levels as follows:

- Level- I (QMS documents /policy document), - Level-II (SMF, VMP & Corporate procedures), - Level-III included site procedures, instruction documents, and - Level-IV included formats, logs and register etc.

In addition to the corporate procedure on design control issuance, each plant has its procedure for document control. The site-specific procedure (document control, issuance and archival for OSD) was reviewed. The SOP issuance logbook was maintained which covered several copies issued and retrieved. A separate logbook was maintained for the corporate QA procedures. The issues related to this section have been adequately addressed by the manufacturer, and the same shall be verified during future inspections. 16. Good practices in production For the OSD facility, the facility was divided into three main areas:

- The Plant I (basement for finished goods warehouse, ground floor for manufacturing and warehouse) and first floor (quality control, water system, and service floor)

- Plant II (basement for warehouse, first & second floor for manufacturing - Plant II A (first & the second floor for manufacturing whereas the second floor dedicated for

immunosuppressant products) In addition, there was a separate area for the small batch manufacturing (SBM). The WHO inspector visited the SBM area used for the manufacturing of submission batches for WHO PQ. It was noted that the area has been shut down since April 2018. The company is planning to convert this area for the manufacturing of hormone products. The inspector visited Plant I which was constructed in 2002. At the time of inspection there were ongoing production operations. The area was classified as ISO 8 and core processing areas were negatively pressurized to the adjacent clean corridor. Common change room (for staff and visitors) was in place whereas separate change rooms were provided for male and female. The second change room was common for staff (male/female) and visitors. In general, the gowning procedure was found adequate and was supported with SOPs and pictorial presentation. For the primary gowning before entering the core processing areas, lint-free bunny suites were provided. The magnehelic gauges were used for the recording of differential pressures once every day. For temperature and relative humidity, data loggers were used which were equipped with alarms located at the service floor. Although there were no separate material airlocks (MAL) and personnel airlocks (PAL) before operator enters to the respective core processing cubicles, over gowning (booty and gown) was provided. All the production equipment were operated through the PLC system. Tooling for the four WHO products were verified. The SAP system

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was used for the inventory management. The manufacturing area was equipped with the following sections:

- Granulation suites (RMG, FBD/FBE, sifter, and mill) - Compression machines (most of them were single rotary, D tooling) - Coating machines

In general, the production area was found clean and tidy. 17. Good practices in quality control Quality Control and Quality Assurance departments are independent of Production and other departments. Head QA & QC reports to President, Global Technical & Quality Affairs, Member of the Board. Adequate resources and personnel were available to ensure that all quality assurance systems were followed. The laboratory was equipped with 6 GCs, 47 HPLCs, and 3 UPLCs. Empower 3.0 and Chromleon 7.2 software was used for Waters and Dionex (Thermo) systems respectively. Unique user ID and passwords were used for accessing Windows and Empower/Chromleon. Three IT administrators were responsible for user management and backup activities and reported to IT QA. The online backup (hot on daily basis and cold on weekly basis) and offline backup (project back up on monthly basis, system audit trail backup on daily basis and message center on daily basis) were performed by the IT administrators. The backup data were restored once per year and verified for correctness. Projects were randomly selected by QA. There were 91 licenses purchased by the laboratory for the operation of the Empower system. User license was inbuilt for Chromleon system. Out of specification (OOS) Handling of OOS/OOT procedure was discussed. The entire process was divided into four phases, namely Phase IA & IB, Phase II-A & II-B. It was noted that OOT was handled using the same procedure as OOS. The procedure provided examples of stability samples wherein more than 5% variation were considered as OOT and handled using the OOT procedure which required that results from raw materials and finished products will be treated OOT if more than 5% variation was found. The tests such as dissolution and content uniformity were handled once the sample did not meet S2 and L2 criteria respectively. The retesting was performed by two analysts in triplicate. RSD was part of the procedure based on the type of tests. Laboratory investigation logbook was maintained for the OSD facility which covered OOS related to raw materials, in-process, stability and finished products. Separate logbooks were maintained for commercial production batches and batches manufactured for the US markets (ANDA). Handling of laboratory events The handling of laboratory events procedure applied to all laboratory events that occurred during analysis. These events were classified into Type-A (before sample analysis) and Type-B (after sample analysis). The procedure was supported with an event investigation form and checklist. The procedure appeared to be acceptable. Trend analysis was reviewed for Oct-Dec 2018. A total of 326 events (151

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Type A and 175 Type B) were identified. Most of the events occurred due to analyst errors (44%) with the stability department the highest. An in-depth analysis was performed, and root cause was identified for most of the events which was addressed through “do’s and don’ts”, purchasing of a pump for column washing and etc. A procedure on Good Chromatographic Practices was in place which described that no trial injections of blank, sample or standard are allowed at any circumstances. It further named the sequence as well as the use of same processing parameters for blank, sample and standard. A good practice guideline for chromatographic practices was available. Manual integration is discouraged, if required the use to be authorized by QC and QA heads. Handling of laboratory event was also in place which described the process for reporting, investigating, evaluating and documenting laboratory event causing non-conformance other than OOS/OOT results. Stability studies The SOP on stability studies was discussed. The procedure was recently revised and samples for 30/65% condition will only be tested if a significant change was observed at 3rd month and 6th month accelerated condition. The SOP on the review of electronic data and audit trail (MFG-211/03 dated 11/01/2019) was discussed. The production and quality assurance was responsible for the review of audit trails and these were recorded in the respective checklists. Loose sheets stapled together were used as audit trail checklists. The procedure stated that “machine stoppages for less than approx. 10 minutes shall not be recorded in BMR”, which should be set on a case by case basis. It was also noted that frequency for the review of audit trails was not justified. The procedure stated that the audit trail will be reviewed once every three months. The issues related to this section have been adequately addressed by the manufacturer, and the same shall be verified during future inspections. Part 3 Conclusion – Inspection outcome

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, Emcure Pharmaceuticals Limited ,located at MIDC, Hinjawadi, Pune, India was considered to be operating at an acceptable level of compliance with WHO GMP Guidelines. 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.

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Part 4 List of WHO Guidelines referenced in the inspection report

1. WHO good manufacturing practices for pharmaceutical products: main principles. WHO Expert

Committee on Specifications for Pharmaceutical Preparations. Forty-Eighth Report Geneva, World Health Organization, 2014 (WHO Technical Report Series, No. 986), Annex 2. Short name: WHO TRS No. 986, Annex 2 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_986/en

/ 2. WHO good manufacturing practices for active pharmaceutical ingredients. WHO Expert

Committee on Specifications for Pharmaceutical Preparations. Forty-Fourth Report. Geneva, World Health Organization, 2010 (WHO Technical Report Series, No. 957), Annex 2. Short name: WHO GMP for APIs or TRS No. 957, Annex 2

http://www.who.int/medicines/publications/44threport/en/

3. WHO good manufacturing practices: water for pharmaceutical use. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fourth-Sixth Report. Geneva, World Health Organization, 2012 (WHO Technical Report Series, No. 970), Annex 2 Short name: WHO TRS No. 970, Annex 2 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_970/en

/ 4. WHO guidelines for sampling of pharmaceutical products and related materials. WHO Expert

Committee on Specifications for Pharmaceutical Preparations. Thirty-Ninth Report. Geneva, World Health Organization, 2005 (WHO Technical Report Series, No. 929), Annex 4 Short name: WHO TRS No. 929, Annex 4 http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf?ua=1

5. Guidelines on heating, ventilation and air-conditioning systems for non-sterile pharmaceutical

products. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fifty-Second Report Geneva, World Health Organization, 2018 (WHO Technical Report Series, No. 1010), Annex 8. Short name: WHO TRS No. 1010, Annex 8 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_1010/

en/ 6. Supplementary guidelines on good manufacturing practices: validation. WHO Expert Committee

on Specifications for Pharmaceutical Preparations. Fortieth Report. Geneva, World Health Organization, 2006 (WHO Technical Report Series, No. 937), Annex 4 Short name: WHO TRS No. 937, Annex 4 http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf?ua=1

7. WHO Good Practices for Pharmaceutical Quality Control Laboratories. WHO Expert Committee

on Specifications for Pharmaceutical Preparations. Forty-Fourth Report. Geneva, World Health Organization, 2010 (WHO Technical Report Series, No. 957, Annex 1 Short name: WHO GPPQCL Guidelines or TRS No. 957, Annex 1 http://www.who.int/medicines/publications/44threport/en/

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http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_986/en/





http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf?ua=1








8. WHO Good Practices for Pharmaceutical Products Containing Hazardous Substances. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-Fourth Report. Geneva, World Health Organization, 2010 (WHO Technical Report Series, No. 957), Annex 2 Short name: WHO TRS No. 957, Annex 2 http://www.who.int/medicines/publications/44threport/en/

9. WHO good manufacturing practices for sterile pharmaceutical products. WHO Expert Committee

on Specifications for Pharmaceutical Preparations. Forty-Fifth Report Geneva, World Health Organization, 2011 (WHO Technical Report Series, No. 961), Annex 6 Short name: WHO TRS No. 961, Annex 6 http://whqlibdoc.who.int/trs/WHO_TRS_961_eng.pdf?ua=1

10. WHO guidelines on transfer of technology in pharmaceutical manufacturing WHO Expert

Committee on Specifications for Pharmaceutical Preparations. Forty-Fifth Report Geneva, World Health Organization, 2011 (WHO Technical Report Series, No. 961), Annex 7 Short name: WHO TRS No. 961, Annex 7 http://whqlibdoc.who.int/trs/WHO_TRS_961_eng.pdf?ua=1

11. Model guidance for the storage and transport of time-and temperature-sensitive pharmaceutical

products. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-Fifth Report Geneva, World Health Organization, 2011 (WHO Technical Report Series, No. 961), Annex 9. Short name: WHO TRS No. 961, Annex 9 http://whqlibdoc.who.int/trs/WHO_TRS_961_eng.pdf?ua=1

12. General guidelines for the establishment maintenance and distribution of chemical reference

substances. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-First Report Geneva, World Health Organization 2007 (WHO Technical Report Series, No.943) Annex 3 Short name: WHO TRS No. 943, Annex 3 http://whqlibdoc.who.int/trs/WHO_TRS_943_eng.pdf?ua=1

13. WHO good practices for pharmaceutical microbiology laboratories. WHO Expert Committee on

Specifications for Pharmaceutical Preparations. Forty-Fifth Report Geneva, World Health Organization, 2011 (WHO Technical Report Series, No. 961), Annex 2 Short name: WHO TRS No. 961, Annex 2 http://whqlibdoc.who.int/trs/WHO_TRS_961_eng.pdf?ua=1

14. WHO guidelines on quality risk management. WHO Expert Committee on Specifications for

Pharmaceutical Preparations. Forty-Seventh Report Geneva, World Health Organization, 2013 (WHO Technical Report Series, No. 981), Annex 2. Short name: WHO TRS No. 981, Annex 2 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_981/en

/ 15. WHO guidelines on variation to a prequalified product. WHO Expert Committee on Specifications

for Pharmaceutical Preparations. Forty-Seventh Report Geneva, World Health Organization, 2013 (WHO Technical Report Series, No. 981), Annex 3. Short name: WHO TRS No. 981, Annex 3 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_981/en/

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16. WHO guidelines for drafting a site master file. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-Fifth Report Geneva, World Health Organization, 2011 (WHO Technical Report Series, No. 961), Annex 14. Short name: WHO TRS No. 961, Annex 14 http://whqlibdoc.who.int/trs/WHO_TRS_961_eng.pdf?ua=1

17. WHO Guidelines on good manufacturing practices: validation, Appendix 7: non-sterile process

validation. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-Ninth Report Geneva, World Health Organization, 2015 (WHO Technical Report Series, No. 992), Annex 3. Short name: WHO TRS No. 992, Annex 3 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/WHO_TRS_992_web.pdf

18. WHO General guidance on hold-time studies WHO Expert Committee on Specifications for

Pharmaceutical Preparations. Forty-Ninth Report Geneva, World Health Organization, 2015 (WHO Technical Report Series, No. 992), Annex 4. Short name: WHO TRS No. 992, Annex 4 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/WHO_TRS_992_web.pdf

19. WHO Technical supplements to Model Guidance for storage and transport of time – and

temperature – sensitive pharmaceutical products. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-Ninth Report Geneva, World Health Organization, 2015 (WHO Technical Report Series, No. 992), Annex 5. Short name: WHO TRS No. 992, Annex 5 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/WHO_TRS_992_web.pdf

20. WHO Recommendations for quality requirements when plant – derived artemisin is used as a

starting material in the production of antimalarial active pharmaceutical ingredients. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-Ninth Report Geneva, World Health Organization, 2015 (WHO Technical Report Series, No. 992), Annex 6 Short name: WHO TRS No. 992, Annex 6 http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/WHO_TRS_992_web.pdf

21. Guidance on good data and record management practices. WHO Expert Committee on

Specifications for Pharmaceutical Preparations. Fiftieth Report Geneva, World Health Organization, 2016 (WHO Technical Report Series, No. 996), Annex 5 Short name: WHO GDRMP or WHO TRS No. 996, Annex 5 http://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex05.pdf

22. WHO general guidance on variations to multisource pharmaceutical products. WHO Expert

Committee on Specifications for Pharmaceutical Preparations. Fiftieth Report Geneva, World Health Organization, 2016 (WHO Technical Report Series, No. 996), Annex 10 Short name: WHO TRS No. 996, Annex 10 http://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex10.pdf

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