20, AVENUE APPIA – CH-1211 GENEVA 27 – SWITZERLAND – TEL CENTRAL +41 22 791 2111 – FAX CENTRAL +41 22 791 3111 – WWW.WHO.INT Shanghai Desano Chemical Pharmaceutical Co Ltd, P.R. China, API 15-18 January 2019 This inspection report is the property of the WHO Contact: [email protected]Page 1 of 14 Prequalification Team Inspection services WHO PUBLIC INSPECTION REPORT (WHOPIR) Active Pharmaceutical Ingredient Manufacturer Part 1 General information Manufacturers details Name of manufacturer Shanghai Desano Chemical Pharmaceutical Co Ltd Corporate address of manufacturer 1479 Zhangheng Road, Zhangjiang High Tech Park, Shanghai 201203, P. R. China Inspected site Name & address of inspected manufacturing site if different from that given above 417 Binhai Road, Laogang Town, Pudong New Area, Shanghai, 201 302, P. R. China Synthetic unit /Block/ Workshop All workshops except workshop L18 Inspection details Dates of inspection 15-18 January 2019 Type of inspection Routine Introduction Brief description of the manufacturing activities Production and quality control of anti-retroviral and anti-malarial APIs and their intermediates General information about the company and site Shanghai Desano Chemical Pharmaceutical Co. Ltd. (Desano) is a limited company that was established in 2002. Its headquarters are located on Zhangjiang High-Tech Park, Shanghai 201203. The company markets their APIs mostly in China, India, South Africa, Brazil, Russia, Thailand while exploring US, EU and Australian markets. The site continues to manufacture APIs for PEPFAR and Global Fund projects. The manufacturing facilities are located approximately 50Km southeast of Shanghai city centre and around 20Km from Pudong International airport and they became operational in 2006. The manufacturing site is divided by a public road into East (smaller area) and West wings. The site consists of several separate workshops constructed in rows and assigned alphanumerical identification codes based on row and number of building. Some of the workshops are divided in manufacturing buildings, each numbered on the outside. Some of the buildings are further subdivided and labelled as A, B or
Transcript
20, AVENUE APPIA – CH-1211 GENEVA 27 – SWITZERLAND – TEL CENTRAL +41 22 791 2111 – FAX CENTRAL +41 22 791 3111 – WWW.WHO.INT
Shanghai Desano Chemical Pharmaceutical Co Ltd, P.R. China, API 15-18 January 2019 This inspection report is the property of the WHO
Prequalification Team Inspection services WHO PUBLIC INSPECTION REPORT
(WHOPIR) Active Pharmaceutical Ingredient Manufacturer
Part 1 General information Manufacturers details Name of manufacturer
Shanghai Desano Chemical Pharmaceutical Co Ltd
Corporate address of manufacturer
1479 Zhangheng Road, Zhangjiang High Tech Park, Shanghai 201203, P. R. China
Inspected site Name & address of inspected manufacturing site if different from that given above
417 Binhai Road, Laogang Town, Pudong New Area, Shanghai, 201 302, P. R. China
Synthetic unit /Block/ Workshop
All workshops except workshop L18
Inspection details Dates of inspection 15-18 January 2019 Type of inspection Routine
Introduction Brief description of the manufacturing activities
Production and quality control of anti-retroviral and anti-malarial APIs and their intermediates
General information about the company and site
Shanghai Desano Chemical Pharmaceutical Co. Ltd. (Desano) is a limited company that was established in 2002. Its headquarters are located on Zhangjiang High-Tech Park, Shanghai 201203. The company markets their APIs mostly in China, India, South Africa, Brazil, Russia, Thailand while exploring US, EU and Australian markets. The site continues to manufacture APIs for PEPFAR and Global Fund projects.
The manufacturing facilities are located approximately 50Km southeast of Shanghai city centre and around 20Km from Pudong International airport and they became operational in 2006. The manufacturing site is divided by a public road into East (smaller area) and West wings. The site consists of several separate workshops constructed in rows and assigned alphanumerical identification codes based on row and number of building. Some of the workshops are divided in manufacturing buildings, each numbered on the outside. Some of the buildings are further subdivided and labelled as A, B or
History The site is regularly being inspected by WHO since 2007. The table below summarizes inspections carried out in the last 5 years:
NRA Country Year GMP Status CFDA P.R. China 2018 Compliant ANVISA Brazil 2018 Compliant CFDA P.R. China 2017 Compliant COFEPRIS Mexico 2017 Compliant FDA U.S.A 2017 Compliant MHRA/TGA United Kingdom/ Australia 2017 Compliant CFDA P. R. China 2017 Compliant CFDA P. R. China 2016 Compliant CFDA P. R. China 2016 Compliant CFDA P. R. China 2016 Compliant COFEPRIS Mexico 2015 Compliant FDA U.S.A 2015 Warning Letter CFDA P. R. China 2015 Compliant ANVISA Brazil 2014 Compliant WHO 2014 Compliant
Brief report of inspection activities undertaken – Scope and limitations Areas inspected Pharmaceutical Quality System
Documentation Facilities and Equipment Utilities Production Quality Control Packaging and labelling
Restrictions N/A
Out of scope Workshop L18 since no WHO prequalified API is manufactured in this workshop.
Abbreviations Meaning AHU Air handling unit ALCOA Attributable, legible, contemporaneous, original and accurate API Active pharmaceutical ingredient APR Annual product review BMR Batch manufacturing record BPR Batch production record CC Change control 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 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 KF Karl Fisher LAF Laminar air flow LIMS Laboratory information management system MB Microbiology MBL Microbiology laboratory 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 SMF Site master file SOP Standard operating procedure URS User requirements specifications UV Ultraviolet-visible spectrophotometer
Part 2 Summary of the findings and comments
1. Quality management
A formal documented system of quality assurance was established, with procedures covering all expected key quality elements being in place. Most of procedures and GMP related documents were in Chinese. The Quality Unit was independent of production. Operations were specified in written form and GMP requirements were essentially being met. Procedures were in place for notifying responsible management of regulatory inspections, serious GMP deficiencies, quality defects and related actions. Product and processes were monitored and these results considered during batch release. Regular monitoring and reviews of the quality of APIs were being conducted according to documented schedules and procedures. Quality risk Management (QRM) The company had a risk assessment procedure that described how it was to be applied and the extent of effort to be commensurate with the level of risk. Risk assessments were rooted within the various areas of the quality systems such as within change controls, deviations etc. In most cases risks were identified and quantified by grading the possibility of occurrence and the severity/impact. In general, the risk ranking tools and risk assessments reviewed were of a good standard.
A Product Quality Review (PQR) procedure was presented and it defined the responsibilities for those departments that were required to provide data for the review. QA had responsibility for ensuring that these reviews were completed according to agreed timelines. PQRs had to be drafted by the end of January and approved by the end of March, each year. PQRs included a review of critical control parameters, deviations, changes, raw material and supplier status, validation status of equipment and utilities, complains, recalls, returns, rejected batches, OOS, OOT and stability studies. There was a provision for carrying out reviews for APIs that no batches were manufactured the previous year. The 2018 PQRs were in preparation at the time of inspection and a plan was available. The 2017 PQRs for Lumefantrine, Artemether, Efavirenz and Ritonavir were checked. The company used Process Capability Index calculations as well as Upper and Lower Control Limits to assess the process control.
2. Personnel The company had an organization chart that showed that there was clear separation between the responsibilities and reporting of the quality and production units. There were approximately 870 employees on site. Personnel met during the inspection appeared to have knowledge of GMP principles and showed that they received initial and continuing training, including hygiene instructions, relevant to their responsibilities. All new staff were required to have a pre-employment medical check and this was repeated annually. Training was divided in three levels: induction training, on the job training and periodic training. HR was responsible for collecting topics for training and creating an annual matrix plan based on job profiles. QA was responsible for review and approval of the training plan. Measures were taken to prevent unauthorized people from entering production and QC areas and appeared to be effective. The job description and training record of Head QA was reviewed. Head QA was responsible for release of the API. The duties of reviewing a batch record could be delegated to other QA personnel.
3. Buildings and facilities The manufacturing facilities were divided by a public road into East and West wings. The site consisted of many separate manufacturing buildings, each assigned an alphanumerical identification. Some of the buildings had been further sub divided and labelled as A, B or C to further designate manufacturing activities. In general, inspected workshops and facilities were found to be well organized, adequately maintained and fit for purpose.
There were two solvent tank farms on site (B12 and C19) as well as two solvent stores (A11 and B11). Some of the solvent tanks required maintenance. Solvents in drums were sampled in the quarantine area. There was also a solvent recovery plant (C20) where methanol, ethanol, ethyl acetate, DMF and toluene were recovered/recycled. Recovery was product specific and specifications for recovered solvents were established. When sufficient storage was exhausted, recovered solvents could be transferred from C20 to tanks in the solvent farms but there was no procedure in place describing the necessary measures and operations. Appropriate CAPA were implemented following this inspection.
Solid raw materials were stored in warehouse A12 which included sampling and dispensing facilities. Relevant SOPs and photos of entry procedure were on display and a copy of the approved vendor list was available. Temperature limits for the warehouse of solid raw materials were set at max. 35°C. APIs were stored in warehouse A15-2. Temperature at A15-2 warehouse was maintained 15-30°C and relative humidity at 25-75%.
The water plant was located in building A15-1. City water was used as the feed water and it was processed through a series of filters including three carbon columns, two RO membranes and two mixed bed ion exchange (one stand by). All pipework was labelled and there was on line conductivity monitoring. There was a monthly program for sampling and testing.
Access control to manufacturing buildings was established. Lighting in the areas visited during the inspection was considered adequate. The flow of materials and personnel through facilities were designed to prevent mix-up and cross contamination. Adequate ventilation, air filtration and exhaust systems were provided. In general, final purification steps (crystallization, centrifugation, drying, sieving, micronization) were carried out in Grade D rooms. Environmental qualification of Grade D areas was carried out every five years but no justification was documented. Some design and operational weaknesses were observed and discussed in Part 3, below
4. Process equipment In general, process equipment and materials of product contact were suitable. Reactor systems, and utilities, were installed to allow reflux, distillation, extraction, crystallization, drying and micronization required to make the APIs of interest. Tools and equipment were uniquely identified, and status labels were generally used. There was a maintenance program that covered planned maintenance activities across the site. There was a schedule of maintenance and any overdue maintenance activities were required to be reported, investigated and actioned by raising a deviation. There were different maintenance periods for equipment. Similarly measuring equipment were labelled including calibration status. There was a list of equipment to be calibrated and each piece of equipment had a unique identification number. The calibration program included equipment such as pressure meters and temperature probes.
5. Documentation and records Documentation system was generally well established. Procedures on creating SOPs and on control of quality documents and records were available. The issuance, revision, superseding and withdrawal of documents were controlled. Documents related to the manufacture of intermediates and APIs were prepared, reviewed, approved and distributed according to written procedures. It was noted that certain procedures were not sufficiently detailed and certain operations like transfer of recovered solvent from C20 to solvent farms were not described in a procedure. All documents were controlled by QA and masters were identified by having the original signatures of authors and approvers. Specifications were established for raw materials, intermediates and APIs. BMRs were retained for each batch processed. Batches were numbered according to a written procedure of product batch number. Similarly, material codes and batch numbers for recovered solvents followed established procedures. Different labels were used for rooms, equipment, tools and material. These were defined in the relevant SOPs.
There were written procedures describing the receipt, labelling, quarantine, storage, and handling of materials, as well as procedures for sampling, testing and approval or rejection of materials. Vehicles delivering raw materials were stopped at the gate and after a preliminary check they were accompanied by personnel from the logistics department, to the warehouse. The planning department was responsible for informing the warehouse for upcoming deliveries on a weekly basis. A list of approved suppliers was available at material receipt areas. QA was responsible for updating this list quarterly or earlier as appropriate. Solid raw materials and solvents in drums were placed in quarantine upon receipt. Material reaching retest date were moved from the “released” area of the warehouse to quarantine but no quarantine labels had to be affixed on them. Finished APIs were stored at A15-2 warehouse
The company had a supplier approval procedure that covered raw and packaging materials as well as other consumables. Materials were classified in three categories namely, 1. starting materials and intermediates, 2. packaging materials and solvents used in production and 3. any other material. This classification was used for qualifying suppliers and material and for requesting appropriate supportive documentation. Results of routine testing of materials as well as review of quality issues and periodic audit of suppliers (3-5 years) was used for an annual review and evaluation of suppliers. A list of approved suppliers was established, and it was reviewed by QA every three months or in case of a change. An annual audit plan of suppliers was prepared by the end of March each year. The 2018 audit plan was presented. Spot checks on the qualification and technical agreements of Artemisin suppliers was performed.
7. Production and in-process controls In general, production operations followed defined procedures. Process flows (with IPCs) and routes of synthesis were available. Access to production premises was restricted to authorized personnel. Weighing and measuring devices were of suitable accuracy for the intended use. Calibration procedures and records for scales were presented. Standard weights and their certificates were available. Closed systems and dedicated pipes were used for material transfers from reactors to centrifuges. Examination of the flow of the manufacturing process and relevant equipment was in line with the BMRs examined during the inspection.
The following APIs were manufactured during the inspection:
Process validation of Atazanavir Sulphate was conducted in C18C. A risk assessment on the manufacturing process was carried out and critical control parameters were identified. Extra testing was performed, and test results were compared with the original process validation.
8. Packaging and identification labelling of APIs and intermediates Intermediates were handled, as required, in dedicated containers. For quarantined/released APIs two different labeling approaches were followed depending on whether the batch was for a specific customer order or for stock. Yellow quarantine labels were hung from sealed API containers intended for a specific customer order. These labels were removed upon release and blue labels were affixed on the containers. Blue labels were not affixed on API containers intended for stock. These APIs could be further repacked, if necessary, based on customer demand. If milling or blending was required full testing was repeated.
Manufacture of drum seals was contracted to a third party. Identification code of each seal was determined and maintained by Shanghai Desano and consisted of one letter and five numbers. Seal id codes were generated based on a procedure, were sequential in order and were registered in a logbook in order to ensure uniqueness
9. Storage and distribution APIs were stored in warehouse A15-2 that included a cold room (2-8°C) which was used for quarantined materials, APIs and retained samples requiring cold storage. The cold room was crowded. Temperature mapping of the warehouse and cold room were available. Temperature at A15-2 warehouse was maintained 15-30°C and relative humidity at 25-75%.
10. Laboratory controls The analytical and microbiological laboratories were inspected. The premises were located on the first and second floor of building A18 and generally they were of an acceptable standard and well equipped. Documents were organized in an appropriate manner and retrieval was achieved in a timely manner. Some raw material specifications were checked at random. Testing and specification of primary packaging material (PE bags) was reviewed. Calibration of laboratory scales took place daily and it included accuracy and range. Full calibration was performed every quarter and it included, linearity, accuracy, eccentricity and repeatability. There were twenty-six HPLCs installed operating under Empower 3 v. 7.3. Six levels of access rights were established. It was noted that Windows XP were installed in one workstation in order to be able to retrieve chromatograms from Empower 2. Reference and working standards were available and they were appropriately stored. Validity of compendial standards was checked monthly.
A Validation Mater Plan was available. Procedures for validation and qualification of equipment, systems, utilities, processes and analytical methods were in place. Environmental qualification of Grade D areas took place every five years, but this frequency was not scientifically justified. The latest qualification of centrifuge SSB-1000 was checked. In addition, process validation of Atazanavir conducted in building C18C and process validation of the Lamivudine precipitation step after pH adjustment were reviewed. The cold room qualification was also reviewed. It was qualified every two years and the exercise took place in the summer for three days.
12. Change control and deviations There was a change control procedure that covered changes including but not limited to changes to documents, production, raw materials, suppliers, utilities, analytical methods and instruments, cleaning, computer systems and packaging. Change control was initiated by the affected department with changes classified as minor, major or critical. An associated risk assessment was created and reviewed by QA. Timelines for implementation, closure and assessment of adequacy were established.
Deviations were managed according to an established procedure and a review was performed every three months. A report summarizing the review findings was drafted and archived. Log books for CC and deviation were available for review.
13. Rejection and re-use of materials
The company had in place an SOP for recovery and usage of recovered solvents. Recovered solvents were product specific. Initially recovered solvents were stored in tanks in plant C20 and then transferred to dedicated tanks in the solvent plant. The following solvents were recovered from different stages of manufacture; Methanol, Ethyl acetate, DMF, Ethanol, Toluene. Specifications for recovered solvents were spot checked
14. Complaints and recalls Product recalls were handled according to SOP “Handling of Product Recall” SOP-B-QA-028-07. QA was responsible for making the recall decision and for coordinating all relevant actions. However, QC and Director were responsible for the close out of the recall. Recall were classified in three categories according to health impact and urgency. The parameters to evaluate the effectiveness of recall were not detailed. Mock recall of Tenofovir batch: DBH101-C18C-180201 carried in September 2018 was reviewed.
Complaints were handled according to a written procedure. Complaints could be initially received and registered by any department and reported to QA. QA was responsible for classifying the complaint and initiate root cause investigations
Manufacturing of WHO prequalified APIs was not contracted out. Technical agreements with service providers as well as suppliers of raw materials were in place
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, Shanghai Desano located at 417 Binhai Road, Laogang Town, Pudong New Area, Shanghai, 201 302, P. R. China was considered to be operating at an acceptable level of compliance with WHO GMP Guidelines for APIs. 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. Part 4 List of GMP Guidelines referenced in the inspection report
1. 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 WHO TRS No. 957, Annex 2 http://apps.who.int/medicinedocs/documents/s20119en/s20119en.pdf
2. 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/
3. WHO good manufacturing practices: water for pharmaceutical use. WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Forty-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 TRS No. 961, 957), Annex 1 http://www.who.int/medicines/publications/44threport/en/
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
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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/
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 guidance 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 Multisource guidance or WHO TRS No. 996, Annex 10 http://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex10.pdf
23. Stability testing of active pharmaceutical ingredients and finished 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 10. Short name: WHO TRS No. 1010, Annex 10 http://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex10.pdf
24. Production of water for injection by means other than distillation. WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Fifty-fourth Report. Geneva, World Health Organization, 2020 (WHO Technical Report Series, No. 1015), Annex 3. Short name: WHO TRS No. 1025, Annex 3 https://www.who.int/publications-detail/978-92-4-000182-4
25. Good chromatography practice. WHO Expert Committee on Specifications for Pharmaceutical
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26. Points to consider for manufacturers and inspectors: environmental aspects of manufacturing for
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