inspection report for who...o “user rights assignment of ecm (openlab)” o “shimadzu...

20, AVENUE APPIA – CH-1211 GENEVA 27 – SWITZERLAND – TEL CENTRAL +41 22 791 2111 – FAX CENTRAL +41 22 791 3111 – WWW.WHO.INT

Page | 1 WHOPIR Zhejiang Hisun Pharmaceutical, Yantou Campus, China- API 18-22 March 2019

Prequalification Team Inspection services WHO PUBLIC INSPECTION REPORT

Active Pharmaceutical Ingredients Part 1 General information Manufacturers details Name of manufacturer Zhejiang Hisun Pharmaceutical Co., Ltd

56 Binhai Road, Jiaojiang District, Taizhou City, Zhejiang Province, P.R.C. Post code: 318000 Longitude (121°50’), Latitude (28°66’) DUNS number: 654211754

Corporate address of manufacturer

46 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province, P.R.C. Telephone Number: +86-576-88827900 Fax Number: +86 576 88827 887

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

Zhejiang Hisun Pharmaceutical Co., Ltd Yantou Campus 56 Binhai Road, Jiaojiang District, Taizhou City, Zhejiang Province, P.R.C. Post code: 318000 Longitude (121°50’), Latitude (28°66’) DUNS number: 654211754

Unit/block/ workshop number

Yantou Campus: Buildings Y21, Y22, Y55, Y66 and Y58 QC laboratory – building WS05 at Waisha Campus Address: 46 Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province, P.R.C. Post code: 318000 Longitude (121°46’), Latitude (28°68’) DUNS number: 654211754

Manufacturing license number

Zhe20000291, Pharmaceutical Manufacturer Tablets, Hard Capsules, API, Sterile API, etc.

Inspection details Dates of inspection 18 - 22 March 2019 Type of inspection Routine, in conjunction with the European Union inspection team

Note: EU inspection team inspected the following buildings and APIs: • Y 36 (idarubicin HCl, pirarubicin, methotrexate, cytarabine, cytarabine HCl

and cyclophosphamide) • Y 37 (mesna, gemcitabine, cladribine, lenalidomide, fludarabine phosphate,

gefitinib, palbociclib and regorafenib) • Y 38 (bicatulamide, letrozole, anastrozole and dasatinib) • Y 39 (gemcitabine HCl, cladribine, lenalidomide, cytarabine, fludarabine

ph. and cyclophosphamide) • Y 33/Y 35 (bleomycin sulfate, doxorubicin HCl, mitomycin and

daunorubicin HCl) • Y 50 (vinorelbine, doxorubicin HCl and epirubicin)

http://www.who.int/



Y 20 Introduction Brief description of the manufacturing activities

Yantou Campus: production of APIs and intermediates

General information about the company and site

Zhejiang Hisun Pharmaceutical Co., Ltd. (hereinafter Hisun) was founded in 1956, being a company listed as a state-owned corporation in Shanghai A Share Stock Exchange in year 2000. Hisun is authorized by the Chinese Competent Authority and inspected regularly. A pharmaceutical production license has been issued by NMPA (China Authority). Hisun exports more than 80% of API products to over 70 countries and regions. Hisun Taizhou site consists of three campuses within a short driving distances.

History The site had been inspected by the following authorities:

Authority Date/s of inspection

Scope of inspection

Facility/block/unit covered by inspection

CFDA (China)

June 20-22, 2014 API Waisha Campus, Yantou

Campus Germany Authority July 9-16, 2014 API & FPP Waisha Campus, East

Campus, Yantou Campus MCC/South African

August 18-20, 2014 API & FPP Waisha Campus, East

Campus, Yantou Campus

WHO September 9-13, 2014 API & FPP Waisha Campus, East


US FDA March 2-7, 2015 API & FPP Waisha Campus, East


WHO March 13-20, 2015 API & FPP Waisha Campus, East

Campus, Yantou Campus CFDA (China)

April 20-25, 2015 API & FPP Waisha Campus, East

Campus, Yantou Campus Cofepris (Mexico)

May 25-29, 2015 API Waisha Campus, Yantou

Campus CFDA (China)

October 22-24, 2015 API Waisha Campus, Yantou

Campus CFDA (China)

November 10-15, 2015 API & FPP Waisha Campus, East

Campus, Yantou Campus Cofepris (Mexico)

January 25-29, 2016 API Waisha Campus, Yantou

Campus ANVISA (Brazil)

March 21-25, 2016 API Waisha Campus, Yantou

Campus CFDA (China)

March 30-April 1, 2016 API Waisha Campus, Yantou

Campus Cofepris (Mexico)

April 18-29, 2016 API Waisha Campus, Yantou

Campus Spain-Demark-

May 30 to June 3, 2016 (Re- API & FPP Waisha Campus, East


http://www.who.int/



WHO Joint inspected in April 2018)

Health Canada (Canada)

July 18-29, 2016 API & FPP Waisha Campus, East


ANVISA (Brazil)


Campus

CFDA (China)

November 31 - December 2, 2016

API Waisha Campus, Yantou Campus

US FDA January 16-19, 2017 API & FPP Waisha Campus, East


February 22-25, 2017 API Waisha Campus, Yantou

Campus J-MAFF (Japan)


Campus Cofepris (Mexico)


Campus CFDA (China)

April 24-26, 2017 API Waisha Campus, Yantou

Campus Health Canada (Canada)-TGA (Australia) Joint

May 22 - June 2, 2017 API & FPP Waisha Campus, East


Cofepris (Mexico) June 5-9, 2017 API Waisha Campus, Yantou

Campus

US FDA August 7-11, 2017 API & FPP Waisha Campus, East


August 24-27, 2017 API Waisha Campus, Yantou

Campus CFDA (China)


Campus CFDA (China)

September 19-21, 2017 API & FPP Waisha Campus, East


Cofepris (Mexico)

October 30-November 3, 2017

API Waisha Campus, Yantou Campus

CFDA (China)

December 1-3, 2017 API Waisha Campus, Yantou

Campus

WHO December 7-15, 2017 API & FPP Waisha Campus, East


December 21-22, 26-27, 2017 API & FPP Waisha Campus, East

Campus, Yantou Campus CFDA December 21- API Waisha Campus, Yantou

http://www.who.int/



(China) 27, January 7-12, 2018

Campus

CFDA (China)

January 23-24, 2018 API Waisha Campus, Yantou

Campus

Koshar January 31, 2018 API Waisha Campus, Yantou

Campus AEMPS-VMD-DMA (Spain-UK-Demark) Joint

April 9-14, 2018 API & FPP Waisha Campus, East


CFDA (China)

April 17-22, 2018 API & FPP Waisha Campus, Yantou

Campus CFDA (China)

June 25-30, 2018 API Waisha Campus, Yantou

Campus CFDA (China)


Campus CFDA (China)

August 21-23, 2018 FPP Waisha Campus

PMDA (Japan)


Campus

WHO December 4-7, 2018 FPP

Waisha Campus (TB357 -Levofloxacin Tablet, Film-coated 250mg TB358 - Levofloxacin Tablet, Film-coated 500mg)

Brief report of inspection activities undertaken – Scope and limitations Areas inspected See Part 2 below Restrictions N/A Out of scope Products out of scope of WHO PQ WHO APIs covered by the inspection

• Cycloserine • Linezolid • Capreomycin sulfate • Moxifloxacin hydrochloride

Abbreviations Meaning ADE Acceptable daily exposure ADR Adverse drug reaction AHU Air handling unit ALCOA Attributable, legible, contemporaneous, original and accurate API Active pharmaceutical ingredient APQR Annual product quality review APS Aseptic process simulation AQL Acceptance quality limit BMR Batch manufacturing record BPR Batch production record CC Change control CCEA Complete, consistent, enduring, available

http://www.who.int/



CFU Colony-forming unit 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 LoD Loss on drying MB Microbiology MBL Microbiology laboratory MF Master formulae MFT Media fill Test MR Management review NC Non-conformity NCA National control authority NCL National control laboratory 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

http://www.who.int/

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



SIP Sterilization in place SMF Site master file SOP Standard operating procedure URS User requirements specifications UV Ultraviolet-visible spectrophotometer WFI Water for injection

Part 2 Summary of the findings and comments

1. Quality system Principle Production and control operations were specified in written form and GMP requirements were essentially being met. Managerial responsibilities were specified in written job descriptions. Product and processes were monitored, and the results were reviewed as part of the approval process of batch release. Regular monitoring and reviews of the quality of pharmaceutical products were being conducted according to documented schedules and procedures. QA functions were arranged on various levels (Site, production units etc.) All three campuses were under the same quality system, with the same senior management. Testing for release and release procedure took place in Waisha campus where the headquarters of Taizhou Site are located. Data integrity policy the following SOPs were briefly discussed: • “Data integrity management procedure”. SOP was applicable to all GXP activities on site, paper and

electronic documents and addressed ALCOA+CCEA principles. • “Computerized system backup and data migration management procedure”. Daily and weekly backups

were performed automatically to the server located at the East campus. • “Computerized system management procedure” addressed GXP computerized system levels,

classification and qualification requirements with the Attachment “Computerized system list” presented to the inspectors.

• “Disaster recovery management procedure” and H0-SOP-20005/2 “Computerized system for data server management procedure” addressed the servers log/register and various servers available and used by the Taizhou Site.

• “Computerized system user access management procedure in lab”. SOP specified the various access levels. The following documents were briefly discussed:

o “User rights assignment of ECM (OpenLab)” o “Shimadzu LabSolutions server and client operation procedure” o “Lab computerized system user list format” o “Lab computerize system user access change request form”

http://www.who.int/



Management review (MR) SOP “Management review” is a Corporate level procedure. Quarterly reviews were applied by the Taizhou Site; yearly period was defined for the Corporate level. Common reviews for APIs and dosage forms were drawn by the Taizhou Site. 2018 Q4 report was requested for inspection and briefly discussed. Product Quality Review (PQR) SOP “Product annual quality review management procedure” and SOP was briefly discussed. Cpk was used to evaluate process capability. It was applied for critical and quantitative parameters for intermediates and final APIs. PQR Linezolid (2018.01.01 – 2018.12.31) was briefly discussed. The following SOPs applicable for APIs and FPPs were briefly discussed: • “Deviation management procedure”. Classification was performed by responsible person from QA

department. Deviations were trended 3 monthly and annually. According to the SOP deviations should be investigated and closed out within 25 working days. If the time was exceeded, an extended investigation request was to be approved by the Quality Director. A number of deviation investigation records were briefly discussed.

• “Investigation tools – application management procedure”. The following tools were used for root cause investigations:

o Ishikawa diagram o 5 Why`s o Events flow analysis o Brain storming o Pareto diagram

• “Corrective and preventive action management procedure”. CAPAs were trended biannually and annually. Trends for 2018 (for APIs) site were presented to inspectors.

• “Returned product management” • “Complaint management procedure”

Complaints on APIs were mainly received by the sales department which submit information to the quality unit. Customer service phone number was mainly relevant for FPPs. A “Complaint administrator” was assigned for each case. Complaints were trended biannually and annually. Trends for 2018 (for APIs) were presented to inspectors. Complaints were classified into 5 levels. Classification was performed by responsible person from QA department. A number of complaint investigation reports were briefly discussed.

• “Product recall procedure”. The Company stated that there had been no recalls in the Site history. Five levels for product quality issues were defined. According to the SOP, the Site Quality Director had the central role in deciding on a recall.

• “Change control” and a number CC records were briefly discussed.

Documentation Documents related to the manufacture of intermediates and APIs were prepared, reviewed, approved and distributed according to written procedures. SOPs were displayed at appropriate points. The issuance, revision, superseding and withdrawal of documents were controlled and maintaining revision histories. Documents coded as H0 were common to API and FPP.

http://www.who.int/



The following SOPs were briefly discussed. • “Drafting and management of documents” • “Management procedure of quality stamp”

2. Production system Production operations followed defined procedures. Significant deviations from the initial protocol were recorded and investigated, root causes were determined and CAPAs were implemented where necessary. Checks on yields and reconciliation of quantities were carried out. Access to production premises was restricted to authorized personnel. Written procedures were available for cleaning of production equipment, containing essential details as observed on the example of the equipment train at the last refining stage in Y58 for WHO products. Procedures were product specific, relevant instructions were included in manufacturing process descriptions (MDP) with production cleaning records. Procedures were also available for cleaning the connecting pipeline between buildings Y21 and Y22 in Capreomycin production. General procedure governed production equipment cleaning and management, attention was paid to pipelines for product transfer, dismantling of difficult to clean areas in product change-over and annual dismantling of product-dedicated equipment. Equipment logbooks were maintained, as observed on the example of equipment in Y58 clean area. 3. Facilities and equipment system Production premises used for APIs under the WHO PQ programme were located, designed, constructed, adapted and maintained to suit the operations to be carried out. Yantou campus had a number of separate buildings and workshops. Separate AHUs were installed at each production building to supply air to “clean areas”. Production equipment was identified by numbers; main equipment had double numbering: one for building management purposes, the other used in actual processes and respective documents. Production was carried out in glass-lined or SS (304) reactors. SOP “Leak detection operation procedure for gloves of isolator” (glove box used for charging starting materials) and “Maintenance procedure for glass-lined reactor” were briefly discussed. APIs under the WHO PQ programme were manufactured at the following buildings and workshops: (the term “workshop” was used from organizational aspect, a workshop could involve several buildings / parts of buildings): Cycloserine

Building Workshop Y58 208

http://www.who.int/



Moxifloxacin Hydrochloride


Linezolid


Y66 JT

Capreomycin sulfate

Building Workshop Y22 (North wing) 108

Y31 105

Capreomycin sulfate production premises The Company was planning to move the upstream process (fermentation) to building Y21, Capreomycin will be continued to be produced using dedicated equipment. Y21 was inspected. The following activities will be carried out in Y21: • Media preparation • Fermentation, upper parts of dedicated fermenters • Strain inoculation. Capreomycin strains were inoculated in a dedicated room in grade A LAF,

surrounded by grade C environment. At the time of the inspection production of Capreomycin Sulphate was not carried out. Process validation was planned for 4th quarter 2019. From Y21 Capreomycin Sulphate will be transferred to Y22 via a dedicated pipeline for downstream processing including extraction. Y22 was inspected. New equipment were installed in Y22: • High pressure plate-and-frame filter • Nanofilter • Ultrafilter Y22 clean area (process after ultrafiltration) was stated to be unchanged. SOP “Maintenance procedure for fermenter” and fermenters No XX and YY maintenance logbooks were briefly discussed and checked. Fermenters were made from SS 304. Daily, monthly, quarterly and yearly maintenance was described. Maintenance was carried out using check-lists.

http://www.who.int/



Cycloserine and Moxifloxacin Hydrochloride production premises Inspectors inspected facilities in building Y58 – chemical synthesis and clean rooms. Production activity at the time of the inspection was preparation of crude API. No activities performed in Y58 clean rooms. Centrifuge filter bags and flexible transfer hoses were stated to be product dedicated. Air to clean rooms was supplied by one AHU, final HEPA filters were installed in production rooms. Pressure differentials were monitored and recorded every 4 hours. Primary and secondary filters were changed according to set-up pressure drop limits and discharged. Replacement of filters was recorded. AHU spare filters were stored at Waisha campus, in the engineering warehouse. The Company stated that AHUs of similar design were provided for other clean rooms – these were not visited during the inspection. Linezolid production premises Inspectors inspected building Y66 – condensation area (for various APIs) and facilities in building Y55 (south) – chemical synthesis. No production activities were going on. Clean rooms were in building Y55 (north). The crude API (solid) was transported from Y55(S) to Y55(N) in polybags. Purified water system (PW) There were 7 PW generation systems at the Yantou campus. PW generation plant in Y61 was visited. This system had 8 distribution loops and supplied PW to building Y58 and Y55. Engineering diagrams were available, and version controlled. PW water was generated by two RO units. PW was in continuous recirculation below 25 ℃. Velocity and T were monitored on return loop and recorded every 4 hours. Integrity tests on air filters installed at PW tanks were carried out every 6 months. Sand and carbon filters were automatically back-flushed daily. Sanitisation procedures were in place for the RO unit and PW distribution system; essential instructions were provided, details on valves to be closed/opened were not provided in the SOPs. The pipeline from RO unit to PW collection tank was discussed. Separate PW system was installed in building Y22 to supply PW for Capreomycin sulfate production workshop; deionized water produced at Y61 was delivered by pipeline to Y22 where PW was generated by EDI and RO; RO was further distilled to obtain WFI.

http://www.who.int/



Laboratory premises for QC analysis of APIs and FPPs were located at Waisha campus and were separated from production areas: • Sample receipt, retention sample storage and stability chambers. Retention samples were stored in

mobile racks in good order • QA office • APIs QC laboratory • APIs and FPPS QC laboratory for cytotoxic/genotoxic and oncological products • FPPs QC laboratory • Method development laboratory • Health care products QC laboratory • Microbiological laboratories, separated for APIs and FPPs Laboratories were well equipped with instruments and software tools for managing analyses. HPLCs, GCs, IRs and UV were networked. Sufficient space was given to avoid mix-ups and cross-contamination. Adequate storage space was provided for samples, reference standards, solvents, reagents and records. 4. Laboratory control system At the Waisha campus, separate QC laboratories (chemical/instrumental and microbiological) were provided for APIs and FPPs. At the Yantou campus, in-process tests were carried out in 7 IPC laboratories. IPC located at building Y55 (north) was visited during the inspection. This IPC performed tests for production carried out in buildings Y55, 58, 53 and 52, workshops 208 and 209. All HPLCs and GCs were networked. Audit trails were enabled. The following documents were briefly discussed: • “Injection procedure for determination by GC/HPLC method” • “Integration and processing method for chromatograms” • “Lab unexpected event handling procedure”. SOP was applicable to abnormal lab events, for example

sample spillage, system suitability failure etc. Unexpected events were trended biannually and annually. Trends for 2018 were presented to inspectors.

• “Investigation procedure for OOS/OOT test results of chemical results”. OOS/OOT results were trended biannually and annually. Trends related to APIs for 2018 were presented and reviewed. The SOP was applicable to raw materials, packaging materials, intermediates and FPPs and stability studies. OOS-API-XX was briefly discussed

• “Management procedure for verification and review in laboratory” and annex XX • “Authorized second person verifier list in QC laboratory”. According to the company procedure, batch to

batch analytical raw data, including audit trails, was reviewed by another analyst. QC supervisor or assigned analyst once per month reviewed one analytical data from one instrument covering all types of instrument. Audit trails for WHO products in MS Excel were requested from the Company, random cross-checks were carried out and no discrepancies noted.

• “Investigation procedure for OOS/OOT for microbiology analysis”. • “Materials sampling standard operation procedure”, explained APIs, manufactured on site, sampling

procedure

http://www.who.int/



Cycloserine working reference standards were dispensed in amber vials in a balance room and stored in freezer at -15 – 25 ℃. Expiry date was assigned as the respective API re-test date (3 years), re-test/re-qualification was carried out annually. 5. Materials system The following warehouses were inspected: • Solid starting materials • Solid starting materials and packaging materials • Solvents storage in drums • Finished API warehouse • “Old solvents tank farm” • “New solvents tank farm” Materials in the mentioned warehouses were stored under appropriate conditions, in an orderly fashion to permit batch segregation and stock rotation. Material management/reconciliation was handled manually on stock cards. Sampling of starting materials and solvents in drums was carried out in dedicated sampling rooms provided with local exhaust. Separate entrances were provided for materials and personnel. Sampling of primary packaging materials was carried out in the warehouse within a movable LAF sampling booth. Nets in yellow colour were used to separate materials under quarantine from released materials. Locked, separate caged areas were provided for rejected materials. Temperature mapping of cold rooms and other warehouses was performed annually (one year during summer, subsequent year during winter). Alarm system was challenged annually. The following SOPs were briefly discussed: • “Returned product management procedure”. The SOP was applicable to all types of products

manufactured on site • “Recovered solvents management procedure”. The Company stated that recovered solvents were not

used for WHO products. • “Reprocessing and reworking management procedure. Re-processing and re-working of APIs required

QA involvement. “Evaluation and tracking record” was drawn for each case. • “Operation procedure of materials storage tank into and out”. Solvents tanks were cleaned once in a year • “Materials management procedure in workshops” Waste was stated to be collected in building 7; inspectors visited the building; the quantity of containers was not significant at the time of the visit.

http://www.who.int/



6. Packaging and labelling system Packaging and labelling was not carried out during inspection. 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, a decision on the compliance Zhejiang Hisun Pharmaceutical Co., Ltd Yantou Campus located at 56 Binhai Road, Jiaojiang District, Taizhou City, Zhejiang Province, P.R.C. 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 GMP or 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. 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

http://www.who.int/

http://apps.who.int/medicinedocs/documents/s20119en/s20119en.pdf

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



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 HVAC Guidelines or 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. 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

http://www.who.int/



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

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






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/

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

http://www.who.int/






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

http://www.who.int/



http://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex05.pdf

