Quality and ACTs. Quality and ACTs: A WHO Prequalification Perspective. Dr AJ van Zyl. Head of Inspections. World Health Organization

Transcription

1 Quality and ACTs Quality and ACTs: A WHO Prequalification Perspective Dr AJ van Zyl Head of Inspections World Health Organization The Leela Kempinsky Hotel Mumbai, India 29 September

2 In this presentation Quality issues Prequalification Assessments Inspections APIs, FPPs and CROs Trends 2002 to 2009 Outcomes 2

3 Major infectious diseases Deaths caused by major infectious diseases diarrhoea malaria hepatitis leptospirosis Union Ministry of Health

4 Major infectious diseases Deaths caused by major infectious diseases 4000 diarrhoea malaria 2500 hepatitis typhoid leptospirosis Union Ministry of Health

5 Examples of Counterfeit 5

6 2003: Africa. Seven country study 30 50% failed * Samples were judged to have failed if content was <93% or >107%, and dissolution <80% in 45 minutes. Content 6 Dissolution Sulphadoxine/pyrimethamine % failure* Ga bo n Gh an a Ke ny a Mo Ma za mb li iqu Su e Zim da n ba bw e Ga b on Gh an Ke a ny a Mo za Ma mb l i iqu e Su Zim da ba n bw e Chloroquine tablets % failure* * Samples were judged to have failed if content was <90% or >110%, and dissolution <65% in 30 minutes. Content Dissolution

7 Quality issues. Quality concerns Anti malaria products 96 samples (chloroquine and antibacterials) collected in Nigeria and Thailand >36% failed pharmacopoeia standards (Shakoor O et al, 1997) Fake artesunate: 38% ('01); 53% ('03) in Myanmar 89% Laos Wellcome trust: 22 of 27 locations (in 15 only fakes) (Lancaster IM 2006) Fake "Coartem" in Ghana Lacking API Products tested by the FDB of Ghana overwhelming presence of poor quality medicines; seized from pharmacies and wholesalers (J Martey F Person: Augsust 2009) 7

8 WHO GMP and Inspection of API manufacturers Author Country (Product)s Test / outcome Lon et al Cambodia Mefloquine DHA Artemether unregistered % 79 fail TLC and % 27 DT Dondorp et al Myanmar, Lao, Vietnam, Cambodia and Thailand Artesunate Mefloquine not Artesunate 53% contained less 9% than 10% API Newton et al Cambodia, Myanmar, Lao, Thailand, Vietnam Artesunate not Artesunate 38% no API 29% Rozendaal et al Cambodia Mefloquine Artesunate vendors sold 71% fake Artesunate 8

9 Ensuring quality How to ensure quality of anti malarial products? Prequalification evaluation and inspection Specifications and monographs Starting materials Key intermediates Finished products GMP Sampling and testing 9

10 Ensuring quality Prequalification Vision Mission Through evaluation and inspections Building national capacity for sustainable manufacturing and monitoring of quality medicines. 10

11 ?Q10. When and where in the prequalification process will inspections be done The diagram below presents a simplified presentation of the steps in the prequalification process and where inspections will take place. Applicant Assessment team WHO PQ Inspection team WHO PQ If compliance )dossier and inspections( = prequalification (listing of product) Prepare a product dossier in accordance with the guideline Consult the EOI's to see which products are in the prequalification process Submit product dossier and product sample Submit a Site Master File :Respond to the questions Submit additional data Screen dossier. If accepted, assessment starts Request additional data Inspection of API site )GMP (ICH Q7 Inspection of FPP site )WHO (GMP Assessment of additional data Manufacturers and CRO to take corrective and preventive actions ()CAPA's 11 Maintenance ()variations Inspection of clinical site ()GCP/GLP Request corrective actions and data Review and.assess CAPA Possible follow up inspection WHOPAR WHOPIR Assessment Routine inspections, complaint investigation etc Non compliance: Suspension Non compliance: Notice of concern Sampling and testing of products and verification of supply of prequalified products

12 Assessment procedure Product dossiers received HIV TB Malaria R Health Malaria 2008

13 Under evaluation in WHO Prequalification Programme On 31 January 2009 : 68 products for treatment of HIV/AIDS and related diseases 41 products for treatment of tuberculosis 17 products for treatment of malaria 11 reproductive health products Total

14 ICH Q7 Ensuring the quality of API: Specifications / monographs and GMP (ICH Q7) From which step? Answer is in the guideline text and table API extracted from plant sources the introduction of the API starting material into the process Application of GMP should increase from the step identified to final steps 14

15 Increasing GMP requirements WHO GMP and Inspection of API manufacturers 15

16 Prequalification Programme for Medicines API Section S.2. Manufacture,.3.2Description of manufacturing process and process controls β artemether Artemisinin DHA α artesunate configuration at 10 should be inversed 16

17 Prequalification Programme for Medicines API Section Control of Materials/ Starting material of the API Definition of API starting material as per ICH Q7 may be different to the concept of "Starting material for synthesis" used in assessment where it defines the starting point of the synthetic process of an API to be submitted in the dossier Starting material for synthesis in the dossier may precede the ICH Q7 "API starting material" by several steps in the synthetic process In general, the starting material for synthesis should be a synthetic precursor one or more synthetic steps prior to the final API intermediate Pharmaceutical sciences Questions and answers Therapeutic Products Directorate, Health Canada 17

18 Ensuring quality Questions that arise: Is there a need to control starting material? What should the specification be? Who should define the quality? Manufacturer? Manufacturer of FPP? External party e.g. regulatory / pharmacopoeia? An example Artemisinin. Then what about others? Extractors? Link to PQd product? In what way (SRA)? 18

19 Ensuring quality MONOGRAPHS FOR ARTEMISININ DERIVATIVES: Artemether, Artemisinin, Artemotil, Artenimol and Artesunate and their associated dosage forms) first published in 2003 (Vol 5. 3rd Edition, Pharm Int. Certain aspects of these monographs were revised before inclusion in the 4th Ed Focus then on the development of new monographs for the fixed dose combination preparations in line with WHO policy. Lumefantrine and, Artemether and lumefantrine tablets adopted October 2007 Artemether and lumefantrine oral suspension October

20 Ensuring quality MONOGRAPHS FOR ARTEMISININ DERIVATIVES: Review and revisions Large amount of user feedback and comment has been received Further revision of the published monographs was needed, in particular for: chromatographic tests for related substances and Assay Expert Committee New drafts available 20

21 WHO GMP and Inspection of API manufacturers To get started (API manufacturer): Listed as a manufacturer of API in a product dossier Assessment in progress. Risk assessment Submit a SMF Announce inspection Provide tentative inspection plan Inspect, prepare inspection report corrective action 21

22 WHO GMP and Inspection of API manufacturers Parameters considered during risk assessment may include: 22 Polymorphism Solubility in water Route of Synthesis Solvents used Impurities Sterile API Fermentation Toxicity Activity/potency Particle size Other properties to be considered Site compliance information (WHO/EDQM/Other)

23 WHO GMP and Inspection of API manufacturers WHO GMP for APIs accept ICH Q7 principle text II. QUALITY MANAGEMENT III. PERSONNEL IV. BUILDINGS AND FACILITIES V. PROCESS EQUIPMENT VI. DOCUMENTATION AND RECORDS 23 VII. MATERIALS MANAGEMENT VIII. PRODUCTION AND IN PROCESS CONTROLS IX. PACKAGING AND IDENTIFICATION LABELING OF APIs AND INTERMEDIATES X. STORAGE AND DISTRIBUTION XI. LABORATORY CONTROLS XII. VALIDATION

24 WHO GMP and Inspection of API manufacturers Product quality review Deviations change control OOS in process controls Vendor qualification Contamination, cross contamination and mix ups Validation and qualification Process validation Equipment, HVAC, water 24

25 WHO GMP and Inspection of API manufacturers Number of inspections per year Inspections

26 WHO GMP and Inspection of API manufacturers 2002 to (India )33 25 (China )10 India China South Korea Vietnam Countries inspected (S. Korea )1 (Vietnam )1

27 WHO GMP and Inspection of API manufacturers China: 3 India: (10) 2005 (9) (3) 2002 (1) Year Observations Inspections Observations Inspections Average observations per inspection

28 WHO GMP and Inspection of API manufacturers Manufacturer Disease Observations Major Country A HIV 4 0 India M HIV 10 3 India S HIV 9 0 Korea S TB 23 3 India S Mal/HIV 10 0 China 28

29 WHO GMP and Inspection of API manufacturers Examples of observations of non compliance in 2007 Batch records: a complete centrifugation operation recorded process step not yet reached starting time operation, the end time and all required details BMR not completed although the step was already in progress No start time of the cooling process no records of the temperature for every 30 minute as required in the BMR equipment logbook no entry The SOP cleaning of. was incomplete No evidence of: dedicated bags labeling of storage drums Risk of cross contamination Inappropriate release of a batch lack of defined responsibilities procedure not followed QA not involved 29

30 WHO GMP and Inspection of API manufacturers 30 Manufacturer Disease Observations Major Country B TB 43 4 India C HIV/ Mal 11 India G Mal 22 China G Mal 27 China I Mal 33 2 India L TB 20 6 India L TB Investigation India M TB 19 India M HIV Investigation ()38 M HIV 28 India S HIV Investigation China Z Mal 11 China 10 India

31 WHO GMP and Inspection of API manufacturers 2008 Number of inspections 2008 Disease Total number of observations Major Country 4 TB India 3 HIV *77 10 India 2 Mal *44 2 India 1 HIV Investigation China 3 Mal 60 China HIV and Mal (11) * 31 India. 9 inspections, 22 Major. China. 4 inspections, 0 Major

32 WHO GMP and Inspection of API manufacturers Examples observations in 2008 Cleaning Lack of validation Choice of solvent used (10x less soluble). Insufficient cleaning: Residues after campaign cleaning Stagnant colored liquid 32

33 WHO GMP and Inspection of API manufacturers Materials management was found deficient for the following : SOP for vendor qualification not implemented or followed. samples from consecutive batches were not analysed, trial batches were not done; questionnaire was not sent, received and assessed no audit was performed before the supplier was approved. The supplier was audited, the outcome was "not satisfactory" no corrective action was proposed or implemented by the supplier but it was "approved" Products were purchased from suppliers not included in the approved vendor list; and distributors were on the list of approved suppliers, without identification of the specific approved and qualified manufacturers 33

34 34

35 WHO GMP and Inspection of API manufacturers Inappropriate material handling e.g.: The warehouse temperature was monitored but not controlled. It reached 34 C even as some materials were required to be stored in a cool and dry place. Several drums were marked as sampled and approved, although the drums were still sealed. Several drums (6) of the same approved batch of ABC were noted with a broken seal no "sampled" label. Labels affixed on drums were dirty, torn, and unreadable. 35

36 WHO GMP and Inspection of API manufacturers The SOP on change control: Was not implemented Didn't include the checks to be performed for a major change whenever appropriate e.g.: the impact on stability, The need for validation or qualification, impurity profile, regulatory requirements, Was introduced without updating the corresponding forms. The specification of the key raw material XYZ was revised without following the SOP The analytical method implemented was changed and not validated. Several changes and additions to the master batch manufacturing document were not covered by appropriate change control. 36

37 WHO GMP and Inspection of API manufacturers 2009 Manufacturer 2009 Disease Observations Major Country B TB 24 7 India M HIV 23 3 India S TB 15 6 Vietnam K Mal 23 1 China S Mal / HIV 23 1 China 37

38 WHO GMP and Inspection of API manufacturers Examples of major non compliances (2009) Quality management Deviations not reported PQR incomplete and not interpreted Buildings and facilities Water systems; HVAC poor design and controls Equipment cleaning show product residue after cleaning Documentation Recording of operations Batch record not reflecting all steps and full of errors Materials management Sampling (number of samples, release date before manufacturing date) 80 containers of key starting material sampled and release but 33 found to be different material during the inspection Storage and use FIFO 38

39 WHO GMP and Inspection of API manufacturers Inspections (disease areas) and number of observations TB HIV/AIDS MAL Ave (total) obs per site Ave (Major)

40 WHO GMP and Inspection of API manufacturers Inspections 150 Total number observations

41 WHO GMP and Inspection of API manufacturers Number of sites 20 Ave number observations

42 WHO GMP and Inspection of API manufacturers 10 9 Materials Management SOPs Cleaning 5 Batch records 4 3 Labeling 2 Cross contamination Major deficiencies

43 Inspections of FPP Manufacturers and Contract Research Organizations (CROs) What about FPP manufacturers? and CROs Norms and standards? Already inspected by Other DRAs 43

44 WHO PICS Qualification and validation.4 India China Validation andprocess validation20 In accordance with GMP, each4.1 pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are.controlled The key elements of a4.2 qualification and validation programme of a company should be clearly defined and documented in a.validation master plan defined in Annex 15 not included) (here Qualification and validation4.3 should establish and provide :documentary evidence that defined in Annex 15 not included) (here the premises, supporting utilities, a(( equipment and processes have been designed in accordance with the requirements for GMP )design ;(qualification or DQ defined in Annex 15 not included) (here 44 Validation of manufacturing57 processes included

45 Inspections of FPP Manufacturers and Contract Research Organizations (CROs) FPP site inspections in: India China Morocco USA Switzerland 45

46 Inspections of FPP Manufacturers and Contract Research Organizations (CROs) Manufacturer 2009 Country N China A India Manufacturer 2008 Country S Morocco N USA G China N China G China 46 and Inspections Inspections China 4 India 1 Morocco 1 USA 1

47 Inspections of FPP Manufacturers and Contract Research Organizations (CROs) Findings: Sampling area design Sampling plans used (identity test of API) No source data for qualification results (HVAC) Hormones produced in the same facility Process validation data unreliable no electronic data maintained Packaging material control FIFO, errors (printing) 47

48 Example reintegration CROs 48

49 Example discrepancies 49

50 Inspection outcomes on the web 50

51 Transparency: WHO Public Reports (WHOPIRs and WHOPARs) Name of manufacturer Aurobindo Pharma Limited, Unit VIII Address Survey N 13 Gaddapotharam (Village), IDA Kazipally, Jinnaram (Mandal), Medak District, Andhra Pradesh India Postal address Same as above Telephone number Fax number Summary of activities of manufacturer )e.g..(manufacturing, packing Indicate dosage forms and type of products (e.g. tablets; cephalosporin containing products) Manufacturing and control of anti retroviral active ingredients, including but not restricted to the manufacturing process of..zidovudine and Efavirenz :Date of inspection March & 14 :Project Prequalification Programme.Part 2: Summary and conclusion of the inspection Summary: 51

52 52

53 Sampling and testing projects in 2008 Quality survey of antimalarials (ACTs and sulfadoxine pyrimethamine) Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Madagascar, Nigeria, Senegal, Tanzania, Uganda 936 samples collected and screened by Minilab, 299 selected for full testing in laboratory (testing ongoing) Ongoing monitoring including inspections 2 samples of Artemether / Lumefantrene 40/240 from 2 batches collected in Cameroon 1 of them noncompliant appearance powder on tablets 7 samples of Artemether/Lumefantrene 20/120 from 4 batches collected in Cameroon 3 of them noncompliant appearance stains and powder on tablets, non uniform colour. Six selected for laboratory testing 53

54 Thank you for your attention 54