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									Essential Medicines Policies,
       WHO, Geneva.
  Technical Briefing Seminar: 2011
  Prequalification Programme: Priority Essential Medicines


             WHO-PQ INSPECTIONS


                   Presented by
                 Deus K Mubangizi
                  Technical Officer
                mubangizid@who.int
                  WHO-PQP Inspections
    In this presentation:
    • Procedures and standards used for WHO-PQP
       inspections

    • WHO-PQ Inspections: avenues for capacity building and
      collaboration

    • Observed deficiencies during Inspection of:
       – FPP and API manufacturers + QC Labs
       – Contract Research Organizations (CROs)

    • Summary and conclusion

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    WHO Prequalification: Inspection
             activities
                                                               *Stringent Regulatory
                                Prequalification                     Authority



                                   APIs,
               WHO route          FPPs,               SRA* route
                                 BE/CROs,
                                  QCLs



     Dossier Q/E           GMP/GCP           Innovators            Generics



                                                     Simplified procedure
                   PQ


                                                                PQ


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       Prequalification Programme: Use of
      Inspection reports from other NMRAs
 Inspectorates whose reports are recognized:
   √ PICS member inspectorates
   √ EU (EDQM + EMA)
   √ USFDA – new member of PICS
 What GMP evidence to submit:
   – SMF – Up-to-date
   – Inspection report - conducted NMT 2 years
       • + CAPAs to deficiencies + final conclusion
   – Product Quality Review – not more than 1 year old
 Review of the report:
    scope covered the specific API
    Is comprehensive and supports the final outcome.
 PQP reserves the right to inspect the API manufacturer – as long as
  product is active in WHO-PQP.
 on-going GMP compliance will be confirmed by WHO
    √ Desk review may only be use once in every 5 years.


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       Prequalification: Inspection Processes
     By a team of qualified and experienced inspectors
       WHO representative (qualified inspector)
       Inspector from well-established inspectorate (Pharmaceutical
        Inspection Cooperation Scheme countries – PIC/S)
       National inspector/s invited to be part and observe the
        inspection
       Observer from recipient/developing countries (nominated by
         DRA of the country)
     Scope:
        Compliance with guidelines:
          GMP for API and FPP sites,
          GCP for CROs,
          GLP for FPP/API factory QCL, CRO-BAL, NQCL, IQCL
       Data verification – data manipulation, falsification,
         (validation, stability, clinical, bioanalytical)

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              Risk-based approach in:
    definition and classification of deficiencies
• Deficiencies are descriptions of non-compliance
  with GMP requirements.
• A distinction is made between deficiencies as a
  result of: -
     – a defective system or,
     – failure to comply with the system.
• Deficiencies may be classified as:
     – Critical Observation – potential risk harm to the user
     – Major Observation – major deviation from GMP/GCP
     – Minor or Other Observation – departure from good
       practice


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                Risk-based approach in:
             Conclusion following an inspection
• When there are "other" observations only:
     – considered to be operating at an acceptable level of compliance with WHO
       GMP.
     – The manufacturer is expected to provide CAPAs.
     – CAPAs are evaluation and followed up during the next routine inspection.
• When the are "other" and a few "major" observations:
     – compliance with WHO GMP/ICHQ7 is made after the CAPAs have been
       assessed.
     – CAPAs for majors to include documented evidence of completion.
     – CAPAs paper evaluated ± an on-site follow up inspection.
• When there are "critical" or several "major" observations:
     – considered to be operating at an unacceptable level of compliance with
       WHO GMP/ICHQ7 guidelines.
     – Another inspection will be required


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    Information put in public domain - available for
         use by NMRAs: WHOPIRs and NOCs

    • These are published in response to the WHA Resolution WHA57.14
      of 22 May 2004, which requested WHO, among other actions:
       – "3. (4) to ensure that the prequalification review process and the results
         of inspection and assessment reports of the listed products, aside from
         proprietary and confidential information, are made publicly available;"
    • A WHO Public Inspection Report (WHOPIR) reflects a positive
      outcome after an inspection
    • A Notice of Concern (NOC) is a letter reflecting areas of concern
      where the non-compliances require urgent attention and corrective
      action by the manufacturer or research organization.




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  Prequalification Programme: International norms,
standards and guidelines used in inspection activities
             to ensure wide applicability




                                   USP
                                    BP
                                 Ph. Eur.
                                 Ph. Int.
                             Other guidelines
                              e.g. ICH, ISO
     http://apps.who.int/prequal/assessment_inspect/info_inspection.htm#2

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          WHO-PQ offers new avenues for
            collaboration in inspection
      WHO-PQ Collaborative Procedure in Inspections
          –    nominated inspectors from NMRAs of selected member states
               are invited to participate in WHO-PQ organized inspections and
               in turn, the NMRAs is given appropriate access to outcomes of
               these inspections.
                • Capacity building of NMRAs inspectors.
                • Facilitating use of WHO-PQ inspection results in national regulatory
                     environment for information and decision making.
                • Facilitation of harmonization through joint inspections and sharing of
                     outcomes.
                • Share the workload and promote avoiding duplicative inspections.
     http://apps.who.int/prequal/info_general/documents/inspection/NMRAs/GUIDANCE_WHO-
            PQM_NMRAs_CollaborativeProcedure.pdf




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         Inspection observers have been from:
            ⃟ AFRO Region - External Observers
            ⃟ WPRO Region – Host country Observers
                               Source of Obsevers by WHO Regions: January 2008 - April 2010




              40


                                                                                                        0
              35




              30




              25




              20
                                                                                                       36
                          18

              15




              10



                                              10
               5           8

                                                                              0
                                                                              2
                                               0              0                               0
               0
                     AFRO               AMRO            EMRO            EURO            SEARO     WPRO
From other country    18                  10              0               0               0        0
From host Country     8                   0               0               2               0        36
               Medicines Prequalification Process

                               Expression
                                of Interest

                               Product dossier
     Assessment                     SMF                   Inspections

 Additional information                                        Corrective
        and data                                                actions


        Compliance                                         Compliance
                               Prequalification
                 Handling of                     Dossier maintenance
                 complaints       Monitoring         (variations)
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                      Zidolam-N
      Zidovudine 300mg, Lamivudine 150mg
          and Nevirapine 200mg tablets
     • Prequalified on 23
       May 2006 with
       reference number
       HA275

     • Manufactured by
       Hetero at its Unit III,
       Andhra Pradesh, India

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       Source of Information: MSF
          12th September 2011

     PHOTO by MSF    Alert from CHMP to MSF




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                    Immediate Investigation
                      13th September 2011
     • Alerted Kenya Pharmacy
       and Poisons Board
        – Had not been notified by
          CHMP (Kenya) or MSF
          (Kenya)
     • Special Inspection of
       Hetero Unit 3:
        –   Retention samples
        –   Manufacturing records
        –   Analysis records
        –   Distribution records
        –   Observed re-analysis of
            retention samples


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                 Findings (1)
     Genuine Zidolam-N   Falsified Zidolam-N
      Batch No. E10076    Batch No. E10076




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                  Findings (2)
           ZIDOLAM-N Batch No. E100766
           GENUINE                           FALSEFIED
 Font style of zero the batch    Font style of zero the batch
  number; is printed as 0.         number; is printed as Ø.
 The spacing between licence  The spacing between licence
  number and the batch          number and the batch number
  number on the bottle label is on the bottle label varies from
  constant in all samples.      one bottle to another.
 The samples of the genuine      Falsified samples bear the
  Hetero batch do not carry a      COIP logo. (The logo is that of
  COIP logo.                       a Canadian nongovernmental
                                   organization.)

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                        Findings (3)
     • Affected batches;
       – E100766, E110467, A9351, A9357, A9366

          • the genuine batches E100766 and E110467 were never
            supplied to the Kenyan market

          • the quantities of Zidolam-N with a reference to “batch number
            A9351, A9357 or A9366”, found in Kenya, exceed the quantities
            manufactured, packed and dispatched by Hetero as batches
            A9351, A9357 and A9366 to Kenya.


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                       Findings (4)
• Results of analysis by Kenya’s NQCL and Hetero:
     – Intact samples comply with the manufacturers’ and with
       international pharmacopoeia specifications.
     – Open samples discoloured with high friability, low assay,
       fungal growth: Possible poor handling by patient.


• Nature of falsification:
     – Relabeling and repackaging of donated batches (whose
       expiry dates are unknown) in order to divert them to the
       commercial market.
     – Extent and conditions under which the falsification (re-
       labelling) was undertaken is unknown and thus the quality
       of the products cannot be fully ascertained
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                    Actions taken
     • Collaborated with Kenya authorities in conducting
       investigation and taking necessary actions.

     • Special inspection of the manufacturing site.
     • Analysis of complaint and retention samples.

     • KPPB ordered a recall of the batches.

     • Issued public notices which were updated as
       more information became available – careful not
       to cause anxiety and fear.
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             Lessons for the future
     • Inadequate market controls and procurement
       procedures:
       – Diversion of donations, relabeling and repackaging.
       – Purchase from middlemen at very low prices without
         question.
       – NMRA not informed promptly.
     • PQ prompt reaction and coordination facilitated
       quick investigation.
     • Collaboration between PQ, MSF, KPPB, KNQCL
       and Hetero was crucial for the success of
       investigations.

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           Recommendation
• Supply chain should be fully known and actions
  should be taken to shorten it wherever possible




• A supply chain is no stronger than its weakest
  link
                23
     Inspection of FPP manufacturers




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      Deficiencies observed during PQ Inspections
                      PREMISES
 • Poor design and construction of
   premises:




                                                   Cross contamination
     – Inadequate segregation.
     – Illogical process flow.




                                                      Contamination
     – Inadequate provision for Utilities: HVAC,
       water, compressed gases




                                                         Mix-ups
 • Poor design and management of
   the HVAC system:
     – Multipurpose plant used re-circulated air
       but had no HEPA filters.
     – Adequate pressure differentials: reversal
       of air flow.
     – No sequence of switching on and off of
       AHUs of adjacent areas.


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         Deficiencies observed during PQ Inspections
                         MATERIALS
     •   Inadequate goods and materials
         management
         –   Starting materials: sourcing and
             sampling – ID per container.
         –   Packaging materials: inadequate
             sampling – ISO2859 or BS6001.
         –   Intermediate and bulk products –
             holding time not set, or justified, or
             respected.
         –   Finished products: Release
             procedures – no adequate review
             by QA or QP.
         –   Rejected materials and products:
             not adequate segregation or
             disposal.
         –   Reagents and culture media: no
             GPT, positive and negative control
         –   Reference Standards: inadequate
             standardisation, storage and use.




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     Deficiencies observed during PQ Inspections
                   QC Laboratories
                  IR: What not to do!




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        Deficiencies observed during PQ Inspections
             QUALITY CONTROL: Microbiology
     • Media Preparation:
        – No positive and negative control
        – No separate room for media preparation

     • Equipment:
        – No separate autoclave for sterilization of media and
          decontamination of used media.

     • Environmental Monitoring:
        – Inadequate exposure of plate method, adequate air sampling or
          swabbing.

     • Validation of Sanitising Agents: no challenge tests using
       the standard stock cultures (103-104/0.1ml) in order to
       ascertain the minimum dilutions to effect a kill.

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        Deficiencies observed during PQ Inspections
         FPP manufacturers: – sterile products
     Poor aseptic techniques:             Environmental monitoring:
     • Extensive movement of              • The viable particle continuous
       operators in Grade A close to        monitoring for Grade A zone
       the open vials.                      does not cover the whole time
                                            period of setting up of the
                                            equipment and the vial filling-
     • Vials that were not stoppered by     capping process.
       the machine taken from the
       conveyor belt into class B area
                                          • Personnel garments and gloves
       and manually placed back into
                                            were not monitored after
       class A to be manually
                                            manufacturing operations in
       stoppered.                           grade A/B areas

     • Inadequate Media Fill Tests


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     Inspection of API manufacturers




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     Out of 126 API sites participating in PQ activities, 49 were
     accepted based on approval by PICS inspectorates and/or
              ICH countries while 31 were inspected.
           INSPECTION STATUS OF API SITES USED IN PRODUCTS UNDER WHO
                               PREQUALIFICATION

                                  140

                                  120

                                  100
                    No of sites




                                   80

                                   60

                                   40

                                   20

                                    0
                                                                                                      HA, MA,
                                        HA   TB   MA   RH   IN       D     HA, IN   HA, TB   HA, MA             Total
                                                                                                        TB
         Not yet Inspected              20   15   8    3    0         0        0      0        0        0        46
         Innovators/PICS                33   3    8    5    0         0        0      0        0        0        49
         Sites inspected - NC           1    4    1    0    0         0        0      0        0        0        6
         Sites inspected - C            10   5    4    0    0         0        2      2        1        1        25

                                                                 Type of API




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                            The sites inspected were the ones producing APIs used in
                            most FPPs (average each API site representing 21 FPPs).
                             Thus maximizing use of available inspection resources.
                                                          NUMBER OF FPPs USING APIs FROM EACH SITE

                               90


                               80


                               70
No of FPPs per API Site




                               60


                               50


                               40


                               30


                               20


                               10


                                0
                                    Sites inspected - C    Sites inspected - NC          Innovators/PICS           Not yet Inspected   All sites
                          Average           21                     15                           3                         2               7
                          Minimum           1                       2                           1                         1               1
                          Maximum           80                     48                          12                         10              80
                                                                                  Inspection Status of API Sites




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        Deficiencies observed during PQ Inspections
                     API manufacturers

                                   10
     • The most frequently found   9                         Cross
                                                             contamination
       deficiencies were:          8
                                                             Batch records
                                   7
        – Material management
                                   6                         SOPs
        – SOPs                     5
        – Cleaning                 4                         Material
                                                             Management
     • Others included:            3
                                                             Cleaning
                                   2
        – Batch records
                                   1                         Labeling
        – Labelling                0
        – Cross contamination           Major deficiencies




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     Inspections of Contract Research
          Organizations (CROs)




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     http://apps.who.int/prequal/




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           Prequalification Programme: International norms,
         standards and guidelines used in inspection activities
                      to ensure wide applicability
     •     HANDBOOK FOR GOOD CLINICAL RESEARCH PRACTICE (GCP)
           Guidance for implementation
           http://whqlibdoc.who.int/publications/2005/924159392X_eng.pdf

     •     Guidelines for good clinical practice (GCP) for trials on pharmaceutical
           products. World Health Organization, 1995 (WHO Technical Report
           Series, No. 850), Annex 3.
           http://apps.who.int/prequal/info_general/documents/TRS850/WHO_TRS_850-
                  Annex3.pdf

     •     Additional guidance for organizations performing in vivo bioequivalence
           studies. WHO Technical Report Series, No. 937, 2006, Annex 9
           http://apps.who.int/prequal/info_general/documents/TRS937/WHO_TRS_937__an
                  nex9_eng.pdf

     •     Guidelines for the preparation of a contract research organization
           master file. World Health Organization, WHO Technical Report Series,
           No. 957, 2010 Annex 7, Page 271.
           http://www.who.int/medicines/publications/TRS957_2010.pdf
                                                                                         Other
                                                                                       guidelines
                                                                                        e.g. ICH

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     CRO/BE Inspections: Problems with integrity,
        archiving and retrieval of documents




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     CRO/BE Inspections: Inadequate data integrity
Source data either not available or authenticity
   questionable:
• Source data could not be located to verify entries in VRFs
      –   destroyed accidently by fire or rain
      –   Sponsor claims the data were kept by the CRO, and the CRO
          claims the data were kept by the sponsor

•     Two of the ECGs shown to the inspectors, bearing different
      subject numbers and initials, were found to be identical.

•     Other ECGs bearing different subject numbers and initials
      appear to have been recorded from a single subject. Out of
      95 ECGs copied by the inspectors, 43 appear to have
      been recorded from the same and single subject during
      a single session


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   The following images are lead III of the screening and follow-up ECGs of
 volunteers AND and KRK, respectively, as copied during the inspection. They
              show no difference in QRS complex morphology.

     • Lead III, screening ECG, subject AND


     • Lead III, follow-up ECG, subject AND


     • Lead III, screening ECG, subject KRK


     • Lead III, follow-up ECG, subject KRK
     •


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         CRO/BE Inspections: Data manipulation –
         inappropriate manual integration of peaks
• Manual reintegration of peak was
  done       inappropriately    and
  inconsistently    for   all peaks
  inclusive internal standard
     –   For some samples checked, especially QCs or
         standards close or outside the 15% of their
         nominal concentration, the baseline of the
         chromatograms were modified manually. This was
         not done appropriately and consistently for all
         peaks inclusive internal standard. For modified
         integration, initial integration was not available.
• No paper or electronic audit trail of
  manual integration available.
• Each analytical run did not include
  calibration and quality control
  samples.


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   CRO/BE Inspections: Data manipulation - Identical
 chromatograms had different peak areas but the same
                    area percent




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        Deficiencies observed during PQ Inspections
               QC Laboratories: Conclusions

     • Data manipulation and misrepresentation is not
       acceptable to the WHO and according to the law
       of most national regulatory authorities (could
       result in the publication of NOC or NOS on
       behalf of the WHO).
     • The honest way is always the "right way".
     • Good ethics are key to reliable data.
     • Always prioritize data integrity – not quick batch
       release at any cost.


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                       WHO-PQ Inspections
                     Summary and Conclusions
•    API, FPP and CRO/BE Inspections are an important part of
     the WHO-PQP evaluation and continuous monitoring process      ధన్యవాదాలు
•     International norms, standards and guidelines are used in
     inspection activities to ensure wide applicability
•    Collaborative and Risk management principles are applied
     to ensure efficient use of available resources
•    Information put in public domain - available for use by
     NMRAs: WHOPIRs and NOCs
•    Inspection results show that there are still a lot of poor
     manufacturing practices out there. Collaborative effort and
     skills are needed to ensure access to medicines of assured
     quality. Results show that WHO-PQP has made
     tremendous contribution in this respect.
•    The support of NRAs in providing co-inspectors and
     observers is appreciated. This is good for:
      –   Tapping into international skills
      –   Ensuring transparency
      –   Facilitating ownership
      –   Contributing to capacity building



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