Document Sample
MEETING 5 April 2006
Room CR1/CR2 Market Towers


MHRA:                            External:
Mr G Heddell        (Chair)      Mr D Mogg         Pharm. Quality Group
Mrs B Sinclair-Jenkins           Dr C Abouzeid     BIA
Mrs L Byers                      Mr J Harwood      NHS Prod. Ctte.
Ms M-E Frith (Secretariat)       Mr B Dougherty    Ass.Commerical
Mr M Birse                                         Special Manufacturers
Mrs A Davis - Item 11            Dr T Bateman      BGMA
Mr P Hargreaves                  Ms D Kenworthy    DH
Mr I Thrussell                   Mr T Root         NHSEROPA
                                 Mr A J Garlick    BAPW
                                 Ms S Shah         PAGB
                                 Mr R Bateman      NHS QC Ctte.
                                 Mr M Murray       ABPI
                                 Mr S Sidani       NMMA
                                 Mr V Fenton-May   Nat. Assemb. Wales
                                 Mr V Edy          BARQA
                                 Mr D Waddington   NMMA
                                 Dr E Ferguson     NOAH

Apologies for Absence:

Mr R Freudenberg    BAEPD        Mr D Olszowka     MHRA
Mr J Farrell        DH           Mr N Goulding     MHRA
Mrs P Warrington    Scot. Exec   Mr R Brookes      NHS PPC
Mr W Scott          Scot. Exec   Mr N Hodges       JPB QP Assessor Panel
Mr T Scott          NI Office    Dr M Willoughby   BHMA
Mr H Tracy          DTI
Mr S Bellis         BGMA
Mr I Jenkins        VMD
Dr J Todd           VMD

1.    Introduction

1.1   Welcome

1.1.1 Gerald Heddell welcomed everyone particularly new members:

         Vic Edy Chair of British Association of Research Quality Assurance
          replacing Dr Hanif Patel;
         Richard Batemen, new chair of NHS Pharmaceutical QA Committee
          Quality Assurance replacing Martin Knowles;
         Mr David Waddington representing Mr Suham Sidani Natural
          Medicines Manufacturers Association;
         Diana Kenworthy who was attending on behalf of DH, and
         Dr Tim Bateman who was attending on behalf of BGMA.

2.    Minutes of the last meeting and Matters Arising.

2.1   The Minutes of the previous meeting were in principle agreed apart
      from the following grammatical errors:-

      1.1.2 - 1st sentence should state… was to be Martin Knowles’ last
      2.1.1 - Should state Annex A.
      3.2    - 1st sentence should state The MHRA’s new website was
      4.1.4 - 1st sentence should state …the 30th…. 2nd sentence should
               state … will trigger a regulatory inspection of an API
      4.1.13 - 3rd sentence should read…. The offence of supplying non-
               GMP compliant APIs was directed at a person who
               knowingly supplied a non-GMP compliant material.
      4.2.1 - 2nd sentence should state … will be subject to routine
               inspections by the MHRA.
      4.2.2 - 2nd sentence should state… monitoring by the MHRA…
      4.2.3 - 1st sentence ….reactions to the MHRA (haemovigilance).
      4.2.7 - Should have a full-stop at the end of the end of the paragraph.
      4.3.5 - 2nd sentence should state ….Tissues and Cells Directive
               would regulate the starting material if they are not covered by
               other regulations.
      4.3.7 - 1st sentence should state... V’Iain Fenton-May confirmed
               that the NHS, that collects and store such material, may still
               have to recognise the change.
      4.4.1 - 1st sentence should state ….the proposed changes to the
               European Commission’s Guide to Good Manufacturing
      4.4.3 - 2nd sentence…Concept papers on the revision of some
               annexes have…
      4.4.4 - 3rd sentence should state …Annex 19 to take samples…
      4.4.5 - 2nd sentence should state … would be too onerous…

          4.4.6 - 1st sentence should state …revision was reached…
                  2nd sentence should state…had to return to the ad-hoc
                  Inspection Working Group.
                - 7th sentence should state … all interested parties from all
                  Member States….
          4.4.7 - 5th sentence should state…. will prioritise API inspections,…
          4.5.1 - 1st sentence should state….– manufacture of Herbal
                - 2nd sentence should state … been reached between the -
                  EMEA and the European Commission…
                - 4th sentence should state … A working party has been
          4.5.2 - Should state… is available from the Office of Public Sector
                  Information website:.
          5.2.1 - 2nd sentence should state… workload relating to tissue banks,
                  blood establishments, overseas inspections, API
                  inspections, QC laboratory inspections and GSL
          5.6   - 1st sentence should state … is available on the EMEA
                - 2nd sentence should state… GMP certificates, the
                  inspection report format…
          6.8   - 1st sentence should state…. voluntary inspections of IMP
                  sites in third Countries…
                - 2nd sentence should state ….have so far been successfully
                - 3rd sentence should state…and data-base of the third
          7.2   - 3rd sentence should state… taking samples for checking,…
          7.3   - 1st sentence should state… GDP inspectors are now….
          7.4   - 1st sentence should state… given to the BP conference…
                  the purchasers of medicines.
          9.2   - 1st sentence should state…. by an EU Expert Working
                  Group, the first….
                - 4th sentence should state… Despite this, the working group
          9.5   - 1st sentence should state ..Mike Murray confirmed that it was
                  appreciated that the Commission also understands the
          10.1. - 1st sentence should state… on the need for suppliers of….
          10.2 - 4th sentence should state… already publish lists of

2.2       Matters Arising

2.2.1 Bernadette Sinclair-Jenkins reported that the secondary legislation
      flowing from the 2001 Review, which was implemented on 31 October
      2005, was now in place. The following Guidance Notes were under
      review and were expected to be updated shortly:

         GN 5 Notes For Applicants And Holders Of A Manufacturer‟s Licence;

         GN 6 Notes For Applicants And Holders Of A Wholesale Dealing
         GN 8 What is a Medicinal Product;
         GN14 The Supply Of Unlicensed Relevant Medicinal Products For
          Individual Patients.

2.2.2 The first Blood Consultative Committee had taken place on 13th
      January with a large number of attendees from blood establishments,
      blood banks, and manufacturers of blood products, DH, NHS and
      devolved administrations. A list of invitees had been attached to the
      agenda for this meeting, for information. Hospital blood banks were
      slightly under-represented so additional representatives have been
      identified. It had been agreed that the consultative committee was
      useful and that meetings would be held twice a year.

2.2.3 At a subsequent meeting of the National Blood Transfusion Committee
      it had been agreed that there should be a sub-group reporting to the
      committee which looks specifically at haemovigilance.

2.2.4 GMP/GDP Committee Members were reminded that the Veterinary
      Medicines Directorate (VMD) had dis-applied the Medicines Act 1968
      and now had in place new regulations, The Veterinary Medicines
      Regulations 2005; to regulate Manufacturers and Wholesale Dealers of
      Veterinary Medicines. VMD plan to revoke the regulations annually
      and are currently consulting on The Veterinary Medicines Regulations
      2006, which are available from the VMD website. The consultation
      period will close on the 9th June 2006. Key issues to note were fee
      structures, retail supply and the cascade for the supply and use of
      unlicensed veterinary medicines.

2.2.5 With the legislative changes a Memorandum Of Understanding was
      being developed with VMD. The MHRA will continue to process
      Authorisations on VMD‟s behalf.

3.        MHRA Update

3.1       Gerald Heddell informed the Committee of Lynn Byers‟s imminent
          departure from the MHRA back to Industry and wished to thank Lynn
          for the valued contribution she had made to the MHRA, particularly in
          relation to setting up the regulatory process for blood establishments.

3.2       The MHRA also has a new Director of Information Management, Alison
          Davis who had joined the MHRA in January 2006 from Bristol Myers
          Squibb. Alison would give a presentation later in the programme.

4.    Defective Products 2006

4.1   It was reported that the number of Drug Alerts issued in calendar year
      2005 was 24, of which one was a revision notice. In calendar year
      2006, 14 have been issued by the 5th April with one further planned for
      later in the week.

4.2   For every Drug Alert issued by DMRC there are many other files
      opened. The figures for non-alert files were about 30 per month but had
      recently been rising steadily. In February 56 were opened and in March

4.3   2006 has also seen four Class 1 Drug Alerts compared with two in the
      previous calendar year.

4.4   Labelling and packing areas remain a major source for Drug Alerts and
      other reports. Examples were given from recent reports including a pre-
      filled syringe with the plastic box labelled as containing a different
      active, eye ointment tubes labelled with the wrong active and incorrect
      strength on tablet foils.

4.5   Ian Holloway briefly reviewed content and causes of key defects in
      2006. Several cases of unofficial rework have been notified to DMRC in
      recent months resulting in recalls. These had not been recorded on
      batch documents and the QP had been unaware at the time of release.

4.6   The Committee commented that labelling of packs in recent years had
      become more complicated. However, it was suggested that there was
      also a resource issue as many professionals were retiring, leading to a
      reliance on systems rather than individual‟s thought processes. It was
      agreed that the MHRA would look for ways to publish further
      information. A suggestion was made to perhaps organise a seminar.

                                                             Action: I&S/GH

5.    Update on Legislation & Proposals

5.1   Tissues and Cells Directive

      Bernadette Sinclair-Jenkins reported that:

5.1.1 The provisions of the Tissues and Cells Directive 2004/23/EC would
      come into force on 7 April 2006. The role of the UK competent authority
      for the purpose of this Directive will be shared between the Human
      Tissues Authority (HTA) and the Human Fertilisation and Embryology
      Authority (HFEA) until they merge in 2008 to form the Regulatory
      Authority for Tissue and Embryos (RATE). Until then, the HFEA will
      continue to regulate fertility clinics and the HTA will regulate the
      remaining tissue establishments.

5.1.2 The European Commission adopted Commission Directive 2006/17/EC
      on 8 February 2006. This Directive implements the technical
      requirements of Directive 2004/23/EC for the donation, procurement
      and testing of human tissues and cells and has a deadline for
      transposition of 1 November 2006. The second Commission Directive
      on coding, preservation, storage and distribution is now entering the
      final stages of negotiations.

5.1.3 Directive 2004/23/EC contains a derogation that permits Member
      States to delay implementation until 7 April 2007 for tissue
      establishments bound by existing national provisions. The HTA and the
      HFEA are registering and licensing tissue banks and fertility clinics
      under the Human Tissue Act and the Human Fertilisation and
      Embryology Act respectively in order to take advantage of this

5.1.4 The Department will be launching a formal consultation later in 2006 on
      the Regulations transposing these Directives into UK legislation.

5.2   Proposed Regulation on Advanced Therapy Medicinal Products

5.2.1 The European Commission published a proposal for a regulation on
      advanced therapy medicinal products on 16 November 2005.

5.2.2 The draft regulation amends Directive 2001/83/EC and Regulation (EC)
      No 726/2004. It proposes that tissue engineered products (TEPs)
      containing cells or tissues of human or animal origin should be
      regulated as advanced therapy medicinal products (ATMPs), along with
      gene therapy medicinal products and somatic cell therapy medicinal
      products, both of which are already regulated as ATMPs under
      medicines regulation.

5.2.3 Under the proposal all ATMPs, including TEPs, would be subject to the
      centralised procedure for marketing authorisation co-ordinated by the
      EMEA. A new scientific committee would be established, the
      Committee for Advanced Therapies (CAT) to advise the Committee for
      Medicinal Products for Human Use (CHMP) on ATMPs.

5.2.4 Negotiations are at an early stage, having commenced in January 2006
      in a Council of Ministers Working Group under the Austrian Presidency.

5.3   Changes to the EU GMP Guide:
5.3.1 Following the agreed restructuring of the GMP Guide in 2005 several
      Annexes will have to be revised. As a result of the new structure the
      Annex 18 "GMP for the manufacture of APIs" is not an Annex any
      longer but forms Part 2 of the EU GMP guideline – Part 1 provides the
      GMP requirements for the manufacture of intermediate, bulk and
      finished medicinal products.

5.3.2 Some of the Annexes of the EU GMP Guide are now applicable to API
      manufacturers. For that reason the EMEA plans to revise the following
         Annex 2 (Biologic Substances) (MHRA Lead: Ian Rees) Draft to
          IWP in January. Expect public consultation Qtr 4 or Qtr 1 2007.
         Annex 3 (Radiopharmaceuticals) (MHRA Lead: Keith Jones) WIP
         Annex 6 (Medicinal Gases) (MHRA Lead: Malcolm Olver) WIP
         Annex 7 (Herbal Medicinal Products) (MHRA Lead: Paul
          Hargreaves) Out for public consultation – Possible implementation
          Qtr 3 2006.
5.3.3 The new guideline structure will likely lead to an amendment of chapter
      5, part 1, defining the requirements for the qualification of suppliers.
      In addition the EMEA plans:

         to complete the revision of Annex 1, sterile products, this primarily
          includes changes to the paragraphs on classified area monitoring,
          media fills, vial sealing. Currently in consultation with a closing date
          of 30 April 2006. (MHRA Lead: Paul Hargreaves) Public comments
          to or .

         to revise or amend Annex 14 (Blood Products) (MHRA Lead:
          Barbara Morris) WIP Implementation target Qtr 3 2007

         to revise or amend Annex 16 (Qualified Person and Batch Release)
          (MHRA Lead: tba).

         New Annex 20 (Risk Management) Proposal for a new annex to
          incorporate ICH Q9 principles.
5.3.4 Revisions to Chapter 1 (Product Quality Review) – Came into force
      January 1, 2006 – Expectation that a first Product Quality Review will
      be performed in 2006 for a minimum review period of at least 6 months.
      Subsequent reports should normally cover a full 12 months‟ period.
5.3.5 Revisions to Chapter 5 (Quality Control) – Comes into force June 1,
      2006 – Deals with “commercial lot” stability testing and makes new
      reference regarding retention samples in 6.14 (refers to new Annex
5.3.6 Minor revision to Chapter 8 (complaints and recall) which helps raise
      awareness that a quality defect may be a result of counterfeiting activity
      came into force 1 Feb 2006.
5.3.7 The new Annex 19 (provisions on retention samples) also comes into
      force June 1, 2006.

5.3.8 The new guidelines will take into account new developments (new
      technology, PAT) and will secondly seek to emphasise risk
      management in both the content and development of the guideline.

5.4   GCP Directive

5.4.1 The Commission Directive on Good Clinical Practice (2005/28/EC) was
      published in the Official Journal on 9 April 2005. The UK proposed that
      it would transpose the Directive, through an amendment to the
      Medicines for Human Use (Clinical Trials) Regulations 2004/SI 1031.
      MHRA issued a consultation letter on 15 November 2005, MLX 328.
      The MLX proposed amongst other things that the current list of
      principles based on ICH would be replaced with those in the Directive.

5.4.2 The consultation period closed on 7 February. In total 74 responses
      were received – 36 had no comment, 7 agreed with the proposals, 33
      made specific comments. The clarification of the following areas was
      requested „serious breach of GCP‟, the retention of documents by
      ethics committee, „specific modalities‟. A summary of the results of the
      consultation is being prepared for the website.

5.4.3 I&S Division met with Solicitors to agree the final draft of the
      Regulations. The Regulations should be laid in Parliament by the
      beginning of May to come into force by the end of May 2006.

6.    Rules and Guidance for Pharmaceutical Manufacturers and

      It was reported that the I&S Division had established a project to review
      and revise the „Orange Guide‟, to update it in line with the reviewed
      legislation. Our target publication date is October 2006.

7.    Inspection update

7.1   New Inspectors

      The following was reported to the Committee:

             Two new GMP Inspectors have joined the team, Ian Stewart
              who will be based in York and Neil Raw based at Market
             There have also been a number of promotions Ian Thrussel is
              now Expert Inspector and Mark Birse, Richard Andrews, Richard
              Funnel, Mike Woodhall and Keith Jones are Senior Inspectors.

7.2   Current Organisation

      The Hitchin regional office is closing soon and the MHRA has acquired
      the lease on a property in Falcon Way, Welwyn Garden City. The
      Inspectorate is expected to move around the end of May.

7.3   PIC/S Assessment

      The MHRA will be assessed by PIC/S (Pharmaceutical Inspection Co-
      operation Scheme) the week commencing 25th April. The scope of the
      assessment is GMP Inspectorate. The lead assessor is Tor Graberg of
      the Swedish Regulatory Authority. There are two other assessors, one
      from Malaysia and one from Portugal. The assessment will consist of
      audits of the quality management system at Market Towers and York,
      as well as two observed inspections. At the next Consultative
      Committee the Inspectorate will give feedback.

7.4   Risk Based Assessment

7.4.1 For the 2006/7 financial year the MHRA intends moving to more of a
      risk based approach to inspection frequency. There are some
      constraints in legislation and the compilation of community procedures.
      For example the largest interval between GMP inspections is defined
      as 3 years. For national inspections the UK has historically worked on
      a 2 year frequency, with super-sites being inspected every year. The
      new frequencies will be based on the perceived risk in the sector e.g.
      wholesale dealers POMS versus GSL sites and then based upon the
      inspection history of individual sites. Those with a poor inspection
      history will warrant more frequent inspections. The way in which the
      inspectorate activity is measured is also changing. Historically it has
      been to inspect all sites within 27 months of the previous inspection.
      From this month it is to inspect all high risk sites and 95% of the
      scheduled inspections.

7.4.2 The inspection of GCP sites will also expand this financial year. The
      plan for non-commercial organisations is to inspect 30 hospitals trusts
      and 10 charities.

7.5   GMP Deficiencies

      Mark Birse, Senior Inspector gave a presentation to the Committee on
      commonly seen GMP deficiencies within small scale manufacture and
      large scale manufacture. A copy of the presentation is attached to this

8.    GMP Certificates

8.1   The 2001 Review introduced the requirement to issue GMP certificates
      within 90 days of an inspection. The Inspectors Working Party has
      developed a format for GMP certificates. This has been finalised in the
      last couple of weeks. The new format means that the MHRA‟s
      computer system, Sentinel needs to be changed. The format contains
      lists of dosage forms, some of which are not on our current licences.
      The EMEA has also defined a new format for manufacturers‟
      authorisations. Again, Sentinel will need to be changed. The two are

       interlinked as data held in the MA will be used to populate the GMP
       certificate. The Sentinel system is being enhanced to cope with these
       changes, with a likely implementation date in July/August. Meanwhile
       the Inspectorate will issue manual certificates. A couple have already
       been produced, for API manufacturers and issuing them should
       become routine from May. The MHRA does not intend to issue
       certificates retrospectively unless a company needs one for a specific

9.     Update on Excipient Directive

       The last meeting of the team was held in November 2005 and it
       included a meeting of “Interested Parties”. The way the Directive
       needs to be structured is quite unusual as the basic GMP requirements
       have to be placed in the directive rather than in guidance. The
       requirements cannot be greater than those for APIs. Work has taken
       place to compare the current regulations/guidance for food cosmetics,
       excipients (IPEC/PQG guide) and APIs. The intention is for the
       Commission to launch a consultation for the excipient industry and
       pharmaceutical industry users of excipients. This is likely to take place
       in April. The overall approach is very measured to ensure the
       legislation is appropriate. Bronwyn Phillips is taking on the role of
       rapporteur following Lynne Byers departure.

10.    Requirements for APIs – Annex 18 – Presentation by David Mogg

10.1   Atypical Actives

10.1.1 David Mogg reported on the difficulties concerning the requirements for
       APIs; specifically that the supplier be audited to assure that they meet
       Annex 18, has thrown up a few problems for industry where a material,
       manufactured as an excipient, is in fact declared as an active.

10.1.2 Users of actives need to assure by audit, that the supplier of an active
       meets the requirements of Annex 18. This is sensible for those actives
       that are „solely of medicinal function’. However there is a small number
       of chemicals declared as actives that are NOT „solely of medicinal
       function’; they have other and often a more normal use in other areas -
       materials I have termed „atypical actives’. As an example, glycerine
       has more than 1500 known end uses.

       2001 figures (
        24% in food
        23% in personal care products - skin, hair soap etc
        17% oral care product - mainly toothpastes and mouthwashes
        11% in tobacco
        8% in the manufacture of polyether polyols for urethanes
        7% for pharmaceuticals
        7% others - cellophane, explosives, plasticizers

          3% alkyd resins manufacture

10.3   Current Position

10.3.1 Some 39 atypical actives have been identified by PQG members; they
       fall into the following categories: Antiseptics, Aromatic natural products,
       Glycerine, Honey, Inorganic bicarbonates, carbonates, chlorides,
       citrates, nitrites, oxides, sulphates, Lactulose, Lanolins, Kaolin, Organic
       acids, alcohols, chlorides, myristates, Paraffins, Plant derived oils,
       Phenols, Simethicones, Starches.

10.3.2 Broadly the response from suppliers when questioned about Annex 18
       ranges from:

       Suppliers who produce mainly for food and personal care and the
       volume produced for pharma is small:

        No audit allowed, and will not complete a questionnaire
        Will allow an audit but won‟t do anything, to
       Suppliers where the chemicals are a major and important part of their
       portfolio and / or the purchasing companies also manufacture personal
       care or food products and are an important part of the supplier‟s
       customer base:

          Will allow an audit and will try to meet Annex 18 but may take time
          Will allow an audit and will meet Annex 18 as a matter of priority

10.3.3 As a result there are QPs currently in the situation of being unable to
       assure that certain suppliers meet Annex 18 and are genuinely
       concerned since they have reached an impasse.

10.3.4 However, QPs would not continue to certify batches if they were at all
       worried that the finished product may not meet essential requirements
       for quality, safety and efficacy. This is based upon an assessment,
       albeit perhaps not a formal assessment, of the hazards and associated
       probabilities of risk to patient safety in continuing to use the materials.

       Options available
        Cease to manufacture and withdraw product from the market
        Continue to try to persuade existing supplier to comply with annex
          18 and if not able, withdraw product from the market
        Continue to try to find an annex 18 compliant supplier and if one
          cannot be found, withdraw product from the market
        Find new compliant supplier and go through the process of
          validation, proving equivalence, stability and vary licence.
        Continue with existing supplier with the agreement of the MHRA,
          having performed a formal hazard analysis and risk assessment
          and established no or minimal risk.

10.4   Preferred Option from PQG members

10.4.1 From talking to members of the PQG who responded to an e-mail, the
       industry preferred option is to use a formal, documented and QP
       agreed, hazard analysis and assessment of the probability of risk to the
       quality of the material arising from any hazards: with audit not required
       if unable to do so.

10.4.2 Points considered in the hazard analysis:

          History: quality problems in supplied material / adverse events
           attributable to the active / complaints attributable to the active
          Nature of the supplying company: well-known / reputable / produces
           for food or personal care who themselves have as tight if not tighter
          Route of administration: oral or topical
          Quantity of material within the product
          Length and type of exposure to the patient
          Other uses for the material: foodstuff / personal care / oral care
          Nature of manufacturing plant: dedicated / general purpose
          Nature of the manufacturing process: hazards arising from the
           chemicals used in the process / biological and-or animal derived
           materials used / consistency / continuous / batched
          Ability of sampling and analytical testing to find non-compliant
          Consequences of physical, chemical or microbiological failure of
           undetected non-compliant material subsequent to its use in a
           finished product
          Nature of the process in making the medicinal product: ability to find
           non-compliant material / filtering out contaminants / heating /
          Supply chain: length / stages of manufacture at different sites /
           packaging / brokers used

10.4.3 From this an assessment should be made of the probability of non-
       compliant material not being detected by the supplier and being
       supplied to the purchaser, going undetected by the purchaser, being
       used in a medicinal product and affecting the patient.

10.4.4 David Mogg was thanked for highlighting the difficulties around the new
       requirements. Although the difficulties were appreciated and
       understood, the issue was European wide and would need to be
       addressed at that level. Lynne Byers suggested as a way forward that

      the issue is taken on by appropriate “interested parties” such as the
      EFPIA to take forward at a European level for discussion.

11.   Sentinel

11.1 Alison Davis gave a presentation about the Sentinel Programme
     explaining the MHRA high level objectives, and the impact of the
     programme. The implementation of the programme was creating major
     changes in working practices for example all current business systems
     were being replaced, which will improve quality and consistency and on
     completion, will create a seamless information flow between the MHRA
     and all companies registered with the MHRA, with tools to manage the
     complete application life cycle of all business processes.

11.2 The preferred option for the format of eApplications will be the
     Common Technical Document (eCTD). The Information Management
     Directorate would be happy to work with companies to test the eCTD.

11.3 Queries were raised about Clinical Trial Authorisations and Variations
     to licences. Portal feedback should be sent to .

11.3.1 To register for the portal companies should connect to the portal web
       site (attention should be drawn to the fact that
       this is an https address - more secure - and also that there is no www).
       The front page has a link for users who wish to register.

12.   Date of Next Meeting

      Date of the next GMP/GDP Consultative Committee 10 am 20th
      October 2006.


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