GMP/GDP CONSULTATIVE COMMITTEE
MEETING 5 April2006
Room CR1/CR2 MarketTowers
Present:
MHRA:External:
Mr G Heddell (Chair)Mr D MoggPharm. Quality Group
Mrs B Sinclair-JenkinsDr C AbouzeidBIA
Mrs L ByersMr J HarwoodNHS Prod. Ctte.
Ms M-E Frith(Secretariat)Mr B DoughertyAss.Commerical
Mr M Birse Special Manufacturers
Mrs A Davis - Item 11Dr T BatemanBGMA
Mr P HargreavesMs D KenworthyDH
Mr I ThrussellMr T RootNHSEROPA
Mr A J Garlick BAPW
Ms S ShahPAGB
Mr R BatemanNHS QC Ctte.
Mr M MurrayABPI
Mr S SidaniNMMA
Mr V Fenton-MayNat. Assemb. Wales
Mr V Edy BARQA
Mr D WaddingtonNMMA
Dr E FergusonNOAH
Apologies for Absence:
Mr R FreudenbergBAEPDMr D Olszowka MHRA
Mr J FarrellDHMr N GouldingMHRA
Mrs P Warrington Scot. ExecMr R BrookesNHS PPC
Mr W ScottScot. ExecMr N HodgesJPB QP Assessor Panel
Mr T ScottNI OfficeDr MWilloughbyBHMA
Mr H TracyDTI
Mr S BellisBGMA
Mr I JenkinsVMD
Dr J ToddVMD
1.Introduction
1.1Welcome
1.1.1Gerald Heddell welcomed everyone particularly new members:
- Vic EdyChair 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.
2.1The 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 meeting.
2.1.1-Should state Annex A.
3.2-1st sentence should state The MHRA’s new website was launched…
4.1.4-1st sentence should state …the 30th…. 2nd sentence should state … will trigger a regulatory inspection of an API manufacturer.
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 compliantmaterial.
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…
4.2.3-1stsentence ….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.
4.3.7-1stsentence should state... V’Iain Fenton-Mayconfirmed 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 Practice.
4.4.3-2nd sentence…Concept papers on the revision of some annexes have…
4.4.4-3rdsentence 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 products,…
-2nd sentence should state … been reached between the - EMEA and the European Commission…
-4th sentence should state … A working party has been formed…
4.5.2-Should state… is available fromthe 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 wholesalers.
5.6-1st sentence should state … is available on the EMEA website.
-2ndsentence should state… GMP certificates, the inspection report format…
6.8-1stsentence should state…. voluntary inspections of IMP sites in third Countries…
-2nd sentence should state ….have so far been successfully inspected.
-3rd sentence should state…and data-base of the third country…
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 problem.
10.1.-1st sentence should state… on the need for suppliers of….
10.2-4th sentence should state… already publish lists of authorised….
2.2Matters Arising
2.2.1Bernadette 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 Licence;
- GN 8 What is a Medicinal Product;
- GN14 The Supply Of Unlicensed Relevant Medicinal Products For Individual Patients.
2.2.2The 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 inviteeshad 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.
2.2.3At 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.
2.2.4GMP/GDP Committee Members were reminded that theVeterinary 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.
2.2.5With 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
3.1Gerald 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.
3.2The 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
4.1It 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.
4.2For 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 58.
4.32006 has also seen four Class 1 Drug Alerts compared with two in the previous calendar year.
4.4Labelling 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.
4.5Ian 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.
4.6The 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
5.1Tissues and Cells Directive
Bernadette Sinclair-Jenkins reported that:
5.1.1The 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.
5.1.2The 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.
5.1.3Directive 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 derogation.
5.1.4The Department will be launching a formal consultation later in 2006 on the Regulations transposing these Directives into UK legislation.
5.2Proposed Regulation on Advanced Therapy Medicinal Products
5.2.1The European Commission published a proposal for a regulation on advanced therapy medicinal products on 16 November 2005.
5.2.2The 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.
5.2.3Under 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.
5.2.4Negotiations are at an early stage, having commenced in January 2006 in a Council of Ministers Working Group under the Austrian Presidency.
5.3Changes to the EU GMP Guide:
5.3.1Following 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.
5.3.2Some of the Annexes of the EU GMP Guide are now applicable to API manufacturers. For that reason the EMEA plans to revise the following Annexes:
- 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.
5.3.3The 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.
5.3.4Revisions 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.
5.3.5Revisions 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 19).
5.3.6Minor 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.
5.3.7The new Annex 19 (provisions on retention samples) also comes into force June 1, 2006.
5.3.8The 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.
5.4GCP Directive
5.4.1The 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.
5.4.2The 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.
5.4.3I&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 Distributors
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 October2006.
7.Inspection update
7.1New 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 MarketTowers.
- 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.
7.2Current Organisation
The Hitchin regional office is closing soon and theMHRA has acquired the lease on a property in Falcon Way, Welwyn Garden City. The Inspectorate is expected to move around the end of May.
7.3PIC/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 MarketTowers and York, as well as two observed inspections. At the next Consultative Committee the Inspectorate will give feedback.
7.4Risk Based Assessment
7.4.1For 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.
7.4.2The 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.
7.5GMP 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 note.
8.GMP Certificates
8.1The 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 reason.
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.