Mark SantilloRegional QA OfficerSouth Devon Healthcare NHS TrustGroup Chairman

Structure of presentation� Background and purpose of the Group

� Update on progress since last year� Stability documents

� Laboratory surveys

� Coordination of R&D

� Proposals for review of stability data

� Syringe integrity testing projects

Structure of the group� Sub-group of the National NHS Pharmaceutical QA Committee

� Sub-group of the Pharmaceutical Production Committee

� Sub-group of the Pharmaceutical Aseptic Services Group

� Liaison with Extemporaneous Products Working Group

� Minutes fed into TSET Technical Services Education and Training and other groups as appropriate

Purpose of the group� To act as an expert and informed body on

pharmaceutical research and development within the NHS.

� To co-ordinate pharmaceutical research and development activities within the NHS and act as a consultative resource on the subject

� To create an environment where Pharmaceutical R & D flourishes within the NHS

� To produce and review guidance in the area of pharmaceutical development and research

� To provide, support and encourage opportunities for education and training in issues relevant to the speciality.

Purpose of the group (continued)� Develop key roles of catalysing innovation in practice

and of promoting its uptake.

� To encourage publication of research carried out within the NHS and to review data and articles ahead of publication where appropriate.

� To provide a forum for the exchange of views, ideas and information in the field of pharmaceutical research and development.

� To provide R & D focus for the QC Symposia and other meetings.

National NHS Stability Database� Aim to produce a peer reviewed and fully approved stability

database for use throughout the NHS

� Critically review all stability data in existing databases (which are now largely out of date) in published studies or from work produced within the NHS or supplied to the NHS by commercial or academic organisations.

� Facilitate a smooth change over where contracts change or where there is an interruption to contract supply

� Encourage sharing of data across (but not outside) the NHS

National NHS Stability Database�Problems� Obtaining of funding to enable the project to proceed

� Huge amount of historic data to review� Much of the historic work was not done to today’s standards

with genuinely stability indicating assays

� Much of the data does not stand up to robust scrutiny

� Information is widespread and in many formats, often the original data may not be easily available

� Reluctance to share work - IP issues

Solutions� Funding from the CMU (not forthcoming)

� Funding from within the NHS� All Trusts would potentially benefit from the outcome

� However, the work will take some time to complete and funding needs to be up front

� Also current economic situation within the NHS

� Funding from industry� Anybody out there interested

� Hence the project has stalled

Review of new data� Group will review new data or data / studies that needs to

be freshly reviewed

� Studies which are suitably robust will be reviewed and approved for use across the NHS

� Including studies to support NHS technical services units and also procurement departments looking to procure safe and robust Specials

� Review of supporting data where required for contract changes

Review of new data� Submit any studies that may be useful (even those that

show a lack of stability)

� Existing / old studies can also be considered (but bear in mind the group all have full time jobs at base)

� Group will review and will put approved data on QCNW website

� This will give access to the NHS to peer reviewed and approved studies – in house reassessment will be restricted to checking that study criteria are met.

Industry / commercial specials suppliers� Data can be submitted to the group in a confidential

manner (CDA template available)

� The group can review and approve (or reject) the data and supply of the products across the NHS

� Particularly useful for biologicals data where the expertise to interpret at a local level may not be available

Stability documents� A Standard Protocol for Deriving and Assessment of

Stability. Part 1 - Aseptic Preparations (small molecules)

� Version 2 published in December 2010

� New studies should be designed to comply with this document

� Studies will be reviewed against the standards in this document

� Available within the NHS and also to industry (submitted in contracting documentation) and commercial specials suppliers (on request)

Stability Documents� A “Standard” Protocol for Deriving and Assessment of

Stability. Part 2 Large molecules

� Currently being drafted for discussion at December 2011 meeting

� Aiming to publish in spring 2012

� May prove difficult to get consensus

� Likely to prove difficult to come up with a specific standardised approach due to the fundamental differences in ‘large molecules’ and their usage.

� Will require a raft of techniques physical, chemical and biological / biochemical

Other documents� Aseptic medicinal products ; assessment of shelf life

following the change in supplier of starting material: Proceedings of the NHS National Pharmaceutical Research and Development Group.

� Due for publication towards the end of 2011� Advise on contact changes and purchasing decisions

� Case studies and frequently asked questions

Other documents� Bevacizumab pre-filled syringes stability assessment

paper (Due to be published)

� Other documents will be available through the QCNW website

Syringe integrity testing� Protocols for the Integrity Testing of Syringes� Update of YCD

� Incorporation of a physical dye intrusion test alongside the existing microbiological integrity test

� Review of the existing test (John Rhodes poster) as to consider organism motility as well as size (E.Coli vs Brevundimonas dimiuta )

� Incorporation of positive controls into both tests

Dye intrusion test� Apparatus:

� Dye Bath – a cylindrical watertight container of suitable dimensions and construction

� Roller Mixer : with variable rotation speed

� Method� Sample 20 syringes from a single manufacturer’s batch.

� Fill each syringe with water or drug solution under test.

� Reduce the volume to the graduation representing a maximum of 75 % of full scale on syringe. Securely apply the hub.

Dye intrusion test (continued)� Apply an internal vacuum by drawing back the plunger to

the graduation representing 100% of syringe volume in position to maintain the internal vacuum.

� Secure the barrel in place with a retaining pin or screw placed though a pre-drilled hole in the plunger

Dye intrusion test (continued)Dye intrusion test (continued)� Place the syringes into the dye bath in an upright position.

� Add a single positive control syringe (see later) in the centre of the group of syringes.

� Seal the bath and rotate by 90 degrees so bath is on its side. Ensure all syringes are fully submerged and the lid of the bath is secure.

� Place the dye bath onto the roller mixer and rotate at 30 rpm for 2 hours.

Dye intrusion test (continued)� Dye solutions:

� 0.2% amaranth or 0.4% methylene blue (nominated dyes for eye dropper bottle efficacy of closure test and therefore considered suitable for this test.

� The extinction of dye should be shown to be unaffected by the sample solution under test.

� Positive control� Prepare a syringe from the batch tested and incorporate a

fine thread of stainless steel wire running parallel to the barrel between the plunger seal and the inner barrel wall

Dye intrusion test (continued)Positive Control

Dye intrusion test (continued)� Remove the dye bath from the roller mixer, remove the

individual syringes and positive control.

� Release the internal vacuum by removal of the retaining devices (screw or wire) and thoroughly wash the external surfaces.

� Dispense a quantity of each syringe and the positive control into a suitable cuvette or Nessler cylinder. Examine visually for the presence of dye using the contents from an untested control syringe as the reference.

� Validated spectrophotometric methods may also be used

Dye intrusion test (continued)� Advantages

� More sensitive than the microbiological test due to the smaller molecular size

� Can run the test with product filled syringe (particularly where the product may have an impact on syringe performance)

� Can be quantitative if using validated spectrophotometric techniques

� However, microbiologial integrity is still what we are ultimately interested in so both tests have their place.

Syringe Integrity testing� Project 2 –coordination of integrity testing data

� Please submit any syringe integrity testing data that you have

� Include details of the method used but please still share the data even if the standard methodology has not been used

� This will allow a picture to be formed of all the integrity data that we have within the NHS

� So far results from about 10 Trusts have been submitted

Laboratory Collaborations� Laboratory survey carried out during 2010 to gauge R&D

activity within the NHS

� List of laboratories interested in being involved in coordinated research established

� Also used as a circulation list for information requests and passage of information

� Not too late if you want to be included on the list

Laboratory Collaborations� First coordinated study underway

� Stability of a range of drugs in syringes for a syringe manufacturer

� Eight studies coordinated across six NHS laboratories

� Standard charging model across all organisations involved

� Hopefully the first of many

Database of NHS pharmaceutical research activity

� Still an aim of the group to set up a database

� Preventing duplication and encouraging collaboration and sharing of information

� IP issues are a problem

� Does seem to be an increased willingness to collaborate in product development

� Moving forward NPSA 20?

Safer Neuraxial devices� Changes to standard syringes for intrathecal and neuraxial

administartion� Implications for drug stability

� Syringe / closure integrity testing

� Many variations being developed, all will need to be assessed

� Target date for implementation put back to April 2012

� Project currently underway in Wales looking at integrity and performance

� Stability studies will need to follow

Other areas� To encourage publication of research carried out within the

NHS

� Articles and posters

� PTQA MSc projects and other original research

� How do we do this?

R&D activity� Are you actively involved in pharmaceutical R&D or do

you know someone who is

� Please get in touch with the group we can always use corresponding members and it will make future projects easier to co-ordinate

Contact details� Mark Santillo Chair mark.santillo@nhs.net

� Phil Weir Secretary Phil.Weir@stockport.nhs.uk

� Andrew Barnes A.Barnes2@uea.ac.uk

� Wayne Goddard Wayne.Goddard@nth.nhs.uk

� Sarah Hiom Sarah.Hiom@CardiffandVale.wales.nhs.uk

� Mark Jackson Mark.Jackson@lrippu.nhs.uk

� Julie Simpson Julie.Simpson@uhb.nhs.uk

� Nick Precious nick.precious@moorfields.nhs.uk

� Don Wallace Don.wallace@belfasttrust.hscni.net

� Thanks to the members of the group in help with putting together this presentation specifically to Phil Weir for his work in development of the dye intrusion test.

� Any Questions?