1

Investigation into Microbiological

Integrity Testing of Surety® Syringes

Revised Edition

Marc BuckinghamSurety® Business Manager

May 2013

1.0.0 Summary

Surety®, manufactured by INTERVENE, is a non-Luer connector system designed in response to a

National Patient Safety Agency (NPSA) Patient Safety Alert directing clinicians to use non-Luer products

in spinal (intrathecal), epidural and regional block procedures. The NPSA appointed an External

Reference Group (ERG) to establish the content of update newsletters pertaining to the alert, and to

achieve compliance with its requirements.

As part of the validation of Surety® syringes for the storage of medicines, INTERVENE commissioned

microbiological integrity testing carried out in 2011. In total, 120 Surety® syringes were tested. One

positive culture was found which seemed to be attributed to human error. Consequent to this result

INTERVENE commissioned further tests in 2011 and 2012, which resulted in no positive cultures.

The ERG commissioned independent microbiological integrity tests of Surety® syringes in 2012, during

which two positive cultures were found. Subsequent tests using dye-intrusion, which is considered a

more robust test1 produced no positive results.

The causes of positive results have been investigated, including the methods by which Surety® syringes

were manufactured, supplied and tested for microbiological integrity.

The report concludes that contributory factors which led to the positive test results include:

● The fact that the NPSA guidelines (used by INTERVENE) did not include, or

specifically direct manufacturers to the 'NHS Pharmaceutical Quality Assurance

Committee Microbiological Protocol for the Integrity Testing of Syringes' (The Yellow

Book), though it made reference to that document.

● The Yellow Book, which sets out the process by which Luer syringes should be

tested for microbiological integrity, does not consider the availability of non-Luer syringe

caps or connectors (such as Surety®). There are no instructions given for the term 'fill

and cap' (of syringes).

● Surety®-slip syringes, which are not recommended for the storage of medicines,

were supplied to and tested by the laboratory commissioned by INTERVENE.

● Pharmacy units employ various methods for applying different syringe caps (such as

caps presented in a syringe cap tray, or individually wrapped, or featuring tamper-proof

mechanisms). Operatives used to a specific product may use a technique inappropriate

for others, resulting in lack of operator compliance with the intended use.

● Syringe caps not applied properly may become loose during transportation,

particularly when small syringes are transported together, giving rise to a higher

likelihood of contact between syringe caps or with the transportation container. By the

same token, this action may result in the tightening of syringe caps applied incorrectly.

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The report explores the use of a protocol for the application of Surety® syringe caps, and demonstrates

that it can reduce the risk of incorrect syringe cap application. It is recommended that the protocol,

detailed in the report, is made available to anyone using or considering Surety® syringes for the storage

of medicines.

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Table of Contents

1.0.0 Summary 2

2.0.0 Background 6

2.1.0 Cross-Connections and Neuraxial Connectors 6

2.2.0 National Patient Safety Agency (NPSA) Alerts 6

2.3.0 Non-Luer Connector Systems 6

2.4.0 NPSA External Reference Group (ERG) Criteria for Microbiological Integrity Testing

7

2.5.0 NHS Microbiological Protocol for the Integrity Testing of Syringes (The Yellow Book)

7

2.6.0 Microbiological Integrity Testing of Surety® Syringes 7

2.6.1 MVS Microbiological Integrity Tests of Surety® Syringes (MVS 2011a, MVS 2011b and MVS 2012)

7

a) MVS 2011a 7

b) MVS 2011b 7

c) MVS 2012 8

2.6.2 SMTL Microbiological Integrity Test of Surety® Syringes (SMTL 2012) 8

2.7.0 Dye-intrusion Integrity Testing of Surety® Syringes 8

2.7.1 Quality Control Northwest Dye-intrusion Integrity Test of Surety® Syringes (QCNW 2012)

8

2.8.0 Pharmaceutical Aseptic Services Group (PASG) statement 2013 9

3.0.0 Investigation Plan 10

3.1.0 PASG requirements 10

3.2.0 Investigative remit 10

3.3.0 Requirement for additional testing 10

4.0.0 Investigation into Microbiological Integrity Tests 11

4.1.0 Microbiological Integrity Testing by MVS (Interviews with MVS staff 21 February and 01 March 2013)

11

4.2.0 Microbiological Integrity Testing by SMTL (Interviews with SMPU and SMTL staff on 19 March 2013)

13

4.3.0 Capping of INTERVENE Surety® Lock Syringes - Microbiology Laboratory Report, University Hospitals Nottingham NHS Trust, 2013

15

4

5.0.0 Discussion 17

6.0.0 Conclusions and Recommendations 21

7.0.0 Syringe capping Procedure 23

8.0.0 Acknowledgements 24

9.0.0 References 25

10.0.0 Appendices 26

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2.0.0 Background

This section describes the relationship between the organisations and processes surrounding the

investigation.

2.1.0 Cross-Connections and Neuraxial Connectors

Medical devices have traditionally used a universal connector designed by Dr Hermann Luer in the

19th Century2. The Luer connector (which now features both -slip and -lock variants) allows universal

connectivity between medical devices.

Following an incident at Nottingham University Hospitals NHS Trust in January 2001, in which a

patient was given a dose of vinca-alkaloid medication intrathecally, resulting in his death, Professor

Kent Woods prepared a report for the Department of Health: 'The Prevention of Intrathecal

Medication Errors' (April 2001). The report identified the need for non-Luer systems, which would

prevent the cross-connection of devices used for administering intrathecal medication3.

2.2.0 National Patient Safety Agency (NPSA) Alerts

On 24 November 2009 the NPSA published Patient Safety Alert NPSA/2009/PSA004, regarding

'Safer spinal (intrathecal), epidural and regional devices’ – Parts A and B.

Part A of the alert states: “From 1 April 2011* all spinal (intrathecal) bolus doses and lumbar puncture

samples should be performed using syringes, needles and other devices with connectors that will

not also connect with intravenous equipment.”4

Part B of the alert states: “From 1 April 2013 all epidural, spinal (intrathecal) and regional

anaesthesia infusions and bolus doses should be performed with devices with connectors that will

not also connect with intravenous equipment.”5

In order to establish the content of this NPSA alert and to achieve compliance with its requirements,

an NPSA External Reference Group (ERG) was formed comprising healthcare professionals and

representatives from the healthcare industry. The ERG provides guidance on the implementation of

the alert and the content of Update Newsletters.

The ERG produced a list of testing criteria, which includes mechanical and microbiological aspects,

in order to evaluate new non-Luer connection systems.

2.3.0 Non-Luer Connector Systems

In response to the NPSA alerts, manufacturers of medical devices brought to market various

alternatives to the standard Luer connector. These include: CorrectInject® (Smiths Medical),

UniVia® (Becton Dickinson Medical), Hall-Lock® (Flexicare), Neurax® (B-Link), and Surety®

(INTERVENE)6. Each manufacturer produced a range of syringes and accessories, including those

used by pharmacy departments to store medicines, which require testing according to the ERG

criteria.

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2.4.0 NPSA External Reference Group (ERG) Criteria for Microbiological Integrity Testing

The Neuraxial Update Newsletter (Issue #2, February 2011) states “The importance of

microbiological integrity testing of prefilled neuraxial syringes”. The newsletter describes the

requirement for 20 syringes to be tested and gives details of whole- and partial-immersion testing of

syringes. The document makes reference to the 'NHS Pharmaceutical Quality Assurance Committee

Microbiological Protocol for the Integrity Testing of Syringes' and includes a picture of a distinctive

yellow document (referred to as ‘The Yellow Book’) in which the NHS protocol is found. The

description of the test in the newsletter is a summary of the protocol in The Yellow Book. However,

NPSA guidelines do not specifically direct manufacturers to follow The Yellow Book protocol6.

2.5.0 NHS Microbiological Protocol for the Integrity Testing of Syringes (The Yellow Book)

This document, on which the summary found in the Neuraxial Update Newsletter (Issue #2, February

2011) is based, is the current standard for syringe integrity testing in the UK7.

2.6.0 Microbiological Integrity Testing of Surety® Syringes

2.6.1 MVS Microbiological Integrity Tests of Surety® Syringes (MVS 2011a, MVS 2011b and

MVS 2012)

a) MVS 2011a

MVS (Microbiological Validation Service) Ltd (Sheffield) is an accredited and reputable

testing centre for pharmaceuticals and medical devices. In 2011, MVS were instructed by

INTERVENE to conduct testing on Surety® syringes, and were provided with information for

the testing to be conducted. This information comprised the test details provided in the

NPSA newsletter6. It did not make reference to the full NHS protocol described in The Yellow

Book. The report on this test (see Appendix 10.1.1), involving 12 Surety® syringes of various

sizes, was published in January 2011. The results show that one Surety® syringe had

allowed the ingress of inoculated organism during the whole immersion-test, hereby referred

to as a 'positive test result'.

The LOT numbers of the syringes supplied for MVS 2011a (100901) correspond to Surety®-

lock syringes.

The report (MVS 2011a, Appendix 10.1.2) states,

“It was noted at the end of the test that for the sample where B. diminuta was present

inside the syringe, the cap could be pushed on further until it clicked in place. It may be

concluded that the failure was almost certainly due to the syringe not being adequately

sealed.”8

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b) MVS 2011b

Following the results of MVS 2011a, a second test was carried out by MVS at the request of

INTERVENE in July 20119. The results of this test were combined with the initial test results

to produce a new report. On the insistence of Professor Shams, MVS omitted the positive

test result described above, as it was considered to be the result of operator error. Mr

Gidney proposed at the time, and Professor Shams agrees in hindsight, that the inclusion of

the positive result, with an explanation as to its presence, would have been more

appropriate.

The LOT numbers of the syringes supplied for MVS 2011b correspond to Surety®-lock and

Surety®-slip syringes9.

c) MVS 2012

A third test on 120 Surety® syringes (20 of each size) was carried out by MVS in April 2012,

following the protocol described by the NPSA guidance, as instructed by Professor Shams.

The report (see Appendix 10.1.3) found no inoculated organism in the Surety® syringes

tested10.

The LOT numbers of the syringes supplied for MVS 2012 correspond to Surety®-lock and

Surety®-slip syringes10.

2.6.2 SMTL Microbiological Integrity Testing of Surety® Syringes (SMTL 2012)

On the direction of the ERG, the Surgical Materials Testing Laboratory (SMTL) at Bridgend

conducted microbiological integrity testing of Surety® syringes. During the whole immersion

tests two Surety® syringes showed positive test results for inoculated organism. The report (see

Appendix 10.2.0) noted that “1 sample had a loose cap at end of testing, contamination in both

samples confirmed as inoculated organism.”11 These are also referred to as a 'positive test

results'.

The LOT numbers of the syringes supplied for SMTL 2012 correspond to Surety®-lock

syringes11.

2.7.0 Dye-intrusion Integrity Testing of Surety® Syringes

2.7.1 Quality Control North West Dye-intrusion Integrity Test of Surety® Syringes (QCNW

2012)

Following the results of SMTL 2012, the NPSA External Reference Group instructed Quality

Control North West (QCNW), to conduct 'dye-intrusion testing' of Surety® syringes.

According to QCNW,

“The dye intrusion test is a useful tool for assessment of syringe integrity under

conditions matching those used for patient products. It also introduces a physical

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challenge via the negative pressure exerted inside the syringe which would not normally

be experienced. This added dimension to the testing highlights and multiplies any

weakness in the physical integrity”

All Surety® syringes passed this test1 (Appendix 10.3.0).

The LOT numbers of the syringes supplied for QCNW 2012 correspond to Surety®-lock

syringes.

2.8.0 Pharmaceutical Aseptic Services Group (PASG) Statement 2013

Following the results of the dye-intrusion tests, the PASG issued a statement, which was reported in

the NPSA Update Newsletter (Issue #5, February 2013). The report suggested that the

microbiological results from MVS 2011a should be investigated. The newsletter states that a final

PASG position statement would be published following this investigation12.

* subsequently delayed by 12 months, as indicated in the Neuraxial Update Newsletter

Issue #2, February 20116

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3.0.0 Investigation Plan

3.1.0 PASG Requirements

A conference took place between Dr David Cousins, (Head of Safe Medication Practice, NPSA),

aseptic pharmacists Mr Peter Rhodes, (Chairman, PASG) and Mr David Lovett (Leicester), Mr Peter

Phillips (Director, SMTL) and QA pharmacist Mr Mark Santillo (Torbay Hospital). Mr Rhodes

subsequently spoke with Mr Marc Buckingham (Surety® Business Manager, INTERVENE Ltd) by

telephone on 18 January 2013. Mr Rhodes stated, “We are no longer deeply anxious, but we need

answers as to why we obtained the previous (positive) results”. He explained that it was necessary

to show a “due and proper process” in ensuring the safety of Surety® syringes, and that although he

felt this was complete with the dye-intrusion testing, it was still necessary for the microbiological

testing results to be investigated and accounted for.

3.2.0 Investigative Remit

This investigation sought to identify reasons for the positive test results demonstrated in the

microbiological integrity testing, in particular the differences in methodology used by different

laboratories, and on different occasions. The aim was to ensure that there are no fundamental

problems with Surety® syringes and provide objective evidence to enable PASG to advise its

members that Surety® devices are safe to use when storing medication.

3.3.0 Requirement for Additional Testing

On 14 February 2013, Mr Buckingham and Professor Iden Shams (Technical Director, INTERVENE

Group Ltd) visited Mr Santillo in Torbay Hospital to discuss the specific questions and concerns of

the PASG requiring investigation and response. Also discussed was the need for analysis of the

mechanics of the Surety® system in order to identify how the design of Surety® syringes may

influence microbiological integrity. Mr Santillo stated that there was no requirement for further

integrity testing.

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4.0.0 Investigation into Microbiological Integrity Tests

4.1.0 Microbiological Integrity Testing by MVS (Interviews with MVS staff 21 February and 01

March 2013)

On 03 December 2010 Professor Shams sent an email to Mr Kevin Gidney (Director, MVS Ltd),

requesting that MVS Ltd conduct tests on Surety® syringes as follows (taken from the email

between Professor Shams and Mr Gidney)13:

Microbiological Integrity Test comprising

a) 20 syringes filled with sterile Tryptone Soya Broth (TSB) sealed with the appropriate cap.

These broth filled syringes to be pre-incubated at 20-25C for 7 days, then 30-35C for 7 days

to ensure that the aseptic fill has been carried out correctly and that contents are sterile.

Turbidity or microbial growth to be reported

b) Whole Immersion Test

c) Inoculate a container(s) housing the syringes immersed in broth (TSB) with 1ml of the

18-24 hour culture of Brevundimonas diminuta. Incubate the containers for 14 days at 30-

35C. Following incubation remove syringes from the broth culture and examine each syringe

for turbidity/growth showing Brevundimonas diminuta access into the syringe. The integrity

of the syringe/hub system is confirmed providing that the broth in all syringes remains free

from growth.

d) These instructions included no direct reference to The Yellow Book. Mr Gidney reported

that he was not aware that the results of these tests would claim compliance to any such

methodology. Furthermore, no mention was made of the method for attaching syringe caps,

nor were instructions given regarding the testing of syringes or syringe caps after filling,

during incubation, or before whole immersion-testing.

Prior to testing in January 2011, MVS received samples stock of 10, 5, 3 and 1ml syringes (10 of

each) from LOT number 100901 which corresponds to Surety®-lock syringes. Mr Gidney reports that

not all of the syringes had LOT numbers with them. Lock syringes require a twisting-technique when

applied to a needle or cap. INTERVENE instructed that only 12 syringes should be tested in the first

instance.

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The test was conducted by Mrs Tracy Thornton, temporary operator at MVS Ltd, who described the

test procedure in an interview with Mr Buckingham as follows:

a) The Surety® syringes were filled with broth in sterile conditions in a suitable cabinet

b) After drawing the broth into the syringe, the syringe cap was applied in the following

manner:

● The syringe cap was placed on the flat work-surface in the cabinet

● The syringe was held by the barrel

● The syringe tip was pushed into the syringe cap until it 'clicked' closed

● No further checks of the syringe cap were made

● The syringes were placed together into a plastic bag, cap-downwards, which was

sealed and placed into a basket in the incubator.

c) Following incubation, the syringes were removed from the bag and placed in individual

bags with the broth containing bacteria.

d) Bags were handled by the sealed 'top' of the bag at all time.

The test report (MVS 2011a) produced on 13 January 2011 (see Appendix 10.1.1), showed a

positive test result in a 5ml syringe. Following the test, Mrs Thornton noted that the syringe cap could

be “...pushed on further, until it clicked, as if sealing”8. A telephone conversation between Professor

Shams and Mrs Elise Crowther (Managing Director, MVS Ltd) ensued, and a formal complaint was

filed with MVS, reference number 8, on 01 March 201114.

Professor Shams held the opinion that the operator had made an error, and had not applied the

syringe cap properly. This opinion can be corroborated by remarks made by Mrs Thornton, who

stated that 'pushing the cap on further' (highlight by the author) was possible. This does not

correspond to the mechanical action when applying a syringe cap to a lock syringe. Professor

Shams stated in interview with Mr Buckingham that he did not discuss the methos of syringe capping

with with Mrs Crowther because he assumed that this would be obvious.

Following a discussion with Professor Shams regarding the positive test result (on which the report

stated “It may be concluded that the failure was almost certainly due to the syringe not being

adequately sealed”) Mrs Crowther agreed to reissue the test report without reference to the positive

test results, and to carry out further tests according to the guidance set by the NPSA, as provided by

Professor Shams. These results were combined with the test results from MVS2011a.

The NPSA guidance was at the time the recommended criteria for the testing of non-Luer systems,

and may be regarded as a précis of The Yellow Book, which makes reference to the NHS protocol,

but does not state that it is only a summary, nor does it make it clear that those performing this test

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should use the full ‘Yellow Book’ protocol.

On 29 March Mrs Crowther emailed Professor Shams confirming her requirement for samples of

syringes for further testing, with LOT numbers. In this email, Mrs Crowther mentioned that the initial

test8 included two different types of syringe cap: “...one a push on type and one a screw on type”.

The email also makes reference to testing “...in strict accordance with the specified method...” but

does not state which method: Professor Shams' initial emailed instructions, the NPSA guidance, or

The Yellow Book. Professor Shams' reply explained that the test was required with lock syringes and

screw-type caps and that samples would be provided. INTERVENE has only ever manufactured one

type of syringe cap for Surety® syringes, but two types of syringe: it is the syringe which determines

whether the mechanism is -slip or -lock. Mrs Crowther's comments suggest that there may have

been both -slip and –lock syringes tested. LOT numbers for the Surety® syringes supplied for MVS

2011b correspond to both Surety®-lock and Surety®-slip syringes.

During interview, Mrs Thornton was shown a Surety® lock syringe and cap. She reported that both

were different to those used in the test; that is, “the syringes (that were tested) did not have 'lugs'”

(suggesting they were Surety®-slip syringes), and that “the caps were not the same – there was no

'thread'”. Mrs Thornton explained that on applying the caps she pushed the syringe onto the cap

“hard, with no twist”. She reported no audible or palpable sign, for example a 'click' or dramatic

change in resistance, demonstrating it was engaged properly. This may suggest that slip syringes

were used.

Following MVS 2011a, Mrs Thornton, Mr Gidney and Mrs Emily Rodgers, Operations Director, MVS

Ltd state that they discussed the report at length, including the manner in which the syringe caps

were applied. Mrs Thornton agreed that it was likely she was 'more careful' in applying the caps

during MVS 2011b and MVS 2012. These subsequent tests were completed by Mrs Thornton and

reports produced, showing no positive test results in either MVS 2011b or MVS 2012. MVS 2012

comprised a larger number of Surety® syringes (20 of each), consistent with instructions given in

The Yellow Book.

Neither MVS 2011 (a and b) nor MVS 2012 test reports bore reference to any specific methodology

for the application of syringe caps, and no such methodology was provided by INTERVENE. Syringe

caps were not checked or tested after fitting, storage, transportation or incubation.

4.2.0 Microbiological Integrity Testing by SMTL (Interviews with SMPU and SMTL staff on 19

March 2013)

On 06 December 2012, Surgical Materials Testing Laboratory (SMTL) Ltd published a report on the

testing of a range of non-Luer connector syringes from INTERVENE (Surety®), Smiths Medical

(CorrectInject®), and Flexicare (Hall-Lock®). The report demonstrated that the testing conducted

was consistent with that described in The Yellow Book.

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The report stated that filling of the syringe was conducted at the University Hospital of Wales, Cardiff:

“The syringes were filled with Tryptone soya broth (TSB) in EU grade A environment

provided by positive pressure, unidirectional air flow isolators, with type D transfer

chambers, sited in an EU Grade D clean room, at the University Hospital of Wales .

Operators carrying out process are trained in aseptic technique, carry out similar

processing each day and have their technique revalidated every 6 months. Syringes

were filled avoiding manual contact with critical areas of the syringe during filling. The

syringe caps were placed loosely onto the syringes from their packaging using no-touch

technique and then manually tightened before being transferred from the Grade A work

zone.”12

The report shows two Surety® syringes produced positive test results, in that they showed

contamination with what was confirmed to be inoculated organism following the full immersion test.

Notes on the report state:

“1 sample had a loose cap at end of testing, contamination in both samples confirmed

as inoculated organism.”12

During an interview with Mr Buckingham on 19 March 2013, Mr Paul Spark (Laboratory Manager, St

Mary's Pharmaceutical Unit [SMPU], Cardiff) confirmed that his staff had filled the syringes for SMTL

as stated in the report. Mr Spark could not confirm who had actually performed the filling, as he was

not there when the work had been carried out on a Saturday morning “...as a favour... to Mr Peter

Phillips at SMTL”. As such, no product, batch or operator records of the filling operation had been

kept, which is contrary to the routine record-keeping for the unit when filling syringes with medicines.

Mr Spark explained that the syringes had been filled by hand, as they might be for filling with

chemotherapy drugs. Mr Spark stated that this was not part of the normal procedure at SMPU. He

confirmed that the caps were not checked after filling, and he could not confirm whether the filled

syringes were transported to SMTL via hospital transport or Royal Mail.

Mr Spark confirmed that his staff’s competencies were validated using the test described in the

'Aseptic Dispensing in the NHS' book every 6 months, but that this did not include any test for fitting

or checking caps. Mr Spark informed Mr Buckingham that there would normally be a worksheet

describing the process in detail, but not on this occasion. Mr Spark considered filling syringes with

TSB to be a “...straightforward and simple procedure”.

In order to identify the methods normally used in the unit, Mr Spark accompanied Mr Buckingham

into the aseptic unit at SMPU. The syringes used in the SMTL testing were not filled in this unit,

however Mr Spark assured Mr Buckingham that the processes were the same. Mr Buckingham was

introduced to Mr Matthew Lamb and Ms Joanne Brown, who allowed him to observe the process of

filling and capping syringes with medication using the isolators in the clean room. The observed

process was as follows:

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a) Mr Lamb filled syringes with medicine, then capped them using tamper-proof caps in a

cap tray. This involved holding a syringe in one hand and inserting the tip into the cap (held

in the cap tray). The caps used in this unit include a mechanism (part of the tamper-proof

feature), which confirms that the cap is on properly. The filled and capped syringes were

then removed from the cabinet and given to Ms Brown.

b) Ms Brown checked the syringes and labelled them. No further check of the cap was

made – physical or visual – and the syringe was dropped into a bag (syringe cap down) and

placed into a tray.

c) Mr Spark confirmed that all syringes filled at this unit used tamper-proof caps and that,

though some caps were not presented in a tray, there was no opportunity to see them being

fitted. Mr Spark stated that there was no reason to believe the process had been any

different when filling Surety® syringes.

During the interview with Mr Buckingham, Mr Phillips confirmed that records of LOT numbers of the

syringe samples were recorded and the syringes were inspected after their arrival from the

manufacturer. They were then sent via hospital transport to SMPU for filling. Dr Pamela Ashman

(SMTL) confirmed that on arrival from SMPU, via hospital transport (this cannot be verified), they

were inspected again. This did not involve checking of the syringe caps to ensure they had been

tightened.

Dr Ashman explained that any leakage of the syringe caps during incubation would show a sticky

residue in the bag, but clarified that this was not part of the checking process. This was confirmed by

Mr Phillips, who verified that there was no local protocol in place for checking for leaks during

incubation. Dr Ashman believed that there was no residue, and confirmed that “bags are

manipulated by the top, with the syringes placed in the bag cap-downwards”. Dr Ashman stated, “I

don't remember seeing any cap-up syringes”.

Following identification of the two 20ml syringes which showed positive test results for inoculated

organism, Dr Ashman confirmed that one of the caps was loose, but still on the syringe. The other

cap was firmly attached.

Mr Phillips confirmed his instructions to SMPU were: “Half-fill and cap the syringes aseptically and

return to us at SMTL”. He confirmed that SMPU uses BBraun Tamper Evident caps.

Mr Phillips confirmed that the unit followed The Yellow Book, a protocol with which they are familiar.

He stated that this protocol was discussed with Ms Rachael Burton, who represented Aseptic

Pharmacy on the Wales Neuraxial Connectors Reference Group, and worked with Mr Paul Spark in

SMPU.

Mr Phillips explained that SMTL had followed The Yellow Book with some well-documented

amendments. For example, small syringes were filled differently for partial-immersion testing. All

other aspects were as described in The Yellow Book.

15

4.3.0 Capping of INTERVENE Surety® Lock Syringes - Microbiology Laboratory Report,

University Hospitals Nottingham NHS Trust, 2013

Following advice by Mr Santillo, the pharmacy production unit at the Queen's Medical Centre,

Nottingham (QMC) was employed to perform the testing of syringe cap application using Surety®

syringes. The test was performed as follows:

a) 100 Surety® syringes of various sizes were filled with 2ml air and capped 'as normal'

b) The syringes were placed in a bag according to local procedures (cap-downwards)

c) The pharmacy technician (Mrs Samantha Garside) was interviewed to ascertain how the

syringe caps were applied. A demonstration was given as to how the Surety® connector has

been designed to form a seal. A protocol for achieving this has been drawn up (see 7.0.0).

The technician was asked to demonstrate that she understood the protocol and could

implement the stages described therein.

d) A further 100 Surety® syringes were filled with 2ml air and capped according to the

agreed protocol and placed into a bag in the same way as the first batch.

e) The bags were transported and stored in such a way that might simulate the stresses

placed on each device, were they to be filled with medicines and stored in line with local

protocol.

f) Following 7 days of storage, the bags were opened. The Senior QC pharmacy

technician (Mr Gary Ford), tested them for air-tightness, and reported his findings. Mr Ford

was not involved with the filling and capping of the syringes.

Mr Ford's report (QMC 2013) (see Appendix 10.4.0) found the following:

a) Sample size of 100 Surety® syringes - filled and capped with no training or local

protocol, 11 failed. Reasons for failure were a) not remaining air-tight, or b) the caps

dislocating completely.

b) Sample size of 100 Surety® syringes - filled and capped after training and the

introduction of a protocol, a) none failed the air-tightness test and b) no caps were

dislocated.15

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5.0.0 Discussion

5.1.0 Product performance can be attributed to the following:

5.1.1 Product design: is the product designed to perform the intended task in the intended

environment, for the intended user?

Luer-lock and Luer-slip syringes utilise a 6° taper and require a twisting mechanism to engage

the syringe to a cap, hub or other connector. The Luer-slip achieves connection when the male

Luer tip is pushed into the female Luer connector, and then twisted slightly to engage a

watertight seal through friction. Luer-lock features a threaded barrel on the male syringe-tip,

which engages with 'lugs' on the outside of the female cap, hub or connector by rotation. The

additional friction of the lugs inside the barrel thread offers extra protection from inadvertent

disconnection compared with Luer-slip. Key features of Luer taper connectors are defined in ISO

594 standards. The Luer taper has provided a reliable seal for connecting medical devices since

the 19th century.2

Surety® uses the same 6° taper as Luer, and employs the same connection mechanism:

Surety®-lock features 'lugs' on the female syringe-tip, which engage with threads inside the male

Surety® cap, hub or connector; Surety®-slip features an interface between female syringe-tip

and male connector, using friction to form a watertight seal. A picture of the Surety® connection

can be found in Appendix 10.5.0.

Surety® has not changed in design since testing began in 2010. Despite comments made by

Mrs Rodgers (MVS 2011a8, and during interview with Mr Buckingham), there has never been

any more than one design of Surety® syringe cap. The mechanism for –lock and -slip syringes is

determined by the design of the Surety® syringe, not the cap.

5.1.2 Product manufacture: is the product manufactured to the requirements of the design,

taking into account all tolerances, and with a level of quality to ensure it is capable of the

intended purpose?

The moulds for Surety® syringes have been examined to ensure that components produced are

within design tolerances. Surety® has been designed to provided a reliable seal within these

tolerances, using the same 6° taper used in Luer connectors. Moulds for the syringe-tips are the

same for all Surety® syringes (see Appendix 10.6.0).

● MVS 2011a used products with LOT number 100901, which corresponded to

Surety®-lock syringes. However, some of the syringes used in that particular test were

not supplied with LOT numbers, and so it cannot be proved that Surety®-Slip syringes

were not tested as well. According to Mrs Thornton, at least some of the Surety®

syringes tested by MVS were of the -slip variant, which INTERVENE does not

recommend for the storage of drugs. This is further evidenced by the second test

17

conducted at MVS (MVS 2011b), which appears to have included a large number of

Surety®-slip syringes. It may be regarded as surprising that so many slip syringes

passed the test at all, given their lack of a cap-locking mechanism. This is testament to

the efficacy of the 6° taper.

● Surety® syringes tested by MVS and SMTL in 2012 used syringes from the same

batches. The two 20ml syringes which produced positive test results at SMTL were from

LOT number SL020-KD-L11. However, none of the MVS-tested syringes from products

with LOT number [#-KD-11] showed positive results, which suggests that this is not due

to a faulty batch.

5.1.3 Product quality: is the product tested and managed in accordance with quality

standards?

QC testing of manufactured product is to ISO 14835 (see Appendix 10.7.0).

5.1.4 Product supply: is the product supplied in timescales, quantities and formats which allow

it to perform?

The supply of Surety® syringes to MVS for the first test (MVS 2011a) may have included -slip

syringes, as reported by Mrs Thornton, but this cannot be confirmed using existing records at

MVS or INTERVENE. The supply of Surety® syringes to MVS for the second test (MVS 2011b)

certainly included -slip syringes. If -slip syringes were supplied for MVS 2011a, this may have

contributed to the positive test result, although the -slip syringes in the MVS 2011b did not give

positive results.

All Surety® syringes supplied for SMTL 2012 were of the lock-variant, and so no supply issue

can be said to have contributed to the positive test results in this instance.

5.1.5 Product use: is the product used in the manner in which it was intended, and in the

appropriate environment, by the appropriate user? Do 'normal use' and 'intended use' differ in

any way?

Surety® can achieve a reliable seal by rotating the Surety® syringe into a corresponding

Surety® connector 180°. A further 90° turn is possible within the thread of the syringe cap, but

without over-tightening (causing difficulty in removing the cap when required).

a) Syringe capping

The method by which syringes are filled and capped differed in the 3 units visited during this

investigation. There is no description of the process for 'filling and capping' syringes in The

Yellow Book7.

● At MVS, syringes were capped by placing the cap on a flat surface, and pushing the

syringe down onto the cap. This method does not account for lock-syringes, which

18

require a turning motion to apply the cap, nor slip-syringes, which use a slight twist when

applying the syringe to engage the connector surfaces with friction. No specific

difference in the method for applying the syringe caps between MVS 2011a, MVS 2011b

and MVS 2012 was identified, though the operator pointed out that this part of the

process was discussed prior to embarking on MVS 2011b.

● At SMPU, syringes were capped using a syringe cap tray, using syringe caps which

featured a tamper-proof mechanism. The cap tray was held by the operator in one hand,

and the syringe in the other. On engaging the syringe with the syringe cap in the tray, the

operator twisted the syringe until it was observed to have applied properly using a visual

cue, at which point the cap was withdrawn from the tray. There was no opportunity to

see caps not presented in a tray applied to syringes in the unit. No procedure for

checking the caps was observed. SMTL did not check the caps were properly applied,

though Dr Ashman stated that, in light of the positive test results in SMTL 2012, she may

have done so, were she to repeat the test.

● At QMC, syringes were initially capped by the operator who held the syringe and

cap in each hand, and twisted them together. No indication as to how much or how hard

the cap should be twisted was given, nor could guidance for this be found in any written

procedure or other document. Following discussion and the creation of the syringe cap

application procedure (see 7.0.0), all caps were applied using the method supported by

the product design, and subsequently tested by the QA pharmacist.

Were the failures caused by operators applying syringe caps incorrectly, one would expect

syringes capped in different ways to perform differently. Syringes tested prior to discussion of

syringe cap application at MVS, SMTL and QMC resulted in positive test results (in MVS 2011a

and SMTL 2012), and loosened or dislocated caps in all three units. After a discussion which

included the method of applying syringe caps (at MVS and QMC), and the creation of a protocol

for applying syringe caps (at QMC), no Surety® syringes displayed positive results.

At each testing unit, capped Surety® syringes were placed together in a bag, syringe cap

downwards against the bottom of the bag, and handled by the top of the bag. Syringe caps were

in contact with the bottom of the bag (and in the case of small-barrel syringes, with each other).

Syringe caps not properly secured may have loosened as they rubbed against one another and

the bottom of the bag. This may have been exaggerated by the narrow barrel of smaller

syringes. The effect of this was demonstrated in QMC 2013, in which 11 of the 100 syringes

tested prior to any discussion on the method of syringe-cap application failed to remain attached

to their syringe (in particular those of small syringes). After the discussion and written protocol no

caps became untightened during transportation. If it is possible that the action on the syringe

caps during transportation may result in loosening, then the same action can feasibly cause a

loose cap to tighten. This may explain why one of the syringes which showed a positive test

19

result in SMTL 2012 presented a 'tightly fitting' cap.

5.1.6 The effect of temperature

The incubation stage of microbiological integrity testing (MVS 2011a, MVS 2011b, MVS 2012

and SMTL 2012) involved periods were syringes were stored at 25°C and 35°C. This increase in

temperature can manifest changes in the component materials as they expand and contract due

to the effect of heat energy. This expansion and contraction acts upon the mated surfaces of the

connection and, if the forces overcome the friction, then the seal fails. The Luer taper connector

performs well in this test because the effect of heat at these temperatures does not cause the

seal to fail. Surety® uses the same taper as Luer, though with smaller dimensions, and therefore

the same rule applies: the Surety® connection is not overcome by the forces on the mating

surfaces caused by heat during incubation at 25°C and 35°C.

5.1.7 Product adaptation: has the product been adapted in any way, and how does this factor

into its performance?

There is no evidence that any of the Surety® syringes or caps tested were subject to any

alteration prior to testing.

5.1.8 Testing Methods

a) MVS 2011a did not follow any official protocol, but rather followed the limited instructions

provided by Professor Shams. In particular, the number of syringes tested was too low (3 of

each size, rather than 20 of each size). The method of testing, however (partial- and full-

immersion in broth) was the same, and so could not have contributed to the positive test

result obtained.

b) MVS 2011b and MVS 2012 followed the guidelines set out by the NPSA ERG for

microbiological integrity testing of non-Luer syringes, in which the particular difference was

in the number of syringes tested, not the tests themselves.

c) SMTL 2012 followed the full Yellow Book protocol. The partial- and full-immersion tests

conducted at SMTL were the same as those at MVS 2011a (albeit with a larger number of

syringes).

d) The dye-intrusion test conducted by QCNW 2012 represents a relatively new method of

testing integrity, which introduces additional testing factors such as the negative pressure

inside the syringe. These additional factors make dye-intrusion testing more robust than

microbiological integrity testing using broth, and so the lack of positive test results of

Surety® syringes during this test indicates the safety of Surety® syringes for storage of

medicines.

20

6.0.0 Conclusions and Recommendations

6.1.0 Information on testing of non-Luer syringes

a) NPSA guidelines for microbiological integrity testing of non-Luer syringes made

reference to, but did not include the full details of The Yellow Book. The initial request for

MVS to conduct testing on Surety® syringes in 2010 included the NPSA guidance, but did

not refer MVS to The Yellow Book, resulting in the test not meeting the requirements of the

NPSA.

● The NPSA should consider making future guidelines clearer, and specifically instruct

readers (who may not be familiar with pharmaceutical procedures) to refer to the

complete Yellow Book document.

b) The Yellow Book, which instructs users to 'fill and cap' syringes for microbiological

integrity testing, does not specify what is meant by the phrase 'fill and cap', and gives no

guidelines or instruction as to how this should be achieved. No consideration is given to the

use of different types of syringe cap, which may be presented in different ways (such as in a

syringe cap tray).

● The NHS should consider revising this document, making reference to the different

syringe caps and syringe capping methods available, and recommend that users refer to

manufacturer's instructions-for-use (IFU) before performing this procedure.

6.2.0 Supply of Surety® syringes

Tests conducted at MVS in 2011 included Surety®-slip syringes, which may have contributed to the

positive test result.

● Manufacturers providing syringes for such tests in future should consider whether

-lock or -slip connector variants should be tested, and ensure the appropriate products

are supplied to the testing organisation.

6.3.0 Microbiological Testing Methods

a) MVS 2011a and MVS 2011b included devices not tested in accordance with The Yellow

Book, in particular the number of syringes tested. MVS 2012 was conducted in full

accordance with NPSA guidelines for microbiological integrity testing of non-Luer syringes,

which makes reference to (but does not include all of) The Yellow Book protocol. These tests

differed only in the number of syringes tested, therefore these differences could not have

contributed to the positive test result in MVS 2011a.

b) The test conducted at SMTL appears to have followed the full protocol as set out by The

Yellow Book. Departures from this protocol, explained by Mr Phillips, are documented and in

no way could have affected the performance of the devices during the tests.

21

6.4.0 Syringe capping

Positive test results of Surety® syringes during microbiological integrity testing can be attributed to

the method of applying the syringe caps. None of the protocols used by MVS or SMTL included any

reference to the method of applying syringe caps, nor the checking of them after application, and no

such methods were described by INTERVENE. Syringe caps applied to Surety® syringes without

consideration for the method of doing so resulted in some positive test results. Following discussion,

and the creation of a protocol for applying syringe caps consistently, no tested syringes showed

positive test results. This demonstrates that, by following a protocol for the capping of Surety®

syringes, significant improvement in operator compliance can be achieved.

● Manufacturers of non-Luer syringes should consider the method by which the

product is designed to achieve a reliable seal, and provide IFUs and training support to

help pharmacy operatives perform this to a consistently high standard.

● Any organisations, including pharmacy units, contemplating the use of non-Luer

connector products for the storage of medicines should consider the method for applying

syringe caps. The protocol described in 7.0.0 is the appropriate method for applying

Surety® syringe caps.

● Laboratories conducting microbiological integrity testing should consider putting in

place procedures for syringe capping, to ensure that it is done consistently.

6.5.0 Syringe transportation

During transportation, if syringe caps are not properly applied there is a risk of them becoming

dislodged or loosened. The syringe cap on the syringe that showed a positive test result in SMTL

2012, which Dr Ashman described as 'firmly in place', may have been tightened by the same action

which may cause loosening during transportation.

● When transporting small syringes, whose caps may be at higher risk of interference

by other objects, consideration should be given to minimise this risk, such as avoiding

transporting large numbers of small syringes in the same bag.

6.6.0 PASG position statement

● Following the performance of Surety® syringes in the dye-intrusion tests conducted

by QCNW, and the findings of this investigation, the PASG should consider Surety®

syringes safe and appropriate for the aseptic filling and storage of medicines.

22

7.0.0 Syringe capping Procedure

7.1.0 Capping the Surety® Syringe

a) Hold the Surety® syringe barrel with forefinger and thumb of one hand, ensuring

graduation marks are facing forward, and the syringe-tip is facing toward the Surety®

syringe cap.

b) Hold the rim of the syringe cap with forefinger and thumb of the other hand, ensuring the

male component is facing towards the Surety® syringe.

c) Engage the syringe-tip and syringe cap, with both forefingers uppermost.

d) Rotate either the Surety® syringe, Surety® syringe cap or both 180º (half-turn)

clockwise so that each forefinger is now in line with the thumb on the other hand.

e) Release the Surety® syringe cap and reposition the forefinger and thumb so that they

line up with those on the Surety® syringe.

f) Rotate another 90º (quarter-turn) so that the forefingers and thumbs are in between one

another.

7.2.0 Testing the Surety® Syringe cap

a) Half-fill a number of Surety® syringes with air, and cap them following the procedure

above.

b) Store the syringes as per normal procedures.

c) Test the air-tightness of the cap by pushing and drawing back on the Surety® syringe

plunger.

d) Test the position of the cap by rotating it back 180º. If it engages at all, then the previous

position was properly engaged.

23

8.0.0 Acknowledgements

For help directing and reviewing this investigation, thanks to Mr Mark Santillo of South Devon Healthcare

NHS Foundation Trust.

Thanks are also due to Mr Peter Rhodes (Chairman, PASG) and Dr David Cousins for facilitating a

mutual understanding of the objectives and remit of this investigation.

For conducting the syringe capping test at Queens Medical Centre, Nottingham, special thanks to Mrs

Samantha Garside (Chemotherapy Lead Technician) and Mr Gary Ford (Senior QC Pharmacy

Technician).

For editing, proofing and authorising the final report, thanks to Mr Matthew Root (Managing Director,

INTERVENE Ltd) and Professor Iden Shams (Technical Director, INTERVENE Ltd).

This investigation would never have been possible without the willing, open and candid involvement by

all involved in this matter:

● Mr Kevin Gidney, Mrs Emily Rodgers, Mrs Elise Crowther and Mrs Tracy Thornton at

MVS Ltd.

● Mr Paul Spark, Ms Joanne Brown and Mr Matthew Lamb at SMPU, Cardiff.

● Mr Peter Phillips, Dr Pamela Ashman, Mr Matthew Aldermann and Mr Paul Hay at

SMTL, Bridgend.

24

9.0.0 References

1) Robert, Christopher (2012). Investigation into the Structural Integrity of Surety® Lock Syringes

through Dye Intrusion Test. Stockport NHS Foundation Trust, Quality Control North West.

http://www.ivltd.co.uk/ivltd.co.uk/Surety_Evidence_files/Surety-Dye-Intrusion-Test-Report-V3.pdf

2) "Luer Taper." Wikipedia. 1 March, 2013. 19 April 2013. <http://en.wikipedia.org/wiki/Luer_taper>.

3) Woods, Kent (2001). The Prevention of Intrathecal Medication Errors. A report to the Chief

Medical Officer. Department of Health, London. http://www.aagbi.org/sites/default/files/Kent

%20Woods%20report.pdf

4) National Patient Safety Agency Patient Safety Alert. Safer spinal, epidural and regional

anaesthesia devices – Part A. November 2009. www.nrls.npsa.nhs.uk/resources/type/alerts

5) National Patient Safety Agency Patient Safety Alert. Safer spinal, epidural and regional

anaesthesia devices – Part B. November 2009. www.nrls.npsa.nhs.uk/resources/type/alerts

6) National Patient Safety Agency External Reference Group Update Newsletter – February 2011.

http://www.patientsafetyfirst.nhs.uk/ashx/Asset.ashx?path=/Medicationsafety/NPSA-Neuraxial

%20Update%20Newsletter-Feb%202011-final.pdf

7) NHS Pharmaceutical Quality Assurance Committee. Microbiological protocol for the integrity

testing of prefilled syringes. 1st Edition. February 2006.

http://www.tset.org.uk/jsmallfib_top/upload/documents/Micro%20Protocol%20-%20integrity

%20testing%20of%20syringes%20Publication%20version%20OCT%2005.pdf

8) INTERVENE Group Ltd (February, 2011). Microbiological Integrity Testing of Surety® Syringes,

MVS Ltd, Sheffield

9) INTERVENE Group Ltd (July, 2011). Microbiological Integrity Testing of Surety® Syringes, MVS

Ltd, Sheffield

10) INTERVENE Group Ltd (2012). Microbiological Integrity Testing of Surety® Syringes, MVS Ltd,

Sheffield

11) Ashman, Pamela. Microbiological Integrity Testing of Syringes, report number 12/3783/2, 2012.

SMTL, Bridgend

12) National Patient Safety Agency External Reference Group Update Newsletter – February 2013.

http://www.patientsafetyfirst.nhs.uk/ashx/Asset.ashx?path=/Medicationsafety/NHSCB

%20Neuraxial%20Update%20Newsletter%20-%20%20February%202013.pdf

13) Professor Iden Shams, personal correspondence, December. 3, 2010

25

10.0.0 Appendices

10.1.0 MVS microbiological integrity test report of Surety® syringes

10.1.1 MVS 2011a

10.1.2 MVS 2011b

10.1.3 MVS 2012

10.2.0 SMTL microbiological integrity test report of Surety® syringes 2012 (SMTL 2012)

10.3.0 Quality Control Northwest dye-intrusion test report of Surety® 2012 (QCNW 2012)

10.4.0 Capping of INTERVENE Surety® Lock Syringes - Microbiology Laboratory Report,

University Hospitals Nottingham NHS Trust, 2013 (QMC 2013)

10.5.0 Picture of Surety® Connection

10.6.0 Surety® Moulds Declaration

10.7.0 Certificate of conformity to ISO 14835

26

MVS microbiological integrity test report of Surety® syringes

Appendix 10.1.1: MVS 2011a

27

Appendix 10.1.2: MVS 2011b

28

29

30

Appendix 10.1.3MVS 2012

31

Appendix 10.2.0: SMTL microbiological integrity test report of Surety® syringes 2012 (SMTL 2012)

32

Appendix 10.3.0: Quality Control Northwest dye-intrusion test report of Surety® 2012 (QCNW 2012)

33

34

Appendix 10.4.0: Capping of INTERVENE Surety® Lock Syringes - Microbiology Laboratory Report,

University Hospitals Nottingham NHS Trust, 2013 (QMC 2013)

35

Appendix 10.5.0: Picture of Surety® Connection

36

Appendix 10.6.0: Surety® Moulds Declaration

37

38

10.8.0 Appendix 10.7.0: Certificate of conformity to ISO 14835

39