Adrenaline Auto-injectors - Medicines and Healthcare products ...

Adrenaline Auto-injectors: A Review of Clinical and Quality Considerations

04 June 2014

Contents Abbreviations ....................................................................................................... 3 1

Lay Summary.................................................................................................. 4

2

Introduction .................................................................................................... 6 2.1

2.1.1

The issues.......................................................................................... 6

2.1.2

History of auto-injectors ...................................................................... 6

2.2

3

4

5

Background .............................................................................................. 6

Anaphylaxis.............................................................................................. 8

2.2.1

Incidence and treatment ...................................................................... 8

2.2.2

Pharmacokinetics of adrenaline ............................................................. 9

2.2.3

Doses needed to treat anaphylaxis ...................................................... 10

Quality Aspects ............................................................................................. 10 3.1

Drug Substance:- adrenaline .................................................................... 10

3.2

Design and Operating Principle of auto-injectors ......................................... 10

3.3

Finished product specification ................................................................... 12

Non-Clinical Evidence ..................................................................................... 14 4.1

Gelatine models ...................................................................................... 14

4.2

Pig models ............................................................................................. 16

4.3

Non-Clinical Conclusion ............................................................................ 16

Clinical Evidence ............................................................................................ 17 5.1

Intramuscular vs subcutaneous injection .................................................... 17

5.1.1 5.2

Site of injection ...................................................................................... 19

5.2.1 5.3

Conclusion ....................................................................................... 21

Appropriate needle length ........................................................................ 22

5.3.1 5.4

Intramuscular versus subcutaneous injection conclusions ...................... 19

Clinical Comment .............................................................................. 25

Post-marketing data ................................................................................ 26

5.4.1

Exposure data .................................................................................. 26

5.4.2

Clinical Comment:............................................................................. 28

6

Discussion and recommendations .................................................................... 28

7

Independent Advice Received .......................................................................... 30

References ......................................................................................................... 32


Abbreviations AAI

Adrenaline Auto-injector

ADR

Adverse Drug Reaction

BP

British Pharmacopoeia

BMI

Body mass index

Cmax

Maximum plasma concentration

CT

Computed tomography

DoH

Department of Health

EVDAS

EudraVigilance Data Analysis System

IM

Intramuscular

ISO

International Organization for Standardization

MAH

Marketing Authorisation Holder

NHS

National Health Service

Ph Eur

European Pharmacopoeia

PIL

Patient Information Leaflet

PK

Pharmacokinetic

RMS

Reference Member State

SC

Subcutaneous

STMD

Skin To Muscle Depth

Tmax

Time to maximum plasma concentration

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1 Lay Summary Adrenaline auto-injectors (AAIs) are intended for self-administration of adrenaline solution as an emergency, on-the-spot treatment during the early onset of symptoms of an anaphylactic reaction. As the progression of anaphylactic shock can be rapid, individuals with known allergy profiles are prescribed AAIs to carry with them at all times and they should be familiar with the operation of their specific auto-injector. The Medicines and Healthcare products Regulatory Agency (MHRA) has undertaken a review of all AAIs licensed in the UK on the recommendation of a coroner’s report into a death of a patient who had used such a device to self-treat anaphylaxis. This paper mainly discusses two of the issues raised by the coroner: 1. The most effective site for injection and the clarity of instructions 2. The most appropriate auto-injector needle length for injections into the muscle (intramuscular or IM) rather than injections into the fatty layer under the skin (subcutaneous or SC) administration The review has also considered information supplied with these products and whether clearer instructions and advice to prescribers, patients and carers could be provided in order to improve outcome. Anaphylaxis is a severe type of allergic response and is a life-threatening condition that can escalate into something very serious extremely rapidly. It can be associated with marked swelling of the face and neck causing constriction of the throat and upper airway, tightness of the chest and difficulty in breathing, a raised skin rash and sometimes a marked decline in blood pressure causing collapse of the patient. Known factors affecting severity of an anaphylactic episode include the degree of exposure to the substance responsible for the allergic reaction (the “allergen”) and other factors such as associated poorly controlled asthma, recent illness or strenuous exercise after exposure to the allergen. Fortunately, fatalities occurring as a result of anaphylaxis are rare and even less common when AAIs have been used. It is vital however that these devices are used correctly and an important part of the MHRA review has been to clarify information provided with these products to ensure as far as possible their correct use. Anaphylaxis can be fatal and in these unfortunate cases, death usually occurs very soon after contact with the allergen. Some allergens act faster than others. Food allergens can cause breathing to stop (respiratory arrest) after approximately 30–35 minutes; insect stings can cause collapse from shock after 10–15 minutes; and allergic reactions to medicines given by injection can cause death within 5 minutes. Therefore the speed of treatment of an anaphylactic reaction is of great importance and can have a significant impact on the patient’s recovery. It is widely accepted that an injection into the muscle is the best way for treatment with adrenaline to be administered. Even if the injection does not reach into the muscle, it will still have some effect, but it may take longer to relieve the symptoms of anaphylaxis. The best place for the injection is considered to be the side of the thigh in the middle between the hip and the knee, as recommended in the Resuscitation Council Guidelines. This review considered the data regarding all possible injection sites and concluded that patients should continue to use the middle of the thigh, as this represented the best location and minimised the risk of the needle going too deep and hitting bone or accidentally injecting adrenaline into a blood vessel or tendon which could cause additional problems. As everyone has different body shapes, concerns were raised about the length of the needle within the actual auto-injector devices and whether or not these were long enough to inject adrenaline into the muscle of all patients needing treatment for anaphylaxis. It is difficult to study how deep the needle goes into the thighs of patients using these devices. Models using blocks of gelatine and pork tissue have been used to represent the thigh and measure how far the adrenaline travels after being propelled from an auto-injector device following injection. The pork tissue model is considered more like the human thigh than the gelatine model but both models provide some data

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that shows that the spring-loaded auto-injectors can project the adrenaline beyond the end of the needle to as much as twice the depth that the needle penetrates. However, not all of the pork tissue studies confirm this. Furthermore, the models cannot fully mirror the real-life situation where other factors exist including local tissue blood flow and barriers such as fibrous tissue layers surrounding muscle, all of which may have an impact on how efficiently the adrenaline can penetrate into the muscle tissue. Two studies19,20 measured the skin to muscle distance in adults and in children and showed that the skin to muscle depth is greater than the length of the needle (15mm) in many people, particularly women due to a different distribution of fat from men. These studies also showed that Body Mass Index (BMI) and skin to muscle depth are not directly linked and people with low BMI may have still have thighs with a high skin to muscle depth. The AAI devices are spring loaded and the manufacturers claim that the adrenaline is injected forcibly into the muscle tissue. This is supported by non-human studies which provide some reassurance that the adrenaline does penetrate beyond the exposed needle length. However, as outlined above, there are additional factors that may influence how well the adrenaline penetrates. The MHRA’s report was presented to and evaluated by independent panels of experts (Commission on Human Medicines (CHM) and the Chemistry, Pharmacy and Standards Expert Advisory Group) in January 2014 and a number of recommendations were made. The experts advised on improvements to the information for healthcare professionals and patients on the management of an anaphylaxis episode, they proposed that manufacturers should conduct studies to evaluate injection delivery and should improve the quality standards for AAIs. The full list of recommendations made is provided in this report. The recommendations are currently being taken forward by the MHRA for consideration at a European level. This will enable the different AAIs authorised across Europe to benefit from this review.

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2 Introduction 2.1 Background 2.1.1 The issues Adrenaline auto-injectors (AAIs) are intended for self-administration of adrenaline solution as an emergency, on-the-spot treatment during the early onset symptoms of anaphylaxis. As the progression of anaphylactic shock can be rapid, individuals with severe allergies are prescribed AAIs to carry with them at all times and they should be familiar with the operation of their specific brand of auto-injector. A coroner’s report raised four areas for consideration and investigation in relation to the death of a patient following use of an AAI for emergency treatment of an anaphylactic episode. The four areas were: 1. 2. 3. 4.

The need to contact emergency services after first use of auto-injector even if symptoms are abating The most effective site for injection and clarity of instructions The most appropriate auto-injector needle length for IM injection rather than SC administration The best position for transporting a patient following an anaphylactic event

The MHRA was asked to address the first three items. Item 1 was addressed by the MHRA during 2012. All marketing authorisation holders (MAHs) were required to clearly state in the Patient Information Leaflet (PIL) and/or labelling of all AAIs licensed in the UK that the patient should call 999 even if symptoms appeared to be abating. Although the review did not specifically address Item 4, it did consider whether improvements could be made to the information supplied by the manufacturers of these products, relating to instructions to be followed by the patient/carer and healthcare professionals at the scene of the emergency, as well as advice for follow-up. Therefore the scope of this paper is primarily to address items 2 and 3. In order to help with this review the MAHs for EpiPen (Meda Pharmaceuticals Ltd), Jext (Alk-Abello A/S) and Emerade (Namtall AB) were asked to provide: (a) (b) (c) (d) (e)

Evidence that a complete dose of adrenaline solution is delivered intramuscularly throughout the proposed shelf life of the product Evidence that the above can be delivered through clothing Any post-marketing clinical evidence that the product (adrenaline plus device) is effective in the treatment of acute anaphylaxis A summary of out of specification (OOS) results from stability studies conducted on all product strengths over the past three years Product complaints history (reported by either patients or healthcare professionals).

2.1.2 History of auto-injectors Auto-injectors were developed in the 1960s for military use following research between the American military and NASA. The original objective was to develop a self-injecting device that would inject atropine, the antidote for nerve agents in biological weapons. From this original design platform the AAI was developed and was introduced into the medical field approximately 25 years ago in the United States of America. The first marketing authorisation in Europe was for EpiPen® which was granted a Marketing Authorisation in Germany in 1989 and in the UK in March 1996. Subsequently other brands of AAIs were licensed: Anapen®, Jext® and most recently

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Emerade®. Anapen® is no longer marketed in the UK but is still available in other EU countries. Scope of review Currently the following AAIs are licensed in the UK for use in adults and children and were included in the review: Table 1: Licensed AAIs Product name

Container closure detail

Product licence number/Type of licence

EpiPen® Adrenaline (Epinephrine) Auto-Injector 0.3mg

Pre-filled cartridge encased in an autoinjector

PL 15142/0245

Marketing Authorisation Holder’s name and address

MEDA Pharmaceuticals Limited, Skyway House Parsonage Road

EpiPen® Jr. Adrenaline (Epinephrine) Auto-Injector 0.15mg Jext 150 micrograms solution for injection in prefilled pen

PL 15142/0246

Pre-filled cartridge enclosed in an autoinjector

Jext 300 micrograms solution for injection in prefilled pen Emerade 150 micrograms, solution for injection in prefilled pen

United Kingdom

PL 10085/0052 ALK-Abelló A/S Bøge Allé 6-8 PL 10085/0053

Pre-filled syringe encased in an autoinjector

Takeley, Bishop’s Stortford, CM22 6PU

DK-2970 Hørsholm Sweden

PL 42457/0001

Emerade 300 micrograms, solution for injection in prefilled pen

PL 42457/0002

Emerade 500 micrograms, solution for injection in prefilled pen

PL 42457/0003

European

NAMTALL AB Rapsgatan 7, SE-754 50 Uppsala, Sweden

European

No new clinical studies were required to be submitted in support of the original applications.

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2.2 Anaphylaxis 2.2.1 Incidence and treatment Anaphylaxis is a severe, life-threatening systemic reaction that can affect all ages. The clinical syndrome may involve multiple target organs, including skin, respiratory, gastrointestinal and cardiovascular systems. The essential underlying mechanism is the presence of biologically active chemical mediators such as histamine and tryptase released from mast cells or basophils. The complex signalling cascades that regulate mast cell activation have been extensively investigated and described in the literature 1. The true incidence of anaphylaxis is unknown. Epidemiological studies have shown differing results owing to differences in both definitions of anaphylaxis and the population groups studied; however the incidence is increasing in recent years. Prescribing of adrenaline increased by 97% between the years 2001 and 2005. It has been estimated that by the end of 2005 there were 37,800 people in England that had experienced anaphylaxis at some point in their lives2. There are very limited data on trends in anaphylaxis internationally, but data indicate a dramatic increase in the rate of hospital admissions for anaphylaxis in England, increasing from 0.5 to 3.6 admissions per 100,000 between 1990 and 2004: an increase of 700% (Figure 1)5.

Most of the data for the incidence of anaphylaxis have been derived from hospital databases, and it is widely believed that anaphylaxis is under-recognised and underreported3. Anaphylaxis can be triggered by any of a very broad range of allergens, but those most commonly identified include food, drugs and venom (including wasp and bee stings). The relative importance of these varies very considerably with age; with food being

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particularly important in children and medicinal products being much more common triggers in older people. Anaphylaxis remains a significant cause of mortality. Of 164 fatal reactions identified between 1992 and 1998 in the United Kingdom, around half were caused by drugs. Of those not caused by drugs, half were related to venom and most of the remainder to food3. With the increase in food allergies, the Office of National Statistics (ONS) started recording deaths from anaphylaxis due to food allergies separately from anaphylaxis due to other causes in 2002. When anaphylaxis is fatal, death usually occurs very soon after contact with the trigger. From a case-series, fatal food reactions cause respiratory arrest typically after 30–35 minutes; insect stings cause collapse from shock after 10–15 minutes; and deaths caused by intravenous medication occur most commonly within five minutes. Death never occurred more than six hours after contact with the trigger Studies of fatal and near-fatal anaphylaxis in humans delineate risk factors for anaphylaxis such as pre-existing asthma, a current asthma attack, food allergies (particularly peanuts, tree nuts and shellfish), reaction to trace amounts of foods and use of non-selective β-blockers4. Other factors include recent infection, intense exercise after the exposure and concurrent exposure to other allergens such as pollen in pollen allergic individuals. Treatment Early intramuscular adrenaline is the optimal treatment for patients suffering anaphylaxis5. Most studies of fatal anaphylaxis show that a lack of, or delay in, administration of adrenaline is a frequent factor in death, whereas early administration of adrenaline even in severe attacks is associated with survival. The median time to respiratory or cardiac arrest is reported to be 30 minutes for food- and 15 minutes for venom-induced anaphylaxis, so adrenaline usually needs to be administered before medical help is available. However, self-injectable adrenaline is underused even when it is available4. The recommended dose for auto-injectors is 300-500 µg for adults and 150-300µg for children depending on body weight (10 µg/kg). One injection from an auto-injector should be given immediately when symptoms are recognised and a second injection can be given 5-15 minutes later if symptoms are not improving. Therefore patients known to be at risk of anaphylaxis should have access to at least two AAIs. The Resuscitation Council guidelines advise that patients should always be observed after treatment for anaphylaxis, for at least 6 hours and up to 24 hours in adults and for 12 to 24 hours in children, as symptoms can recur up to 24 hours after the initial reaction (this is called a biphasic reaction). The incidence of biphasic reactions is reported as 1-20% and unfortunately it is not possible to predict which patients will experience a biphasic reaction.

2.2.2 Pharmacokinetics of adrenaline Adrenaline is a naturally occurring substance produced by the adrenal gland in the body and secreted in response to exertion or stress. Endogenous plasma concentrations of adrenaline in normal subjects are in the range 30–160 ng/L. Adrenaline is rapidly destroyed in the gut if swallowed and therefore needs to be given by injection. The effects of adrenaline after subcutaneous (SC) injection (injection into the fatty tissue beneath the skin) are produced within 5 minutes but increase more slowly, taking 30 minutes to reach optimal levels compared with a more rapid peak after intramuscular (IM) injection (injection into the muscle)6.

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The amount of adrenaline in the blood is halved in about 2.5 minutes. However, by subcutaneous or intramuscular routes, local constriction of the blood supply slows the absorption, so that the effects build up and last much longer than the half-life of 2.5 minutes would predict7. Adrenaline does have side effects, mainly on the heart (fast or irregular heartbeat, or angina).

2.2.3 Doses needed to treat anaphylaxis Even though adrenaline is considered to be the optimal drug for use in connection with anaphylactic or threatening anaphylactic reactions, very little is known about what doses or plasma concentrations are required in this context. The recommended dose of adrenaline is usually within the range 5-10 µg/kg bodyweight but higher doses may be necessary in some cases. When adrenaline is delivered by an auto-injector device the following are recommended doses: in children between 15 kg and 30 kg in weight the usual dose is 150 µg and in adolescents and adults the recommended dose is 300 to 500 µg. There is a risk of overdosing small children with a body weight of under 15kg with an auto-injector so these are not generally recommended for such small children. The following intramuscular doses are recommended in the Resuscitation Council Guidelines which are specified as being in the context of administration by a healthcare professional: > 12 years:

500 µg IM i.e. same as adult dose 300 µg if child is small or prepubertal

> 6 – 12 years:

300 µg IM

> 6 months – 6 years:

150 µg IM

< 6 months:

150 µg IM

Most patients only require one dose but the dose can be repeated after 5-15 minutes if symptoms do not improve or recur. The scientific basis for the recommended doses is weak. The recommended doses are based on what is considered to be safe and practical to draw up and inject in an emergency.

3 Quality Aspects 3.1 Drug Substance: adrenaline The European Pharmacopeia (Ph Eur) is a publication detailing the official European quality standards for ingredients of medicinal products. The quality of the drug substance adrenaline is controlled according to the Ph Eur. specification in all of the licenced AAIs.

3.2 Design and Operating Principle of auto-injectors All AAIs comprise a sterile adrenaline solution filled into a container consisting of either a glass cartridge (also known as a carpoule) or pre-filled glass syringe with a fixed needle. In all cases they are made from glass suitable for injections. There are two fundamental designs for AAIs licensed in the UK:

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-

the cartridge type injector for example EpiPen® and Jext®

-

the syringe type injector for example Emerade®

Each auto-injector brand has a different delivery/administration system. Likewise the firing mechanism which provides the force behind the actual injection process which pierces the skin and enters the outer (antero-lateral) thigh is unique to each brand. The assembled auto-injectors are enclosed in a “carry case” to protect them from mechanical shock and damage. In the cartridge type injectors the volume of adrenaline solution that the auto-injector contains (the fill volume) is significantly larger than the actual volume of adrenaline solution intended to be injected (the delivered volume) so unused solution remains in the activated auto-injector after use. In the case of EpiPen the volume of adrenaline delivered is the same in both the adult and the paediatric injectors: the concentration of adrenaline in the solution is adjusted to give the different doses (150 µg for paediatric use and 300 µg for adult). Conversely the paediatric and adult versions of JEXT and Emerade auto-injectors contain the same concentration of adrenaline solution but the delivered volume is adjusted to achieve the correct paediatric dose. As delivered volume relates to the quantity of adrenaline actually injected it is a critical test for all AAIs to ensure delivery of the intended dose throughout the shelf life of the product. During a conventional manual injection i.e. one given by a healthcare professional to an individual in a medical setting, the force to move the solution in a pre-filled syringe is provided by the thumb pushing the plunger. An auto-injector is generally intended for self-administration by an individual or by a family member or friend. Prior to use the plunger and needle are concealed within a plastic shell. The injector is activated by pulling off a cap or pressing a button and either swinging the AAI towards the thigh or placing it against the thigh. A coiled spring is then released inside the auto-injector which pushes the plunger to inject the solution into the patient. The adrenaline solution is pressurised to varying degrees depending on the design of the AAI. When the autoinjector is used the needle is propelled forward to pierce the skin and deliver the solution. Discussion on the design of AAIs There has been considerable discussion in the medical community and in patient groups regarding the suitability of the needle length used with AAIs with respect to the ability of the injectors to deliver the adrenaline solution to the optimal body compartment i.e. into the thigh muscle tissue. All UK licensed products claim to deliver an intra-muscular injection of adrenaline. The way the AAI is used (its method of operation), the force behind the adrenaline solution and how these factors contribute to the dose delivery have also been debated. Evidence of how these factors influence the site of deposition in the tissue is based on limited studies using non-clinical models. These three issues (a) needle length (b) method of operation and (c) applied mechanical force are discussed in greater detail below. (a) Needle length As there are differences in AAI design and method of operation, the total needle length cannot be considered on its own, as a portion of the needle remains within the device once fired - unlike a manual injection. The extended needle length measurement

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provides an indication of the effective needle length available to deliver the adrenaline solution into the body and should be controlled. Schwirtz and Seeger11 reported “the mean exposed needle length was 15.36 mm (standard deviation [SD] 0.22) for Jext and 15.02 mm (SD 0.25) for EpiPen”. Nonclinical evidence exists -using both ballistic gelatine and porcine models - to support that adrenaline solution from both EpiPen and JEXT auto-injectors penetrate some distance into body tissues beyond the needle tip (Refer to section 4. Non-Clinical Evidence, for study detail and discussion). This suggests that there are additional factors to take into consideration when determining where the adrenaline solution is actually deposited in the body:1. the method of operation of the respective auto-injectors, and 2. the force applied to the plunger by the firing mechanism. (b) Method of operation In all AAIs a safety cap is removed immediately prior to the actual injection sequence. The safety cap is at the opposite end of the device from the needle and once removed the device is considered to be “armed” for use. There are two principal methods used for the self-injection of adrenaline using auto-injectors. These are the “swing and jab” method or “place and press” method. EpiPen® utilises the swing and jab method of administration while JEXT® and Emerade® utilise the place and press method. The method employed is related to the activation force required for each delivery system. It is possible that there is some degree of tissue compression during both the “swing and jab” technique and the “place and press method”. This may result in a net decrease in the skin to muscle distance (STMD), enabling the solution to penetrate deeper into the tissues. (c) Force applied to the plunger by firing mechanism/power pack As liquids cannot be compressed, the adrenaline solution is pressurised to varying degrees depending on the individual device design and construction. This phenomenon theoretically causes the solution to be expelled beyond the needle tip to varying degrees and is device dependent. This is confirmed by studies where ballistic gelatine has been used as a substitute for human tissue (Refer to section 4. Non-Clinical Evidence). However, it is not known how this correlates to administration into live human tissue.

3.3 Finished product specification AAIs comprise a drug product i.e. the adrenaline solution, which is sealed in a glass container, with a device component (the injector) for delivering the solution. These elements form the finished product. The finished product specification is a set of characteristics and acceptance limits that each batch of finished product must comply with before it can be released for sale. As a part of this review the finished product specifications were examined for all licensed AAIs. The tests applied to auto-injectors can be sub divided into the following: a. Tests to meet the Ph Eur general requirements for injections b. Tests to monitor adrenaline content, degradation substances and other impurities and levels of important ingredients such as sodium metabisulphite (an antioxidant used to stabilise the adrenaline solution)

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c. Functional tests to monitor the performance of the delivery mechanism d. The British Pharmacopeia (BP) monograph controls the quality of the adrenaline solution to a minimum standard in respect of the content of the active pharmaceutical ingredient, pH and degradation products. The above quality standards are reviewed for each individual product in an application for a marketing authorisation in the European Union. Functional tests related to the delivery mechanism Although these quality characteristics are controlled in the design of the products, they should be brought together in the finished product specification: 1. Delivered volume The delivered volume (the volume of adrenaline solution released when the autoinjector is deployed) requires tight control. 2. Delivery time The time taken to eject the adrenaline solution from the needle (the delivery time) is critical. As anaphylaxis progresses very rapidly, delivery time should be measured for all AAIs and should reflect a rapid delivery time in the order of seconds. 3. Exposed needle length The design of an auto-injector should ensure that consistent extended needle length occurs when the device is activated by a patient. 4. Activation Force All auto-injectors need to be activated by the patient before use. This is achieved by removing the safety cap and either swinging or pressing the needle end of the device to the thigh. These operations should be possible for both adults and children; however the safety cap should not come away too readily either, to prevent accidental removal. The force required to initiate the injection cycle should be consistent during storage to ensure that AAIs are usable throughout the shelf-life period. Discussion on functional testing The approach to functional testing varies between manufacturers. Our recommendation is that the acceptance criteria for functional tests should be based on a critical evaluation of historical long-term stability data with consideration of the impact on the delivered dose. Critical quality attributes which ensure the correct dose is delivered within defined time limits should be included in the release and shelf-life specification requirements. AAI product defect reporting and product recalls In the past two years quality defects have been reported regarding Anapen® and JEXT. A recall was issued by the MHRA Defective Medicines Report Centre (DMRC) for all strengths of Anapen in 2012, based on finished product testing failures to deliver the correct volume and/or delivery time failure. The JEXT quality defect was announced by the Reference Member State (RMS) Sweden and a Class II recall notification was issued by the DMRC in early December 2013. In January 2014 Sweden (RMS) issued a Class II recall notification for Emerade due to suspected technical defects, at this point the

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product had not been launched within the UK. In addition there was a recall in October 2013 concerning another auto-injector product (which does not contain adrenaline) as a small number of syringes potentially had needles protruding through the needle shield. Assembly of “ready to use” injectable drug products is complex and these incidents suggest that additional controls might be necessary. AAIs are intended for single use and are classified as medicinal products with an integral delivery system (device). The device aspects of AAIs should be designed and qualified by the manufacturers to be fit for purpose with relevant supporting data on the development and manufacture of the device submitted in the marketing authorisation application reviewed by the Licensing Authority. Although the AAIs do not require a CE mark, they should be compliant with the relevant sections of standards published by the International Organization for Standardization (ISO), for example BS EN ISO 11608 Needle-based injection systems for medical use. They should meet the essential requirements of Annex 1 of the Medical Device Directive. The marketing authorisations for AAIs should be reviewed with respect to ensuring the finished product specifications and in-process controls (IPCs) for the device assembly process are adequately described and that a summary of the following is provided. 1. The design and qualification of the delivery system i.e. the device development history. 2. A summary of identified critical failure modes for the delivery system. 3. Updated finished product specifications including appropriate functional tests with sample size tested per batch and the acceptable quality level (AQL) for each test. 4. An overview of how the essential requirements of Annex 1 of the Medical Device Directive are met. Product Stability Update At the request of the MHRA, the manufacturers of the licensed AAIs provided updated stability data for their products to the MHRA for review.

4 Non-Clinical Evidence Two main non-clinical models have been cited in the MAH’s response to the MHRA’s request to provide further information on their products; gelatine and porcine tissue. Both have been used in the study of ballistics and weapons research. A brief discussion is presented below of both models in the context of their usefulness for assessing the performance of injector pens in delivering adrenaline to the muscle layer.

4.1 Gelatine models Ballistic gelatine is reported as being designed to simulate living soft tissue (Nicholas and Welsch, 2004)8. It is regarded by the US military as the standard for evaluating the effectiveness of firearms against humans because of its convenience and acceptability over animal or cadaver testing. Use by the military would appear to have resulted in the acceptance of the use of gelatine in ballistic and other research and it has been referred to in some publications (including those cited by the MAH) as a ‘validated tissue simulant’. However, its use appears to be based more on custom and practice than inherent suitability. It was first used in 1960 and various techniques were used to measure the kinetic energy of a projectile travelling through a block of gelatine. Early models were not compared to living tissue in a quantitative or reproducible way.

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In the first of many papers in the mid to late 1980s, researchers at the Letterman Army Institute of Research (LAIR) used both live swine (50-70 kg) and gelatine blocks to test bullets and subsequently compared the results9. Although the paper did not include specific comparisons between gelatine and animal tissue, the LAIR team and many other researchers afterward cited this published paper as the foundation for using Fackler’s gelatine model as an approximate or equivalent substitute for animal tissue. A paper by Fackler and Malinowski (1985)10 states that the depth of penetration measured in living swine leg muscle was reproduced in the gelatine within 3%. These findings and the convenience of using non-animal or non-cadaveric tissue appear to have led to the use of gelatine on its own. While the conditions and preparation of the gelatine have been standardised to some extent, and can be used to compare the behaviour of projectiles within that limited context, the model cannot be regarded as fully representative of living tissue, primarily because it is homogeneous rather than heterogeneous. The different types and textures of animal tissue, particularly bones, cannot be regarded as being adequately simulated in a gelatine alone system. Also, differences in the gelatine such as method of preparation, concentration and temperature mean that consistency between laboratories cannot be guaranteed. The acceptance of the model for ballistics has led to its use in investigating the track of injections from auto-injectors. In this context, it could be suitable for investigating the depth to which a drug might be injected, as the only tissues to be penetrated are skin and fat, unlike in ballistics research, where the full range of tissues could be encountered. It might be acceptable, for example, to use gelatine models to rank devices against one another for depth of penetration, but it would not simulate clinical conditions as closely as live animal or human tissue. A study comparing three injector pens was reported by Schwirtz and Seeger (2012)11. Three AAIs (Jext, EpiPen® and Anapen) were tested for, amongst other features, the injection depth and estimated volume of black ink delivered into ballistic gelatine. The mean maximum injection depths in gelatine within 10 seconds were 28.87 mm (SD 0.73) for Jext, 29.68 mm (SD 2.08) for EpiPen® and 18.74 mm (SD 1.25) for Anapen (Figure 2). The length of the EpiPen® and Jext needles is 14.3 mm and the Anapen needle is 8.9 mm to 9.9 mm.

Figure 2: Photographs showing the total injection depth into gelatine 10 seconds after activation of Jext (A), EpiPen (B), and Anapen (C), measured as the vertical distance from the surface of the gelatine to the lowest part of the ink area using digital image processing.

(Photographs copyright of Schwirtz and Seeger, 201212)

A previous pilot study reported by the same authors (Schwirtz and Seeger, 2010) 12 included a simulation of firing two AAIs through clothes, EpiPen® Junior and Anapen® Junior. Each auto-injector was fired into ballistic gelatine in the presence or absence of a

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piece of denim (a double seam of Levi’s blue jeans). The activation force was recorded, and the effective (exposed) needle length was measured by a calliper after the device was removed from the ballistic gelatine. The presence of denim did not alter the activation force or effective needle length of either of the AAIs.

4.2 Pig models Based on current knowledge, the pig as an animal model for human skin is generally accepted as being the most representative of human skin13 and it is commonly used in pharmaceutical development for local tolerance and skin penetration studies. Given the difficulty in generating clinical data on injector pens, the use of the pig for this purpose is considered appropriate and the most valid model currently available. The MAH for Epipen® has cited a study conducted by the US military on the depth of penetration into porcine thighs achieved by the EpiPen® to address the question of its performance in obese patients14. Adrenaline from 21 EpiPen® devices was mixed with methylene blue as a colour tracer and triggered into the lateral aspect of 21 cadaver pigthighs. The results show that with an exposed needle length of 14.3 mm, the mean ± SD delivery depth from the skin to the muscle was 26.9 ± 5.4 mm (p12.7 >15.9 greater than needle length (mm) Proximal thigh, no. (%) 17 (27) 19 (61) Mid-thigh, no. (%) 10 (16) 9 (29) Distal thigh, no. (%) 1 (2) 4 (13) Mid-calf, no. (%) 0 (0) 0 (0) IQR, Interquartile range *The median (IQR) is based on triplicate measurements

All children 93 (100) 6 (3-10) 54 (58) 20.8 (14.5-38.6) 114 (96-141) 16.8 (15.7-19.1) 56 (51-68)

12.0 (8.6-16.9) 8.8 (7.0-12.9) 7.9 (5.9-9.6) 8.5 (7.0-9.8)

36 (39) 19 (0) 5 (5) 0 (0)

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Figure 5 Percentage of children whose skin surface-to-muscle depth was greater than the Epipen (children > 30kg) or Epipen Junior (children