PREFILLED SYRINGES:
`THE CONTAINER OF CHOICE FOR TODAY’S INJECTABLES
`
`www.ondrugdelivery.com
`
`Novartis Exhibit 2021.001
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`“Prefilled syringes: the container of
`choice for today’s injectables”
`
`This edition is one in a series of sponsored themed
`publications from ONdrugDelivery Ltd. Each issue focus-
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`
`During 2008 we will be covering the following topics:
`
`June: Pulmonary Drug Delivery
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`and Excipients
`
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`
`“Prefilled syringes: the container of choice for today’s
`injectables” is published by ONdrugDelivery Ltd.
`Registered Office: Cedar Cottage, Newtimber Place Lane,
`Newtimber, West Sussex, BN6 9BU, United Kingdom.
`Registered in England: No 05314696.
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`The views and opinions expressed in this issue are those of the authors.
`Due care has been used in producing this publication, but the publisher
`makes no claim that it is free of error. Nor does the publisher accept
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`
`Front cover image “Inspection of staked needle” reproduced with
`kind permission from Nuova Ompi (www.stevanatogroup.com)
`
`CONTENTS
`
`The rise of prefilled syringes from niche
`product to primary container of choice:
`a short history
`Mathias Romacker, Dr Thomas Schoenknecht
`& Dr Ronald Forster
`Amgen Inc
`
`EZ-FillTM: Offering A New Choice In Glass
`Pre-Fillable Syringes
`Dr Michael N. Eakins
`Eakins & Associates
`
`4-5
`
`7-10
`
`Stelmi Rigid Needle Shield: The Successful
`Concept With The Anti Pop-Off Patented Design
`Jean-Pierre Merceille
`Stelmi S.A.
`
`14-16
`
`Current considerations and future directions
`for E-beam sterilisation in the prefilled
`syringes market: an overview
`By Guy Furness
`
`Company profile
`Hyaluron Contract Manufacturing
`
`18-20
`
`23
`
`The next generation of ready-to-use prefillable
`syringes: first in silicone-free solutions
`Bernie Lahendro
`West Pharmaceutical Services
`
`24-26
`
`Understanding the complexities involved in
`manufacturing and meeting customer’s
`expectations in delivering prefillable syringes
`Mr Harsh Shandilya
`Sewa Medicals Limited
`
`New Technologies for the Processing of
`Syringe Nests
`Klaus Ullherr
`Robert Bosch GmbH Packaging Technology
`
`28-30
`
`34-36
`
`New Market Insight into Prefilled Syringes and
`Closure Systems: Primary Data from Patients,
`Nurses, Physicians and Industry Experts
`Dr Arno Fries and Burkhard Lingenberg
`Gerresheimer AG
`
`39-41
`
`2
`
`
`
`www.ondrugdelivery.com
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`Novartis Exhibit 2021.002
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`www.pda.org/prefilled2008
`
`The Universe of Pre-filled
`Syringes and Injection Devices
`
`Regulators and industry experts will share case studies and
`address issues such as supplier qualification, materials of
`construction and considerations, filling and manufacturing,
`regulatory and compliance, safety systems and alternative
`injection devices.
`Don’t miss your chance to attend this one-of-a-kind meeting.
`This forum won’t be back in the United States until 2010!
`
`October 6 – 7, 2008
`San Diego, California
`
`Conference | Exhibition
`
`Novartis Exhibit 2021.003
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`INTRODUCTION
`THE RISE OF PREFILLED SYRINGES FROM NICHE PRODUCT
`TO PRIMARY CONTAINER OF CHOICE: A SHORT HISTORY
`
`Demographics in developed countries
`suggest that aging societies will see
`an increased usage of pharmaceuticals.
`Many of the innovative products will be
`large molecules like monoclonal anti-
`bodies, proteins and peptides which, for
`the foreseeable future, will all need to
`be delivered via the parenteral route.
`Prefilled syringes are now the
`primary container of choice for most
`parenteral drug delivery systems. This
`is due to a number of factors – chief
`amongst them the greater medication
`safety and increased convenience from
`using a prefillable device. Alternatives,
`like a vial and syringe combination,
`require several procedures in prepara-
`tion for the entire injection of the drug.
`Today the global market for pre-
`fillable syringes comprises more than
`2.2 billion syringes; over half are pro-
`duced as sterile versions, ready to be
`filled without further activities prior to
`filling. The rest are supplied as so-called
`bulk syringes, where washing, siliconi-
`sation and assembly with rubber parts
`have to be performed close to filling.
`The origins of
`the prefilled
`syringe’s rise as the preferred con-
`tainer were in the extremely success-
`ful market introduction of syringes
`as the drug delivery unit for heparins
`by Sanofi and Rhône Poulenc-Rorer
`(both now Sanofi-Aventis) in Europe
`in the early 1980s.
`Prior to this, prefillable syringes
`were seen as relatively insignificant
`niche market products. The follow-
`ing years saw demand for prefillable
`syringes explode, and they were soon
`used in all major therapeutic classes
`for inject able drug formulations.
`The breakthrough was achieved
`mainly by the clear advantages prefilled
`syringes have over traditional vials and
`ampoules, as the use of a prefilled
`syringe often involves nothing more
`than removing the syringe from the
`package and performing the injection.
`Together with the low overfill required
`for prefilled syringes compared to a
`classical vial, new markets in the bio-
`tech area were explored by the prefilled
`syringe. Over the last few years the
`
`main market for prefillable syringes
`opened up from Europe and spreading
`towards the US and Asia; both of the
`latter two up until recently being typical
`vial-based drug container markets.
`During the 1990s and early 2000s
`the prefilled syringe had become
`the primary drug delivery container.
`However, new challenges were raised,
`including broadening their field of
`application to biotechnology and new
`safety regulations.
`A number of other changes and new
`or different requirements have impacted
`on the prefilled syringe market over the
`past few years. We have seen a steady
`increase in the technical requirements
`on the (to-date) usually glass-based
`delivery container platform.
`Break resistance and tighter toler-
`ances for finger flanges and glass cone
`dimensions have changed the quality
`requirements for syringes. In addi-
`tion more complex formulations and
`protein-based active substances chal-
`lenged the common syringe produc-
`tion technology to increase process
`control for key production steps and
`implement substantial improvements
`in production technology.
`
`SOLUTIONS & ALTERNATIVES
`FOR SILICONE & TUNGSTEN
`
`Siliconisation of the glass barrel is
`one of the key process steps, as
`silicone is the lubricant required to
`allow movement of the rubber plung-
`er through the syringe forcing the
`drug out of the container to finalise
`the injection. Protein molecules can
`interact with silicone and therefore
`the amount of silicone sprayed into
`the barrel has to be controlled. A bal-
`ance must be struck in order to gener-
`ate reasonable gliding characteristics
`while retaining product stability.
`A number of syringe system solu-
`tions have been developed either to
`reduce the silicone amount signifi-
`cantly or to eliminate it. Low silicone
`systems can be achieved either by
`baking the silicone after application
`or by using a reactive silicone sys-
`tem applied as liquid and then being
`
`polymerised.
`Baking the silicone – which requires
`heating the siliconised syringe at a spe-
`cific temperature for an appropriate
`time – results in substantial stabilisation
`of silicone-sensitive drug formulations,
`as presented during the November 2007
`PDA conference on prefillable syringes
`and injection devices in Berlin.
`But it is not only the amount of
`silicone sprayed into the barrel which
`can create issues with drug stability.
`The distribution of the silicone inside
`the syringe should be homogeneous
`and uniform to generate a smooth
`sliding profile for the plunger stopper.
`This is of particular importance when
`syringes are combined with auto-
`injection devices and the administra-
`tion of the drug is not done by manual
`injection controlled by a human hand.
`Another point to be considered is
`the known tungsten sensitivity of some
`protein molecules. Manufacturers
`have developed several ways to reduce
`or eliminate tungsten as a product
`contact material. For glass syringes,
`manufacturers have introduced alter-
`native materials to replace tungsten
`as heat resistant material in key glass
`forming process steps. Such technol-
`ogy is now standard and available to
`stabilise sensitive proteins.
`together
`Tungsten
`residuals
`with silicone issues can be removed
`by using new innovative primary
`containers made from cyclo-olefin
`copolymer (COC) or cyclo-olefin
`polymer (COP).
`One manufacturer has developed
`such a system which is free of silicone
`due to full fluoropolymer film lami-
`nation of the syringe plunger stop-
`per. The fluoropolymer is sufficiently
`lubricious that the barrel does not need
`to be lubricated. Another approach to
`eliminate for example siliconisation is
`the use of chemical vapour deposition
`or plasma technology to generate non-
`silicone lubricant films on the barrel
`or piston, or on both.
`Together with these new technolo-
`gies and multiple accessories around
`the syringe, a real universe of drug
`
`delivery components are available,
`which can be combined to form cus-
`tomised and therapeutic class-focused
`innovative drug delivery systems.
`As an interesting aside, alternative
`drug delivery routes such as nasal,
`intradermal or even needle free are
`being introduced or close to market
`introduction, yielding individually
`patient convenient medication sys-
`tems with a syringe-based primary
`container for the drug formulation.
`
`Mathias Romacker
`Principal Business Analyst
`
`Dr Thomas Schoenknecht
`Director Drug Product &
`Device Development
`
`Dr Ronald Forster
`Director Process
`Development
`
`Amgen Inc
`One Amgen Center Drive
`Thousand Oaks, CA
`91320-1799
`United States
`
`T: +1 805 447 1000
`F: +1 805 447 1010
`
`www.amgen.com
`
`4
`
`
`
`www.ondrugdelivery.com
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`Novartis Exhibit 2021.004
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`CONVERGENCE OF INJECTORS
`WITH PREFILLED SYRINGES
`
`Returning to prefilled systems in needle-
`based applications, perhaps one of the
`most overt developments, most notice-
`able to the patients and medical pro-
`fessionals who use prefilled syringes,
`has been the combination of prefilled
`syringe with safety accessories and
`injection devices. This has transformed
`the prefilled syringe from a humble and
`relatively simple injection device into a
`true advanced drug delivery system.
`Historically we witnessed
`the
`emergence of pen devices for the
`delivery of insulin and human growth
`hormones. Those therapies typically
`required injection daily or even sev-
`eral injections daily, and at variable
`doses. Consequently the devices were
`able to provide multiple doses from a
`convenient primary container like a
`cartridge. A strong focus was on deliv-
`ering the correct described dose and
`innovations included digital devices,
`dose-correction features, larger car-
`tridges, higher doses and smaller dos-
`age increments, to name but a few.
`Frequent injection devices were
`initially reusable, and the users were
`able to perform up to several hun-
`dred annual injections after receiving
`proper training.
`The first pen was launched for
`insulin by Novo Nordisk in 1985.
`It took longer before the prefilled
`syringe achieved its current status of
`the primary container of choice for
`single- use, fixed-dose auto-injectors.
`The prefilled syringe is a different
`primary container for devices. It is typi-
`cally a fixed dose and can be up to 1 ml
`for subcutaneous delivery. This means
`that the plunger stopper needs to travel
`all the way through to the shoulder/end
`of the syringe. Many new therapies for
`indications such as rheumatoid arthritis,
`psoriasis, multiple sclerosis, anaemia
`and Crohn’s disease are fixed doses,
`given less frequently than every day.
`The very first auto-injectors were
`used with disposable (not prefilled)
`syringes. Early models were manufac-
`tured by Owen Mumford. This con-
`cept was then adapted for prefilled
`syringes. As they were reusable, there
`were many steps and they did not
`prevent accidental needle stick injury
`after they had been used.
`With the new indications a different
`patient type emerged – some with dex-
`terity issues – most of them demanded
`as the number one feature ease-of-use,
`
`and consequently as few user steps
`as possible. Other requested features
`were automatic needle insertion and
`dose delivery while the needle should
`not be visible before, during and after
`the injection, and the needle be locked
`away after the injection was finalized.
`
`The injection experience could be
`described best as having just three steps:
`1 Remove the cap
`2 Place device on the injection site
`(and release interlock)
`3 Press the triggering mechanism
`
`More human factor studies have
`been conducted and the outcome is vis-
`ible as it created a wide array of device
`options: No firing button (i.e. Ypsomed’s
`Silberhorn); new and different shapes
`(i.e. Bang & Olufsen Medicom’s
`Leva®), tamper evidence (i.e. BD’s
`Physioject™) or numerical cues
`(i.e. Owen Mumford’s SnapDragon)
`
`The marriage of disposable auto-
`injector and prefilled syringe also has
`its challenges:
`1 Combination products are now
`evaluated like a drug by regulatory
`authorities
`2 Project often includes three partners
`(pharmaceutical company; device
`maker; prefilled syringe supplier)
`3 A larger investment is required as
`assembly of syringe and device is
`necessary; furthermore higher capac-
`ity tools and moulding machines
`may be required for high volumes
`4 Management of robust large-scale
`manufacturing, infrastructure, pro-
`duction flow and device/syringe
`inventories
`5 Tighter specifications for prefilled
`syringe dimensions as delivery of
`whole dose needs to be guaranteed
`
`Examples for the above exhibit-
`ing reduced user requirements are
`Amgen’s SureClick™ device for
`Enbrel® and Aranesp® as well as
`Abbott’s Humira® Pen.
`
`In the years to come the market
`will see more drugs being launched
`with the aforementioned disposable
`auto-injector platforms. New needs
`for innovation may be driven by high
`viscosity drugs and volumes higher
`than 1 ml that need to be delivered via
`the subcutaneous route. Examples for
`the former are The Medical House’s
`ASI and Antares Pharma’s Vibex™.
`
`Leading inspection technology
`for injectables
`
`Cap closure
`integrity and
`cosmetics
`
`Chips and
`cracks
`
`Particulates
`in suspension
`and solution
`
`Piston defects
`and position
`
`InnoScan being the originator of the CVT Inspection Machine
`has implemented 20 years of focused development and
`experience in the 4th generation inspection machines.
`
`
`
`
`
`
`
`
`
`
` Reproducibility
` Highest Detection Rates - DR
` Lowest False Reject Rates - FRR
` Integral suppression of micro-air bubbles
` Suspension, solution, emulsion, lyo,
`media-fi ll
` Patented & proven technology
` Integral High Voltage Leak Detection
`
`Halle 6 · Stand D 40
`
`Sødalsparken 11, 8220 Brabrand, Dänemark
`Tel.: +45/86 26 56 77, Fax: +45/86 26 56 78
`innoscan@innoscan.dk, www.innoscan.dk
`
`Novartis Exhibit 2021.005
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`Where Drug Development, Delivery,
`Manufacturing and Packaging converge.
`
`There is a point where everything comes together. Where creativity and talent intersect
`with experience and capability. Where you can move forward with security and confidence.
`
`For years, Catalent Pharma Solutions has been at the vertex of the industry, providing
`innovation and operational excellence across the supply chain. With our proprietary
`technologies, expertise and global infrastructure, we can be a catalyst for your products'
`success from development straight through to commercialization.
`
`With Catalent, you will find the services you need to get your products to market faster.
`That is the point of best returns.
`
`For more information, contact us at +1 866 720 3148, email us at
`sales@catalent.com, or visit www.catalent.com.
`
`© Copyright 2007, Catalent Pharma Solutions.
`All rights reserved.
`
`Novartis Exhibit 2021.006
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`EZ-FILLTM:
`OFFERING A NEW CHOICE IN GLASS
`PRE-FILLABLE SYRINGES
`
`Prefilled glass syringes have shown strong gains in sales in the last few years and the annual
`increase is predicted to continue. In this article, Dr Michael Eakins, Principal Consultant of
`Eakins & Associates, describes how Nuova Ompi has planned and executed a new production
`facility for glass prefillable syringes presented in a tub format by utilising internal synergies
`within the Stevanato Group together with partnering with leading equipment suppliers and
`consultants from the pharmaceutical industry.
`
`Global pharmaceutical sales continue to show
`steady growth with the total world market being
`estimated at US$643 billion in 2006, an increase
`of 7.0% over 2005.1 The market share for inject-
`able drugs, representing about 24% of the route
`of drug administration, is outpacing the total
`market growth by increasing at approximately
`10% annually.2
`There are a number of compelling rea-
`sons cited for this observed increase. Firstly,
`for example, both the number of products in
`
`THERE HAS BEEN A CHANGE IN
`THE LAST TWO YEARS IN THE WAY
`PHARMA COMPANIES ARE LOOKING
`AT THE INTRODUCTION OF PREFILLED
`SYRINGES FOR THEIR PRODUCTS.
`
`development and marketed products from the
`biotechnology industry has grown and are pre-
`dicted to continue to increase further. The phys-
`ical nature of these biotechnology-derived drugs
`means that they are administered by injection.
`Second, new treatments for diseases and chronic
`conditions have been developed especially in
`the areas anaemia, multiple sclerosis, oncology
`and rheumatoid arthritis. Thirdly, in the past, a
`healthcare worker or physician would adminis-
`ter the injection. Today an increasing number of
`drugs are being self-administered by the patient
`and the packaging of a drug in a pre-filled
`syringe as against a vial reduces the number of
`
`steps for the patient and therefore the risk of
`dosing errors. This procedural simplification
`equally applies to health care workers too.
`For the pharmaceutical company there are
`the benefits of a reduced overfill in a prefilled
`syringe compared with a vial (especially when
`the drug is very expensive to produce) and
`that the correct therapeutic dose is ready to
`administer. Furthermore, for the pharmaceutical
`industry there is competitive pressure within a
`therapeutic area and also lifecycle management
`to protect the branded product
`when it loses its exclusivity.
`For 2006, the sales of pre-
`filled syringes were $33 billion
`(22.5% of the total injectables
`market) and showed an 18% rise
`over 2005. The total number of
`units sold worldwide is over 1.2
`billion with Europe still leading
`the US with 48.5% of the total
`versus 32.6% in the US.2
`Given the view that these drivers will not
`only continue but also increase in the future,
`it is confidently predicted that the prefilled
`syringe market will continue to grow and out
`perform other container systems for parenteral
`drugs with numbers expected to top 2.4 billion
`syringes by 2010.3
`Unfortunately this success has lead to a
`problem. In my experience working with phar-
`maceutical companies, there has been a change
`in the last two years in the way companies are
`looking at the introduction of prefilled syringes
`for their products. Until recently, the usual
`sequence was to launch the product in a glass
`
`Dr Michael N. Eakins
`Founder and Principal Consultant
`Eakins & Associates
`(New Jersey, US)
`
`T: +1 609 448 3411
`E: mneakins@comcast.net
`
`Nuova Ompi, Glass Division:
`T: +39 049 9318111
`F: +39 049 9366151
`E: nuovaompi@stevanatogroup.com
`
`Stevanato Group
`via Molinella 17
`35017 Piombino Dese
`Padova
`Italy
`
`US Headquarters:
`T: +1 267 757 8747
`F: +1 267 757 8701
`E: ompiofamerica@stevanatogroup.com
`
`Ompi of America, Glass Division
`Stevanato Group
`41 University Drive
`Newtown, PA 18940
`United States
`
`www.ez-fill.com
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`www.ondrugdelivery.com
`
`7
`
`Novartis Exhibit 2021.007
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`vial and then at a later stage introduce a glass
`prefilled syringe either as a replacement or as an
`optional container. With the continued success
`of the product, the third stage was to introduce
`a pen-injector or an auto-injector with the drug
`still housed in a glass container.
`Now many companies have decided to launch
`their parenteral product in a prefilled syringe
`from the outset, rather than in a vial, which
`means that they will need a supply of prefilled
`syringes to conduct not only their initial compat-
`ibility and development studies but also their
`formal stability and Phase III clinical trials.
`So what is the problem? In a word – sup-
`ply. Pharmaceutical companies are finding it
`difficult to obtain the relatively small number
`of samples required for their development
`studies in a reasonable time with delivery
`timelines being quoted as 9-12 months in
`some cases. This is especially the case with
`companies that have not worked with prefill-
`able syringes before and have no leverage of
`a current order. The prefillable syringe suppli-
`ers are struggling to keep up with the rising
`demand of products that are already on the
`market and there is no spare capacity.
`It is therefore very opportune that Nuova
`Ompi has developed EZ-fill™ as a new
`source of prefillable syringes in a nested tub
`format. The development of this product has
`been achieved in a unique way as it has uti-
`lised a tripartite approach of combining the
`expertise and experience within the Stevanato
`Group together with leaders in the field
`of syringe assembly machinery (Bausch +
`Ströbel, among others) and consultants from
`pharmaceutical companies.
`The Stevanato Group consists of the Glass
`Division that manufactures glass containers
`from tubing glass with Nuova Ompi being
`the largest part and the Engineering Division
`that designs and builds machines for the
`production and quality control of containers
`from tubing glass and consists of SPAMI and
`Optrel companies. The project to develop
`EZ-fill™ represented a synchronised effort
`between the Glass and Engineering Divisions
`to ensure that the Stevanato Group had com-
`plete control over the entire production proc-
`ess that combines glass technology with engi-
`neering experience (see figure 1).
`In order to explain what this means in practi-
`cal terms for manufacturing a prefillable glass
`syringe, we need to take an in-depth examina-
`tion of the key steps in the process. A descrip-
`tion of the manufacturing process for EZ-fill™
`can be divided into the formation of the glass
`barrel, followed by the placement of the fully
`assembled barrel in the tub configuration. While
`the design and construction of prefilled syringes
`
`Figure 1: The S.P.A.M.I. barrel-forming line leading to the controlled environment area.
`
`Figure 2: Inspection of staked needle
`
`has been described elsewhere4, a summary of
`the process for manufacturing glass barrels can
`be described as cutting Type I borosilicate glass
`cane to the desired length, heating both ends and
`forming the nozzle and finger grip, inserting as
`staked needle if required, annealing, washing
`and siliconising. This description, while correct,
`does not convey the complexity of the technol-
`ogy involved in order to produce a device con-
`sistently of the highest quality.
`The first critical step is the barrel-forming
`process. At Nuova Ompi this is performed by
`the latest generation of machines from SPAMI
`that are designed to monitor the glass tempera-
`tures continuously during the nozzle and finger
`grip forming process and this information is
`fed back to the flow meters controlling the gas
`mixture of the burners. This precise temperature
`control together with the components being held
`and moved by specialized gripers and high pre-
`cision servo motors combine to produce barrels
`with tight dimensional tolerances and reduced
`critical defects.
`After forming, the barrels undergo 100%
`dimensional inspection by the Novis camera
`system, which is an internal development of
`SPAMI with special attention being given to the
`critical area of syringe cone. The barrels then
`enter the lehr tunnel for annealing at tempera-
`
`tures of over 500ºC, an important process that
`removes the internal strains developed in the
`glass during the forming process. Temperature
`monitors are placed at multiple points in the
`tunnel to control the thermal cycle accurately
`and ensure reproducible results. Following the
`lehr, additional cosmetic inspections are per-
`formed in a clean-room prior to the next steps in
`the process. Needle insertion for staked needle
`products can now be performed using custom-
`ised high-speed assembly units operating in
`the cleanroom, which include 100% automated
`inspection for needle deformation, clogged nee-
`dles and adhesive distribution.
`The EZ-fill™ production area at Ompi is a
`new purpose-designed building that is dedicated
`to prefillable syringes. The design of the build-
`ing was made with input from consultants from
`pharmaceutical companies to achieve the most
`advanced and efficient facility for producing
`devices so critical to the pharmaceutical industry.
`Areas of key importance were the air handling
`system, water for injection supply, layout of the
`clean rooms and the use of modular designs. The
`facility design allows for capacity expansion to
`respond to the needs of the market.
`The barrels, already controlled and assembled
`with needle, enter this facility in a controlled and
`interlocked area to be loaded through a detraying
`
`8
`
`
`
`www.ondrugdelivery.com
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`Novartis Exhibit 2021.008
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`machine in an overall environment classified at
`ISO level 75 (equivalent to the superseded FED
`STD 209E Class 10,000) and progress into a
`series of modular chambers under laminar flow
`(see figure 2). The Bausch + Ströbel designed
`production line consists of a detraying machine,
`a washing / siliconisation / rubber closure assem-
`bly and then the tub nesting machine.
`The barrels are washed with water for injec-
`tion only (no recycled or purified water used)
`and dried with air filtered through a 0.22 micron
`sterilising filter.
`The next step is the key process of siliconi-
`sation of the barrel and the needle (if present).
`Here Medical Grade silicone is applied to the
`internal surface of the barrel via a diving spray
`nozzle that is inserted for the full length of the
`barrel and applies silicone as the nozzle moves
`back down the barrel. The transparency of the
`glass is measured by sensors before and after the
`application of the silicone, checking each barrel
`to ensure that the correct amount of silicone has
`been applied. Non-siliconised or excessively
`siliconised barrels are automatically rejected.
`
`The external needle surface can also be sili-
`conised at this point. A needle shield, rigid needle
`shield or tip cap is then applied and the syringes
`moved to the nesting machine Automatic inspec-
`tion devices check for: the presence of the nee-
`dle shield; clogged needles; silicone presence;
`pierced shields; total length; shields or caps
`having popped-off; and breakages. General and
`cosmetic inspection on the package is 100%
`guaranteed during a production run.
`The final steps place the nested syringe
`barrels into polystyrene tubs, seal with a
`Tyvek sheet, package in Tyvek/plastic sterib-
`ags and case-pack allowing for sterilisation
`with ethylene oxide. Equal attention is given
`to the cleanliness of the packaging compo-
`nents as to the production of the syringe barrel
`itself. The tub, nest, Tyvek liner and Tyvek/
`plastic steribag are all produced under ISO
`level 7 conditions (see figure 3).
`A Validation Master Plan has been fol-
`lowed to qualify the utilities, machines and
`instruments and to validate the processing steps
`and the cleaning and sterilisation operations.
`Externally, annual audits are conducted with
`suppliers. Strict compliance is maintained with
`European and US GMP requirements and a
`Type III Drug Master File is maintained with
`the FDA. Nuova Ompi has been ISO 9001
`certified since 1994 and Nuova Ompi achieved
`the accreditation to Chinese SFD in 2003. It
`achieved also conformance with ISO 14001
`environmental management systems
`In summary, EZ-fill™ is now available in a
`tub format in 0.5 ml, 1.0 ml and 1.0 ml long sizes
`with a staked needle, and customers have the
`choice of formulations from Helvoet Pharma,
`Stelmi and West Pharmaceutical Services for
`the needle shield formulation. EZ-fill™ is also
`available in 1.0 ml and 2.25 ml sizes with a luer
`tip and a choice of formulations from Stelmi and
`Helvoet for the tip cap. Additional presentations
`are under development (see figure 4).
`
`CONCLUSION
`
`The planning and execution of the manufacture
`of EZ-fill™ has been achieved by harnessing
`the synergy within the Stevanato Group of
`long-term experience in forming glass con-
`tainers of the highest quality using the latest
`machinery for forming and inspecting syringe
`barrels to provide a synchronised solution.
`Equally important is the establishment of a
`partnership with key suppliers and consultants
`from the pharmaceutical industry to design and
`build a new manufacturing facility to meet the
`growing needs of the pharmaceutical industry.
`EZ-fill™ offers the industry a new choice for
`glass prefillable syringes.
`
`Figure 3: Tub format
`
`Figure 4: Selection of syringes
`
`Figure 5: Summary of available formats
`
`Copyright © 2008 ONdrugDelivery Ltd
`
`www.ondrugdelivery.com
`
`9
`
`Novartis Exhibit 2021.009
`Regeneron v. Novartis, IPR2020-01317
`
`

`

`ABOUT NUOVA OMPI:
`
`Nuova Ompi is the glass-tubing converter in
`Italy and among the top leaders in its market.
`The company, with its sister companies of
`the Glass Division, Alfamatic (located near
`Rome, Italy) and Medical Glass (located in
`Bratislava, Slovakia) produces with its team of
`1,050 employees more than more than 1.7 bil-
`lion glass containers per year for pharmaceutical
`use, generating sales of approximately €145
`million (US$230 million), designating 70% for
`export. The standard production from neutral
`glass tubing includes: syringes with and without
`needle; screw neck pilfer-proof blow back and
`pill vials; dental cartridges; and pen cartridges
`and ampoules.
`Nuova Ompi has started to supply EZ-fill™
`syringes clean, sterile and ready to fill. The next
`development of this concept will offer the market
`the advantages of the EZ-fill™ concept for other
`major container types, including vials and car-
`tridges. This allows clients to continue the trend
`of delegating services to partner suppliers while
`improving operational efficiency. The most
`recent phase in Stevanato Group’s expansion is
`the construction of a new manufacturing facility
`
`for glass containers at a 50,000 m2 site in Mexico,
`near Monterrey. Initiated in late 2007, the initial
`phase will include 6,500 m2 of production space
`that will be enlarged, starting from 2011, reach-
`ing 11,500 m2 with an overall investment of €37
`million. This new production site is designed to
`support over 500 million high quality containers
`serving the production of the growing require-
`ments in the Americas zo