Prefilled Syringes the Trend for Growth Strengthens

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PREFILLED SYRINGES THE TREND FOR GROWTH STRENGTHENS

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“Prefilled syringes: the trend for growth strengthens” CONTENTS

This edition is one in a series of sponsored themed publications from ONdrugDelivery Ltd. Each issue will focus on a specific topic within the field of drug delivery, and contain up to eight Introductory comment articles contributed by industry experts. Guy Furness 3

Full contact information appears alongside each Trends and requirements on prefillable syringes: article. Contributing companies would be delighted past, present and future developments to hear from interested readers directly. Dr Thomas P Schoenknecht ONdrugDelivery would also be very pleased to (Buender Glas GmbH) 4-8 pass on to authors, or answer as appropriate, any queries you might have in relation to this publication or others in the series. Meticulous attention to detail: the key in prefilled syringe production Forthcoming editions cover: nasal drug delivery; Horst Koller, Walter Schiess (Schott AG) 10-12 oral drug delivery; delivering injectables; novel biomaterials for drug delivery; safer injections; Reducing time-to-market: nanotechnology in drug delivery; transdermal successful drug manufacturing delivery; and pulmonary delivery, among other Dr Juergen Koch topics. To find out more about receiving or (Vetter Pharma-Fertigung GmbH & Co. KG) 14-17 participating with any of these issues, please contact ONdrugDelivery Ltd. Packaging in prefilled syringe systems: Contact: selection and evaluation Guy Furness, Publisher Frances L DeGrazio T: +44 1273 831 370 (West Pharmaceutical Services, Inc.) 20-22 E: [email protected]

Current market and key trends of devices used in self-injection Joël Cotten (BD Medical - Pharmaceutical Systems) 25

“Prefilled syringes: the trend for growth Company Profile: strengthens” The Medical House plc 29

Published by ONdrugDelivery Ltd, Cedar Company Profile: Cottage, Newtimber Place Lane, Newtimber, Ypsomed AG 30 West Sussex, BN6 9BU, United Kingdom. Registered in England: No 05314696. Copyright © 2006 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 liability for the consequences of any decision or action taken (or not taken) as a result of any information contained in this publication.

Front cover image, Validated washing process for aseptically prefilled application systems, reproduced with kind permission from Vetter Pharma- Fertigung. The image also appears on page 16 of this issue in Vetter’s article entitled: “Reducing Time to market: successful drug manufacturing”.

INTRODUCTION

Some of the cornerstones upon which the grow at a compound annual rate of 3.3% wild or staggering. prefilled syringes sector’s growth has been between 2004 and 2011. “A major portion They are not going lead built are: (16.8%) of this revenue is set to come from the to a transformation of fastest growing prefilled syringes sector,” it medicine as we know it in the same way that, • the continuing growth of the injectables adds. Another 2005 publication from Frost and for instance, intelligent biomechanical implants market, underpinned by the growing number Sullivan, The European Prefilled Syringes and other micro- and nanotechnologies might. of biotech product launches Market, estimates that “the European market Instead, with prefilled syringes, we encounter • the growing emphasis on safety, particularly for prefilled syringes is worth $300 million and measured, solid improvements over previous, sharps safety is growing at 8-10 % per annum”. conventional systems. • the increasing realisation that a delivery So how have prefilled syringes achieved this? There are many examples, but one which system’s convenience, speed of use and ease Looking in from outside, almost every aspect of typifies the type of benefit I am referring to is of use benefit treatment outcomes the prefilled syringes sector appears balanced that prefilled syringes contain the precise • the rising numbers of high-cost drugs and well grounded. I believe this is the key. amount of drug that is to be injected. In reaching the market, which make it important For example, in terms of their technological contrast, vials and ampoules have to contain to reduce or eliminate overfill and other complexity, prefilled syringes are positioned more liquid than the actual dose in order for the sources of wastage. midway along the spectrum of delivery systems. correct amount to be withdrawn, so the excess They fall between high-technology devices like formulation is wasted. Especially with These and other drivers have been aqueous droplet inhalers or needle-free jet expensive biotech products, elimination of discussed previously in various publications injectors, and simple, “low-tech” systems such wastage allows the manufacturer to make (including in ONdrugDelivery’s 2005 issue, as traditional syringe and vials, for example, or significant cost savings. Prefilled syringes Prefilled syringes: innovations that meet the oral capsules and blister packs. Prefilled reduce wastage of pharmaceutical product. This growing demand), and are touched upon in syringes are neither extremely high-tech, high- kind of ostensibly unremarkable advance does several of the articles that follow here. value products, nor are they mere commodities. not typically make the front covers of eminent Growth drivers, although the prerequisite for journals, but the millions of dollars that can be success, cannot bring about success on their own. RISK AND REWARD saved certainly causes drug manufacturers and Organisations must come forward to develop drug purchasers to sit up and take notice. technologies and products to meet the need. This Similarly, from the point of view of the risk The restrained nature of the prefilled is what I would like to discuss here. What to pharmaceutical and biotech companies, syringes sector is even borne out in the way it characteristics of the companies involved in prefilled syringes fall into the low- to medium- presents itself to the pharmaceutical industry. prefilled syringe production, and of their products risk category among the available delivery As evidenced by the articles contained within and technologies, have led to their success? options for a given product. this issue from prefilled syringe producers, First, it is important to qualify that prefilled Switching to a prefilled syringe format is component manufacturers and fillers, the focus syringe sales are indeed continuing to grow. not a totally risk-free process of course. for success – instead of being on lofty claims or Evidence from recent announcements made by Stability of the drug within the device (since a a constant push for ambitious innovations – the major prefilled syringe producers suggests prefilled syringe is both container and delivery appears to be on perfecting and excelling in so. Gerresheimer pharmaSystems’ (Buender device), for example, is a source of risk. their stated capabilities. Prefilled syringe Glas’s) financial results release for the first Lubrication of the plunger within the barrel is companies do not inhabit a fantasy world of quarter of 2006 states: “The positive another. A prefilled syringe might be stored for ingenious, revolutionary technologies that development in the RTF-syringe segment some time before it is used and it is essential might just, if they’re lucky, achieve astounding continued with considerably higher sales in that the plunger moves freely when required to success one day. Rather, meticulously planned Q1/2006 as opposed to Q1/2005.” Similarly do so, and does not become stuck to the barrel and monitored manufacturing and filling BD, in its 2005 annual report, highlights the during storage. Proper processes must be in processes generate real products today. Sterility, contribution of prefilled syringes. It said that a place to minimise the chances of these failsafe processes, quality checks, back-up lines 6% increase in its US revenues was generated problems hindering a product’s approval. and timeliness are strong themes, and they crop “primarily from strong sales of safety- However, these risks are minimal and easily up in several of the articles published here. engineered devices and prefillable syringes”. identifiable compared with, for example, the Again and again, we gain a sense of Likewise, Schott’s 2004/5 annual report says: “knowns” and “unknowns” involved in opting moderation and stability. Even the very growth “The strongly growing sterile syringes business to develop, say, the first systemic inhalable which we are attributing to the prefilled sector was extended this year.” format of a previously injection-only product. syringe sector’s poise – with an annual rate in Independent market analyses paint an The same balance is seen when considering the high single digits – seems considered and equally positive picture. Frost and Sullivan’s the reward side of the risk and reward equation. deliberate rather than a runaway boom 2005 report, The US Pharmaceutical The claims made by prefilled syringe companies happening at breakneck speed. Packaging Market, says that the US about how prefilled syringes can improve and pharmaceutical packaging market is set to add value to pharmaceutical products are not Guy Furness, Publisher

TRENDS AND REQUIREMENTS ON PREFILLABLE SYRINGES: PAST, PRESENT AND FUTURE DEVELOPMENTS

More than 25 years ago it was difficult to promote and market prefilled syringes. Single- and multi-dose vials and even ampoules were the standard and the prefilled syringe was virtually an unknown product, used only for a narrow range of therapeutic classes. The syringe configurations available at that time were known in processing as slow, costly and labour intensive so marketing advantages like convenience, safety, dose accuracy needed to be promoted constantly. The innovative breakthrough of the invention of the so-called all-glass syringe signalled the start of this drug delivery system’s continuing story of success, writes Dr Thomas Schoenknecht, Director of Product Development/Product Management at Buender Glas.

Prefilled syringes as we know them were initial- the processing of prefilled syringes, enhance pro- ly introduced in Europe in the 1980s. At that time ductivity and introduce cost efficiency. This again syringes were predominantly cartridge-based. raised the profile of the prefilled syringe and aware- The innovation of a syringe made completely out ness of these products in the marketplace. of a glass tube with a needle glued into it opened new ways for an effective processing in filling MAJOR ADVANCES IN PREFILLED operations. With this type of syringe, mass-mar- SYRINGE PROCESSING ket drugs such as anti-coagulants (heparins) and vaccines could be addressed on the market. As During the 1980s, an increasing number of phar- those therapeutic classes showed strong organic maceutical companies began filling prefilled growth over the years, so did the numbers of pre- syringes in-house. How did this become possible? filled syringes used. In the early days of prefilled syringes, pre- Although the names of the major players filled syringe manufacturers would supply so- involved in manufacturing prefilled syringes called “bulk syringes”. Various processes, such have changed as result of the various mergers and as syringe-barrel washing, siliconisation of the acquisitions that have taken place, essentially the barrel and, if applicable, the needle also (to same companies are still involved as back then. smooth the surfaces for easier administration, Among the main heparin marketers were Sanofi and to prevent the non-specific binding of the and Rhône-Poulenc (both now Sanofi-Aventis), formulation with the device), and sterilisation, Pharmacia (now Pfizer) and Roche. Examples of had to be carried out after manufacture but Dr Thomas P Schoenknecht Director, Product Development/ large vaccine manufacturers were Institut before filling. This was done either by the phar- Product Management Merieux (now Sanofi-Pasteur), SmithKline (now maceutical company or a contract filler. GlaxoSmithKline) and Behringwerke (now In order to make prefilled syringes accessible T: +49 52 23 16 42 42 Chiron Vaccines/Novartis Vaccines). to a wider range of pharmaceutical customers, pre- F: +49 52 23 16 43 16 New indications for those first therapeutic siliconised, pre-sterilised syringes were devel- E: [email protected] classes were launched, heparins were brought oped. They were presented in a tub and were ready into the US, drug prices were fairly high, and so to be filled. Buender Glas supported this trend by Buender Glas GmbH the franchises grew substantially year after year. launching its RTF (Ready-To-Be-Filled) Syringes. Erich-Martens-Strasse 26-32 Those growing numbers made it attractive for The US market with a shorter history of pre- 32257 Bünde the producers of prefilled syringes to invest into filled syringes, was particularly keen on the Germany and optimise their production. Machine makers advantages this format gave, to the extent that it www.buenderglas.com were motivated to explore opportunities to improve is now exclusively an RTF syringe market.

which can be used in normal fill- Systems and Types S ing line environments. afe ty S yst n em njectio In recent years, more isolator s Auto-I and RABS technology has been Pre-filled A B C edle-free Com installed in the market, meaning Ne Syringes ponents Staked-in Luer- Luer I that stoppers have to be trans- Readyject ntr Needle Cone Lock al aderm Syringes as Syringes Syringes Syringes N al ferred into these production environments in a more sophisticated manner. Buender Glas, together Figure 1: Prefilled syringes: the basis with French isolation technology Dual-Chamber-Syringes for a variety of delivery technologies specialists Getinge La Calhene, With a growing number of prefilled syringe has developed a system based A, B and C available in glass or plastic processing lines established in pharmaceutical on the worldwide-recognised Figure 2: Prefilled syringes: a variety of options companies and a wide array of contract fillers Getinge La Calhene DPTE being available, prefilled syringes have become Isolator transfer port technology (see figure 5). with a PE housing, which is produced in a co- the gold standard for many additional applications. The system contains a DPTE 105 port unit injection process, generating a device which is Today the prefilled syringe as a drug deliv- together with a PE bag system. The transfer port produced completely under particle-reduced ery container (system) is the basis for other drug system is available with all stopper sizes and for production conditions. 1 delivery platforms (see figure 1). all rubber formulations required from the major Together with thinner needles such as /2 - inch Currently there are different types of prefilled rubber suppliers. All of them have modern latex- 29-gauge needles, a pain perception reducing syringes available, as shown in figure 2. The drug free formulations available which will be used for drug delivery system is available in pre-sterilised delivery system based on this container consists of tip caps or needle shields as well as for stoppers. ready-to-use (RTF) or bulk version (see figure 6 the syringe itself, together with a needle shield in Needle shields are also available in new on the next page). the case of staked-in needle syringes, or a tip cap innovative materials such as thermoplastic elas- The TPE-based RNS is fully steam or gamma for the Luer/luer lock syringes, and a plunger stop- tomers (TPEs). Buender Glas has developed a sterilisable and can be used with standard bulk per made from modern innovative rubber formula- new rigid needle shield (RNS), made from TPE syringe configurations or is available within the tion, such as those available from compa- RTF-based drug delivery system plat- nies such as West Pharmaceutical Services, form of Buender Glas. Helvoet Pharma and Stelmi. Finally, the Beside the goal of minimising pain system itself requires a plunger rod. Syringe barrel perception on the patient side, tamper evi- Sophisticated contract fillers like dence and anti-counterfeiting is becoming Needle shield/Tip Cap Vetter Pharma, Federa/Cardinal Health more important and is of great interest for and Baxter Pharmaceutical Solutions Plunger stopper the pharmaceutical market. Gerresheimer made such prefilled syringe configura- pharma Systems is offering a new innova- Plunger rod tions an easily available option for phar- tive design for such a tamper-evident maceutical companies that would initially Luer-lock closure (TELC). shy away from investing in filling those The device consists of a Luer-lock kinds of syringes themselves. Figure 3: Basic components of a prefilled syringe system adapter made from polycarbonate and Nowadays the latest processing a closure unit made from TPE. The equipment can fill up to 24,000 syringes whole device is produced in a co-injec- per hour. tion mode, thereby avoiding further Beside the standard components form- particle contamination of the whole ing a drug delivery system as described in syringe system, which can occur with figure 3, other accessories for syringes other tamper evident or rigid tip cap- such as backstops could be combined with based solutions. the syringe system. Backstops function as In addition to the TPE-based device, finger flange extenders, offering better Figure 4: Back Stop as flange extender for better handling TELC is also available in a configuration handling of the syringe during injection and eliminating inadvertent plunger stopper removal described in more detail in figure 7 on next and eliminating inadvertent plunger stop- page. Here a rubber insert has to be assem- per removal (see figure 4). Nowadays, bled after the co-injection production pro- such systems are available from all cess of the TELC itself. The main advan- syringe producers such as Buender Glas. tage of this configuration is given in the For closing the syringe, rubber for- broad range of different rubber closure mulations covering the requirements of formulations available. These can be all relevant pharmacopoeas (USP, EP incorporated into the TELC enabling an and JP) are available from the different easy transition from one Luer or Luer-lock producers of pharmaceutical rubbers. syringe configuration with a given rubber In the case of plunger stoppers these formulation for the Tip Cap, to the tamper units are available in standard configura- Figure 5: Stopper in transfer port configuration covering evident version of the TELC using the tions, gamma-sterilised in double bags, the needs of RABS and isolator technology same rubber closure.

Functionality in case of reassembly:

dispose

• guided • residue free • hooks indicating twist-off aperture motion • inhibiting full closure

DesignDesign: twist off cap

Version A Version B with rubber insert cap fully made of TPE

Figure 6: New needle design together with innovative materi- rubber sealing als (TPE) open ways to reduce pain perception

The whole system is fully steam or gamma change in the pH value luer adapter sterilisable, and can be used either on standard of the diluents stored in bulk syringe units as innovative closure system or the syringes with time.

can be used ETO-sterilised, together with the RTF This problem has been ( Intersection ) ( Intersection ) syringe configurations available at Buender Glas. observed for several solvent syringes and, Figure 7: Tamper-evident Luer-Lock closure TELC NEW REQUIREMENTS especially for WFI syringes, the USP defined upper limit of pH 7 ly soluble sodium sulphate plus water and ammo- Pharmaceutical companies are considering the has to be observed. nia. The reaction is summarised in figure 8. prefilled syringe as the most appropriate way of The shift in pH occurs because the glass used A study comparing the pH-increase in non- presenting an increasingly wide range of injectable for the syringes is a USP type I glass which con- treated and treated syringes filled with double dis- products. This is underlined by the fact that the tains borosilicate. Syringes are formed by heating tilled water clearly showed a tremendous pH-sta- prefillable syringes market is growing at more than the glass thereby sodium oxide is transferred to bilisation of the treated syringes. After heating the 10% annually. As the scope of the syringe applica- the surface of the glass syringe. As sodium oxide syringes to 121°C for one hour, the pH of the water tion broadens, prefilled syringes will be expected is characterised by a very limited solubility, the in the non-treated syringe increased from 5.5 to 6.6 to meet a growing number of requirements, which remaining oxide cannot be removed during the while the pH of the WFI in the treated syringe con- will be discussed in the following sections. cleaning process of the syringe using WFI. figuration only increased from 5.5 to 5.9. However, over time the ions on the inside of the DILUENT SYRINGES syringe are released into the non-buffered solution SILICONE-SENSITIVE DRUGS – for example, the WFI. This eventually results in The number of drugs that are only stable as a an increase in the concentration of hydroxide ions, Many of the recently developed drugs – espe- lyophilised powder, and must therefore remain in yielding a change in the pH value. cially in the area of biotech – have shown an this form until just before administration, is To overcome this issue Buender Glas had increased sensitivity towards free silicone. increasing, especially for biotech drugs. For developed an ammonium sulphate pre-treatment However, siliconisation of the inside of the glass sophisticated drug delivery, prefilled diluent process. Ammonium sulphate is sprayed into the barrel and the plunger stopper is essential for the syringes have become an option. The volumes of glass barrel before the tempering process of the functionality of the syringe. most diluent syringes used range from 0.5-5 ml. formed syringe is started. The heat energy Buender Glas has established a process that A challenge with diluent or saline syringes induces a chemical reaction whereby the heavy, allows silicone to be “baked” on to the inside of used in this application field is an undesirable soluble sodium oxide is transferred into the high- the syringe, preventing the formulation of free silicone in the drug containing solution. The process, which is applicable to most pre- Na SO + 2 NH + H O filled syringe types, including RTF syringes, is Na O + (NH ) SO Na22SO44 + 2 NH33 + H22O Na22O + (NH44)22SO44 based on spraying an emulsion of medical grade Δ H silicone oil into the glass barrel. During the fol- HeavyHeavy solublesoluble lowing heat treatment, low chain-length frac- inin waterwater ExcellentExcellent solublesoluble tions of the silicone oil evaporate and a given inin waterwater fraction of the silicone oil with longer chain length forms hydrogen bonds as well as cova- lent bonds with the glass. This process is avail- Figure 8: Reaction scheme for ammonium-sulfate treatment able in standard siliconisation grades as well as

15 Compatible Non-compatible 10 Force [N] Force 5

0 010203040 Syringe length [mm]

Gliding force curves measured with typical auto-injection speed of 280 mm / min

Figure 9: Pin used for forming the cone bore Figure 10: Gliding forces in 1 ml, long syringes

in individual customer-specific versions in order ensure delivery of the entire dose. This can be for the syringe presentation itself requires a to cover specific requirements. achieved by a homogeneous surface coating change in the standard packaging unit. For the yielding a uniform silicone distribution over past five years, E-Beam sterilization has been HEAVY METAL REDUCTION the whole glass barrel, thereby generating a applied increasingly in combination with isola- stable constant gliding force along the whole tor equipment used for syringe filling. In such a Over the last few years it has become increas- syringe length. filling line, tubs with syringes were moved on ingly clear that biotech drugs are sensitive to A second point, which has to be considered their way to the filling line through a curtain of heavy-metal contamination in glass syringes. An carefully, is the potential side-reaction of the fast electrons, high enough in energy to sterilize analysis of reported negative interactions indi- drug active substance with the silicone in the the outside of the tub containing the syringes cated one specific metal ion, Tungsten, as a crit- syringe. As a result, quite often the lowest possi- and to create ozone inside the tub. ical one. Although not an integral component of ble silicone concentration is allowed only and This ozone formation has to be minimised as the glass composition of the syringe, Tungsten is the whole system, consisting of the auto-injector ozone is a highly reactive radical, which can inter- used during the forming process of the syringe (spring constant) and syringe, has to be fine- act with the drug to be filled in the syringe imme- by a pin, which is required to form the cone bore tuned to yield the optimal solution. The factors diately after moving through the E-Beam curtain. and thereby withstand the melted glass during that must be balanced are: the auto-injector char- The reduction of the ozone formation is the forming process of the syringe cone. acteristics; syringe characteristics such as break- practically achieved by inserting a specific inner The use of the pin, in this case a Tungsten out force; gliding force; silicone distribution; lid made from Dupont’s Tyvek®, which is pin, is illustrated in figure 9. The Tungsten pin and the silicone requirements of the drug itself. placed on top of the syringes. This lid absorbs is used to form the opening bore of the syringe In figure 10, a gliding-force diagram mea- the energy from the electrons as they moving 1 cone by moving into the bore when the forming sured on a 1 ml long, /2-inch needle syringe is through the outer closing of the tub. Such con- tools form the cone characteristics. Due to the shown, demonstrating in blue the curve mea- figurations are available for all typical sterile temperature of the viscous glass, with time the sured on a syringe with optimal silicone charac- syringe configurations at Buender Glas. tungsten pin becomes smaller as it releases ions teristics, compared with the red curve, which into the viscous glass. These Tungsten ions can shows a non-optimal silicone distribution. THIN NEEDLES create the known side reactions with the drug. This problem can be overcome by using PACKAGING REQUIREMENTS The increasing demand from end-users for tech- Tungsten-free pins, which requires a specific nologies that provide convenient injections is handling on the glass forming lines. Using In recent years, new technologies such as E- one of the major factors driving the prefilled established technology, tungsten-related prob- Beam sterilisation of sterile syringe packaging syringe market. This demand for convenience lems with drug solutions can be solved. At units, and further requirements on particle con- gives companies within the sector an excellent Buender Glas, all syringe formats in the product tamination limits of the clean rooms by the pack- opportunity to differentiate themselves. portfolio can be formed using the tungsten-free aging configuration, were clearly specified by the

technology if requested by the customer. end users of the syringes. Buender Glas was able Syringe to follow these requirements from the outset. + Needle SELF-INJECTED DRUGS As a result, sterile ready to use (RTF) syringes Gluing are delivered to the customers only in cardboard- Final QC: A growing number of injectable products can be free packaging containers made from Acrylux, • transmissibility •axiality self-administered at home. Often auto-injectors which can be opened without a knife or any other • tight fit of needle will be used. At present, a stand-alone syringe is sharp opening device which can create particles. UV usually inserted into a re-usable auto-injector, For the same reasons, a double bag is required hardening but for the future a trend for disposable devices around the tub that contains the syringe. Such a Coating: • dipping into coating bath is expected. packaging configuration is also a standard at • removal of excess material • tempering process As the prefilled syringe is emptied using Buender Glas. power from a spring rather than a manual pro- In addition to the packaging configuration but 100no contact% control to butneedle no contacttip during to wholeneedle production tip flow. during whole production flow. cess, the siliconisation of the glass barrel is of improvements triggered by particle reduction major significance. It has to be complete to requirements, a specific sterilisation technique Figure 11: Packaging improvements

Uppermost in the thoughts of many patients TPE-based RNS. The company is of the opinion OUTLOOK receiving injections are pain and discomfort. To that a thinner needle will reduce the individual overcome this negative image, syringes are subjective pain perception. However, other In the years ahead, offering the benefits of pre- placed, for example, into an auto-injector in important needle characteristics also have to be filled syringes will become a must for many order to hide the needle visually for the con- considered in order to minimise pain perception. injectable drug manufacturers. Easier and more sumer as they get their shot. Firstly, there are the basic needle-quality cost-effective processing, a clear regulatory path, Similarly, increasing the numbers of bevels characteristics, such as the requirement for a and new innovative creations around it will drive on a needle tip has also been used as a market- hook-free needle tip and smooth surfaces. These growth. The market will expand still further as ing argument to create a more positive atmo- are achieved through a validated, reliable pro- prefilled syringe technology and know-how is sphere for injections. Needle tips with five duction process. Then there are several more applied in the development of prefilled devices bevels instead of the normal three bevels are subtle factors such as the number of bevels, for other routes of administration including nasal available from all needle producers and also angle of bevels and the bevel length. The third applicators, needle-free devices and intradermal used for the production of sterile RTF syringes. set of characteristics – in Buender Glas’s expe- injectors. The future and growth has just begun. Another way of reducing the fear of injec- rience, the most important – comprise the type Buender Glas, being an established player in the tions is to use thinner needles, which reduce the of needle coating and the method of assembling, field with a proven successful track record, is in a pain perception compared with the normal stan- which we have identified in specific tests per- position of strength to capitalise on the opportuni- dard-diameter needles. Such needle types were formed externally at independent laboratories. ties that lie ahead. Innovative concepts will be introduced two years ago for subcutaneous At Buender Glas we have a production phi- realised and launched, and strategic co-operations injections – for example, in combination with a losophy for staked-in needle syringes where the and partnerships will provide the platforms for con- 1 /2-inch needle. A thin-walled 29-gauge needle needle tip, which is the most critical part on a tinuous worldwide growth. Buender Glas seeks to with an inner bore diameter close to that of a needle, is not affected/treated during the whole be the pharmaceutical industry’s partner of choice standard 27-gauge needle was the first to reach assembling process (see figure 11 on page 7). for the development of prefilled syringe systems the market in combination with a prefilled Furthermore, a specific coating process for the and is willing and capable to assist them on the way syringe in a sterilised format, together with a needle is an option which can be used at to develop the optimal drug delivery device for a RNS made from TPE. Buender Glas to produce even with standard given therapeutic class and application. In line with this market trend, Buender Glas needle configurations drug delivery systems is offering a 29-gauge needle with a standard where optimal patient convenience during injec- For more information, please visit our web needle shield and also in combination with a tion is achieved. page at: www.buenderglas.com.

BRAILLE REQUIREMENTS FOR MEDICINAL PRODUCTS One Year On – Where are we Now?

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METICULOUS ATTENTION TO DETAIL THE KEY IN PREFILLED SYRINGE PRODUCTION

Prefilled syringes are used by doctors, nurses and patients alike. While using them to administer a medicine in a couple of seconds, they will rarely spend any time thinking about the amount of know- how and developmental work that actually goes into these small packaging units, which are really much more than just drug containers. In this article, Horst Koller, Head of Scientific & Regulatory Advisory, and Walter Schiess, Product Manager, both of SCHOTT forma vitrum, give an insight into some of the many factors that are addressed during prefilled syringe development and production.

In recent years, the market for parenteral packag- cific requirements of the medication and its par- ing has seen prefilled syringes experience a sub- ticular application. The company has long and stantial increase in demand. Simplicity of admin- proven experience with parenteral packaging, istration, safety for the patient and cost savings expertise with different materials, and access to are the main growth drivers. Prefillable syringes a broad range of resources and in-house tech- enable quick and easy drug delivery, especially in nologies from activities both within and outside Horst Koller cases of emergency. Compared with other phar- the field of pharmaceutical packaging. It is Head of Scientific & Regulatory Advisory, SCHOTT forma vitrum maceutical containers, they present fewer oppor- therefore able to offer customised packaging tunities for mix-up or contamination, and they solutions in terms of material, design, siliconi- reduce the overall cost of administration. At the sation, cosmetic quality, accessories, packing T: +41 71 274 16 00 T: +41 71 274 16 56 (direct) same time, prefillable syringes have become much and sterilisation. Innumerable different combi- F: +41 71 274 16 98 safer and easier to use in recent years, which sup- nations of product features are possible. The E: [email protected] ports the general trend to self-medication. syringe barrel is a good example. It can be made of glass or plastic, coated or uncoated, with free A SYRINGE IS A HIGHLY silicone oil, baked silicone or any new lubricant. COMPLEX SYSTEM SCHOTT CUSTOM DESIGNS A syringe is a highly complex system that must be PHARMACEUTICAL CONTAINERS able to satisfy even the most challenging requirements. After all, not only must it perform func- SCHOTT forma vitrum offers prefillable tionally, it must also protect the medication itself syringes in two materials: highly resistant from impurities such as contamination and, above borosilicate glass, and Topas® cyclic-olefin all, ensure the safety of the patient. Figure 1 maps copolymer (COC). Glass has excellent barrier Walter Schiess out the requirements and relates them to different characteristics, especially when it comes to Product Manager, SCHOTT forma vitrum components of the prefilled syringe itself. vapour and oxygen diffusion, and chemical and To meet these requirements, SCHOTT forma heat resistance. However, glass is not always vitrum develops and manufactures its syringes based the best solution; in addition to being fragile, its T: +41 71 274 16 00 T: +41 71 274 16 07 (direct) on the most stringent of international regulations and alkaline surface can lead to side reactions. In F: +41 71 274 16 12 ISO standards. A multitude of tests are performed such cases, the glass-like clarity and inert, low E: [email protected] on the characteristics of the material and how well adsorption qualities of COC can make it a they function. This is done in accordance with the viable alternative. SCHOTT AG European, US and Japanese pharmacopoeias. If required, the barrier properties of the con- St. Josefenstr. 20 tainer could even be improved by adding a layer CH-9001 GLASS OR PLASTIC, COATED of coating onto the glass or COC polymer. In St Gallen Switzerland OR UNCOATED any case, both the composition of the medication and the intended application are carefully www.schott.com/ SCHOTT forma vitrum is able to custom-design considered following consultation with the cus- pharmaceutical_systems pharmaceutical containers according to the spe- tomer. Only then can a decision be made with

Figure 1: The complexity of prefilled syringe production Figure 2: Syringes are washed with water for injection

respect to the type of packaging that offers the ducts a variety of tests to demonstrate to its cus- mers under clean room conditions. Production is best solution for the customer. tomers that its products deliver both functional- strictly controlled and also validated to ensure it SCHOTT manufactures syringes in glass (forma ity and integrity. The piston and the tip cap are is within the specified limits for particles and 3s® sterile syringe set) in sizes from 0.5-3 ml and up two good examples. On one hand, a closure’s micro-organisms. Syringes being washed with to 10 ml for its TopPac® line made of a COC poly- dimensions must be such that they ensure the water for injection (WFI) are photographed in mer. Other lengths and flanges or modified shoulder appropriate leak tightness. On the other hand, figure 2. shapes are available upon request. With regard to the piston must provide adhesion and sliding After all, it is imperative to make sure that polymers, basically all shapes or sizes are possible, forces for the entire three-year lifetime of the the products to be delivered to the customer, fol- as long as they can be produced using the injection product so that it can still be moved without dif- lowing external sterilisation, are in fact truly moulding technique. Customers can also choose ficulty and the tip cap can be removed. In other sterile products. All types of sterilisation tech- between luer-cone, luer-lock and staked needles. words, it is a question of the right balance nique, such as ethylene oxide (ETO) or gamma For COC, the luer-lock syringe is currently between dimensions and functionality. sterilisation, are validated according to the available as a standard version. Other specifica- To achieve this, SCHOTT forma vitrum has required international norms. tions can be selected with respect to shape, pack- even developed its own tests. The TipCap leak- “Sterile” is an absolute term. However, the ing and closure systems. A tamper-evident cap is age test, for example, examines leak tightness yet assurance that any given item is sterile is a also available, for example. SCHOTT forma vit- ensures ease of use so that the tip cap can still be probability function. The Sterility Assurance rum markets its syringes as complete sets includ- removed using only a reasonable amount of Level (SAL) of a product is defined as the ing all of the required rubber components. force. The so-called tip cap removal torque con- probability of any given unit being non-sterile firms whether this is the case. The respective ISO after exposure to a validated sterilisation pro- THE SMALLEST DETAILS ARE norms also include tests that the piston is subject- cess. The standard SAL is defined as 10-6, that HIGHLY IMPORTANT ed to, such as the axial compression and piston is, one surviving micro-organism per one mil- vacuum that ensure the leak tightness of the prox- lion products. With syringes, even the smallest details are imal side. These various inspections are impor- In order to guarantee customers a product highly important. SCHOTT forma vitrum con- tant because, although the norms include certain shelf life of three years, for example, worst-case points of reference, different materials simply scenarios are developed with regard to sterilisa- behave differently under different conditions. tion and the rubber materials used for the pistons Integrity of the container is not the only aspect and the tip caps. In order to evaluate whether that requires testing. Ease of use is also looked at products could possibly age prematurely, test carefully. Furthermore, ensuring purity during the runs are performed by storing products for three manufacturing process is of particular importance months at a temperature of 40°C, in accordance with prefilled syringes. Standard inspections are with ICH regulations. This roughly equates to performed, for example, on endotoxins, microbial one year of storage at room temperature (ASTM impurities, and particles in the regions of 10 μm 1980F). The containers for immediate use in and 25 μm (a human hair is approximately 50 μm packaging are also tested in real time. in diameter) that are invisible to the human eye, This abundance of inspections performed on but also to rule out visible particles. a regular basis is designed to achieve one goal: SCHOTT forma vitrum performs the tests delivering to pharmacists a high-tech container that were established by pharmaceutical author- that cannot affect a medication adversely. ities in Europe, the US and Japan, and guaran- Together with the product, SCHOTT forma vit- tees that the critical values they describe are rum also supplies its customers with important Figure 3: Syringe production in adhered to or even bettered. The company man- data and information that can be confirmed by St Gallen, Switzerland ufactures its syringes made of glass and poly- customer tests if required.

CONTINUOUS INNOVATION The close contact with the relevant authorities and institutions enables the company to In addition to validating existing products, keep abreast of changes in regulations. new types of packaging are constantly being By finding the right packaging solution in developed. Innovative, highly sensitive and terms of compatibility, safety, protection and often very expensive active agents such as functional performance, SCHOTT forma vitrum biotech or protein solutions, for example, are supports the pharmaceutical industry in provid- often a challenge, even for pharmaceutical ing the best medication to the patient. packaging experts. In these cases, SCHOTT forma vitrum sets the standards not only with ABOUT SCHOTT FORMA VITRUM: its proven expertise and its broad possibilities using glass and polymers, but also as an SCHOTT forma vitrum is one of the world’s expert in the field of surface coatings. The leading suppliers of parenteral packaging prod- proprietary SCHOTT PI-Coating® technique ucts for the pharmaceutical industry. More than can be used for the application of specific lay- 500 production lines at ten different manufac- ers to pharmaceutical glass and polymer con- turing sites located all over the world manufac- tainers to achieve, for example, improved ture more than six billion syringes, vials, chemical stability and inertness, less adsorp- ampoules, cartridges and specialty articles made tion of biomolecules, improved barrier prop- of glass tubing or polymers each year. Excellent Figure 4: Glass and polymer syringes by erties and prolonged shelf life of drugs in raw materials, the most modern manufacturing SCHOTT forma vitrum polymer containers. techniques and technologies, as well as contin- Safety of patients is the ultimate goal consistently high quality. Clean-room syringe ued research and development efforts have behind all of these activities and developments. production work underway at the St Gallen, resulted in innovative product solutions. Back- This means continual improvements must be Switzerland facility is shown in figure 3 on the up capabilities at various production sites all pursued at every possible level. At SCHOTT previous page. All products are manufactured over the globe offer flexibility, reliability and forma vitrum, this all begins with state-of-the- according to Good Manufacturing Practices safety to the pharmaceutical industry. Prefilled art technology, certified clean-room facilities (GMP), and inspected and tested against cur- syringes will clearly develop into a high growth and strictly controlled processes to ensure a rent pharmacopeias and ISO standards. market for SCHOTT forma vitrum in the future.

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OEM i A4 d i dd 1 1/5/06 10 35 58 OnDrugDelivery Pre filled 6/8/06 22:30 Page 14

REDUCING TIME-TO-MARKET: SUCCESSFUL DRUG MANUFACTURING

The time that it takes to get a drug to market nowadays is increasing and so are the problems that these long timelines are presenting to pharmaceutical and biotechnology companies. Outsourcing represents a strategy that, when properly used, can cut time-to-market dramatically. In this article, Dr Juergen Koch, Managing Director at Vetter Pharma-Fertigung GmbH & Co. KG, explains how Vetter works to help its clients’ products reach the market in the shortest possible time.

Most industries would certainly agree with have the infrastructure and capacity available in Benjamin Franklin’s famous saying “time is terms of both technology and personnel, espe- money”. For the pharmaceutical industry, how- cially if a request comes at short notice. A com- ever, time can mean a lot of money indeed: plete backup system should also be in place to developing, testing, manufacturing and receiv- avoid loss of production. ing approval for a new and potentially life-sav- ing drug can take up to 12 years of very inten- THE KEY: PLANNING AND sive work, with investments that can cost up to ORGANISATION $1 million a day. Whether the drug will be a hit is, of course, unknown. The challenges are Reduction in time-to-market can be accom- exacerbated by two additional factors: the plished in any phase of a drug’s development, growing stringency of official evaluation and but in the later phases reductions can be planned approval processes, and the fact that patents on with a far better chance of success. Vetter drugs are of limited duration, leaving only a Pharma-Fertigung GmbH & Co. KG, a leading small window for the developing company to independent specialist in the production of asep- actually earn back investments before the tically prefilled application systems, gears its patents lapse. operations toward fast response times. One option for reducing time-to-market rests One recent project, for example, involved a in outsourcing, whereby the contract manufac- customer that needed to fill a liquid parenteral turer must be examined very carefully. Here fol- drug with a best possible time-to-market. The low some key considerations: transfer took place in January 2005, filling occurred in April and the regulatory filing pro- • It should be able to provide full service, from cess (i.e. submission with six-month data) pre-project consultation to packaging, as this including validation and packaging, was com- offers the best opportunities to speed up the pleted by November. Three key factors that Dr Juergen Koch Managing Director entire production and packaging process. made this possible: conscientious planning, • An experienced contract manufacturer will integrated process management and sufficient have standardised protocols that will need capacity available on time. T: +49 751 3700 0 F: +49 751 3700 4000 only a little tweaking for each new drug. This E: [email protected] can shorten the validation process consider- ENSURING COMMUNICATION ably and speed up the approval process with Vetter Pharma-Fertigung GmbH the relevant regulatory agencies. The company’s development service is at the & Co. KG • A good working relationship between the con- core of all of its projects. The same team that Schuetzenstr. 87 tract manufacturer and regulators, with a does all the development and clinical manu- 88212 Ravensburg sound track record, can also make a positive facturing is also involved in the transfer to the Germany contribution to the approval process. commercial manufacturing process. This www.vetter-pharma.com • And finally, the contract manufacturer must ensures that intimate knowledge of the drug

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and filling process is carried over in order to FIRST STEPS help with any problems that might later arise. It also avoids the need to spend time on Once the green light has been given knowledge transfer. for the project, a specialised Vetter The development service and representatives of team establishes communication commercial manufacturing evaluate all cus- with a team from the client’s side. tomer inquiries, including reviewing the product Each team has a dedicated project specifications and manufacturing requirements, manager to ensure faster and as well as the available technical options. The smoother communications. An time factor is dependent on whether Vetter intensive consulting and planning applies a process that has already been validat- stage follows to determine the pro- ed, or whether it designs, implements and vali- duction process that will move the dates a brand new one. product from development to market production with no major delays. The necessary work steps are then defined and formulated as a checklist, including milestones to measure project progress.

A BLUEPRINT FOR EFFICIENT DEVELOPMENT

The primary packaging system also needs to be selected at this point. The solution should be one with 1a: The dual-chamber syringe Vetter which the manufacturer is very Lyo-Ject® – recipient of the Worldstar familiar, since important parts of Packaging Competition Award 1998, the process can be applied as tem- 1st prize at the Eurostar Packaging plates. The checklist will include Figure 2: Inner view of Vetter’s state-of-the-art labo- Competition 1998, and winner of the ratory freeze-dryer 20th German Packaging Competition all the equipment that needs to be 1997 ordered in time for the commercial production phase. In the project mentioned tivity, filling and pumps. The checklist is the ref- above, specification of the primary packaging erence point that indicates who must perform and procurement of components began on the which task, and by when. same day, as did the transfer of chemical analyses and, of course, process documentation. CONTROLLING PROCESS QUALITY

THE PROCESS Once the preliminary planning stage has been concluded and a detailed process roadmap has Well-designed, integrated project management been drawn up, the actual testing and filling can synchronises all processes so that they dovetail begin. The first step is a small-scale feasibility at the earliest possible moment. The complex fill, which is done by hand and entirely under 1b: 1 ml single-chamber syringe with V-OVS®. The originality seal V-OVS® filling of a lyophilised parenteral formulation laboratory conditions. This supplies a quick indi- guarantees the evidence of integrity of can illustrate this. Vetter has its own patented cation as to whether lyophilisation is even an syringes from filling to administration dual-chamber syringe, Lyo-Ject® (see figure option. Each lyophilisation run generates a pro- 1a), which requires double filling: with the sub- tocol with a report that describes moisture con- stance to be lyophilised and with the solvent fol- tent, reconstitution behaviour, chemical stability, lowing the lyophilisation process. (A single turbidity, appearance, mechanical stability of the chamber syringe, and single chamber cartridges, lyo-cake, and application functionality. The manufactured by Vetter, are pictured in figures specifications of the product are also determined, 1b and 1c, respectively) including whether it should be packed as a single After selecting the system, the development dose or multi-dose, as well as fill volumes and team reviews the entire filling process – the fill- storage conditions. Interaction between the prod- ing machine, format parts, and so on – so that it uct and the silicon and elastomers is also exam- can begin informing the company’s own suppli- ined, allowing the customer to make a final deci- ers who then, in turn, can deliver the necessary sion on the primary packaging. For the first fea- 1c: Single chamber cartridges parts in due time. The development team also sibility studies, the galenic formulation candi- (0.5-3.0 ml) studies the particularities of the drug and the dates need to be selected. The basis for develop- packing materials to ascertain, among other ing a safe and efficient lyo-cycle is the physical- Figure 1: Systems processed at Vetter things, compatibility with regard to light-sensi- chemical data package. At this stage, the charac-

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specification and qualification factors need to be met and the cleaning process validated (see figure 3). As well, raw materials and packaging materials must be selected, ordered and prepared. To ensure final success, backup supplies must be in place. All of this presupposes a high degree of organisation and co-ordination.

TESTING THE FINISHED PRODUCT

Whether the results of the feasibility study are applicable to bulk filling must also be tested and validated prior to commercial manufacturing. During up-scaling, a number of steps have to be carefully evaluated and calibrated as needed – for example, the thawing procedure of the bulk product, and the definition of bulk handling and mixing properties. Filtration is another important aspect that requires expert attention including: the type of tubing to be used; tubing diameter; and maximum allowed filtration pressure, amongst other factors. The filling profile is then checked with regard to the type of pumping system and aseptic handling. Once everything is functioning properly, the lyo cycle can be put through its tests by performing different runs on minimum and maximum scale, including extensive moisture mapping to verify homogeneity throughout the batch. At this point, the actual filling equipment has been installed and is ready to be tested on scale-up batches.

THE FINAL STEPS

Production of clinical batches (see figure 4) begins as soon as the scale-up batches are con- Figure 3: Validated cleaning processes. The washing process enables high quality in firmed as having been successful. In order to the manufacturing of aseptically prefilled application systems generate precise indicators for the master batch record, a minimum of three batches must be run terisation of the sensitive active pharmaceutical lab technicians to monitor such crucial factors using a minimum of 10% of the future commer- ingredient plays a role (for example. shear sensi- as freezing rates, heating ramp and radiation cial batch size. These batches can be used for tivity and pH-shift). One rule of thumb is that the effects, the impact of the pumping system, etc. registration purposes. The crucial factors in more information generated by the feasibility Vetter’s laboratory freeze-dryer is shown in fig- determining the success of the batches are good fill, the less time required for adjustments during ure 2. Each lyophilisation run is documented manufacturing practice (GMP), the possibility the commercial manufacturing stage. It is quick- and the resulting samples are stored for informal of human use, and release of the batches by er to do adjustments, changes or corrections in stability testing, usually at 2-8°C, room temper- quality control and the qualified person. the lab than on the filling line. ature, 40°C/75% relative humidity. In-house The up-scaling runs produce material for sta- capacity (storage analytics) of the CMO can fur- bility batches, which can also be used for clini- PARALLEL JOBS ther speed up this process. cal studies after the stability tests have produced positive results. In the aseptic filling process, Completion of the feasibility phase provides the THE SCALE-UP PROCESS each step in a project is geared towards greater development service with one or two galenic safety and speed in the final stages. Figure 5 formulations to work with. The first milestones Though determining the best cycle and formula- depicts syringes leaving the filling machine. must be achieved very carefully to avoid prod- tion together with the customer takes about three Prior to commercially manufacturing the drug, uct-related incidents, such as product stability months, this doesn’t mean that the rest of the team however, a detailed risk analysis must be carried issues causing launch delay. The lyo-cycle must has to sit on its hands. While the development ser- out in all steps of the process, followed by vali- then be run several times, simulating large-scale vice is working on the formulation and designing dation, which must be conducted on at least one conditions in order to fine-tune the process and the best filling process, the rest of the team can set full batch for the European and US markets. determine ideal freezing, and primary and sec- to work preparing the scale-up process. The pro- All critical parameters are examined and test- ondary drying conditions. This also allows the duction equipment must be procured and set up, ed, such as holding times, mixing properties and

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process. Validation also extends to various shipping aspects, including the container, the packaging and the means of transportation. A validation protocol and a report are generated in the process, to be used for all future commercial batches. The customer, with support from Vetter, sub- mits these documents to the regulatory authorities. If the batches still have sufficient shelf life, they can be used for the product’s market launch. The end of the validation process Figure 5: Aseptically prefilled syringes leave the filling machine signals commercial manufacturing. Experienced teams, integrated process man- REDUCING TIME-TO-MARKET: agement and active communication between all SUMMARY units and team members are crucial. Most important, however, is assiduous planning in the earliest When it comes to reducing time-to-market for stages to ensure that all steps in the process are their new drugs, pharmaceutical companies should properly choreographed to save as much time as focus their attention on the last phase of develop- possible. It is vital that the contract manufacturer Figure 4: Aseptic filling of syringes within ment, namely packaging and all that it entails. The has a good track record with regulatory agencies the framework of clinical study processes involved in this phase are precisely such as the FDA, EMEA and others. Finally, as an full-day production (robust processing). planned, and valuable time can be saved at this outsourcing partner, the company should be high- Simulating worst-case conditions is one way to stage. If, as is often the case, the company is not ly trustworthy and financially stable. In a word, it cover all of these bases. Another is to validate an doing the packaging itself, it is important to find a should be a global leader in its field. optional minimum and maximum batch size to contract manufacturer with the know-how, exper- Copyright © 2006 Vetter Pharma-Fertigung build flexibility into the commercial production tise, and infrastructure to do the work efficiently. GmbH & Co. KG

2006 ONdrugDelivery Ltd www.ondrugdelivery.com 17 OnDrugDelivery Pre filled 6/8/06 22:31 Page 18

SEE US AT AAPS NATIONAL BIOTECHNOLOGY CONFERENCE 2006, BOSTON, USA, BOOTH # 313

Vetter Produces Quality by Design. Day by Day.

Vetter Development Service Vetter Commercial Manufacturing Vetter Solutions Development of Primary Fill & Finish Services Dual-Chamber Technology, Packaging Materials Packaging Services i. e., freeze-dried/solvent, liquid/liquid Process Development Pharmaceutical Analysis Anti-Counterfeiting Solutions Regulatory Affairs Service Regulatory Affairs Service Tamper-Evident Closure Clinical Manufacturing Systems Pharmaceutical Analysis Transfer to Vetter Commercial Dosage Forms: Manufacturing Syringes, Cartridges and Vials

Vetter is an independent international specialist in the production of aseptically pre-filled application systems. Vetter provides support for its clients from the initial phases of development and regulatory approval process through to the successful product launch and commercial manufacturing. Vetter is renowned for its quality, innovation and loyalty as a strategic partner for its pharmaceutical and biotech clients.

For US inquiries please call +1-215-321-6930. For EU inquiries please call +49-751-3700-0.

www.vetter-pharma.com OnDrugDelivery Pre filled 6/8/06 22:31 Page 19

Discover the latest scientific and technological developments at SMi’s… Drug Delivery Global Summit 20th & 21st September 2006, Central London

Hear international case studies and expert perspectives from leaders in the field, including: Sponsored by • David Stern, Executive Vice President, Metabolic & Endocrinology, Serono • Dr Eric Tomlinson, President & Chief Executive Officer, Altea Therapeutics • Dr Martin Woodle, President & Chief Scientific Officer, Intradigm Corporation • Steven White, Senior Director, Product Development, Epic Therapeutics, Baxter Healthcare • Dr Tom Tice, Executive Vice President & Chief Scientific Officer, Brookwood Pharmaceuticals • Dr Mason Diamond, Vice President, Clinical & Regulatory Affairs, TyRx Pharma • Dr Luk Chui Li, Director, Global Drug Delivery, Abbott Supported by • Dr Jörg Rosenberg, Associate Director, Pharmaceutical Development, SOLIQS, Abbott • Dr Ola Nerbrink, Principal Scientist, Device Chemistry & Biology, Novo Nordisk • Dr David Brayden, Chairman, UK-Ireland Chapter, Controlled Release Society d Key issues that will be addressed at the conference include: • NOVEL DRUG DELIVERY SYSTEMS: Hear about the latest developments in drug delivery design and how to comply with Good Manufacturing Practice • NANOTECHNOLOGY: Discover how advances in nanotechnology can advance the drug delivery industry through novel design and application • TARGETED DRUG DELIVERY: Consider how targeting drug action can revolutionise medical treatment and understand the latest developments that can make this a reality • CONTROLLED RELEASE: Appreciate the science and technology behind long-acting parenterals and the design, development and manufacturing considerations for implants and injectable formulations • CHALLENGES IN DRUG SOLUBILITY AND ADSORPTION BARRIERS: Recognise the pitfalls associated with hydrophobic drugs, their delivery and action • NETWORKING OPPORTUNITIES: Meet the key industry leaders, make valuable contacts and learn from their experience and expertise

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A Current Trends in Global Pharmaceutical Alliances: Doing the Deal (PM) 19th September 2006, Central London In association with: PharmaVentures

B The Effective Transdermal Delivery of Protein Drugs, Vaccine Antigens and Highly Water-Soluble Low Molecular Weight Drugs (AM) 22nd September 2006, Central London In association with: Altea Therapeutics

C Liposomes as Carriers for Vaccines and Nucleic Acids (PM) Special Price for 22nd September 2006, Central London In association with: Polymun Scientific Academic Researchers

Register online at www.smi-online.co.uk/drugdeliv.asp Alternatively fax your registration to +44 (0) 870 9090 712 or call +44 (0) 870 9090 711 GROUP DISCOUNTS AVAILABLE OnDrugDelivery Pre filled 6/8/06 22:31 Page 20

PACKAGING IN PREFILLED SYRINGE SYSTEMS: SELECTION AND EVALUATION

Selecting components for a prefilled syringe system is an important consideration for pharmaceutical manufacturers. Here, Ms Frances DeGrazio, Vice-President, Quality Assurance & Regulatory Affairs Americas at West Pharmaceutical Services, describes some of the regulations surrounding container closures for prefilled syringes, and how West’s processes and testing protocols ensure that the high standards are maintained.

A syringe system generally consists of a barrel UNDERSTANDING THE manufactured from glass or plastic, a needle CONTAINER CLOSURE GUIDANCE with an elastomeric needle shield or a luer lock/luer cone, and a rod with an elastomeric The FDA guidance, “Container Closure Systems plunger on the tip (see figure 1). The plunger for Packaging Human Drugs and Biologics”, contacts the drug during administration. In a addresses the evaluation of packaging and delivery prefilled syringe system, the plunger may also systems for pharmaceutical drug products. contact the drug during storage, which may last According to the guidance, each NDA and ANDA up to two years. should contain enough information to demonstrate Manufacturers must understand the that a proposed container closure system and its requirements for prefilled syringe systems components are suitable for the intended use. included in the FDA’s Guidance for Industry, Packaging suitability is based on four “Container Closure Systems for Packaging attributes: protection, safety, compatibility and Human Drugs and Biologics” and conduct the performance (function and/or drug delivery). extractables/leachables testing that the guid- For injectable dosage forms, the guidance spec- ance recommends. ifies the procedures to test the interaction

Frances L DeGrazio Vice-President, Quality Assurance & Regulatory Affairs Americas

Contact: Jennifer L Riter Business Development Manager T: +1 610 594 3137 E: [email protected]

West Pharmaceutical Services, Inc. 101 Gordon Drive Lionville PA 19341 USA Figure 1: A syringe system generally consists of a barrel manufactured from glass or plastic, a needle with an elastomeric needle shield or a luer lock/luer cone and a rod www.westpharma.com with an elastomeric plunger on the tip.

between the drug and its packaging components. Associated components, such as those used only at the time a dosage is administered and secondary packaging materials, are also included in the review.

EXTRACTABLE AND LEACHABLES IN PRIMARY CONTAINER CLOSURE SYSTEMS

Factors that must be considered in evaluating container closure systems include the materials used to construct the components, surface treat- ments applied to the components, processing aids, the dosage form’s active ingredients and excipients, sterilisation, and other related processing and storage conditions. Extractable testing studies are recommended even if containers or components meet compen- dial suitability tests. Testing under stressed conditions should demonstrate that the extractable Figure 2: Extractable screening during safety studies is an important step when profile is acceptable for the dosage form and that choosing the appropriate closure for a prefilled syringe or drug vial. levels observed will not be approached or exceeded during the shelf life of the drug product. extractables can be achieved through analytical mines that these leachables cannot be detected Leachables are substances identified in a testing, such as liquid chromatography/mass by that particular method. defined laboratory regimen by simulating use spectrophotometry (LC/MS), gas chromatogra- Sometimes methods development studies are conditions. Typically, leachables are a subset of phy spectroscopy/mass spectrophotometry expanded to improve sample preparation before extractables. (GC/MS), inductively coupled plasma (ICP) analysis with a particular instrument. In one case, and infrared (IR). client samples required dilution with an equal EXTRACTABLE AND LEACHABLES The laboratory would identify a potential volume of tetrahydrofuran (THF) to enhance the TESTING CRITERIA extractables list for the specific plunger rubber solubility of the leachables. Samples were then formulation. The laboratory will engage in meth- centrifuged at a preset time and speed to allow Extractables/leachables testing determines: ods development and conduct an assessment to presence of a clear THF top layer. The laboratory • that the materials of the container closure sys- determine the potential for analytical interference, then analysed this layer to allow for proper detec- tem components are safe for their intended use. the limits of quantification (LOQ) and typical per- tion of compounds at required concentrations. It • that the container closure system components centage of recovery of spiked extractables in non- was also determined that the clean-up step do not interact with the drug to cause unac- degraded and degraded drug product or placebo. between sample injections should be made with ceptable changes in the quality of either the If there is significant interference during acetonitrile to maintain column performance. drug or the packaging components. method feasibility testing, such as HPLC col- • that the container closure system provides the umn deterioration, retention time shortening and Methods validation for detection of leach- dosage form with adequate protection, includ- poor recovery after multiple injections for ables in placebo or drug product is based on rec- ing seal integrity and the ability to reseal leachables, the laboratory then deter- ommended industry practices and International where applicable. Conference for Harmonisation (ICH) guide- • that the container closure system lines. A validation plan for each identified test functions in the manner for method should be developed and approved which it was designed. by the client.

TESTING PROCESSES RISK MITIGATION STRATEGIES

Extractable screening during safety Syringe plungers with a fluorocarbon studies is an important step when barrier film can help reduce the risk of choosing the appropriate plunger for a product loss caused by interaction of the prefilled syringe (see figure 2). Test meth- drug and the plunger and the loss of the drug ods must be specific to the drug product or through adsorption and absorption (see figure 3). placebo in order to evaluate interferences, lin- earity and other critical factors accurately. Figure 3: Syringe plungers with a A barrier film can: Pre-screening procedures should begin with fluorocarbon barrier film can help • protect the shelf life of packaged drugs reduce the risk of product loss caused a basic evaluation of syringe plunger options. • enhance drug/plunger compatibility by interaction of the drug and the The protocol can involve multiple temperatures plunger and the loss of the drug through • have exceptional lubricity for enhanced and conditions for acceleration. Identification of adsorption and absorption. machineability and processing

Figure 4: New state-of-the-art polyisoprene needle shield formulas, using dried natural rubber-free nitrosamine, are MBT-free and ensure good compatibility between the elastomeric component and the drug product.

A fluorocarbon film provides an effective THE ADVANTAGES OF Final packing of the components into carriers barrier against organic and inorganic extracta- READY-TO-STERILISE COMPONENTS suitable for introduction into sterilisation units is bles to minimise interaction between the drug typically performed in a Class 100 clean room. To and the plunger and maintain the plunger’s seal Another industry trend is the growing use of improve cleanliness, component manufacturers integrity. The fluorocarbon film reduces absorp- ready-to-sterilise elastomeric components for may ship the products in plastic cartons packed on tion and adsorption of the drug product, and the which the component manufacturer performs plastic pallets to minimise particle contamination. low surface energy of the film provides lubricity the washing and preparation steps usually done without the need for silicone oil. by the pharmaceutical manufacturer. CONCLUSION In the past, natural rubber- and polyisoprene- The ready-to-sterilise process allows the based needle shields and tip caps were subject to drug manufacturer to focus on drug develop- The FDA guidance, “Container Closure ment, not component Systems for Packaging Human Drugs and “THE READY-TO-STERILISE PROCESS cleaning, and brings the Biologics”, defines criteria for extractable and additional benefit of a leachable testing of packaging components. ALLOWS THE DRUG MANUFACTURER TO standardised process for Pharmaceutical companies may have to initiate FOCUS ON DRUG DEVELOPMENT, NOT component preparation. testing that will require time and money that A component manufac- must be built into the qualification and stability COMPONENT CLEANING” turer’s ready-to-sterilise studies early in the product development cycle. process should be fully Container closure pre-screening of plungers for cracking through exposure to light and/or fresh validated by pharmaceutical GMP standards prefilled syringes helps assure their suitability for air. This cracking resulted either in cosmetic and the manufacturing should be completed use with the dosage form and establishes appropri- defects or even worse in seal integrity issues. under cGMP standards. ate methodology to test leachables using validated New state-of-the-art polyisoprene needle The certificate of analysis should provide methods. These tests minimise risk and allow for a shield/tip cap formulas, using dried natural rub- bioburden, endotoxin and particulate test data successful product launch in a timely manner. ber free nitrosamine, are MBT-free and ensure on each wash load; product should not be Pharmaceutical manufacturers may reduce good compatibility between the elastomeric released without meeting the standard specifi- risks associated with the container closure system component and the drug product (see figure 4). cations for the process. Ready-to-sterilise by selecting syringe plungers with fluorocarbon These polyisoprene formulas minimise the risk components should be washed in a pharma- barrier film, state-of-the-art polyisoprene-based of coring through the needle and are significant- ceutical-grade washer with a final rinse in needle shield/tip cap formulas and by specifying ly less sensitive to environmental conditions. USP water for injection. ready-to-sterilise components.

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CURRENT MARKET AND KEY TRENDS OF DEVICES USED IN SELF-INJECTION

In this article, Mr Joël Cotten, European Product Manager at BD Medical – Pharmaceutical Systems, gives a view of the more established sections of the injectables market. Using examples from the field of self-injection devices, he highlights the reasons for their success, and some of the obstacles that needle-free injection has faced, with the lack of a standardised container foremost among them.

There are many ways to categorise the types of by the patient. The leading pens are re-usable, devices used in self injection. Many authors are allowing the patient to reload the pen with a new speaking of pens, auto-injectors, syringe injec- cartridge (1.5 ml or 3 ml) for additional treat- tors, needle free devices or other pumps for ment. Two important trends are apparent in the insulin. We propose to define the devices for cartridge and pen markets today. self-injection in terms of the type of primary containers they use: • A 3 ml cartridge appears to be the leading volume used by the pharmaceutical companies. • The single- or double-chamber cartridges, With the market evolving to disposable pens, which are used in pens. the larger-volume cartridge allows for a • The prefillable staked needle syringes, which greater number of injections. are used in auto-injectors, but can be used alone by patients. • Patients are pushing for increased convenience • Other primary containers that could be rigid, and smaller needles. For example, 31-gauge such as vials used in needle free devices, or thin wall pen needles like the BD Micro- collapsible, which may be used in products Fine™ and BD Ultra-Fine™ are increasingly such as the BD™ Micro-infusor. These other popular (see figure 1). Mr Joël Cotten primary containers are used in non-classified European Product Manager self-injectors. Thanks to the proven success of pens in the diabetes market, a number of additional thera- T: +33 0 4 76 68 36 64 The current market of cartridges, prefillable peutic classes are presenting their products in a F: +33 0 4 76 68 35 05 syringes and other containers for self injection self-injection device. The treatment of women’s E: [email protected] is growing at rate close to 14% in terms of num- infertility, osteoporosis, and growth hormone bers of units. Each sub-market follows different deficiency are some of the markets using pens Worldwide Headquarters trends. Part of the non-classified self-injectors, such as that shown in figure 2. BD Medical - Pharmaceutical Systems needle-free injectors have had some difficulty The convenience of cartridges and pens 11, rue Aristide Bergès following the market growth. This is probably means that they will soon be used for the treat- 38800 Le Pont de Claix because of a lack of a convenient and universal ment of diseases such as cancer, Alzheimer’s France primary container, which is present in other sub- disease, Parkinson’s disease, and Hepatitis C. US Headquarters markets. For example, the BD Hypak™ syringe Although liquid drugs are easy to fill in a 1, Becton Drive is used for auto-injectors, and standard 1.5 ml or cartridge, new developments from the Franklin Lakes, NJ 07417 - 1886 3 ml cartridges are used in pens. biotechnology industry have created drugs USA that are not stable in a liquid format for a T: 1 800 225 3310 ... PENS AND CARTRIDGES long period of time. These drugs require a From outside the US: dual chamber cartridge to keep the drug sep- T +1 201 847 4017 Most pens and cartridges are used to administer arate from the diluent. The leading company F: +33 201 847 4847 insulin. The devices allow for multiple injec- in this industry to support this technology is www.bdpharma.com tions with variable dosing that can be adjusted Vetter. It offers a selection of cartridges that

Figure 2: BD™ self-injection pen

can be used by re-usable pens or disposable liquid dry injectors such as the BD™ LDI (see figure 3). Figure 1: Thin wall BD pen needles ... PREFILLABLE SYRINGES AND AUTO-INJECTORS Although the NFI technology is Historically, prefillable syringes were not fre- exciting because of the absence quently used in self-injection. Their focus was of the needle, companies have to help the professional healthcare workers in yet to be successful with the the fields of the vaccination and heparin therapy. development and launch of a In the late 1990s, the emergence of biotech product on a large-volume drugs to treat multiple sclerosis, rheumatoid basis. A limited market of drugs arthritis, and anaemia, created a need for can utilize this technology devices to help patients inject themselves. These because of its current high pro- drugs also came with decreased frequency of duction cost. In addition, pain is injections relative to insulin – ranging from still questionable when NFI are daily to once every two weeks. non-correctly performed. The upshot is that demand for disposable Recently, needle-free injec- auto-injectors filled with a prefillable syringe, tor companies have begun ini- such as BD’s Hypak Physiolis™ syringe (see tiatives to compete with auto- figure 4), has increased. injectors for injecting mono and fixed doses. However, the … NON-CLASSIFIED SELF-INJEC- lack of a universal primary TORS USING COLLAPSIBLE AND container has impeded the abil- RIGID PRIMARY CONTAINERS ity of needle-free injectors to present an alternative to the The size of the self-injection market has stim- disposable BD Hypak™ auto- ulated development of other non-classified injectors that are in the market. self-injectors beside pens, cartridges, prefill- Nonetheless, leading devices able syringes and auto-injectors. Some of these such as the pens and auto-injec- new self-injectors were initially developed tors mentioned earlier, are not using proprietary primary containers, such as answering all of the market’s the insulin pump. needs, so additional technolo- Another technology that emerged from the gies have come to the market. treatment of diabetes is the needle-free injection For example, focusing on (NFI) using a rigid container able to accept high the subcutaneous delivery of pressure during the injection of the drug. small volumes, pens and auto- Figure 3: The BD™ LDI

Figure 5: The BD™ Microinfusor

injectors are ignoring demand for: injections of Microinfusor, which is shown in figure 5, volumes above 1ml; injections of viscous would appear to be a strong challenger in the drugs; and injections that need to last more established self injection market. than 20 seconds. The innovative BD™ Microinfusor is answering these demands and is one the first Art.06/Self-Injection article/ENG/01 devices to facilitate injections with needles as BD, BD Logo and all other trademarks are the Figure 4: BD Hypak Physiolis™ syringe small diameter as 30 to 34 gauge. The BD™ property of Becton Dickinson and Company.

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Copyright © 2006 ONdrugDelivery Ltd www.ondrugdelivery.com 27 OnDrugDelivery Prefilled6/8/0622:31Page28 drug therapy. and contributetotheoptimizationof differentiate pharmaceuticalproducts conventional drugdeliverymethodswhich We to delivercost-effective alternatives industry requires inapackagingpartner. and experiencethatthepharmaceutical Pharmaceutical Systemsprovides theexpertise the pharmaceuticalindustry. delivery systems,designedtofittheneedsof dedicated todevelopingprefillable drug BD Medical BD Medical Because DrugDeliveryisamatterofconfidence - PharmaceuticalSystemsis BD Medical - PharmaceuticalSystems - aetrldu deliveryneeds. drug parenteral solutionssuitable for all regi process know-how, weare abletopropose presence andourpharmaceuticalpackaging ourworldwide achieve theirgoals.With with supportandresources tohelpthem services, weprovide pharmaceuticalcompanies abroad rangeofinnovativedevicesand With patients’ needsforcomfort. safety andconvenienceaswellfulfilling meet healthcare professionals’ demandsfor All ourprefillable devicesare designedto onal marketand www.bdpharma.com Fax: (1)2018474847 Outside ofU.S.:(1)2018474017 Tel U.S.:(1)8002253310 Franklin Lakes,NJ07417-1886USA 1, BectonDrive U.S. Fax: 33.4.76.68.35.05 Tel: 33.4.76.68.36.36 France 38800 LePontdeClaix 11, rueAristideBergès W Pharmaceutical Systems BD Medical orldwide Headquar Headquar ters ters

COMPANY PROFILE – THE MEDICAL HOUSE

The Medical House (TMH), based in the UK, designs, develops and manufactures delivery systems which enable simple, safe and comfortable self-injection, even by those patients who have an aversion to needle-based injection. Working closely with its partners, TMH has developed a range of needle-based disposable auto-injectors and needle-free jet injectors for the delivery of injectable products.

THE ASI AUTOSAFETY INJECTOR The ASI offers: INJECTABLE CHALLENGES • Simple, completely automated injection The ASI disposable auto-injector system is process which involves only two user steps TMH’s delivery technologies provide specifically designed to incorporate pre- • process includes needle insertion, injec- bespoke systems to meet a wide range of filled glass syringes. Figure 1a shows the tion, and automatic needle retraction requirements associated with injectable prod- device and figure 1b is a cut-away diagram. • used needle and syringe captured safely ucts, including solutions to specific chal- Utilising TMH’s patented, proprietary inside the used auto-injector after delivery lenges such as: auto-injector technology, the ASI provides a simple, cost-effective and versatile means • Needle hidden from the patient at all times • Presentation of creating competitive advantage for • before, during and after delivery • prefilled syringe, vial, cartridge TMH’s pharmaceutical and biotech compa- • addressing patients’ aversions ny partners, including Martindale Products, • Injection volume a division of Cardinal Health, and a number • Compatibility with a number of the most • fixed, variable, part-volume delivery of other industrial collaborators. In addi- common prefillable glass syringes tion, TMH is currently working with a • facilitating rapid, cost-effective commer- • Therapeutic European government agency to develop a cialisation programmes • subcutaneous, intramuscular and intrader- disposable auto-injector for a specific mal injection emergency application. • Minimal number of device components • emergency, elective • providing an inherently reliable, economic and versatile system • Formulations • liquid, lyophilised, powdered, viscous • Enhanced capability to deliver viscous (e.g. sustained release) formulations CONTACT TMH TO DISCUSS YOUR • incorporating narrow-gauge needles INTERESTS AND REQUIREMENTS a • short injection duration /01.Link to Business. • proprietary system to protect against risk To discuss your specific requirements, inter- of syringe damage from injection forces ests and opportunities, or to discuss potential collaboration, please contact TMH directly • Integrated, automated reconstitution of using the details provided above. dry (e.g. lyophilised) components

COMPETITIVE ADVANTAGE David Urquhart TMH’s ASI system creates competitive Managing Director advantages for our partners by: [email protected]

b • Minimising dependence on clinical expertise Laura Hetherington • enabling patients to manage their therapy Marketing & Product Support • reducing costs of healthcare provision [email protected]

• Overcoming patients’ needle aversions The Medical House PLC • improving compliance with optimal therapies 199 Newhall Road Sheffield • eliminating the incidence of needlestick S9 2QJ UK injuries and risk of disease transmission T: +44 (0) 114 261 9011 F: +44 (0) 114 243 1597 Figure 1: The ASI AutoSafety Injector (a) • Facilitating rapid response in emergencies external appearance and (b) cut-away www.tmh-drugdelivery.com view showing the inside of the device. • Responding to large-scale injection needs BD, BD Logo and all other trademarks are the property of Becton, Dickinson and Company. ©2006 BD. A06/BDM-PS products range/ENG ©2006 BD. A06/BDM-PS products of Becton, Dickinson and Company. the property BD, BD Logo and all other trademarks are Copyright © 2006 ONdrugDelivery Ltd www.ondrugdelivery.com 29 OnDrugDelivery Pre filled 11/8/06 00:01 Page 30

COMPANY PROFILE – YPSOMED

Ypsomed is the largest independent developer and manufacturer of custom-made injection systems for self-administration, and has more than 20 years’ experience in the development and manufacture of injection pens and pen needles. Pens form the core of its product range, spanning a wide spectrum from simple disposable pens to those with variable dosing and electronic display right up to highly complex injectors with multifunctional electronics. It also manufactures compatible pen needles with a unique click-on function for its own and all other widely available pens.

The demand for new customised injection in Switzerland and throughout a European devices continues to grow as injectable sales and distribution network. biotech drugs are developed in existing and new therapeutic areas where sophisti- All products are developed and manufac- cated injection devices improve patient tured in Switzerland, where internal capabil- compliance and the success of the therapy. ities include R&D, tool-making, injection Some drugs require frequent, variable moulding, clean-room production and dose injections while others require less assembly facilities. It has production sites in frequent, fixed does injections. Larger Burgdorf, Grenchen and Solothurn. injection volumes, the need for fixed Ypsomed provides not only the marketing doses and the often high viscosity of drugs and technological expertise, but also the are increasing the demand for auto-injec- production expertise according to the latest tion devices. regulatory requirements for both low and high-volume production. Ypsomed Ypsomed’s core technology is constantly manufactures in FDA-registered facilities, expanding to cover new therapy and is inspected regularly, and supplies devices patient needs. Its range includes disposable approved for all leading markets including and re-usable auto-injector platforms for the US, Europe and Japan. the treatment of autoimmune diseases and for new cancer therapies. A broad-based Ypsomed’s safe, reliable solutions have earned technology platform and around 100 the company credibility with its many partners patents means that Ypsomed can meet and countless patients. The long-standing virtually all partner needs in the growing quality of its products and its responsible con- market for self-injection systems. duct form the cornerstones of the company’s excellent reputation. It has well-established Ypsomed was created in 2003 from one of partnerships of many years with numerous the two divisions formerly owned by the leading pharmaceutical and biotech manufac- well-known Disetronic Group. It employs turers such as Sanofi-Aventis, Genentech, over 1,100 people at several production sites Ypsomed disposable auto-injector Lilly, Pfizer, Roche and Serono.

Ian Thompson Manager Business Development Ian Thompson’s article, “New-generation auto-injectors: T: +41 34 424 32 23 taking self injection beyond F: +41 34 424 31 51 M: +41 79 778 28 72 prefilled syringes”, published in E: [email protected] ONdrugDelivery’s 2005 Prefilled Syringes issue, is available at: Ypsomed AG Brunnmattstrasse 6 www.ondrugdelivery.com/ CH-3401 Burgdorf publications/ypsomed_2005.pdf Switzerland

www.ypsomed.com

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