Elastomeric Closures for Parenteral Applications

ROHSTOFFE UND ANWENDUNGEN RAW MATERIALS AND APPLICATIONS

Parenterals . elastomeric closures . injection vials . infusion bottles . Elastomeric Closures for pre-fillable syringes Parenteral Applications Parenteral drug preparations are sterile preparations intended for administration by injection, infusion or implantati- Parenteral closure types and designs plug diameter, flange thickness, total on into the human or animal body [1]. Parenteral drugs are administered by in- stopper height and penetration thick- Especially for injection and infusion ap- jection, infusion or implantation. The ness. The latter refers to the thickness of plications very often elastomeric closu- parenteral drug route is different from the rubber membrane that a small dia- res are used to guarantee the seal inte- e.g. the oral route or from the route of meter needle or a larger diameter hollow grity of the entire drug package. This inhalation. For injection and infusion ap- spike has to penetrate in order to get ac- article gives an insight into the required plications very often rubber closures are cess to the contents of the vials and eit- property profile of such closures. used to guarantee the integrity of the her inject a reconstitution medium or seal that is formed by the elastomeric withdraw the solution from the vials for closure and another component of the administration to the patient. Most of Elastomere Teile für Parenteralia total drug package. Since parenteral these dimensions are standardized in drugs are rendered sterile before they are corresponding standards issued by the Parenteralia . Elastomerdichtungen . put in the market, preservation of seal International Organization for Standar- Injektionsfläschchen . Infusionsfla- integrity by itself comes down to preser- dization [2]. For design purposes it is ne- schen . vorgefüllte Spritzen vation of sterility of the drug until the cessary to understand that tolerances of time it is administered to a patient. rubber parts cannot be as tight as for Parenterale Medizinprodukte sind steri- plastic parts. le Präparate, die für Injektion, Infusion Stoppers for vials and bottles It is clear that the two rubber closures oder Implantierung im Körper ange- These closures are the sealing compo- that are shown in Figure 1 have a clearly wendet werden. Besonders für Injek- nents that are used for closing glass or distinct geometry. This is because one of tions- und Infusionsanwendungen wer- plastic vials or bottles that contain either the two is a lyophilization stopper. In the den häufig Elastomerdichtungen einge- a drug that is dissolved in a liquid medi- lyophilization process, the drug in its li- setzt um die Integrität, und somit die um, most often aqueous, or a drug that is quid state, this means in solution, is filled Sterilität der Gesamtverpackung zu ge- present in a solid form and that needs to into the vials. The freeze-drying closure is währleisten. Dieser Artikel gibt eine be dissolved in an appropriate solvent put on the vial in a halfway down positi- Übersicht über die Anforderungen an right before administration to the pati- on (Figure 3), so that there is a vent ope- solche Dichtungen. ent. The size of the glass or plastic containing between the inside of the vial and ner may vary from small vials that have a the area around the vial. It is after a free- total volume between 3 ml and 30 ml to zing step that through this opening, sub- larger bottles with a nominal volume limation of the then formed ice takes between 50 and 1 000 ml. Glass vials and place under the influence of underpres- bottles are far more used than their plas- sure in the lyophilization chamber and tic counterparts. The elastomeric closu- heat that is transferred to the vials by the res on vials and bottles are kept in place shelves of the freeze-dryer on which the by an aluminium or aluminium/plastic vials are standing. At the end of the lyo- cap that is crimped over the stopper and philization cycle the stoppers then are underneath the neck of the vial or bottle. fully pressed down into the vials by the With a view to preservation of sterility shelves of the freeze-dryer. crimping needs to be done in an appropriate way. Stoppers for vials and bottles consist of a flange having a larger diameter and a plug part having a smaller diameter. Author The plug part fits into the vial or bottle neck while the flange part rests on the Renaud Janssen, Datwyler rim of the vial. Closures in this category Sealing Solutions, Alken are usually subdivided by their size. The- se subdivisions include 13 mm stoppers Corresponding author: and 20 mm stoppers for small volume Renaud Janssen, Ph. D. parenterals, and 28 mm, 29 mm and 32 Global Director of Scientific mm stoppers for large volume parente- Affairs rals. These sizes do not correspond with Datwyler Pharma Packaging any diameter of the closure itself, howe- Industriepark 1519

Figures and Tables: ver they indicate the largest diameter of B-3570 Alken (Belgium) By a kind approval of the authors. the vial neck. Important dimensions of E-mail: renaud.janssen@ datwy- this type of stoppers are flange diameter, ler.com

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1 Fig. 1: typical closures 3 for serum and for free- Flip Cap Lyophilisation Stopper ze-drying vials

Serum Stopper

2 Flange Fig. 3: lyophilization vials and their stoppers

Blowback pical for non-dental applications, such as insulin and growth hormone cartridges, Plug is that the cartridge contains multiple drug dosages. After administration of each dose, the rubber disc must adequately reseal so as to preserve drug sterility Fig. 2: section of a serum stopper with blowback and to prevent loss of medicinal product, and at every next dose the plunger must Components for pre-fillable syringes ponent that makes a seal between the again smoothly move over a small dis- and for cartridges inside of the syringe and the outer world. tance. More and more drugs are packaged in Basically the syringe is delivered with pre-fillable syringes or cartridges, in ad- either a needle already being present Components for disposable syringes dition to or instead of a vial presentation. (‘staked needle’) or with a prevision to Apart from pre-fillable syringes and cart- Pre-fillable syringes are claimed to have place a needle at the time of administra- ridges a very large amount of rubber distinct advantages over vials, including tion. In the first case the needle will be plungers is used in disposable syringes ease of use, dose accuracy and minimiza- protected by a rubber needle shield. In that are used to administer parenteral tion of product loss in the emptied pa- syringes without staked needle, the lat- products to patients (Figure 4). ckage. Once filled, the syringe acts as a ter function is taken over by another A similarity between a disposable and container for the drug, in the same way rubber component, called ‘tip cap’. a pre-fillable syringe is that in both cases as a vial or bottle does. Another prominent tendency at this the plunger must be able to move Pre-fillable syringes at a minimum time is to package drugs in cartridges. smoothly, with a well-controlled force to consist of a barrel in glass or plastic, plus These cartridges may be intended to be start the movement and with a well- two different elastomeric sealing com- used in self-administration devices, like controlled force to sustain the move- ponents (Figure 4). There is an ‘internal’ insulin pens or growth hormone pens, or ment as long as this is needed. A very component that makes a seal on the in- may be intended for administration by important difference however between ternal diameter of the barrel. This com- medical staff as is the case for a cartridge the plungers in pre-fillable and in dispo- ponent most commonly is called a ‘rub- with a dental anaesthetic. Like pre-fillab- sable syringes is the contact time with ber plunger’. After filling of the syringe le syringes, cartridges are equipped with the drug. For a pre-fillable syringe this this plunger is in long-term ‘intimate’ rubber plungers. However, the second time is expressed in years, whereas for a contact with the drug, just as the cavity sealing element most frequently con- disposable syringe plunger it will be mi- of the stopper plug is in case of a vial sists of a rubber disc being assembled in nutes or hours. This difference has an application. Over the entire lifecycle of an aluminium cap (Figure 5). The cap impact on the type of material that the the drug the plunger must maintain an with assembled elastomeric liner is crim- plunger is made of. A pre-fillable syringe adequate seal on the inner side of the ped onto the front end of the cartridge. plunger is designed in order to ensure barrel. However, at the time of administ- In this case, two rubber components adequate gliding behaviour as well as to ration of the drug to the patient, the (plunger and disc) are in long-term con- aim for low levels of material that could plunger also must exhibit efficient gli- tact with the drug. At the time of admi- be extracted from the rubber into the ding behaviour in the barrel in order to nistration the disc is perforated by a drug product, while disposable syringe adequately transfer the syringe contents double-ended needle, one end making plungers are predominantly designed to into the patient. Apart from the ‘internal’ contact with the cartridge contents and ensure acceptable administration beha- component, there is an ‘external’ com- the other end being the patient end. Ty- viour. www.kgk-rubberpoint.de KGK · 1-2 2013 19 ROHSTOFFE UND ANWENDUNGEN RAW MATERIALS AND APPLICATIONS

4 5 Dental Cartridge Components

Plunger for disposable syringe Needle Cover and Tip Cap

Plunger for prefilled syringe Fig. 5: (dental) cartridge components.

Rubber compounds for application in closures for parenterals

Fig. 4: elastomeric components for pre-fillable and for disposable syringes. Plungers on the left, needle shield and tip caps on the right. Halobutyl compounds For parenteral applications, the most wi- dely used compounds for long-term con- It shall be clear that the enumerati- turer implements measures to work in tact applications (vial stoppers and plun- on of parenteral closure types that is progressively cleaner areas and to pro- gers for pre-fillable syringes and cart- given above does not pretend to be ex- tect the products or intermediates from ridges) are pure halobutyl compounds haustive. There are several others types contact with the environment, including (bromobutyl or chlorobutyl) or are blen- like e.g. elastomeric components for the manufacturing personnel. In practi- ded compounds where the halobutyl po- injection ports on flexible bags, parts ce this comes down to implementing lymer is the main elastomer. The three used in blow-fill-seal applications and systematic cleaning programs in all are- capital reasons for this are that halobutyl several others that were not menti- as, sound gowning procedures for opera- elastomers allow for the lowest possible oned so far. tors, for their supervisory personnel and gas permeability, which is of primary for plant visitors, and appropriate mea- importance for oxygen and moisture The manufacturing process for elasto- sures to protect products from environ- sensitive drugs, next that halobutyl com- meric closures mental contamination. For washing and pounds allow using the cleanest curing The majority of elastomeric closures for packing areas, it is common that they systems, which in turn guarantees the parenterals is manufactured using ther- are classified, e.g. according to ISO lowest possible level of rubber constitu- moset compounds in a compression or 14644-1, ‘Cleanrooms and associated ents to migrate into the drug product, injection-compression moulding process controlled environments -- Part 1: Classi- and finally, that thanks to their low level followed by die-trimming of the parts. fication of air cleanliness’, or according of unsaturation, halobutyls have extre- For the sake of completeness the various to health authority regulations as the US mely good ageing characteristics, al- manufacturing steps are depicted in Fi- Food and Drug Administration (FDA) lowing for the lowest possible anti-oxi- gure 6. Whereas the weighing, mixing, Guidance for Industry, ‘Sterile Drug Pro- dant levels being used and thereby miti- preforming, moulding and die-trimming ducts Produced by Aseptic Processing – gating anti-oxidant or its degradation steps are current for many elastomeric Current Good Manufacturing Practice’ products ending up in the drug product. seals and do not need any explanation [3] or the European Guidelines to Good here, the washing and subsequent dry- Manufacturing Practice, Annex 1, ‘Ma- Poly-isoprene compounds ing operation is typical for rubber closu- nufacture of Sterile Medicinal Products’ Whereas halobutyl compounds stand for res for parenteral use. Washing is being [4]. For plants that are at the top in the impermeability, chemical cleanliness and performed to improve the state of micro- industry it is common that there is a superb ageing stability, it is difficult to biological and particulate cleanliness of system in place that demonstrates con- achieve with these materials the levels of the stoppers. Washing of rubber closures tinuing compliance with these stan- elasticity that are required in some pa- typically is combined with siliconization. dards or regulations, not only for the renteral applications. Notorious in this Siliconization of rubber closures relates environmental compliance of air, but al- respect are multi-puncture applications, to the application of a small quantity of so for the various types of water that are as encountered for instance with stop- silicone oil (polydimethylsiloxane) to the used for washing and rinsing. For closu- pers for insulin vials or with rubber seals closure surface. It is necessary to over- res for parenteral application these wa- on cartridges containing insulin or come the stickiness that is inherent to ter types include Purified Water and growth hormone. For these applications typical rubber formulations that are used Water-for-Injection, that means water typically polyisoprene compounds or for parenteral stoppers. that is of such a high purity and cleanli- blends with polyisoprene as main elasto- Throughout the manufacturing pro- ness that it could be used for direct in- mer are used. Dry natural rubber based cess it is usual that the closure manufac- jection into humans. compounds have been phased out more

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or less a decade ago, because this type of stoppers and coated syringe plungers. of water (Japanese Pharmacopoeia elastomer, justified or not, is associated Coated closures utilize fluoropolymer Pharm. Jap.). In the aqueous extract that with natural rubber latex allergy. coatings, at least in the contact zone is obtained in this way, a number of de- In a number of applications compo- with the drug. Thanks to the presence of terminations are done, like measure- nents made of distinct layers of a halo- the coating, the level of rubber constitu- ment of acidic or alkaline substances, butyl compound and of a poly-isoprene ents that migrates into the drug product measurement of reducing substances, compound are able to bring a solution is still being reduced in comparison with assessment of the UV absorbance spect- that is the best possible reconciliation of the uncoated counterparts in the same rum of the extract, etc. The results of the chemical cleanliness and of superior rubber compound. In this respect one testing have to be within certain ‘Type I’ elasticity. This type of solution can be speaks of a barrier coating. Also, thanks limits or within more loosely set ‘Type II’ applied in the case of seals on insulin to the nature of the fluoropolymer coa- limits as ‘fall-back position’. The idea be- cartridges, where the rubber disc may be ting it is possible to avoid surface silico- hind this is that rubber for parenteral a laminate consisting of halobutyl mate- nization during the final washing of the applications should be as clean as possi- rial facing the drug and with a polyisop- closures, at least for particular coatings. ble and thus meet the Type I require- rene side not in contact with the drug, ments. However for rubber articles whe- however ensuring perfect resealability Properties of pharmaceutical rubber re the mechanical requirements are so upon multiple puncturing. and of closures high that they cannot be met by using the cleanest crosslinking systems, the Other compounds Chemical properties less strict Type II limits allow these com- Whereas most parenteral applications Thermoset rubber products are shaped pounds or products still to qualify as call for low permeability compounds, so- through a curing step at elevated tempe- ‘pharmacopoeia compliant’. me do just the opposite. The most impor- rature. In contact with a drug solution It has become clear that whereas tant example is that of an elastomeric some of the rubber ingredients, of their pharmacopoeial extractable methods needle shield for a pre-fillable syringe. In impurities, of their reaction products or are able to discriminate between cleaner a lot of cases these needle shields are their thermal breakdown products may Type I formulations and less clean Type II pre-assembled on the cleaned and silico- be extracted from the rubber closure. rubber compounds, they are not approp- nized barrels of pre-fillable syringes with The term chemical properties pertains to riate to distinguish between rubber for- staked-in needles, that are packaged in what is extracted from the rubber pro- mulations that have a general low ext- gas permeable tubs and then subjected duct into a solvent. A common way to ractable profile and compounds that are to ethylene oxide sterilization. In order to make an assessment of extractables especially developed to release as little deploy its sterilizing activity, the ethyle- from pharmaceutical rubber is to prepa- as possible to drug formulations. Phar- ne oxide gas must be able to permeate re an extract of the rubber under well- macopoeial methods are not able to of- through the wall of the rubber shield. defined model conditions and then, by fer this because they lack specificity and The needle cover thus must have a high using primarily wet chemistry methods, have almost no chemical identification instead of a low gas permeability. Rubber to measure for extractables. Such me- capabilities. The latter is absolutely ne- compounds used for these needle covers, thods can be found in all major pharma- cessary if an extractable or a reaction therefore are poly-isoprene compounds copoeia [5-7]. All these methods current- product of it with the drug formulation or styrene-butadiene rubbers (SBR). The ly use water as a model solvent and ext- shows up in the medicinal product. In same holds for tip caps. ract rubber by autoclaving it for a speci- that case it is no longer called an extrac- The use of compounds other than fied time at 121 °C in a specified ratio of table, but instead is termed a leachable. halobutyl, poly-isoprene and SBR on the rubber surface area exposed per volume Identification and quantification of parenteral scene is for the most part reof water (United States Pharmacopeia leachables with more sophisticated me- stricted to niche applications. Examples USP and European Pharmacopoeia thods of analytical chemistry is ever mo- are nitrile rubber for use in combination Pharm. Eur.) or of rubber mass per mass re becoming a regulatory requirement with mineral oil based drug formulations, silicone rubber in ophthalmic appli- 6 cations and thermoplastic elastomers for an at this moment restricted number of product types.

Coated closures The compounds for elastomeric components for long-term contact with parenterals are designed to have no or the smallest possible level of interaction with the drug. For most applications, halobutyl formulations are able to achieve this goal. However, in a number of cases requirements are so high that halobutyl compounds still are not adequate enough. For such applications, solutions Fig. 6: Elastomeric Closure Manufacturing Process are offered in the form of coated vial www.kgk-rubberpoint.de KGK · 1-2 2013 21 ROHSTOFFE UND ANWENDUNGEN RAW MATERIALS AND APPLICATIONS

7 cations where the drug carrying medium is non-aqueous. If this is the case, other choices than halobutyl or polyisoprene rubber, or the use of polymeric coatings are indicated.

Functional properties The term functional properties relates to performance characteristics of the closure that are clearly, but more indirectly related to physical properties of the rubber material used. At any rate and for all applications the rubber product shall have adequate sealing characteristics, since this is the only way to guarantee shelf life container/closure integrity and therefore sterility of the packaged drug. For vial stoppers there are other explicit functional performance characteristics. The force needed to penetrate the stopper with a needle or a spike shall not be excessively Fig. 7: gliding curves of 2 different plungers in the same type of syringe barrel high. In terms of rubber compound choice this means that the material hardness for the makers of drug products, because the majority of parenteral applications shall be in an acceptable range, typically as part of risk management strategies it call for low permeability of the rubber 30 – 50 ShoreA. Resealing of an elastome- allows assessment of the toxicological closure (vial stoppers and pre-fillable sy- ric closure concerns its ability to perfectly risk for the patient who is exposed to the ringe plungers), however some applica- reseal after being punctured and after drug. Collaborative initiatives for chemi- tions require just the opposite (needle withdrawal of the needle (or in forthco- cal and toxicological assessment of ext- shields and tip caps for pre-fillable syrin- ming case the spike). Resealing must be ractables and leachables are underway, ges). Tuning permeability can be achie- guaranteed in order to preserve sterility e.g . [8]. ved by the choice of the base elastomer of the vial contents before the next pene- and of the filler. Apart from water per- tration of the closure. Coring, sometimes Drug compatibility meability there is the amount of water also referred to as ‘fragmentation’, is the The term drug compatibility in the case that is withheld in the stopper itself at phenomenon whereby upon puncturing a of an elastomeric closure for parenterals the moment it is placed on the vial. This stopper, small parts of the closure are refers to its capability to preserve identi- moisture over time will partly end up in dislodged by piercing or by abrasion. The- ty, strength, purity and stability of the the drug product. Whereas for aqueous se small particles risk eventually being drug product that it is in contact with. A solutions this will not be an issue, it can injected into patients, which of course is closure that is compatible thus will not be for moisture sensitive products that undesired. interact with the dosage form in such a are filled as powder or that are freeze- Standard pre-fillable syringe plungers way as to cause unacceptable changes in dried. It is to be kept in mind in this res- are not punctured and therefore rese- the quality of either the dosage form or pect that many closures before filling of aling and coring characteristics are not of of the closure itself, an example of which the drug are steam sterilized, which ac- relevance. During the shelf life of the would be by an unacceptable degree of tion offers an excellent opportunity for drug pre-fillable syringe plungers form a swelling. Guidances like [9] exist that the closure to pick up moisture. The risk static seal on the inner wall of the syrin- further discuss the subject of compatibi- of having excess moisture in the stopper ge barrel. At the time the drug is admi- lity of primary packaging components shall be mitigated by choosing appropri- nistered to the patient however, the including elastomeric closures with ate rubber compounds and by develo- plunger must be displaced and the static pharmaceutical dosage forms. ping and controlling adequate closure seal turns into a dynamic seal. Moreover drying cycles. Permanent deformation pre-fillable syringe plungers must be ab- Physical properties (compression set) of the rubber shall be le to smoothly glide in the syringe barrel. Many physical properties of the rubber sufficiently low so as to guarantee pro- This for sure is not a property of the plun- used for parenteral applications play a per sealing behaviour over time. At this ger only, on the contrary it is a functiona- role in the eventual performance of clo- point it shall be remembered that per- lity of the whole system of which the sures made thereof. Some of those pro- manent deformation can significantly plunger makes part. When looking at the perties play an indirect role, but others increase if the rubber closure is subjec- gliding behaviour of syringe plungers clearly have a direct impact. Among the ted to irradiation in compressed condi- one makes distinction between the force latter are gas and moisture permeability, tion. In cases where gamma irradiation is that is needed to make the plunger start moisture absorption and desorption be- used for achieving sterility of the drug moving and the force that is needed to haviour, compression set (permanent de- package, this has to be taken into ac- sustain movement of the plunger. The formation) and, to a lesser extent, sol- count. Finally solvent swell characteris- former is typically called ‘break-loose vent swell characteristics. As indicated tics must be studied, especially for appli- force’ or ‘activation force’, while for the

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latter the name ‘gliding force’ is being plexes that are associated with the cell Another more practical way to classify used. A typical force curve for the gliding wall of Gram-negative bacteria [13]. They particles is to categorize them according of a plunger in a pre-filled syringe is gi- are pyrogenic (fever inducing) in humans. to their size as visible and subvisible. USP ven in Figure 7. For plungers for disposa- Drug products are subjected to controlled <788> refers to microscopic methods ble syringes the same considerations for levels of bacterial endotoxins and since and to light obscuration methods for the gliding behaviour are valid. packaging components are a contributing determination of visible resp. subvisible It is evident that for particular closu- factor, they are to be subjected to cont- particulate contamination in injections. res other functionalities must be consi- rolled levels too. Bioburden and endoto- For the determination of the particulate dered. It would however go beyond the xins on closures for parenterals are pre- state of cleanliness of stoppers, methods scope of this article to describe them all. sent as a result of the manufacturing his- of the same types are used [15]. It is to be tory of the product that evidently does not noted that the number of subvisible par- Biocompatibility take place in a sterile environment. Espe- ticles that are shed by elastomeric closu- The leading reference on biocompatibili- cially steps where closures are temporarily res is strongly related to the closure sili- ty of plastics and of elastomeric closure stored in wet conditions are risk factors. conization, both in quantitative terms materials is the Unites States Pharma- These risks have to be mitigated by appro- (amount of silicone oil present at the copeia, notably USP <1031> [10] , that priate process design and by validation of closure surface) and qualitative terms spends a separate paragraph on elasto- the final washing to which closures are (type and viscosity of silicone oil). meric closures by referencing USP <381>, subjected. The final washing of elastome- ‘Elastomeric Closures for Injections’[5]. ric products that involves high purity and Cosmetic appearance Biocompatibility of an elastomeric mate- cleanliness grades of water is a deconta- Cosmetic appearance of closures for pa- rial is evaluated according to a two-stage mination and depyrogenation step [3] renteral use is also related to particulate testing protocol that is described there, that ultimately defines the microbiologi- contamination, however not in a loose and that in turn refers to USP <87> [11] cal cleanliness of the closures. form, but embedded in the product’s as the first-stage test to be performed. rubber matrix. Particulate matter of this The tests in USP <87> are designed to Particulate cleanliness type can again be endogenous or exoge- measure the response of mammalian Elastomeric closures like vial stoppers nous. It however cannot removed by clo- cells to specific extracts prepared from and pre-filled syringe plungers are part sure washing. Examples are filler partic- the closure material. If the requirements of a packaging system for injectables. les that are not homogeneously mixed of USP <87> are met, then no further Injectables are subject to requirements in, overcured rubber that detaches from testing is required. If however the elasto- on the presence / absence of particulate the mould and that ends up embedded meric material does not meet the requi- matter, including USP <788> [14]. Elasto- in products of the next cycle, differently rements of the first-stage testing as per meric closures thus are linked, be it indi- coloured rubber that inadvertently is pi- USP <87>, then it may still qualify as a rectly, to the particulate cleanliness of cked up before or at the stage of moul- biocompatible material by passing the parenteral products. Particulate cleanli- ding and environmental contamination more forgiving second-stage testing as ness of rubber closures pertains to par- that is vulcanized into the product. Even per USP <88> [12]. USP <88> tests are ticles that are present at the product if embedded imperfections are not likely designed to measure the response of surface in a detachable form. Such par- to cause performance dysfunctions of animals to the injection of specific ext- ticles risk of easily being transferred from the closure, they are undesired from a racts prepared from the elastomeric ma- the closure into the medicinal product. cosmetic point of view, especially in cer- terial under test. Particulate contamination on elastome- tain markets like Japan. Ample efforts ric closures may still have the same ma- are being spent to reduce the occurrence Microbiological cleanliness terial identity as the closure itself or may of imperfections of this type and to sort The microbiological state of cleanliness of be part of the ingredients of that closure out by camera inspection procedures elastomeric closures relates to the pre- formulation (endogenous particles), or those products, that still show up with sence or absence of microbiological con- may be contamination from the closure such defects. tamination at their surface. This contami- manufacturing environment that either Figure 8 below gives rather obvious ex- nation may be present either in ‘living has not been removed by washing or amples of detachable and of embedded form’ (bioburden) or in ‘non-living pyroge- that is the effect of a recontamination visible particulate matter. nic form’ (endotoxins). Bioburden is ex- after washing (exogenous particles). pressed as the number of Colony Forming Units (CFU) that are present at the closure 8 surface. In the majority of cases closure manufacturers do not sell their product sterile (or even ‘sterilized’) but are assu- ring low bioburden levels. Closure sterility is mostly achieved by steam sterilization at the pharmaceutical company that car- ries out the filling of the drug product. Next to bioburden, the absence of bacterial endotoxins is of extreme importance for closures for parenterals. Bacterial en- Fig. 8: Closures with detachable (left) and embedded (right) visible particulate matter dotoxins are high molecular weight com- www.kgk-rubberpoint.de KGK · 1-2 2013 23 ROHSTOFFE UND ANWENDUNGEN RAW MATERIALS AND APPLICATIONS

Machineability res that have been washed by the closu- Conclusion Machineability of elastomeric closures re manufacturer and that then have be- The description that is given above illus- refers to the processes at pharmaceuti- en subjected to a validated gamma irra- trates the diversity and complexity of the cal companies that are used to bring diation treatment at a sterilization con- technical requirements that are imposed closures into their final position on vials tractor, thereby achieving sterility at a on rubber materials for parenteral appli- or in syringes or cartridges. To this end guaranteed sterility assurance level. Fi- cations and on the products made the- filling lines are used that are designed to nally ethylene oxide (gas) sterilization is reof. have a certain capacity in a fully auto- very commonly used for the sterilization mated mode without human interventi- of disposable syringes and in the field of References on other than feeding components to empty pre-fillable syringes on which al- the line. These machines typically invol- ready a needle shield or tip cap have be- [1] European Pharmacopoeia, European Directo- ve feeding bowls in which the elastome- en pre- assembled. Independent of the rate for the Quality of Medicines. ric parts are brought in, then feeding li- mode of sterilization it must be ascertai- [2] www.iso.org. nes or chutes that bring the closure in ned that the sterilization process does [3] US Food and Drug Administration, Guidance the proximity of the vial or syringe and not affect any of the characteristics of for Industry, ‘Sterile Drug Products Produced next a positioning mechanism that as- the products to a level that could lead to by Aseptic Processing - Current Good Manu- sembles individual closures onto or into insufficient performance. For steam ste- facturing Practice’, September (2004). individual vials or syringes. A first prere- rilization especially moisture pick-up [4] The European Commission, EudraLex, ‘The quisite is that elastomeric parts do not and release are to be followed up. For Rules Governing Medicinal Products in the clump when they are brought into a gamma irradiation evolution of physical European Union - Volume 4 - EU Guidelines feeding bowl. Clumping is especially a and performance characteristics shall be to Good Manufacturing Practice - Medicinal risk for halobutyl components. Clum- documented, as well as the formation of Products for Human and Veterinary Use - An- ping can largely be prevented by giving extra closure extractables, qualitatively nex 1 - Manufacture of Sterile Medicinal Pro- an appropriate surface design to the and quantitatively. For ethylene oxide ducts’, corrected version, November (2008). closures and by influencing the sticki- sterilization residual levels of ethylene [5] The United States Pharmacopeia, USP <381>, ness of the surface, by adequate siliconi- oxide and ethylene chlorohydrine must ‘Elastomeric Closures for Injections’. zation or by application of a polymer be studied and monitored. [6] The European Pharmacopoeia, Pharm. Eur. layer and by providing suitable transport 3.2.9, ‘ Rubber closures for containers for packaging. Feeding behaviour in feeder Regulatory status and Change Control aqueous parenteral preparations, for pow- bowls and chutes and positioning on vi- requirements ders and freeze-dried powders’. als or into syringes and cartridges most- The composition of rubber compounds [7] The Japanese Pharmacopoeia, Pharm. Jap. ly again is a matter of adequate surface and of polymer coatings that are used for 7.03, ‘Rubber Closures for Aqueous Infusi- states, but also of continuous monito- parenteral purposes, as well as particular ons’. ring of compliance with dimensional details of the closure manufacturing pro- [8] www.pqri.org. specifications. cess and of test methods that are used to [9] US Food and Drug Administration, Guidance measure certain closure or material pro- for Industry, ‘Container Closure Systems for Compatibility with mode of sterilization perties are considered by closure manu- Packaging Human Drugs and Biologics - Che- Sterilization of parenteral closures may facturers as proprietary information and mistry, Manufacturing and Controls Docu- take different forms. The contact area of therefore are not intended to be disc- mentation’, May (1999). the parenteral closure with the drug losed to third parties. It is typical though, [10] The United States Pharmacopeia, USP product must be sterile during the entire certainly for the USA and for Canada, <1031>, ‘ The Biocompatibility of Materials drug shelf life up to the time of use. This that such confidential information is Used in Drug Containers’. is achieved by either terminal sterilizati- filed with the Health Authorities in so- [11] The United States Pharmacopeia, USP 87 , on of the packaged drug or by aseptic called Drug Master Files for which there ‘Biological Reactivity Tests, In Vitro’. filling where all packaging materials are are certain maintenance procedures to [12] The United States Pharmacopeia, USP 88, sterilized prior to filling. In case of plun- ascertain that the information that is ‘Biological Reactivity Tests, In Vivo’. gers for disposable syringes sterilization contained is up-to-date and accurate. [13] American National Standard - Association always takes place on the assembled Authorizing the involved Health Authori- for the Advancement of Medical Instru- and packaged (empty) syringe. The most ties to consult these Drug Master Files in mentation, ANSI/AAMI ST72:2011, ‘Bacteri- common method to sterilize vial closu- conjunction with a pharmaceutical al endotoxins – Test methods, routine mo- res is by steam sterilization. The most company’s drug application file enables nitoring, and alternatives to batch testing’, typical sterilization temperature that is the Authorities to make a judgement on December (2011). used for sterilization of elastomeric clo- suitability of the information without [14] The United States Pharmacopeia, USP 788, sures is 121 °C, the most typical duration the necessity of this being passed via the ‘Particulate Matter in Injections’. of the exposure to saturated steam at applicant. Changes to the information [15] ISO 8871-3, ‘Elastomeric parts for parente- this temperature is 30 minutes, followed contained in Drug Master Files, but also rals and for devices for pharmaceutical use by drying at elevated temperatures, typi- to information that is commonly shared -- Part 3: Determination of released-particle cally 80 to 110 °C, during prolonged pe- with pharmaceutical customers, must be count’. riods of time (hours). Of increasing im- subject to appropriate Change Control portance is the use of irradiation sterili- and Customer Notification procedures zation. In such cases the pharmaceutical that make part of the closure user chooses to be supplied with closu- manufacturer’s Quality System.

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