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 contai- ning 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 18 KGK · 1-2 2013 www.kgk-rubberpoint.de ROHSTOFFE UND ANWENDUNGEN RAW MATERIALS AND APPLICATIONS 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.

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