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USP publishes draft general chapters on Extractables and on Drug Product Leachables

As part of its 2010-2015 cycle, USP’s Packaging, Storage, and Distribution Expert Committee in Pharmacopeial Forum 39(5), Sept.-Oct. 2013, has published the first drafts of a number of chapters related to packaging.

Among those are the drafts of chapters that provide general information, namely USP <1663>, ‘Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems’ and USP <1664>, ‘Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems’.


Draft USP <1663> on ‘Extractables’ is not prescriptive, but provides an information framework on how to design and execute Controlled Extractables Studies. It describes for example the scientific principles and best practices that apply to extractables studies for packaging components. General concepts and design parameters are discussed with respect to the generation of an extract from the packaging system, component or material. Design parameters include the choice of extraction solvents, techniques and conditions. Processes and analytical methods are subsequently outlined for the discovery, identification and quantitation of extractables.

While draft USP <1664> on ‘Leachables’ is equally non-prescriptive, it too constitutes a framework for the design, justification and execution of leachables studies. Leachables in drug products are of concern not only because they may be harmful to patients if delivered in too high doses, but also because they may compromise drug product stability. The use of safety thresholds as a general concept for leachables assessment is thoroughly discussed, as is the use of analytical thresholds in the characterization of leachables. Consideration is given to the analytical techniques used for leachables characterization and to the validation of quantitative analytical methods. Additional considerations are made related to the use of simulation studies as a link between extractables and leachables studies.

Comments on these draft USP chapters were due by November 30, 2013. Datwyler has naturally committed to submitting a number of comments, particularly with respect to USP <1663> on ‘Extractables’. We will of course keep a close eye on this, and keep you, our customer, up to date on all developments.



Why halobutyl is used for elastomeric closures in parenteral applications ?

There are several excellent reasons why Datwyler employs bromobutyl and chlorobutyl rubber for elastomeric closures in your parenteral applications.

The principal reason is that halobutyl elastomer - halobutyl being a term that groups bromobutyl and chlorobutyl - has the lowest gas permeability among commonly available elastomers. Datwyler knows that low gas permeability is essential in your parenteral applications, and would like to present you with a few examples.


Many active product ingredients are sensitive to oxygen. Ingress of oxygen may lead to degradation reactions in such drugs. Datwyler therefore realizes it is essential that oxygen is eliminated from the packaging of your pharmaceutical products. Halobutyl formulations are best placed to achieve this goal.


Lyophilization products are sensitive to water. For this reason they are formulated as lyophilized products, and not as aqueous-based drug formulations. For the same reason, it is essential that the environmental moisture present in gaseous form in air, does not permeate through the primary packaging, and Datwyler is aware of this. For glass, this is obviously no challenge. For rubber, however, this poses a greater problem, since any rubber formulation is characterized by a particular moisture vapour transmission (MVTR). We know that moisture vapour transmission rates are lowest with halobutyl formulations.


The same lyophilization products very often are packed under a certain vacuum, primarily to facilitate reconstitution of the drug with a diluent immediately before administration of the drug to the patient. The low pressure in the vial helps in aspirating the diluent into vial, thereby easing reconstitution. We know that it is important that the underpressure initially installed at the time of closing the vial is preserved to the optimum degree over the shelf life of the drug. Any minimal permeation of air through the lyophilization stopper would destroy the vacuum in the vial. The permeability of oxygen and nitrogen (air) are lowest with halobutyl formulations.

The halobutyl elastomer used is not the only factor that determines the gas permeability  properties of a rubber compound. However, although other rubber ingredients play a role in determining these properties, the elastomer is the most prominent factor.


Another reason why Datwyler prefers halobutyls when developing your parenteral applications is that they can be crosslinked in the cleanest way. Crosslinking, i.e. vulcanization or curing, is the chemical process that is needed to introduce elasticity in thermoset rubbers such as halobutyls. This chemical process uses a crosslinking system. Crosslinking systems can be simplest and cleanest with halobutyl elastomers, thus ensuring that if they are well balanced, they will contribute minimally to the extractables profile of the resulting rubber used in your application.


A third significant reason why Datwyler uses halobutyl elastomers for your parenteral applications is the inherent ageing stability of the polymer with minimal addition of antioxidants. Lower levels of antioxidants again warrant cleaner extractables in the rubber compound.


Finally, as part of our drive to ensure that information on rubber compounds is as complete as possible, Datwyler is committed to determining and documenting the oxygen and water vapour transmission rates in those compounds that are used in developing your applications.

Changes in Pharm. Eur. 3.2.9, effective January 1, 2014

Pharm. Eur. 3.2.9 ‘Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders’ is the chapter in Pharm. Eur. that is relevant for physicochemical testing of rubber closures. On 1 January 2014 a number of changes will become effective to Pharm. Eur. 3.2.9.

The most significant changes are in the ‘Identification’ section of Pharm. Eur. 3.2.9:

  1.  ‘Identification Test A’ (stretching by hand) is being removed;
  2. Surface FTIR-ATR replaces pyrolysate IR as infrared identification technique. The only exception will be carbon black-filled rubbers where surface ATR is not effective. For such rubbers FTIR-ATR of the pyrolysate will be used.
  3. A ‘staggered’ set of accuracy limits for the ash test has been introduced. The limit of +/-10 % that has so far been applied has not proved feasible for low ash rubber compounds.


In addition to this ‘Water R’ – effectively ‘Purified Water’ – may be used for making Pharm. Eur. 3.2.9 extracts instead of Water-or-Injection.

Other changes are of an editorial or explicatory nature and do not have an impact on the results of testing. Results of Pharm. Eur. 3.2.9 in-process-testing or finished product testing as used by Datwyler therefore will not be affected.

Relevant changes that will be of interest to you, are in respect of Datwyler’s Compound Data Sheets (CDS). We have therefore prepared CDS updates that incorporate these changes where relevant.


Datwyler has been working closely together with other experts in realizing these changes – essential to maintaining the high standards inherent in all the products that we develop and produce for you – and we will continue to do so in the future. We will inform you of any further relevant changes as and when they occur.

Please do not hesitate to contact us if you require further information – we look forward to hearing from you.

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