Drug Packaging Materials: Surviving Scrutiny in the EU
By Keller and Heckman LLP’s Packaging Practice Group
Drug companies and packaging manufacturers alike frequently find themselves asking how the European Pharmacopoeia monographs on container materials, and the provisions of the European Union's Monomers Directive (Commission Directive 90/128/EEC, as amended), fit into the regulatory scheme applicable to drug packaging materials in Europe.
The short answer is that compliance with either or both of these instruments is helpful in facilitating the competent authorities' evaluation of an application for marketing authorization for a new drug, particularly if the drug is a solid oral dosage form.
Strict compliance, however, is not a legal requirement. Consequently, provided that sufficient data can be submitted to the competent authorities to demonstrate that a particular packaging material is safe and suitable for its intended use with the drug at issue, a material that does not comply with the Monomers Directive or with a European Pharmacopoeia monograph may still be used to package the drug.
A brief description of the way in which the EU authorities regulate drug packaging materials may help to clarify.
Drugs, or "medicinal products," are regulated in the EU pursuant to Council Directive 65/65/EEC, as amended. This directive prohibits a medicinal product from being placed on the market in an EU Member State unless a marketing authorization has been issued either by the competent authorities of that Member State or by the European Agency for the Evaluation of Medicinal Products (EMEA). An application for a marketing authorization must contain detailed information on the formulation of the medicinal product, its method of manufacture, the controls used in its manufacture, and information about the drug's packaging and labeling.
Unlike the procedure in United States, which allows packaging manufacturers to provide confidential information on their products directly to the Food and Drug Administration in the form of a Drug Master File, the EU procedure requires that the necessary information on packaging materials be included within the application for a marketing authorization for the finished medicinal product. (Although there is a European Drug Master File (EDMF) procedure available for manufacturers of active ingredients to submit information on their products directly to the authorities on a confidential basis, this procedure is not available to packaging manufacturers.)
Monographs vs. Monomers Directive
The European Commission's Rules Governing Medicinal Products in the European Union (1998 ed.) provide guidance regarding the information that should be submitted to the authorities in an application for a marketing authorization for a new medicinal product. These rules state that, with respect to plastic primary packaging materials, the application should include compositional information and references to relevant European Pharmacopoeia (EP) monographs.
Strict compliance with the EP monographs, however, is not mandatory. Indeed, the authorities recognize that, although specifications (or monographs) for certain container materials have been developed for general application, a wide variety of available containers may not be the subject of a specific monograph, and new container materials are constantly being developed. Consequently, the European Pharmacopoeia explicitly states that "publication of a specification does not exclude the use, in justified circumstances, of containers that comply with other specifications, subject to agreement by the competent authority."
In addition, the Rules Governing Medicinal Products in the European Union state that, particularly for non-parenteral drugs, the provisions of the Monomers Directive should be "taken into account."
Strictly speaking, the Monomers Directive is intended to apply to food packaging materials, as opposed to drug packaging materials. Any polymer that is manufactured from monomers listed on the Monomers Directive may be used in the EU to manufacture food-contact plastic materials, subject to any specific migration limits (SML) or residual limits, such as maximum residual quantity in the material (QM) limits established for particular monomers, and the overall migration limit established for all finished articles (which, in most cases, is 10 milligrams per square decimeter (mg/dm2) surface area of material or article).
The third, fourth, and fifth amendments to the Monomers Directive, in addition to listing new monomers, also list a limited number of additives that may be used in food-contact plastics throughout the EU. A sixth amendment to the Monomers Directive currently is proceeding through the administrative process and is expected to be promulgated soon. This amendment lists additional monomers and additives that will be permitted for use in food-contact plastics throughout the EU.
Because the Monomers Directive is intended to apply to food-contact materials, the Rules Governing Medicinal Products in the European Union make clear that strict compliance with the Monomers Directive is neither necessary nor sufficient to conclude that a particular material is suitable for use in a given drug packaging application. Rather, compliance with the requirements of the EU Monomers Directive for food-contact plastics is viewed only as evidence of the suitability of a material for use in drug packaging applications involving non-parenteral drugs.
Again, such compliance may certainly be helpful in demonstrating to the competent authorities that a particular material is suitable for use in a drug packaging application; however, drug packaging materials are not required to comply with the Monomers Directive.
As a practical matter, compliance with a specific European Pharmacopoeia monograph and/or compliance with the Monomers Directive may help to facilitate the review of the packaging portions of an application for a marketing authorization for a new drug. Nevertheless, companies should not make the mistake of considering such compliance to be mandatory and, thus, overlook possible innovations in packaging for drugs to be marketed in the EU.