Orally Inhaled or Nasal Drug Products (OINDP) represent the highest risk drug products in relation to the potential introduction of impurities via container closure contact.
Some of the inhaled drug products are by far the most pharmacologically effective substances that are administered to humans. This means that the therapeutic effect will take place at very low doses. This effect is especially true in the nonsystemic treatment of pulmonary diseases, where drug administration via inhalation can be considered as a direct topical application to the target organ. However, this also means that potential undesired impurities, present in the drug product as a result of container closure contact, may also show adverse effects (e.g., irritation) at much lower doses than would be the case via other routes of administration. In addition, these inhaled leachables can also be rapidly and almost completely absorbed into the patient’s circulation, causing systemic toxicity.
Container closure systems for inhalable administration are often composed of a series of different parts (e.g., canisters, valves, actuators, spacers, mouthpieces, gaskets), each with their own functionality to guarantee the performance characteristics of the total device. These parts can be made of a list of different materials which are selected for their physical properties. For Metered Dose Inhalers (MDI), rubbers are typically used for the manufacture of gaskets, present in the valve. It is widely known that rubbers – compared to all other polymeric materials – are the most complex materials in their composition (e.g., elastomers, fillers, antioxidants, curing agents, activators, accelerators, pigments, stabilizers, plasticizers). During the rubber curing, a lot of chemical reactions are initiated to obtain the final rubber form and physical properties. These chemical reactions may sometimes lead to the presence of undesired/unexpected reaction products. Because of this complexity in composition and chemistry, rubbers are therefore more prone to leaching compared to many other plastic materials.
In addition, inhalation aerosol formulations typically include organic liquids as the propellant (chlorofluorocarbons, hydrofluorocarbons) or as the vehicle (alcohols). These organic liquids exhibit a strong interaction with most of the rubber and polymeric materials used in the manufacture of the valve. Therefore, potential leaching of compounds from these rubber components, as well as from all other polymeric materials, into the drug formulation is considered as a very serious concern that should be addressed.
Mainly because of the above considerations, Table 1 of the FDA Guidance “Container Closure Systems for Packaging Human Drugs and Biologics” classifies the “Inhalation Aerosols and Solutions” in the highest degree of concern associated with the route of administration. In addition, the likelihood of interaction between the packaging and the dosage form is also considered to be high, while for dry powders for inhalation, the likelihood of interaction is considered to be medium.
The General “Safety” Considerations in the FDA Guidance state that inhalation aerosols and solutions and nasal sprays will categorize under “case 1s”, which requires extractables data combined with a toxicological evaluation, limits on extractables and batch-to-batch monitoring of extractables, together with the standard USP biological reactivity tests. Inhalation powders categorize under “case 5s”. The FDA Guidance “Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products” of 1998 and the Guidance “Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products” of 2002 further specify – per inhalation device or per inhalation device component (e.g., canister, valve components, actuator, mouthpiece, other components) – what kind of extractables and leachables data should be included (e.g., control extraction studies, routine extraction studies, residue tests, the need for pre-extractions, acceptance criteria) in the CMC documentation.
In addition, section G.5 of the FDA Guidance “Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products” also indicates that for semi-permeable container/closure systems the levels of leachables originating from indirect exposure to labels or related materials should be determined with a valid methodology that has suitable detection and quantification limits for the potential leachables.
Paragraph 18.104.22.168 of the recent (2006) EMEA Guideline “Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products,” specifies in more detail what kind of extractables and leachables data should be provided, such as determining the extractables profile, verifying the presence of these identified extractables as leachable compounds during or at the end of the shelf life, conducting safety assessments, establishing safety thresholds and – in certain cases – introducing routine monitoring of components or raw materials if a correlation between extractables and leachables has been proven. Table 4.2.1 and Table 4.2.2 of this guideline stipulates for which type of inhalation product or nasal product respectively, extractables and leachables data should be provided.
The FDA Guidances and the EMEA Guidelines mentioned above are very useful from a regulatory point of view, but a lot of questions remain how to conduct these extractable and leachable studies. To further complicate the picture, regulatory concern regarding extractables and leachables in OINDP’s is directly related to the particular type of OINDP, such as Metered Dose Inhalers (MDI), Dry Powder Inhalers (DPI), Inhalation Solutions and Nasal Sprays. To remove many of the extractables and leachables issues from the grey zone, the Product Quality Research Institute (PQRI) published a comprehensive guidance document: “Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products” (September 2006). This document includes recommended exposure thresholds (SCT, QT) above which individual organic leachables in an OINDP must be qualified and/or evaluated for safety concern.
A decision tree for leachables identification and quantification is also presented. These “safety thresholds” are then linked to the recommended Analytical Evaluation Threshold (AET) which for the first time answers the question of “How low do you go?” In addition to these threshold recommendations, the PQRI-document proposes “best practices” in areas such as OINDP component selection, controlled extraction studies, leachable studies and routine quality control methods.
The materials used for the manufacture of container closure systems for inhalable administration involve typically rubbers, LDPE, HDPE, PP, PBT, POM, ABS, multilayer films, etc. Each material will exhibit its own extraction profile and may therefore contribute to the risk of potential adulteration of the medicinal product. In addition, if the container is made of a relatively permeable material, label migration will be regarded as an additional concern.
To set up the right set of testing conditions for E&L studies, it is imperative to have a good knowledge of the composition of these materials (e.g., production process, solvents used, potential impurities, polymer additives to increase end-use performance or to protect the polymer during its life cycle), but also to have a good understanding of the mechanism of polymer leaching and what the interaction of these materials with pharmaceutical formulations may induce.
Nelson Labs Europe is specialized in qualifying container closure systems for all inhalable applications, starting from the typical compendial EP and USP testing up to a high level of extractable and leachable studies. Nelson Labs Europe was one of the first contract labs to implement the PQRI recommendations into our extractable and leachable services for inhalation applications. Hence, we have developed and optimized PQRI protocols which include the SCT, QT, and AET concepts, outlined in the PQRI documents. In addition, these testing programs require a combination of state-of-the-art analytical techniques, such as Headspace GC/MS, PTV-GC/MS, GC/MS, LC/MS, LC/MS/MS, ICP, and IC. Nelson Labs Europe can also offer its assistance in the elucidation of structural information for critical compounds, using GC-ToF, LC-ToF, FT-MS, or NMR.
Nelson Labs Europe works together with a broad base of container closure manufacturers to develop and qualify their products, as well as with pharmaceutical companies to give guidance in developing a strategy to comply with the regulatory requirements and to assist in their worldwide regulatory submissions.