Biocompatibility Considerations for Orally Inhaled and Nasal Drug Products and Other Drug--Device Combination Products.

Biocompatibility considerations have historically been important for orally inhaled and nasal drug products (OINDPs) and other drug-device combination products, because finished device components and packaging in these products are often in direct contact with formulation and the patient. The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) discusses, in this article, the current regulatory landscape associated with biocompatibility and how biocompatibility is typically assessed for OINDPs, including risk management considerations and navigation of regulatory requirements. The article also describes current challenges related to alignment of regulatory expectations, particularly for drug-device combination products, and proposes some questions and topics for further discussion with regulatory agencies and other stakeholders to help advance alignment.

Considerations when deriving compound-specific limits for extractables and leachables from pharmaceutical products: Four case studies.

Leachables from pharmaceutical container closure systems are a subset of impurities that present in drug products and may pose a risk to patients or compromise product quality. Extractable studies can identify potential leachables, and extractables and leachables (E&Ls) should be evaluated during development of the impurity control strategy. Currently, there is a lack of specific regulatory guidance on how to risk assess E&Ls; this may lead to inconsistency across the industry.

European Regulatory Developments for Orally Inhaled and Nasal Drug Products.

Orally inhaled and nasal drug products (OINDP) are regulated in Europe via national (country) legislation and guidelines and/or legislation established in the European Union and resulting guidelines developed by the European Medicines Agency (EMA). Recent movement in EMA guidance and European Commission legislation implies potential significant changes in OINDP regulation. The UK exiting the European Union ("Brexit") has also raised a number of questions related to OINDP development and regulation in the region.

Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics - Current challenges and approaches.

Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers.

Materials in Manufacturing and Packaging Systems as Sources of Elemental Impurities in Packaged Drug Products: A Literature Review.

Unlabelled: Elemental impurities in drug products can arise from a number of different sources and via a number of different means, including the active pharmaceutical ingredient, excipients, the vehicle, and leaching of elemental entities that are present in the drug product's manufacturing or packaging systems. Thus, knowledge about the presence, level, and likelihood of leaching of elemental entities in manufacturing and packaging systems is relevant to understanding how these systems contribute to a drug product's total elemental impurity burden. To that end, a joint team from the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) has conducted a review of the available literature on elemental entities in pharmaceutically relevant polymers and the presence of these elemental entities in material extracts and/or drug products.

Controlled Extraction Studies Applied to Polyvinyl Chloride and Polyethylene Materials: Conclusions from the ELSIE Controlled Extraction Pilot Study.

The effective management of leachables in pharmaceutical products is a critical aspect of their development. This can be facilitated if extractables information on the materials used in a packaging or delivery system is available to assist companies in selecting materials that will be compatible with the drug product formulation and suitable for the intended use. The Extractables and Leachables Safety Information Exchange (ELSIE) materials working group developed and executed a comprehensive extraction study protocol that included a number of extraction solvents, extraction techniques, and a variety of analytical techniques.

A risk-based approach to management of leachables utilizing statistical analysis of extractables.

To incorporate quality by design concepts into the management of leachables, an emphasis is often put on understanding the extractable profile for the materials of construction for manufacturing disposables, container-closure, or delivery systems. Component manufacturing processes may also impact the extractable profile. An approach was developed to (1) identify critical components that may be sources of leachables, (2) enable an understanding of manufacturing process factors that affect extractable profiles, (3) determine if quantitative models can be developed that predict the effect of those key factors, and (4) evaluate the practical impact of the key factors on the product.

Evaluation of extractables in processed and unprocessed polymer materials used for pharmaceutical applications.

Polymeric materials are often used in pharmaceutical packaging, delivery systems, and manufacturing components. There is continued concern that chemical entities from polymeric components may leach into various dosage forms, particularly those that are comprised of liquids such as parenterals, injectables, ophthalmics, and inhalation products. In some cases, polymeric components are subjected to routine extractables testing as a control measure.

Perspectives on the PQRI Extractables and Leachables "Safety Thresholds and Best Practices" Recommendations for Inhalation Drug Products.

Unlabelled: In 2006, the Product Quality Research Institute's (PQRI) Leachables and Extractables Working Group released a comprehensive and detailed recommendation document related to leachables and extractables for inhalation drug products. The document includes best pharmaceutical development practice recommendations regarding container closure/delivery system component composition and selection, controlled extraction studies, drug product leachables studies, and routine extractables testing for component release. Also included in the document are two safety-based thresholds for leachables in inhalation drug products, the qualification threshold (QT) and the safety concern threshold (SCT), the first such safety-based thresholds for leachables in any drug product type.

Best practices for extractables and leachables in orally inhaled and nasal drug products: an overview of the PQRI recommendations.

The Product Quality Research Institute Leachables and Extractables Working Group includes pharmaceutical development scientists representing industry, government, and academia. The Working Group was created and constituted to address scientific and regulatory questions concerning the pharmaceutical development process for Orally Inhaled and Nasal Drug Products (OINDP) related to organic extractables and leachables. This effort has resulted in the creation of a detailed "Recommendation Document", which was submitted to the U.

Foreign particles testing in orally inhaled and nasal drug products.

The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) presents this paper in order to contribute to public discussion regarding best approaches to foreign particles testing in orally inhaled and nasal drug products (OINDPs) and to help facilitate development of consensus views on this subject. We performed a comprehensive review of industry experience and best practices regarding foreign particles testing in OINDPs, reviewed current guidances and techniques, and considered health and safety perspectives. We also conducted and assessed results of an industry survey on U.