An Overview and Discussion of N-nitrosamine Considerations for Orally Inhaled Drug Products and Relevance to Other Dosage Forms.

The presence of N-nitrosamines in drug products are currently an area of high regulatory and industry scrutiny, having been detected above acceptable regulatory levels in several solid oral drug products. For over 20 years, there has been an expectation that N-nitrosamines be eliminated or controlled to acceptable levels in orally inhaled and nasal drug products (OINDP). As a result, the OINDP industry has developed and implemented risk management processes and considerations to address N-nitrosamines in final drug product, including management and understanding of upstream supply particularly for OINDP device and container closure systems. We provide an overview of N-nitrosamine formation, discuss key current regulatory expectations worldwide for N-nitrosamines in drug products, discuss risk management approaches relevant for drug device combination products, and share analytical "tips" with respect to handling N-nitrosamines chemical assessments.

Framework for sensitization assessment of extractables and leachables in pharmaceuticals.

During the toxicological assessment of extractables and leachables in drug products, localized hazards such as irritation or sensitization may be identified. Typically, because of the low concentration at which leachables occur in pharmaceuticals, irritation is of minimal concern; therefore, this manuscript focuses on sensitization potential. The primary objective of performing a leachable sensitization assessment is protection against Type IV induction of sensitization, rather than prevention of an elicitation response, as it is not possible to account for the immunological state of every individual. Sensitizers have a wide range of potencies and those which induce sensitization upon exposure at a low concentration (i.e. strong, or extreme sensitizers) pose the highest risk to patients and should be the focus of the risk assessment. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium has reviewed the status of dermal, respiratory, and systemic risk assessment in cosmetic and pharmaceutical industries, and proposes a framework to evaluate the safety of known or potential dermal sensitizers in pharmaceuticals. Due to the lack of specific regulatory guidance on this topic, the science-driven risk-based approach proposed by ELSIE encourages consistency in the toxicological assessment of extractables and leachables to maintain high product quality and ensure patient safety.

Spray Pattern and Plume Geometry Testing and Methodology: An IPAC-RS Working Group Overview.

Plume characterization for orally inhaled and nasal drug products (OINDP) provides valuable information during OINDP development. Spray pattern and plume geometry techniques, methods, and technology have evolved over the past 20 years since the publication of the original 1998 FDA MDI DPI draft guidance. The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) discusses the historical context and background to plume geometry and spray pattern characterization studies; provides an analysis of the current regulatory context; addresses results from its industry surveys on application and value of such testing; and presents case studies and best practices-seeking to provide insights to regulatory bodies and other stakeholders. Assessment and consideration of published studies and industry experience note the value of plume geometry and spray pattern in development, and that further data is needed regarding their use in assessing formulation characteristics. Continued dialogue between industry and regulatory bodies is needed to establish the optimum use of these techniques.

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. This manuscript is a cross-industry Extractables and Leachables Safety Information Exchange (ELSIE) consortium collaboration and follow-up to Broschard et al. (2016), which aims to provide further clarity and detail on the conduct of E&L risk assessments. Where sufficient data are available, a health-based exposure limit termed Permitted Daily Exposure (PDE) may be calculated and to exemplify this, case studies of four common E&Ls are described herein, namely bisphenol-A, butylated hydroxytoluene, Irgafos® 168, and Irganox® 1010. Relevant discussion points are further explored, including the value of extractable data, how to perform route-to-route extrapolations and considerations around degradation products. By presenting PDEs for common E&L substances, the aim is to encourage consistency and harmony in approaches for deriving compound-specific limits.

Overview of Brazilian Requirements for Therapeutic Equivalence of Orally Inhaled and Nasal Drug Products.

Brazil has established a framework for provision of generic pharmaceuticals including for orally inhaled and nasal drug products (OINDP) to its populace. This includes the development of guidelines or "resolutions" and normative instructions describing the Brazilian medicines agency's (Anvisa) expectations for demonstrating OINDP therapeutic equivalence. The Anvisa regulatory framework for OINDP therapeutic equivalence, challenges, and comparisons with the US Food and Drug Administration and European Medicines Agency approaches are assessed and discussed.

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. The International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) European outreach working group provides and overview and analysis of the current state of European regulatory activity for OINDP (International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) 2018).

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. Details of these approaches may differ depending on the nature of the final drug product. These may include application, the formulation, route of administration and length of use. Current regulatory guidelines and industry standards provide general guidance on compound specific safety assessments but do not provide a comprehensive approach to safety evaluations of leachables and/or extractables. This paper provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables. These include application of structure activity relationship studies, development of permitted daily exposure (PDE) values, and use of safety threshold concepts. Case studies are provided. The concepts presented seek to encourage discussion in the scientific community, and are not intended to represent a final opinion or "guidelines."

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. To reduce the risk of discovering leachables during stability studies late in the development process, or components that may fail extractables release criteria, it is proposed that extractables testing on polymer resins may be useful as a screening tool. Two studies have been performed to evaluate whether the extractables profile generated from a polymer resin is representative of the extractables profile of components made from that same resin. The ELSIE Consortium pilot program examined polyvinyl chloride and polyethylene, and another study evaluated polypropylene and a copolymer of polycarbonate and acrylonitrile butadiene styrene. The test materials were comprised of polymer resin and processed resin or molded components. Volatile, semi-volatile, and nonvolatile chemical profiles were evaluated after headspace sampling and extraction with solvents of varying polarity and pH. The findings from these studies indicate that there may or may not be differences between extractables profiles obtained from resins and processed forms of the resin depending on the type of material, the compounds of interest, and extraction conditions used. Extractables testing of polymer resins is useful for material screening and in certain situations may replace routine component testing.

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. A risk evaluation for an inhalation product identified injection molding as a key process. Designed experiments were performed to evaluate the impact of molding process parameters on the extractable profile from an ABS inhaler component. Statistical analysis of the resulting GC chromatographic profiles identified processing factors that were correlated with peak levels in the extractable profiles. The combination of statistically significant molding process parameters was different for different types of extractable compounds. ANOVA models were used to obtain optimal process settings and predict extractable levels for a selected number of compounds. The proposed paradigm may be applied to evaluate the impact of material composition and processing parameters on extractable profiles and utilized to manage product leachables early in the development process and throughout the product lifecycle.

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. This was performed on two test materials, polyethylene (PE) and polyvinyl chloride (PVC), that were selected due to their common use in pharmaceutical packaging. The purpose of the study was to investigate if the protocol could be simplified such that (i) a reduced number or even a single extraction technique could be used and (ii) a reduced number of solvents could be used to obtain information that is useful for material selection regardless of product type. Results indicate that, at least for the PVC, such reductions are feasible. Additionally, the studies indicate that levels of extractable elemental impurities in the two test materials were low and further confirm the importance of using orthogonal analytical detection techniques to gain adequate understanding of extraction profiles.

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. To further illustrate current challenges and industry approaches to meeting biocompatibility requirements, we also present results of an IPAC-RS benchmarking survey and case studies.

Cell and Gene Therapies: Challenges in Designing Extractables and Leachables Studies and Conducting Safety Assessments.

Over the past decade, Cell and Gene Therapies (C>) have been an emerging therapeutic area with more than twenty C> drug products approved and over 1000 registered trials. The remarkable progress in these modalities brings new challenges for scientists who evaluate manufacturing and storage materials, including risk assessments for extractables and leachables (E&L). Establishing a business process to qualify materials for these applications is an important risk mitigation strategy in support of these assessments. Process validation verifying process performance and product quality requirements using qualified materials also ensures that leachables from the materials do not result in an impact to process and product. The authors provide an overview of available guidelines and publications relevant to E&L risk assessments that can be used to support ex vivo C> products, highlighting gaps and standardization needs in the areas of biocompatibility and extractables conditions. Finally, the authors present leachable testing strategies, relevant to the specific manufacturing and storage conditions of C> products, and safety assessment considerations for organic and inorganic chemical entities.

Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis.

Quality by design is the foundation of the risk management framework for extractables and leachables (E&Ls) recommended by the Extractables and Leachables Safety Information Exchange (ELSIE). Following these principles during the selection of materials for pharmaceutical product development minimizes the presence of highly toxic substances and decreases the health risk of potential leachables in the drug product. Therefore, in the context of the broad arena of chemicals, it is important to distinguish E&Ls as a subset of chemicals and evaluate this relevant chemical space to derive appropriate analytical and safety thresholds. When considering the health hazards posed by E&Ls, one area presenting a challenge is understanding the sensitization potential and whether it poses a risk to patients. A dataset of E&Ls compiled by ELSIE (n=466) was analysed to determine the prevalence and potency of skin sensitizers in this chemical subset and explore a scientifically justified approach to the sensitization assessment of potential leachables in parenteral drug products. Approximately half of the compounds (56%, 259/466) had sensitization data recorded in the ELSIE database and of these, 20% (52/259) are potential skin sensitizers. Only 3% (8/259) of the E&L dataset with sensitization data were considered potent (strong or extreme) sensitizers following in silico analysis and expert review, illustrating that potent sensitizers are not routinely observed as leachables in pharmaceutical products. Our analysis highlights that in silico potency prediction and expert review are key tools during the sensitization assessment process for E&Ls. The results confirm where material selection is anticipated to mitigate the risk of presence of strong and/or extreme sensitizers (e.g., extractable testing via ISO 10993-10), and that implementing thresholds per ICH M7 and/or Masuda-Herrera et al. provides a reasonably conservative approach for establishing the analytical testing and safety thresholds.

Development of Duration-Based Non-Mutagenic Thresholds of Toxicological Concern (TTCs) Relevant to Parenteral Extractables and Leachables (E&Ls).

The threshold of toxicological concern (TTC), i.e., the dose of a compound lacking sufficient experimental toxicity data that is unlikely to result in an adverse health effect in humans, is important for evaluating extractables and leachables (E&Ls) as it guides analytical testing and minimizes the use of animal studies. The Extractables and Leachables Safety Information Exchange (ELSIE) consortium, which consists of member companies that span biotechnology, pharmaceutical, and medical device industries, brought together subject matter expert toxicologists to derive TTC values for organic, non-mutagenic E&L substances when administered parenterally. A total of 488 E&L compounds from the ELSIE database were analyzed and parenteral point of departure (PPOD) estimates were derived for 252 compounds. The PPOD estimates were adjusted to extrapolate to subacute, subchronic, and chronic durations of nonclinical exposure and the lower fifth percentiles were calculated. An additional 100-fold adjustment factor to account for nonclinical species and human variability was subsequently applied to derive the parenteral TTC values for E&Ls. The resulting parenteral TTC values are 35, 110, and 180 µg/day for human exposures of >10 years to lifetime, >1-10 years, and ≤1 year, respectively. These parenteral TTCs are expected to be conservative for E&Ls that are considered non-mutagenic per ICH M7(R1) guidelines.

Collaborations between Clinical Pharmacologists in Japan and in the United States - Report from the IQ CPLG and JPMA CPTF Meeting in Tokyo, Japan.

The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Clinical Pharmacology Leadership Group (CPLG) held its first meeting of Japan-based representatives at Astellas Pharma headquarters in Tokyo on October 1, 2019. The meeting was also attended by Japan Pharmaceutical Manufactures Association (JPMA) Clinical Pharmacology Task Force (CPTF) members. Overall, nearly 30 clinical pharmacologists representing 14 companies attended the event. The meeting met its goal of enhancing mutual understanding of each organization's activities. In a number of break-out sessions, participants identified scientific topics for potential future collaboration between JPMA CPTF and IQ CPLG.

Development of safety qualification thresholds and their use in orally inhaled and nasal drug product evaluation.

Safety thresholds for chemical impurities and leachables in consumer products such as foods and drugs have helped to ensure public health while establishing scientifically sound limits for identification and risk assessment of these compounds. The Product Quality Research Institute (PQRI) Leachables and Extractables Working Group, a collaboration of chemists and toxicologists from the U.S. Food and Drug Administration (FDA), industry, and academia, has developed safety thresholds for leachables and extractables in orally inhaled and nasal drug products (OINDP), for application in United States pharmaceutical submissions. The PQRI safety concern threshold (SCT) is 0.15 microg/day, and the qualification threshold is 5 microg/day. OINDP are important in the treatment of lung diseases such as asthma and chronic bronchitis, as well as systemic diseases such as diabetes. Analysis of extractables and minimization of leachables in OINDP are vital to ensuring the quality and safety of the final product. It is expected that the thresholds developed by the PQRI Leachables and Extractables Working Group will be used by both industry and regulators to ensure and assess such quality and safety in OINDP applications. In this article, we describe the importance of the PQRI safety thresholds in the OINDP pharmaceutical development process; the background and context of safety thresholds for consumer products; how these safety thresholds were developed using well-established, robust databases and quantitative risk assessment approaches; and how these thresholds can be applied in a pharmaceutical safety qualification process, including FDA regulatory perspectives on the use of safety thresholds for OINDP.

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

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. This review article contains the information compiled from the available body of literature and considers two questions: (1) What elemental entities are present in the relevant polymers and materials and at what levels are they present? (2) To what extent are these elemental entities leached from these materials under conditions relevant to the manufacturing and storage/distribution of solution drug products? Conclusions drawn from the compiled data are as follows: (1) Elemental entities are present in the materials used to construct packaging and manufacturing systems as these materials either contain these elemental entities as additives or are exposed to elemental entities during their production. (2) Unless the elemental entities are parts of the materials themselves (for example, SiO2 in glass) or intentionally added to the materials (for example, metal stearates in polymers), their incidental amounts in the materials are generally low. (3) When elemental entities are present in materials and systems, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, while sources of certain elemental impurities may be ubiquitous in the natural environment, they are not ubiquitous in materials used in pharmaceutical packaging and manufacturing systems and when they are present, they are not extensively leached under relevant conditions. The information summarized here can be utilized to aid the elemental impurity risk assessment process by providing the identities of commonly reported elements and data to support probability estimates of those becoming elemental impurities in the drug product. Furthermore, recommendations are made related to establishing elements of potential product impact for individual materials. LAY ABSTRACT: Extraneous impurities in drug products provide no therapeutic benefit and thus should be known and controlled. Elemental impurities can arise from a number of sources and by a number of means, including the leaching of elemental entities from drug product packaging and manufacturing systems. To understand the extent to which materials used in packaging systems contain elemental entities and the extent to which those entities leach into drug products to become elemental impurities, the Extractables and Leachables Safety Information Exchange (ELSIE) and International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) Consortia have jointly performed a literature review on this subject. Using the compiled information, it was concluded that while packaging materials may contain elemental entities, unless those entities are intentional parts of the materials, the amounts of those elemental entities are generally low. Furthermore, generally only a very small fraction of the total available amount of the entity can be leached under conditions that are relevant to packaged drug products. Thus, risk assessment of sources of elemental impurities in drug products that may be related to materials used in pharmaceutical packaging and manufacturing systems can utilize the information and recommendations presented here.