Selecting appropriate excipients for paediatric dosage form − Paediatric excipients risk assessment (PERA) framework – Part 1

Excipients are often the major component of the formulation that critically affect the dosage form, manufacturing process, product performance, stability and safety. They exert different roles and functions in a dosage form. Selecting excipients with appropriate safety and tolerability is a major hurdle in paediatric formulation development. The suitability of a particular excipient will be dependent on the context of its use with regard to the paediatric age range, acute versus chronic use, and clinical risk–benefit of the disease, active and excipient. Scientists are encouraged to apply the principle of risk–benefit to assess the suitability of excipients to the specific paediatric population. Indicative list of parameters that should be taken into consideration and hierarchy of information sources when assessing the excipients risks is provided by regulatory agencies. However, the approach to be taken and details of how the risk evaluation should be undertaken are lacking. There is a need for a systematic approach to selection of excipients and assessment of the risk of excipient exposure. The Paediatric Excipients Risk Assessment (PERA) framework developed and proposed in this paper provides a structured, systematic decision-making framework via customizable tools and processes that can help to improve the transparency and communications on the selection and justification of use of excipients in a paediatric formulation.

Introduction

Excipients play an integral role in formulation development. Selecting appropriate excipients with the required properties is essential to meeting a product’s design requirements and enhancing patient acceptability [1]. Indeed, according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2 (R2) [2], the excipients chosen, their concentration, and characteristics that can influence drug product performance should be discussed relative to their respective function [3]. When developing medicines for administration to paediatric patients, it is also necessary to consider the safety profile and acceptability of the excipients in the intended patient population, and justify their inclusion [4]. The path for selecting excipients for formulation development for adults in comparison is relatively straightforward since potential excipient safety concerns and contra-indications are mostly well understood. For example, Sorbitol is contraindicated in patients with fructose intolerance and not recommended for use in patients with hypoglycaemia, and Aspartame is contraindicated in patients with phenylketonuria. In contrast, the identification of excipients with appropriate and robust safety as well as tolerability data is a key challenge when developing medicines for children since such data are often lacking. Furthermore, the suitability of a particular excipient will be dependent on the context of its use with regard to the paediatric age range, acute versus chronic use, route of administration, and clinical risk–benefit of the disease, and active pharmaceutical ingredient (API). Scientists are encouraged to consider the relative benefits and risks of using a particular excipient during paediatric formulation development [4] although there appears to be a lack of guidance and standardization about what is adequate or necessary to sufficiently characterize the risk–benefit balance of an excipient in various paediatric populations and disease states.

The concept of risk management is well recognised, and a quality risk management process has been implemented by ICH for the development, manufacturing and distribution of drug substances and drug products, for more than 10 years, with the provision of tools that may be applied to different aspects of pharmaceutical quality [5]. Several publications on excipient risk assessment for products are intended for adults [6], [7], [8]. For example, the International Pharmaceutical Excipients Council (IPEC) in collaboration with the Parenteral Drug Association (PDA) have developed a guide for the risk assessment of excipients for adult dosage forms [9], [10]. Some authors have developed algorithms and quantitative methods for risk assessment of excipients [11], [12]. These methods represent a quantitative assessment of risks using a scoring system within the risk indexes with subsequent ranking and transition to a final qualitative assessment of the excipient risk level. Although these methods provide valuable techniques for excipient risk assessment, they have limited applicability to paediatric formulation development since they do not take into account patient or disease specific factors such as age, dose and severity of illness. Turner et al [13] have developed a risk assessment framework that considers excipients for paediatric patients, however, it is more oriented towards clinicians and health care professionals, than pharmaceutical development scientists. The current European Medicines Agency (EMA) guideline for development of pediatric products provides the list of factors to be taken into consideration for the selection of excipients, and a decision tree considering the evaluation of the safety profile of excipients in paediatric formulations [4]. However, the EMA guideline does not detail the process of risk–benefit assessment and the approaches for mitigating the risks related to exposure of excipients in paediatric population. The risk–benefit balance assessment of current excipients is lacking consistency and transparency. No comprehensive guidelines from the regulatory or formulator’s perspective have been developed yet that would consider the use of excipient at different stages of paediatric product development, except for a guideline on the risk–benefit assessment of the presence of phthalates in certain medical devices [14] and a reflection paper on the use of parabens for oral use [15]

The risk–benefit assessment of excipients for paediatric formulations faces traditional risk assessment challenges including for example, limited availability of robust evidence-based data, diversity in paediatric age sub-sets, and integration of diverse data sources (e.g. from experimental animal studies and human epidemiological studies). In addition, there are challenges in defining how uncertainties could be presented to key stakeholders, including regulatory agencies, and what guidance can be provided to enable decision making by key stakeholders where evidence may be limited. There is scope for improvement and in fact a tremendous need for a systematic approach to the selection of excipients and assessment of the risk–benefit balance of excipient exposure. Many of the problems stem from the foundations of risk assessment, including how to identify risk, how to analyse it, and how to use risk assessment as a tool to improve patient safety. While no single risk–benefit methodology or tool can fully capture all aspects of risk–benefit assessment, the choice of a single approach or combination of methodologies should be matched to the complexity of the problem. Application of a structured risk–benefit assessment framework, core to both efficient paediatric product development and regulatory decision making can lead to better communication and discussions between companies and regulators. Hence, the European Paediatric Formulation Initiative (EuPFI) Excipients Workstream in collaboration with Innovation and Quality Consortium (IQ) Pediatric Workgroup members have designed a Paediatric Excipient Risk Assessment (PERA) framework and a tool that provides a structured method for the selection and overall risk assessment of excipients for paediatric formulations. This part (part 1) of the paper is limited to the description of the PERA Framework. The PERA tool is described in part 2 paper [16] with example case studies to illustrate the applicability of the framework and risk assessment tool.

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Smita Salunke, Anjali Agrawal, Jennifer Walsh, Anthony Nunn, Kevin Hughes, Peter Kuehl, Grazia Caivano, David Clapham, Karen Thompson, Alfred Rumondor, Brian Enright, Philip Sherratt, Selecting appropriate excipients for paediatric dosage form − Paediatric excipients risk assessment (PERA) framework – Part 1, European Journal of Pharmaceutics and Biopharmaceutics, 2024, 114458, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114458.

See also the article on the second part

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