SC IV O. Functionality-related Characteristics of Excipients
This chapter and the Functionality-related characteristics (FRCs) sections in individual monographs are not mandatory and are published for information and guidance.
Preamble
Excipients that have previously been evaluated for safety are used in the formulation of pharmaceutical preparations to bring functionality to the formulation. The intended function of an excipient is to guarantee the required physicochemical and biopharmaceutical properties of the pharmaceutical preparation.
The functionality of an excipient is determined by its physical and chemical attributes and, in some cases, also by its content of by-products or of additives used to improve the intended functionality. In addition, the functionality may depend on complex interactions between the constituents of the formulation and stresses related to the process. Excipient functionality can therefore be evaluated only in the context of a particular formulation and manufacturing process, frequently by the use of a number of analytical methods.
Pharmaceutical development should be science-based and ensure a quality medicinal product. It is defined in the current ICH guideline Q8 Pharmaceutical Development. Its purpose is to provide justification for the dosage form selected, the qualitative and quantitative composition of the medicinal product, the manufacturing process, the critical quality attributes (CQAs) of the constituents and medicinal product, and the critical process parameters (CPPs). The ‘quality by design′ (QbD) concept described in the ICH Q8 guideline requires a comprehensive understanding of the chemical and physical nature of the individual active substance(s) and excipients, and of the way their attributes interact in the formulation and with the manufacturing process.
Pharmaceutical development includes identification of which excipient quality attributes are critical.
A CQA is a physical, chemical, biological or microbiological property or characteristic that must be within appropriate limits to ensure the desired medicinal product quality.
Monographs of the European Pharmacopoeia on excipients are designed to ensure acceptable quality for users. Information on the characters of the excipient, and requirements concerning identity, chemical and microbiological purity and physical characteristics associated with the chemical structure, such as optical rotation, are given in individual monographs and in the general monograph Substances for pharmaceutical use (2034).
Certain excipient attributes, such as the particle size of an excipient intended for a solid dosage form or the molecular mass of a polymeric material used as a viscosity-increasing agent, may however relate to functionality in a more general sense. These attributes are called functionality-related characteristics (FRCs). When the pharmaceutical development work of a specific product has identified the existence of one or more critical FRCs for an excipient, they are considered to be CQAs for that excipient and should be controlled accordingly.
Knowledge of FRCs may facilitate the application of process analytical technology (PAT).
FRCs are included in excipient monographs to aid excipient manufacturers and users in establishing specifications based on standard analytical methods. They provide a common language to support the supply of excipients with specified properties. FRCs may be stated (in the certificate of analysis, for example) by the excipient manufacturer with a reference to the Pharmacopoeia monograph, thus indicating the method used to test a particular characteristic. The FRCs section in individual monographs contains FRCs that are known to have an impact on the functionality of the excipient for the stated uses. The uses and the FRCs listed are not exhaustive due to the multiple uses of many excipients and the development of new uses.
Regulatory guidance
According to current regulatory guidelines, for example the ICH Q8 guideline, the marketing authorisation application should discuss the excipients chosen, their concentration, and the attributes that can influence the medicinal product quality or manufacturability relative to the respective function of each excipient. The ability of excipients to provide their intended functionality and to perform throughout the intended medicinal product shelf life should also be demonstrated. The information on excipient performance can be used as appropriate to justify the choice and quality attributes of the excipient.
During pharmaceutical development, the attributes that are critical to the manufacturing process and quality of the medicinal product are identified. Having identified the critical attributes of the excipients, preferably by a risk-based approach, pharmaceutical development may establish the acceptable range of the critical material attributes including both the physical and the chemical property variation. The FRCs concerned may not be properties controlled by the excipient manufacturer and could therefore be variable. The design of a robust manufacturing process for the medicinal product that limits the effect of the normal excipient variability is preferable.
Evaluation of the physical and chemical grades and, where appropriate, the setting of a specification for the critical attributes and thus the critical FRCs, is part of the pharmaceutical development irrespective of the non-mandatory character of FRCs. This evaluation should be seen in light of regulatory guidance on pharmaceutical development and the appropriate acceptance criteria should be based on an understanding of the extent to which the variation of the critical FRCs can have an impact on the quality of the medicinal drug product. An acceptable range of FRCs may be established within the limits of the design space. The design space may be described as a space in which the quality attributes of the constituents and the process parameters may vary without modification of the quality of the medicinal product.
Physical grades
Excipients that are particulate solids can be available in a variety of physical grades, for example with regard to particle-size distribution, which is usually controlled by the excipient supplier. However, FRCs for these excipients may concern a wide range of properties, resulting from solid-state properties and properties of the particulate solid, which may not be controlled by the excipient supplier.
Properties of particulate solids include for example particle-size distribution, specific surface area, bulk density, flowability, wettability and water sorption. Depending on the size range, the particle-size distribution can be determined by sieve analysis (see general chapter 2.9.38. Particle-size distribution estimation by analytical sieving) or instrumental methods, for example 2.9.31. Particle size analysis by laser light diffraction. The method described in general chapter 2.9.26. Specific surface area by gas adsorption is based on the Brunauer-Emmett-Teller (BET) technique. Methods to characterise flowability and bulk density of powders are described in general chapters 2.9.36. Powder flow and 2.9.34. Bulk density and tapped density. Solid-state properties may have an impact on the wettability (see general chapter 2.9.45. Wettability of porous solids including powders) and water-solid interactions (see general chapter 2.9.39. Water-solid interactions: determination of sorption-desorption isotherms and of water activity) of particulate solids.
Examples of solid-state properties to be considered in the development of solid dosage forms include polymorphism, pseudopolymorphism, crystallinity and density. Techniques to study them are given in general chapters 5.9. Polymorphism, 5.16. Crystallinity and 2.2.42. Density of solids.
Chemical grades
Excipients that are available in different chemical grades are of natural, semi-synthetic or synthetic origin. Individual monographs usually control the chemical composition of excipients that are composed of a mixture of related compounds, for example the composition of fatty acids in vegetable oils or surfactants. There are, however, individual monographs in the Pharmacopoeia each describing a class of polymeric materials that may vary in their composition with regard to the structure of homopolymers, block polymers and copolymers, the degree of polymerisation, the molecular mass and mass distribution, the degree of substitution and in some cases even different substituents on the polymer backbone. This variation may, however, have a profound effect on the functionality of the excipient and should be subject to investigations during the pharmaceutical development, preferably to establish the acceptable range of each attribute being critical to the manufacturing process and quality of the medicinal product.
Functionality-related characteristics section in monographs
Monographs on excipients may have a section entitled ‘Functionality-related characteristics′. This section is included for information for the user and is not a mandatory part of the monograph. The section gives a statement of characteristics that are known to be relevant for certain uses of the excipient. The use for which the characteristic is relevant is stated. For other uses, the characteristic may be irrelevant. For this reason, the section should not be seen simply as a supplement to the monograph. It is the responsibility of the manufacturer of the medicinal product to decide how the information on FRCs will be applied in the manufacturing process in light of the use of the excipient and data from pharmaceutical development.
The information on the FRCs may be given in different ways:
A given characteristic may be the subject of a mandatory requirement in the monograph. If it is relevant for certain uses, it is also referred to in the FRCs section as a relevant characteristic that the manufacturer of the medicinal product may choose to specify for the grade used of a particular pharmaceutical preparation.
The section on FRCs is intended to reflect current knowledge related to the major uses of an excipient. In view of the multiple uses of some excipients and the continuous development of new uses, the section may not be complete. In addition, the methods cited for the determination of a particular characteristic are given as recommendations for methods that are known to be satisfactory for the purpose, and the use of other methods is not excluded.
pharmacopoeial harmonisation
A number of excipient monographs are subject to pharmacopoeial harmonisation among the European, Japanese and United States pharmacopoeias (see general chapter 5.8. Pharmacopoeial harmonisation). Introduction of the FRCs section in the monographs of the European Pharmacopoeia means that the presentation of harmonised monographs differs. Tests for physical and chemical attributes regarded as both quality-related and functionality-related in the European Pharmacopoeia are, in the 2 other pharmacopoeias, included only in the body of the monograph. The different format has no implications on the specification of excipient characteristics for the manufacturer of the medicinal product. Current regulatory guidance recommends the identification and specification of only such critical attributes that impact the manufacturing process and the quality of the medicinal product. The different legal environments of the 3 pharmacopoeias allow for different formats of the monographs without affecting the pharmacopoeial harmonisation status.
Glossary
Critical characteristic or critical quality attribute (CQA)
A physical, chemical, biological or microbiological property or characteristic that must be within appropriate limits or an appropriate range or distribution to ensure the desired product quality.
Critical process parameter (CPP)
A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.
Design space
The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Functionality-related characteristic (FRC)
A controllable physical or chemical characteristic of an excipient that is shown to impact on its functionality.
Process analytical technology (PAT)
A system for designing, analysing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.
Quality by design (QbD)
A systematic approach to development that begins with predefined objectives and emphasises product and process understanding and process control, based on sound science and quality risk management.