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Solid State and Polymorphism of the Drug Substance in the Context of Quality by Design and ICH Guidelines Q8-Q12

Markus von Raumer1 and Rolf Hilfiker2

1 Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, Allschwil, 4123, Switzerland

2 Solvias AG, Römerpark 2, Kaiseraugst, 4303, Switzerland

1.1 Introduction

The way in which the pharmaceutical industry is approaching technical development has evolved very much in the recent years. Fresh concepts coming from other industries have been introduced with the desire to push for a more science and risk-based development approach throughout the product life cycle. Quality by design () in the pharmaceutical industry is an outcome of the efforts to harmonize development quality concepts and understandings by regulatory agencies and resulted in the International Conference of Harmonization (ICH) guidelines Q8 [1], Q9 [2], Q10 [3], Q11 [4], and Q12 [5]. Although first devised for pharmaceutical development (Q8), the QbD concepts and related tools were rapidly recognized as being very helpful for chemical development. A result of this process was the Q11 guideline that provides guidance for drug substance as defined in the scope of the ICH guideline Q6A [6] (this guideline contains the well-known decision trees for polymorphism).

The scope of this chapter is to give a short introduction to the solid-state development process in the pharmaceutical industry and to QbD. Questions on how QbD principles can be applied to solid-state development will be discussed, highlighting how the solid state is an important parameter to be considered in the pharmaceutical development process. For that purpose, some general insights into the relevance of the drug substance () solid state throughout various fields of pharmaceutical development will be given.

1.2 A Short Introduction to Polymorphism and Solid-State Development

Only a brief overview of solid-state development and polymorphism shall be given here. Subsequent chapters in this book will discuss the various aspects in more detail.

Many organic and inorganic compounds can exist in different solid forms [7-12]. They can be in the amorphous (Chapter ), i.e. disordered [13], or in the crystalline, i.e. ordered, state. In accordance with McCrone's definition [8], "The polymorphism of any element or compound is its ability to crystallize as more than one distinct crystal species," we will call different crystal arrangements of the same chemical composition polymorphs (Figure 1.1). Especially in the pharmaceutical context, the term "polymorph or polymorphism" is used more broadly by many authors and regulatory agencies. The amorphous state, as well as hydrates or solvates (both of which do not have the same chemical composition), are tacitly included by the term. Because different inter- and intramolecular interactions such as van der Waals interactions and hydrogen bonds will be present in different crystal structures, different polymorphs will have different free energies and therefore different physical properties such as solubility, chemical stability, melting point, density, etc. (Chapter ). Hence, the crystal form of a solid material in development is often considered a critical quality attribute (, see next section). Of practical importance are also solvates [14], sometimes called pseudopolymorphs, where solvent molecules are incorporated in the crystal lattice in a stoichiometric or nonstoichiometric [12, 15] way. Hydrates (Chapter ), where the solvent is water, are of particular interest because of the omnipresence of water. In addition to the crystalline, amorphous, and liquid states, condensed matter can exist in various mesophases. These mesophases are characterized by exhibiting partial order between that of a crystalline and an amorphous state [16, 17]. Several drug substances are known to form liquid crystalline phases, which can be either thermotropic, where the liquid crystal formation is induced by temperature, or lyotropic, where the transition is solvent induced [18-20].

Figure 1.1 Schematic depiction of various types of solid forms.

Polymorphism is a very common phenomenon [11, 21-25] in connection with small-molecule drug substances. The literature values concerning the prevalence of true polymorphs range from 32% [26] to 51% [27-29] of small organic molecules (molecular weight <600?g?mol-1). According to the same references, 56% and 87%, respectively, have more than one solid form if solvates are included in the count.

In the context of pharmaceutical solid-state development, polymorph considerations are made subsequent to general considerations like salt [30] (Chapter ) or co-crystal [31] (Chapter ) formation. When a compound is acidic or basic, it is often possible to create a salt with a suitable base or acid, and such a salt can, in turn, often be crystallized. Crystalline salts may then again be able to exist as various polymorphs or solvates. From the scientific perspective, solvates can be considered as co-crystals of the active molecule and solvent. In the pharmaceutical industry, the term co-crystal is used in a slightly different way, however. A pharmaceutical co-crystal is a solid, where the constituting molecules are in the solid phase as single components at room temperature. Obviously, solvates, co-crystals and salts will have different properties than the polymorphs of the active molecule. About half of all active molecules are marketed as salts [25, 30, 32]. Recently, also the first co-crystal composed of two active molecules reached the market (Entresto from Novartis [33]). Polymorphs, solvates, salts, and co-crystals are schematically depicted in Figure 1.1. We will use the term "drug substance" for the therapeutic moiety, which may be a solvate, salt, or a co-crystal, whereas the single, uncharged molecule will be called the "active molecule."

1.3 A Short Introduction to Quality by Design (QbD)

Only a brief overview of QbD shall be given here. Pharmaceutical applications thereof were described in a far more detailed and applied way elsewhere [34, 35].

QbD is not a new concept. Indeed, it was introduced in the manufacturing industry in the 1950s. The automobile and electronic industries were early users of QbD as shown in a comprehensive textbook on the subject by Juran [36]. This industry rapidly realized that the process of QbD provides a systematic and structured framework for documenting and presenting a development rationale while acquiring knowledge about the product and the process. As a result, it could be ensured that products were manufactured, which consistently fit the desired quality (and safety, and efficacy, if applied to pharma). In addition to being safe and cost effective, any process must be robust in order to be successfully implemented and transferred. In contrast to the traditional approach for process development, QbD leads to robust processes. Because of its business benefits, many pharmaceutical companies have already implemented or are now implementing QbD methodologies. QbD has recently evolved from a purely regulatory initiative to an industry initiative with strong encouragement from the regulatory agencies who are concerned about product quality issues and possible drug shortages [37].

QbD introduces a formalism for development based on first understanding the product, then understanding the processes leading to the product, and finally of controlling the process over the product life cycle. It starts with defining the development goal in a quality target product profile (). As in any other discipline, knowing what is to be developed makes the development easier or possible at all. This means that, for instance, for the development of a drug product (), the route of application (oral), the dosage form (tablet, immediate release), and the strength (efficacy and safety) should be defined and justified at the beginning of the process. Although definition is somehow easy, justification is more complicated as it requires quite a lot of prior knowledge. Here, knowledge management and the transfer of knowledge throughout the pharmaceutical development help to justify decisions that are taken. For example, preclinical pharmacokinetic results, possibly coupled with in silico considerations, can help to make informed decisions on the DS. A rationale for the solid form and, for example, target particle size can be gained here. Refined with the human PK data of clinical phases I and II, a rationale for phase III and market product can be developed. A QTPP can contain input from all stakeholders, i.e. the patient, the physician, and the pharmacist. Next comes the CQA, which should encompass various aspects related to quality, efficacy, and safety. Any physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (or efficacy, or safety) is a CQA. As an example, the assay of a DP...