Introduction
The form of an active pharmaceutical ingredient (API) can be defined as both the chemical and physical state in which it is isolated and supplied for the development and manufacturing of drug product. Because the nature of the API form required and selected is highly dependent on both the stage of development of the drug and the needs of the formulation being pursued, forms of a given API used for drug product development and manufacturing are variable. The adjective “phaseappropriate” is often applied to early and mid-stage development efforts in order to describe and justify the development approach taken during this interval of the development cycle. Programs at these stages are works in progress, and sponsors are judicious about the depth and breadth of activities needed to maintain progress.
For the sake of simplicity, this article discusses form selection for the API in the context of the key factors that drive API form selection for drugs that are intended to be administered as oral solid dosages. The phase appropriateness aspect is also addressed in terms of serving expedient formulations for early clinical development.
Motivations for Definition of an API’s Solid Form
In the last 20-30 years, the concept of API form selection has emerged as the subject of increasing consideration, scientific investigation and implementation during development and manufacturing. A recent review by Ticehurst (Ticehurst, MD, J Pharmacy and Pharmacology, 2015, 67(6), June, 782) provides a clear, comprehensive rationale for API form selection, and consolidates previous literature on this topic, advocating for a “truly holistic strategy for drug product development”, one key element of which is solid form selection. A few of the statements in the Ticehurst review are worth quoting here, since they speak very eloquently to the impetus for form selection activities:
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“The solid form has the potential to facilitate developability of a potential drug candidate in the preclinical stages, help with acceleration of a compound during development, and provide intellectual property”, and,
“…meeting minimum acceptable criteria for the solid form is essential to having a developable pharmaceutical product that is enduring; however, improvements over the minimum criteria are also important to reduce time and effort in the product development phase.”
To interpret, paraphrase and expand on these statements, there are multiple drivers for a sufficiently thorough solid form investigation and selection at earlier stages of drug development:
- From the point of view of API manufacturing, a better understood and behaved crystalline bulk drug substance with a defined form serves multiple needs:
- Enables rejection of impurities on isolation and purification
- Improves and maintains the ease of filtration, drying, and transfer of the solid
- Enhances storage and shipping stability
- Overall, it streamlines critical final unit operations in the API manufacturing process
- An API with an appropriately defined form also adequately serves the development and manufacturing of the selected dosage form:
- It can provide a bulk drug substance with properties tailored to the needs of the dosage form, such as enhanced density, flow, compressibility and other Mechanical properties, solubility, dissolution rate, and content uniformity
- The advantages conferred by enhanced chemical and physical stability of the API form are often extended to the drug product’s shelf life (stability). Understanding of the form of the API, as supplied for drug product manufacturing, provides a basis for comparison, in the event that the API’s physical properties are altered (either intentionally or inadvertently) as a result of drug product processing conditions. The hope and expectation is that unplanned physical changes do not occur to the API as a result of its conversion to a finished solid oral dosage form, but having a well-defined form to start with allows systematic monitoring of any such changes, since they may cause variability in the performance of the drug product
- Such properties also have the potential to streamline certain unit operations in drug product manufacturing
What is an Appropriate API Solid Form?
An appropriate API form has properties that facilitate its manufacturing – purification, isolation, handling, stability, storage, and shipping. It also supports and enhances the ability to develop a formulation and manufacture the required dosage form.
Among key API properties that influence drug product attributes and performance are:
- Crystallinity
- Polymorphism
- Density
- Solubility
- Stability (chemical and physical)
- Particle size distribution
- Crystal morphology and habit
As will be discussed below, depending on the stage of development and the needs of the dosage form associated with that stage, it may not be possible or necessary to define or understand all of these properties. As mentioned above, the definition of a given API’s solid form tends to be fluid, until later in development. At a minimum, the solid form should be defined to the extent necessary to allow release testing against specifications considered important for API stability, as well as supporting systematic formulation development and consistency in drug product manufacturing.
Putting API Form Selection into Practice During Early- and Mid-Stage CMC Development
API form selection, in early development, is challenging. It needs to happen in a very dynamic environment, in which multiple efforts influencing it are being pursued in parallel including establishment and definition of an API’s properties and manufacturing process, formulation activities (preformulation, formulation development, dosage prototype preparation and evaluation), and particle engineering (if appropriate and necessary). API form selection is ultimately driven by preformulation, formulation development, drug product manufacturing, and preclinical and early clinical study data. The paradox regarding the timing of form selection is that the API is needed before it is sufficiently characterized and its form is defined, in order to perform these initial downstream studies. Therefore, almost by definition, attributes of early API batches manufactured are going to be lacking, because the linkage of API attributes to the dosage form is either tenuous or non-existent.
An underappreciated aspect of form selection is the need to balance and prioritize what properties are necessary to produce, store and stage a sufficiently pure, stable API as opposed to attributes that best serve the intended dosage form. The API attributes ensuring its storage stability under ordinary conditions and those preferred or needed for the target dosage form may not be identical. For example, a highly crystalline API is more stable than a form that is amorphous. This stability and crystallinity is desirable, from the point of view of the ability to reject impurities during the API’s purification and isolation, and its promotion of reasonable storage, shipping and staging conditions. However, if the API has low solubility, and this adversely affects in vivo exposure, the need may arise to look at metastable forms of the API, e.g., stabilized amorphous dispersions or cocrystals, as a compromise form, or to add a processing step to the crystalline API to render it into a metastable form as a drug product intermediate.
There are also certainly instances in early development in which form selection is de-emphasized, such as when the properties (particularly solubility and in vivo absorption) of the API make it amenable to the simplest sorts of early clinical formulations, such as powder in a capsule (PIC) or powder in a bottle (PIB). In many cases, PIC or PIB formulations are neat fills of an API without excipients, so although it is preferable to have a crystalline API for these dosage forms for reasons of enabling API manufacturing and control, more work isn’t always necessary to further enhance the form. Dosages such as PIC or PIB are at an extreme of phase appropriateness, with respect to any adjustments made in order to enable the preparation of these simplest of oral dosages. They are illustrative of the basic formulation development principle of keeping the formulation as simple as possible, only adding complexity as demanded by adequate drug product performance, as dictated by pharmacokinetics and its in vitro surrogates.
Why Should Chemical Development and API Manufacturing Scientists Care About Definition of Solid Form?
The most effective way to perform CMC development is in an integrated fashion, so that there is regular, transparent communication between functions. The requirement for this type of collaboration relates to the paradox stated above, regarding sequencing of preformulation and formulation development activities downstream from initial availability of an API, and the need to try to define a solid form before the impetus for it is fully understood. Often, this is done by characterizing the first API produced as soon as possible, to understand and/or anticipate how the observed properties may affect the dosage form. This drives manipulation of the API solid form, to render it in the most useful form for the end users – the formulators.
Currently, more preformulation assessments are performed as part of chemical development and early API characterization, rather than considering and pursuing it as a discrete activity during formulation development. The preformulation studies actually done at drug product CDMOs tend to function to fill gaps, to complement what has already been done as part of API development and characterization.
Knowledge of the selected dosage form and its route of administration, and how these pertain to API properties allows the API supplier to be more forward-looking and collaborative with their downstream colleagues, rather than siloed. Ultimately, the additional processing necessary to render the API into the most useful form often becomes the responsibility of chemical development and API manufacturing scientists.
Summary
The concept and implementation of API solid form selection is inevitably fluid in the early to middle stages of drug development. This is especially the case when the approach taken is phase-appropriate, where the clinical dosage form is selected on the basis of expediency, in preference to more thorough risk management. Regardless of the extent to which risk is managed in decisions on solid form selection, some manipulation of the API’s form to define it and promote a degree of consistency in its production is critical to the successful development and manufacturing of the initial clinical solid oral dosage form.
The extent of definition and characterization required for an API solid form earlier in the development cycle is a function of its intrinsic properties, as they relate to the requirements of an adequate dosage form. Therefore, the thought and effort necessary to render a given API into a useful form can vary widely from molecule to molecule. In silico and a priori estimations of a molecule’s behavior provides some valuable guidance in form selection. However, in the end, experimental data is what dictates the solid form selected. The “moving goalposts” of phase-appropriateness are compounded by an increase in the proportion of drug candidates having challenging physicochemical properties, as well as the critical input from preclinical and early clinical studies discussed above. This makes decisions on an API’s solid form complex enough that case-by-case, empirical assessments are necessary.
In the end, the need to develop and deliver an appropriate API solid form comes full circle, and lands on the plate of chemical process development and API manufacturing scientists.