Introduction
Integrated chemistry, manufacturing and controls (CMC) development views the entire effort to develop and supply a drug’s dosage form holistically. While there are certainly distinctions between the activities contributing to pharmaceutical development and drug supply, an integrated approach looks for overlap, synergies and dependencies between activities. This approach proceeds with an awareness of the interdependency of component activities, as well as cognizance of activities outside of the realm of CMC that impact and are impacted by CMC strategy. A drug candidate’s molecular properties determine options for preclinical and clinical dosing. However, preclinical and clinical data, once obtained, also drive changes in a drug’s formulation, which can necessitate an adjustment of the physical form of the active pharmaceutical ingredient (API).
This article discusses how chemical process development/API manufacturing can best support preformulation, which is a CMC activity that is pivotal for formulation development and clinical dosage form manufacturing.
The Dynamic Between Chemical Development and Preformulation
While there are many activities that are squarely within either the realm of API development and manufacturing or drug product development and manufacturing, there are certain types of work that bridge these areas. These so-called “gray areas” of CMC development reside within the broad set of activities defined as preformulation. Preformulation is a “critical path” activity in development and manufacturing of the drug product.
Preformulation may be defined as follows:
Laboratory studies to determine characteristics of the API and excipients that may influence formulation, process design and performance.1
The physicochemical characterization of a given drug candidate molecule helps to determine what approaches are available to develop a formulation for its indication and target. Preformulation also has a significant influence on how the final API is generated, isolated, and further processed.
A number of factors compound the ability to obtain consistent, reliable preformulation data:
Obtaining reliable preformulation data is inherently difficult in early development. Initial API batches are usually less well defined, in terms of characterization, than batches produced at later stages of development. This is often complicated by uncertainty about which dosage forms will adequately serve preclinical toxicology and Phase I clinical studies. The target dosage forms for these studies are often in question, and they are likely to be initially conceived as temporary, expedient approaches that are anticipated to be adequate for immediate needs (fit for purpose or phase appropriate). It is increasingly the case that more effort than anticipated is necessary to develop and manufacture these first dosage forms, due to increasing proportions of drug candidate molecules with challenging properties, particularly poor solubility (see below).
Another factor affecting the need to obtain comprehensive preformulation data in a timely fashion is the increasing lack of “traditional” tractability of drug candidates selected and advanced for development. Circa 2015, Aller-Rodriguez et.al.2 cite the following statistics, regarding poorly soluble small molecule drugs:
- They comprise 40% of the 200 top oral drugs marketed in the US and Europe, and 33% of drugs in the USP
- They represent 90% of new chemical entities (NCEs), and 75% of molecules in development
In the period 2010-2015, the FDA approved 150 new drug applications (NDAs) which used enhanced formulation technologies. The currently prevailing (and continually increasing) proportion of these types of drug candidates puts an additional burden on preformulation. Enhanced approaches require that the API’s properties are sufficiently well understood early enough to inform the additional R&D and processing required to develop and manufacture the dosage form. For example, if the decision is made to pursue a spray-dried amorphous dispersion as the drug product intermediate, in order to address poor API solubility and in vivo exposure, a key property of the API to be spray dried is its solubility in volatile organic solvents. Selection of a solvent or solvent system for dissolution of the API to produce the spray drying solution depends on API solubility, as does the spray drying solution physical stability. Seemingly small differences in the purity or degree of crystallinity of the API, or the polymorph of the API, can affect its solubility and the type and volume of solvent necessary to solubilize it.
In addition to the effects of the above two factors, completion of sufficiently thorough preformulation studies is further challenged by compression of development timelines. The duration of an effort from nomination of a candidate to filing of an IND is now often less than 12 months. As a result, many CMC activities are overlapped as aggressively as possible or performed simultaneously. While this addresses the question of speed, it also heightens the risk for errors and poorly informed decisions. It is very hard to be deliberate, systematic and strategic under these circumstances. For example, aggressive sequencing of early API production and toxicology studies consuming the API supply makes it difficult or impossible to render these batches of API into a form that is as tractable as will be necessary for clinical formulation development. Often, the toxicology formulation for INDenabling GLP studies and the clinical formulation differ significantly, but knowledge gained from the development of the preclinical dosage form informs that of the clinical dosage form.
How Can Chemical Development and API Manufacturing Help to Address the Above Issues?
In a short review, Palucki, et.al.3 stress the criticality of identifying a suitable solid state phase of a drug candidate molecule, and they define what is “suitable,” from a pharmaceutical scientist’s point of view:
“…a stable, reproducible crystalline phase in which the inherent physical properties are amenable for use in a conventional formulation.”
The authors suggest finding and producing a well-defined crystalline form of the drug candidate as early as possible. In fact, producing an API with suitable solid state properties, as defined above, is among the most impactful deliverables from chemical development and manufacturing. It is worth noting that not all stable crystalline phases are amenable for use in a conventional formulation, e.g., those of poorly soluble molecules, if performance (i.e., dissolution rate as a surrogate for bioavailability) is taken into consideration. However, in these cases, the aim is to take the stable, crystalline API and then render it into a drug product intermediate (amorphous dispersion, nanoparticles, hot melt extrusion granules, etc.) that is amenable for use in a conventional formulation, i.e., capsule filling or tablet compression.
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Considering the challenges to obtaining meaningful preformulation data discussed above, below are suggestions for how those focused on chemical development and API manufacturing can most effectively support preformulation.
Enable the Ability to Obtain Reliable Preformulation Data at an Early Stage of Development
Every batch produced that is intended for downstream use needs to be characterized to a sufficient extent. At a minimum, in addition to purity and impurity profile by HPLC and NMR, this would include melting point by differential scanning calorimetry (DSC), crystallinity by x-ray powder diffraction (XRPD), and volatile residues, including those from solvates and hydrates, by thermogravimetric analysis (TGA). The extent of analytical involvement will be greater at even the earliest stages of API process development. Working analytical methods need to be developed and implemented sooner, and there is an increased characterization workload, beyond HPLC purity and impurity detection and quantitation. More in depth solid state characterization – crystallinity, polymorphism, thermal properties, particle size distribution (PSD) becomes a necessary aspect of characterization as soon as material is produced on a meaningful scale, to supply downstream preformulation and formulation studies that are pivotal to selection and manufacturing of a first-in-humans clinical dosage form.
Focus on the Delivery of a Well-Defined, Chemically and Physically Stable Crystalline Solid for More In-Depth Preformulation and Formulation Development
A disconnect often exists between the solid state characterization data obtained and its implementation in the development of a process to isolate the target form of the API. This gap needs to be bridged sooner, so that as many early API batches produced as possible leverage the solid state characterization data in order to isolate a useful final form.
The interaction between preformulation and formulation scientists with those producing API for evaluation must be dynamic. Based on an early assessment of batch-to-batch variability, it is worthwhile to strive to achieve consistency in batch properties as early as possible (the tox batch is likely to be an exception, since impurities need to be present in sufficient quantity to be qualified). Feedback should be prompt enough, if possible, to allow production of representative API on the scale required to supply the critical work leading to manufacturing of drug product clinical trial material (CTM) – preformulation, dosage form prototype preparation and evaluation, analytical method qualification, and the demonstration/pilot batch production, analysis and stability study.
Early batches of API can serve different purposes. As discussed above, samples of non-GMP API for preformulation and formulation development need to be representative of the anticipated purity and impurity profile of the API to be used for manufacturing of the dosage form supplied for clinical trials, or clinical trial material (CTM). If this is not the case, the properties and performance of dosage form prototypes produced risk not being predictive or supportive of the properties and performance of CTM. In contrast, the batch of API used for GLP toxicology studies needs to have a sufficient number of impurities and impurity levels to allow their qualification, in order to enable setting of specifications for the GMP batch used to supply clinical drug manufacturing. So, either a portion of the API tox batch needs to be further purified, isolated and characterized for use in preformulation and formulation development, or a separate demonstration batch needs to be produced specifically for this purpose.
Address Timeline Compression as Strategically and Judiciously as Possible
Timeline pressures exaggerate the effects of moving quickly without prioritization of activities. One example is the rapid production of multiple early batches of API that are incompletely characterized or having variable compositions and properties. A lack of batch-tobatch API consistency, or at the very least, a good understanding of the differences between the batches, makes preformulation and formulation development much more difficult and time consuming. Consistency of the properties of API used enables the most meaningful comparison of the effects of varying the composition of excipients and how they are combined and further processed on the stability, manufacturability, and performance of each dosage form prototype. If multiple batches of API are used for preformulation, formulation development and prototype preparation (as is often the case), high batch-to-batch variability of the API’s properties confounds the ability to make such comparisons, and may result in poorly informed decisions at crucial junctures.
Summary
The issues presented in this article are common to all organizations involved in CMC development, regardless of size or resources. However, in the entrepreneurial startup sector, resources, including cash, are the most limited, as is time. The path taken to enhance the perceived and actual value of the drug candidate being developed starts with a direct, prompt assessment of the molecule’s properties, and actions taken based on this knowledge. API manufacturers can leverage the information from this assessment and begin to produce early batches that have consistent, tractable properties. The future potential of the drug candidate, as well as issues to address as progress is made to later stages of development, depend critically on these assessments.
References
- TM Jones, Preformulation Studies, in Drug Discovery Series No. 64, Pharmaceutical Formulation: The Science and Technology of Dosage Forms, The Royal Society of Chemistry, 2018, pp. 1-20
- Aller-Rodriguez, et.al., Strategies for formulating and delivering poorly water-soluble drugs, J Drug Delivery and Technology, 2015, 30, Part B, December, 342
- Palucki, M, et.al., Strategies at the Interface of Drug Discovery and Early Development: Early Optimization of Solid State Phase and Preclinical Toxicology Formulations for Potential Drug Candidates, J. Med. Chem., 2010, 53, 5897