Jeff Williamson is director of Product Development at Lonza.

Jeff Williamson

Pharmaceutical companies are faced with the routine challenge of screening and advancing their active pharmaceutical ingredients (APIs) through a drug product lifecycle. Early investments in the APIs are often costly. Identifying viable candidates for clinical dosage early and eliminating less viable or non-viable candidates are, therefore, crucial in meeting aggressive project timelines. These new APIs have key risk areas that dictate understanding of physicochemical properties when the synthesis process is in early stages. Physical and environmental effects can define these compounds as “challenging” as they move from drug substance manufacturing into drug product development, and therefore, they require additional processing steps or control measures to promote the API into a viable dosage form. Environmental effects such as hygroscopicity, light sensitivity, and the need for containment can pose some initial risks as the API is introduced into the development pathway. 

	Specific processing steps, specialized capsules, and micro-dosing encapsulation techniques are available to address and mitigate environmental and physicochemical challenges, streamline development processes, and accelerate clinical timelines. Precision powder micro-dosing systems facilitate the rapid manufacture of API-in-capsule (AIC) drug products that can be expediently dosed in oral or pulmonary administration routes. These AIC dosage form presentations can reduce API consumption and early-stage evaluation time (Phase I and II) by eliminating the need for specific formulation steps, such as excipient compatibility testing. AIC studies have become a beneficial evaluation technique for highly potent, low-dose applications where accurate micro-dosing is required. 

	Preformulation: Setting the tone for drug products

	Drug substance manufacturers have an exhaustive list of challenges in synthesizing new compounds to bring forth the purest, most stable candidate. Addressing issues such as “lot-to-lot variability” and “scale factor” can be a daunting task for product development teams as they start down the path of evaluating and advancing candidate compounds. Although mitigated by experimental designs, APIs may gain more defined physical risk factors, such as changes in particle size and flow properties, as they progress through the development process, which can have a profound effect on how the dosage form will be developed. 

	A significant number of steps go into both API synthesis and drug product development, and a full understanding of the API characterization is a crucial starting point. It is never too early to investigate physicochemical properties of new compounds, and the data from initial screening is the source for a number of debates between synthesis chemists and drug product development teams. These initial discussions and data should take into consideration the dosing range, potency, hygroscopicity, solubility, flow properties, moisture/light/oxygen sensitivity, and other physicochemical assessments that can affect drug product design and development. Preformulation typically entails x-ray powder diffraction to detect polymorphs, pH solubility profiling, understanding of hygroscopicity through vapor sorption analyses, and particle morphology by scanning electron microscopy and sizing through laser diffraction, allowing design teams to determine if the API is crystalline or amorphous with good or poor flow characteristics. At this stage, product development teams have more information to define the initial target product profile and are challenged with defining an expedient path to a final dosage form. To expedite the program, the API could potentially be introduced into an accelerated pathway by dispensing it solely into a capsule for dosing while other conventional development action steps are in planning stages.

	API in capsule: Micro-dosing systems and approach 

	Micro-dosing can prove essential for accelerating drug product development and quickly introducing a dosage form into various clinical phases. Micro-dosing is essentially the precision weighing and dispensing of powders into capsules using various equipment platforms or techniques. Micro-dosing has become more prevalent with the rising number of highly potent candidate compounds for oncology and other indications. 

	APIs (or blends and other formulations) may be directly encapsulated to accelerate the identification of viable prototypes and move them expediently into clinical studies. Depending on the material physical attributes, API doses as low as 100 micrograms can be encapsulated with minimal variance in weight. In a typical drug product project plan, there are demands on API quantities for analytical method development efforts, excipient compatibility studies, and initial experimental evaluations of formulation and process. API availability can be quite limited in these early stages of evaluation and screening, so an efficient AIC approach can prove crucial in providing a “jump start” to dosage form development, eliminating the need for excipient compatibility studies, and minimizing the usage of APIs. For blends and other formulations, some adjustments may be required in a development program for dose ranging studies. Depending on the physical properties of the powder blends, micro-dosing may be used to provide multiple strengths using the same formulation. 

	The neat API or a powder blend can be encapsulated, used for analytical assessments, and even placed on stability studies while other approaches of drug product development are conducted in parallel or in sequence to support a particular program. More importantly, if the program requires multiple strengths for pre-clinical or clinical dosing, an AIC approach provides the ability to dispense the powders using exactly the same precision weighing process. 

	Xcelodose Precision Powder Micro-Dosing Systems (Lonza) have been widely adopted for early phase AIC studies. 

depicts the operating principles for this technology where powder is dispensed through a mesh screen at the base of a dispense head based on precise tapping technology. Powder is released through the screen by the tapping action of a solenoid on the dispense arm that cradles the dispense head. Parameters defining the tapping process can be tightly controlled and include dispense head type, mesh hole size, number of holes, tapping frequency, and desired dispense rate. These parameters are selected based on the physical characteristics of the material and desired dose. 

	The system accurately controls capsule dosing by continuously monitoring the net weight being dispensed in real-time and automatically adjusting the tapping rate during dispensing. As the weight approaches the target value, the rate of powder delivery is reduced and then eventually stopped when in the fill weight range. Once the dispensing operation is complete, the systems have the ability to recognize and reject units that are under or over weight based on the predetermined fill weight range. These systems also provide comprehensive documentation for the filling operation, including individual weights of each capsule produced in the run. 

	Once the initial preformulation assessments of the API have been performed, and the route of administration is confirmed, decisions can be made for the capsule composition and size. Most of the capsule presentations used for micro-dosing range from Size 4 up to Size 00. Particle size, powder densities, and any necessary salt correction factors further define the size of capsules, while hygroscopicity, chemical structure, and stability of the compounds may define the capsule composition. There are a wide range of capsule presentations available for use in micro-dosing, geared to accelerating drug product development. The conventional approach has been using gelatin capsule shells; however, there are other encapsulation options when formulators are faced with challenges, such as moisture-sensitive APIs or having to encapsulate or store under lower humidity conditions. 

	Alternative polymers have been introduced into capsules for several technical and market reasons, for example, to better avoid unwanted impurities due to moisture ingress with hygroscopic APIs and to avoid brittleness from conventional gelatin capsule shells. Hypromellose and hydroxypropylmethylcellulose (HPMC) capsules (e.g., Capsugel VCaps Plus) have evolved to give drug product formulators more flexibility and stability beyond gelatin presentations-they contain less water, eliminate moisture-driven impurity concerns from the shells, and can withstand lower humidity conditions for encapsulation. Capsules have been used as part of pulmonary delivery devices, which have specific requirements that influence product design, especially because very small amounts of APIs or blends are introduced into them. HPMC capsules are, therefore, typically the preferred capsule for dry powder inhalation (DPI) applications due to efficient capsule clearance upon actuation in DPI devices. 

	Not all APIs are intended for immediate release for performance reasons, such as likely instability in acidic conditions or projection of improved absorption rate further in the gastrointestinal tract. Early formulation and process development of enteric delivery or delayed release dosage forms can add significant development time due to the required coating steps to achieve this functionality. Capsules have been engineered with suitable enteric polymers (e.g., Vcaps Enteric) in the actual shell composition, allowing delayed release or enteric protection of the contents without having to employ time-consuming coating processes. These intrinsically enteric capsules can be readily used in AIC approaches for preclinical and clinical assessments.

	Case studies of micro-dosing applications

In a representative case study, the challenge presented was an HPAPI, low-dose application for initial clinical presentation on an aggressive timeline. The target dose for the clinical program was 0.1-mg fill weight into a size 1 capsule. Several fill evaluations were performed under containment to determine the appropriate dispensing head, tapping frequency, and other parameters for a reasonable yield. Through early experimental evaluations, the parameters were identified to produce capsules on the small-scale Xcelodose 120S and transferred to the higher capacity Xcelodose 600S for GMP production. The yield for this operation was only 46%, which was expected as the fill weight was exceptionally low, though overage was produced to meet the desired quantity with minimal loss of API. The clinical delivery date (i.e., overall program from preliminary evaluations to clinical release dosage form in three months) was met.

Micro-dosing is not only geared towards neat API, though this is certainly the primary application. The technique is also used to introduce blends into capsules when necessary. Using this approach can be tricky because the tapping mechanics and gravity fill can introduce blend segregation, leaving analytical teams chasing a content uniformity issue during testing. In a representative case study, the challenge presented was to provide a pediatric dose of 5 mg using a current formulated capsule of 30 mg strength with a lower fill weight initially. Once again, the timeline challenges of this “one-time” batch did not warrant reformulation and additional stability studies. Using Xcelodose technology, the capsules were produced and tested to ensure uniformity of dosage unit to meet the clinical delivery date. The additional reformulated pediatric capsule development timeline was reduced by an estimated four to six months. 

	In an additional and more challenging “API blend” case study, a comparator study was to be conducted with a commercially available immediate release tablet versus a new API. The problem was that the tablets were a much higher strength than what was needed. To address the need, tablets were actually milled to create a powder blend and filled using an Xcelodose system to the desired strength. The capsules met acceptance criteria for assay and content uniformity and progressed to the clinical dosing.

Micro-dosing can be used for DPI programs as well, as previously mentioned. Particle sizing is typically key for a DPI delivery system, and specialized DPI capsules are often employed to provide optimized capsule clearance. Particle engineering is typically required for DPI applications to ensure an average particle size in the 2.5–3 micron range and a tight particle size distribution. Spray drying is increasingly being used to achieve the required particle size distribution and morphology for effective DPI therapeutic effect. Employing encapsulation of spray-dried API using micro-dosing can rapidly advance dosage form development, using the same filling principles across multiple dosing ranges (see 

. A number of technological advancements have been made with micro-dosing applications at commercial scale, which facilitate efficient late-stage clinical and/or commercial scale up. Harro Höfliger, for example, has developed high-speed capabilities that are able to produce much larger quantities to support late stage clinical and even potential commercial endeavors. The equipment has a different approach than the Xcelodose gravity-fed system but can be readily scaled from Xcelodose-based Phase I–II studies. Such systems allow for rapid-to-market approaches leveraging precision micro-dosing technology for encapsulated API or blends.

	Harro fully automated devices can micro-dose powders using dosators and vacuum drums depending on the fill weight of the capsules. The dosator change parts dispense powders from 5 mg or more into capsule shells, while vacuum and membrane presentations can dispense powders into capsules as low as 0.5mmg/unit. Specifically, the Harro Modu-C MS drum filler uses custom designed drums with precision drilled holes and vacuum systems to produce low-impact forces and powders to introduce them into capsules at high rates of speed. These advancements have resulted in the ability to produce up to 72,000 capsules per hour based on the technology and powder properties. Not only is application speed increased, the quality of the micro-dosing is maintained by a 100% in-line fill mass monitoring and rejection, thus facilitating an overall rapid commercialization for AIC applications.

	Using AIC approaches, pharmaceutical companies have the ability to increase speed to clinic, quickly assess their new assets, and remain cost conscious to investments in development of formulated dosage forms. AIC studies start with API characterization, from which an understanding of the API morphology, solubility, and other key attributes define the drug product design and decision flow diagram. Choosing the right capsule composition and size, employing micro-dosing encapsulation techniques, and leveraging scale-up best practices can help progress these new APIs quickly from concept to the later stage clinical/commercial drug products.

	Jeff Williamson is director of Product Development at Lonza.

	When referring to this article, please cite it as J. Williamson, "Application of API-in-Capsule Best Practices to Accelerate Drug Product Development," 

Pharmaceutical Technology APIs, Excipients, & Manufacturing 

Articles

API-in-capsule approaches enable pharmaceutical companies to quickly assess new drug candidates with reduced API consumption and to increase speed to clinic.