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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Advances in solid and liquid formulation techniques are providing more options.
Advances in solid and liquid formulation techniques are providing more options.
The number and potency of highly potent drug substances are increasing. Formulators working with highly potent APIs (HPAPIs) are increasingly challenged to ensure the safety of both personnel during development and manufacturing and healthcare workers and patients when using the final drug products. That means addressing potential issues with the homogeneity of the formulation, drug content analysis, and proper handling. Advances in microparticle, capsule and syringe technologies, analytical methods, and containment systems are widening the safe formulating options for HPAPIs.
Safety is top priority
Safety should always be at the forefront of any research and manufacturing operation, according to Thomas R. Tice, senior director of global technical marketing at Evonik Pharma Polymers & Services. For HPAPIs and their pharmaceutical dosage forms, Tice notes that research and manufacturing operations must take place in facilities built on design requirements specific to operations involving potent compounds. It is also necessary to use appropriate personal protective equipment (PPE), train staff, and follow established policies as well as appropriate standard operating procedures to protect workers, contractors, and the community. Bryan Knox, senior director of pharmaceutics with Pharmatek, adds that as the number of potent compounds increases, manufacturing practices are increasingly moving away from reliance on PPE alone, with current practices focusing more on containment at the source to prevent operator exposure. To aid this process, many equipment providers now offer options for containment within the design of the equipment.
“When Pharmatek built its facility specifically for the handling of highly potent compounds in 2007, we chose to invest in a dedicated facility for the development and manufacture of highly potent compounds. The facility utilizes a combination of facility design features, isolator technology, and PPE to prevent cross contamination and to ensure the safety of personnel,” says Knox. Evonik, as a company that offers HPAPI development and manufacturing services for oral and parenteral dosage forms, has developed a comprehensive safety assessment strategy, invested in containment including isolators and dedicated rooms, and adopted process-specific engineering and procedural controls, thus allowing the safe handling of potent compounds according to specific operations, Tice told Pharmaceutical Technology.
Formulating low dose HPAPIs
Although highly potent, HPAPIs do not require specific dosage forms. Any formulation strategy for HPAPIs should, in addition to addressing potential issues with proper handling to ensure personnel safety, consider the homogeneity of the formulation and the drug content analysis. “Because unit doses for highly potent drugs typically contain very small quantities of API, ensuring blend and content uniformity and developing accurate analytical methods are particular challenges for low-dose drugs,” says Knox.
There is a precedence in the industry to put highly potent drugs in solution to minimize exposure risk, but with proper environmental, health, and safety systems in place, formulating powders into capsules or tablets is often preferred, according to Knox. Consideration must also be given to the ability to produce a homogeneous product. “Understanding the segregation potential of low-dose drug formulations is an important aspect, because segregation can lead to poor blend and content uniformity, which can affect the manufacturability of the product,” he explains. Assessment of potential segregation should occur during prototype development and initial process development, particularly when using automated equipment where vibration plays a role. Knox also recommends the use of design of experiment (DOE) studies with factorial design to define the design space and avoid potential segregation due to low-dose requirements.
HPAPI formulation processes must be robust and scalable. It is advantageous to have processes that can be scaled down for formulation development such that smaller-scale process equipment can fit into smaller-scale containment and still make formulations representative of what can be made in larger commercial-scale batches, according to Tice. He adds that it is also important to use equipment that can be taken apart and cleaned.
As importantly, appropriate analytical methods with a high level of sensitivity must be identified for the evaluation of low-dose/highly potent drug formulations, regardless of the form of the product. Both excipients and drug product matrices can interfere with detection of HPAPIs due to the high concentration of excipients relative to active ingredient in analytical samples, according to Knox. He notes that ultra-high pressure liquid chromatography (UHPLC) is often preferred over conventional high-performance liquid chromatography (HPLC) for the analysis of highly potent compounds due to its increased sensitivity, which is increased approximately 10 times.
For injectable products, Knox adds that it is crucial to understand the interaction of the packaging contact surfaces with the drug product in solution. In addition, recovery studies should be performed to ensure that the delivered dosage is within acceptable ranges.
Unique delivery systems
While HPAPIs do not have special drug delivery requirements, the dosage form chosen must ultimately address patient safety, compliance, clinical performance, and manufacturability, according to Knox. There are, however, certain dosage forms that provide some advantages because they are more suitable for the lower drug loads associated with HPAPIs.
“Liquid-filled formulations in either soft-gel or hard-shell capsules offer an important oral dosage strategy for highly potent drugs that can cause homogeneity issues when formulated as powders into capsules or tablets,” observes Knox. The technology also has the benefit of being a safer process than the production of capsules and tablets using powders, because dust generation is not an issue.
To obtain capsules and tablets of HPAPIs, fluidized-bed coating technology (Wurster coating), which involves spraying of an HPAPI solution onto nonpareil beads that can then be filled into capsules or pressed into tablets, is an attractive alternative, according to Knox. Mini-tabs can also be used for multiparticulate HPAPI systems where single- or multi-layered coatings contain a functional coat with the active ingredient and a seal coat.
Extended-release parenteral formulations are also well suited for HPAPIs, according to Tice. He specifically notes that extended-release, bioabsorbable poly(lactide-co-clycolide) (PLG) microparticles reduce side effects, improve therapeutic efficacy, and increase patient compliance. “Like other parenteral formulations, the administration of suspensions of injectable microparticles is limited by the injection volume. HPAPIs are ideal for PLG microparticles because they are dosed at microgram and milligram quantities, which means less API (less mass) is needed to meet the injection volume requirements. In turn, HPAPIs can be delivered from PLG microparticles for weeks and months following a single administration,” he explains. These formulation advantages also apply to extended-release, rod-shaped injectable PLG implants.
Given the safety issues and growing number of options for low-dosage drugs, choosing the right dosage form for an HPAPI can be challenging. Pharmatek takes a data-driven approach to this decision, according to Knox. “Our goal is to look at the least complex dosage-form options first, because conventional approaches save on development time and costs.” Success can be obtained with dry blending a formulation for filling capsules or making tablets at drug loads in the 0.01% w/w range, depending on the API properties. Dosage strengths at 10 µg or lower often require special considerations, such as oral solutions, liquid-filled capsules, or granulation and coating techniques with the active ingredient dissolved in a spray solution.
New encapsulation technologies
Evonik has developed the FormEZE technology, an improved microencapsulation process for the manufacture of PLG microparticles. The continuous, closed-equipment process involves an emulsion-based extraction and affords 20% higher yields with less post-process handling, according to Tice. “This process shortens unit operations time, reduces waste, and can be scaled down from commercial-size manufacturing, all advantages when working with HPAPIs,” he says. The emulsion is generated by a packed-bed column that produces a defined, narrow size distribution of microparticles that allows the use of smaller-diameter needles and affords the administration of more microparticles for drug delivery over longer durations.
Another benefit is that the PLG microparticles made using the FormEZE technology are much easier to administer by injection and safer to use, according to Tice. Because of the size distribution of the microparticles and the assurance of no large particles or agglomerates, they do not clog needles during injection. “When injection procedures are less prone to complications, particularly when HPAPIs are involved, improved safety to the patient and the healthcare worker is achieved,” he comments.
Improvements in capsule availability and manufacturing equipment for liquid-filled hard shells are also of note, according to Knox. “The availability of both gelatin and hydroxypropyl methyl cellulose capsules designed specifically for liquid formulations of HPAPIs and micro-spray sealing and banding technologies have enabled greater application of this delivery technology for highly potent compounds. Opportunities for liquid delivery outside of softgels, which can be an expensive technology to invest in during the early stages of development, represent a real advantage,” he states. In addition, liquid-filled hard shell encapsulation machines now have faster filling and sealing speeds and provide more in-line process checking (temperature, speed, fill weight), as well as automatic in-line feedback with process analytical technology.
About the Author
Cynthia A. Challener is a contributing editor at Pharmaceutical Technology.