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Liquid formulations in hard-shell capsules or softgels are becoming a popular option for HPAPIs because of advantages such as improved safety and lower risk of potential exposure and product cross contamination.
Over the past decade, there has been an increasing number of high-potency APIs (HPAPIs) as drug-development activities continue to shift towards more targeted therapies. Although they form a relatively small portion of the API market, HPAPIs are thought to be one of the fastest growing segments in the pharmaceutical industry. The global HPAPI market is expected to hit $25.86 billion by 2022, with oncology being the primary driver for this increasing demand (1).
HPAPIs are known for their ability to target diseases more selectively in smaller doses, hence, reducing the risk of unwanted side effects in patients. “As the patent cliff continues and blockbusters become less frequent, there is more focus on developing targeted treatments for smaller patient populations,” notes Aileen Ruff, vice-president, Business Unit Strategy and Marketing, Advanced Delivery Technologies, Catalent. “For example, the oncology market is expected to exceed $100 billion by 2020 (2), and anti-cancer development activity is trending upwards across all clinical phases. Many of these oncology drugs are considered highly potent or cytotoxic. Within and beyond the oncology space, antibody-drug conjugates (ADCs)--which consist of antibodies conjugated with a small-molecule toxin--are also on the rise for more targeted therapies, with the market estimated at $396 million in 2013 and to grow to nearly $2.8 billion by 2018, registering a five-year compound annual growth rate of 48.1% from 2013 to 2018 (3),” she says.
Ruff also points out that poorly soluble compounds, which now represent 70-90% of the development pipeline (4), are often classified as highly potent. “With this increase in potent compounds, there is a corresponding increase in emphasis on accurate potent classifications and containment strategies to protect manufacturing personnel and patients,” she adds.
Ruff explains that compounds are typically classified for high-potency handling requirements based on an occupational exposure limit (OEL) that is assessed through various means such as toxicological data, risk phrases, pharmacological/dosage data, analogy, and in-silico modelling data.
"Consulting firm, Safebridge Consultants, Inc., has been involved in developing these types of classification systems, but many companies also work with local toxicologists and consultants to design a customized system for their business,” she observes. “Catalent, in partnership with Safebridge, uses a four-band system, with Category 3 (potent) defined as an OEL between 1 and 10 μg/m3 and Category 4 (highly potent) as less than 1 μg/m3.” According to Ruff, if toxicology data are not available, a compound may default to potent status in one of these categories. “While these classifications provide initial guidance on containment requirements, each compound should be evaluated on a case-by-case basis,” she says. “For example, in some cases, such as hormones, a fully segregated facility or suite may be required. In other cases, engineering controls, flexible containment, and/or personal protective equipment (PPE) may be sufficient.”
Formulation and processing considerations
HPAPIs require specialized facilities and equipment to ensure that both personnel and the environment are protected from exposure. In terms of formulation and processing, there are several considerations in the development of a dosage form containing low concentrations of a highly potent drug substance, highlights Robert Harris, chief technical officer at Juniper Pharma Services. “The aim, first of all, is to make the unit dose as small as possible so that the ratio of drug to excipients in the formulation is maximized and more importantly, it helps achieve satisfactory drug uniformity and consistency of drug content.”
For tablets containing 1-5 mg of active, Harris notes satisfactory content uniformity can be achieved by blending the powders followed by direct compression, or by serial dilution of the API with an excipient (i.e., trituration) and sieving the powder blend through a suitable mesh screen. He adds that the choice of excipients is also a crucial factor in the formulation and process development of a homogeneous and segregation-free, low-dose tablet. The use of partially pre-gelatinized starch as a filler, for example, has been shown to achieve better drug uniformity compared with other commonly used fillers, says Harris.
For tablets containing less than 1 mg of active, the preferred approach, according to Harris, is to pre-dissolve the required amount of API in a suitable solvent and spray the drug solution onto a carrier excipient such as lactose or microcrystalline cellulose, either using high-shear granulation or fluid-bed granulation. The high-shear granulators and single-pot processors, such as IMA Pharma’s Roto Cube, allow the entire granulation process--from loading of raw materials to discharge of dry granules--to be carried out in a single, contained bowl. “This approach is particularly suited to HPAPIs because contact between product, personnel, and the environment is eliminated. The spraying, granulating, and drying activities all take place within a single, contained bowl,” explains Harris. He recommends applying a coating to tablets containing HPAPI, adding that the coating will help prevent dust generation from attrition of the tablet cores during handling.
Liquid formulations in hard-shell capsules or softgels are becoming a popular option for HPAPIs because of the advantages they offer. “These formulations have long been recognized as one of the most successful drug-delivery technologies for challenging compounds,” observes Kevin Li, product manager, Pharmaceutical Softgel, Catalent. “In addition, softgel technologies have a proven commercial record of bringing potent drugs to market, such as hormones, vitamin D analogues, and other cytotoxic compounds.”
Unlike tablets and capsules that involve powder production, liquid formulations do not present issues such as dust generation, and the hazards of product cross-contamination are minimized. Moreover, the processing of liquid formulations is more convenient and does not require complex and expensive engineering controls. According to Harris, the highest risk is during the initial powder-handling stages (i.e., during dispensing of the drug and when it is being added to an aliquot of the vehicle). “These steps are typically performed in an isolator or containment hood,” he says.
Article DetailsPharmaceutical Technology
Vol. 40, No. 1
When referring to this article, please cite it as A. Siew, "Liquid Encapsulation for HPAPIs," Pharmaceutical Technology 40 (1) 2016.