It is currently estimated that over 25% of all drug products in development have highly potent or highly toxic active pharmaceutical ingredients (API) and require some form of specialized handling. In oncology this figure is likely closer to 70%.1 These types of products represent a growing sector of investment in the pharmaceutical industry, with the market value from existing and new product launches expected to double between 2018 and 2025.2
New therapeutic treatments are frequently targeted to act locally at the site of therapy, which can reduce side effects and result in significantly lower dosages required. While these treatments offer huge benefits to the patient, the pharmaceutical industry faces the challenge of developing these API into safe and effective low-dose products – including consistently producing very low-dose products, e.g., microgram doses – while maintaining safety for operators during processing. Encapsulated liquid-based products offer a proven approach to overcome many of the challenges associated with the development, scale-up and commercial manufacturing for these highly potent API (HPAPI), from safer handling to producing more accurately dosed and homogeneous formulations for low-dose products.3
Liquid-Filled Capsules
Liquid-fill technology is not new, and it benefits from a long history of continued innovation and market precedence. The original softgel patent dates from 1834, with the current process evolving from that created by RP Scherer in the 1930s. Hard-shell liquid-fill capsules were a further innovation from Cuine et al of the University of Strasbourg, producing several papers on the potential advantages of this technology in the 1970s. In the early 1980s, several additional publications from other authors presented the potential advantages for content uniformity and reduction of airborne contamination.4
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While commercially available products in the consumer health and nutrition sector were already utilizing softgel technology in the 1980s, key milestones for the technology in both hard and soft capsules in the pharmaceutical segment happened later that decade with the commercial approval and commercialisation of Vancocin® capsules. This product demonstrated the potential to produce an oral dosage form with a sensitive molecule that had been challenging for more traditional product approaches. Sandimmune’s® position as the first commercially successful lipid-based bioavailability-enhanced formulation further demonstrated the potential benefits of liquid-based technology (the product, containing the active ingredient cyclosporine, also represented a breakthrough in transplant management). A number of new products have since been launched using lipid-based formulations with softgel or liquid-filled hard capsule technology to address the continuing challenge of poor solubility.
Although liquid-fill capsule products continue to be seen principally as a mechanism to increase bioavailability for poorly soluble drugs;5 they are also increasingly evaluated to address lowdose HPAPI challenges.4 The technology allows the incorporation of an API powder into a liquid formulation as either a solution or as a suspended solid, which then removes the risk of subsequent airborne powder during manufacture and can also improve homogeneity for low-dose products. Market precedence is firmly established, as is the technology required for developing, scaling and manufacturing liquid-based capsule products with challenging, potent or toxic API. A few examples of marketed liquid-filled products with these challenging compounds in both hard capsule and softgel formats include hormones or related compounds, like promestriene, progesterone or dutasteride, vitamin A analogues such as isotretinoin and Vitamin D analogues like colecalciferol and ergocalciferol. Currently, it is estimated that 40% of liquid-filled hard capsule products in development utilize HPAPI.6
Benefits of Liquid-Fill Capsules
Liquid-fill capsules can provide benefits in terms of quickly scaling up a product to commercial manufacturing volumes, as the four-step process of liquid filling – dispense, mix, fill and seal – can be scaled up more rapidly than other types of formulation processes, primarily due to most of the process being independent of scale. While liquid filling is not without its challenges during scale-up, it provides an option for companies looking to generate high-potency oral products with a relatively straightforward process of reaching commercial scale. As such, the technology is utilized as a rapid product development and screening tool for promising compounds with poor solubility, specialized handling requirements and other formulation challenges.
Liquid-fill capsules offer a number of specific benefits for manufacturers developing and scaling up low-dose HPAPI formulations.7 First, liquid filling can provide perfect homogeneity for low-dose products, through the generation of a solution. Where occasionally this is not possible, enhanced homogeneity can still often be achieved, as the high shear mixers utilized are efficient at rapidly de-agglomerating and dispersing powder into a homogenous dispersion. Further, particle size reduction can be achieved as part of an in situ process, integrating a bead mill recirculating through the mixing vessel.
The liquid-fill process can also offer safer and more efficient handling – by incorporating the powder API into the liquid excipients, the risk from exposure of powder handling for further manipulation and processing is removed. This approach ensures that operators are under no risk of airborne powder exposure through the majority of the manufacturing process. The liquids can also be readily pumped between processes, ensuring efficient handling is retained.
A third benefit is that liquid-fill capsule products do not require reformulation due to changes in the production scale, as the mechanisms employed during manufacture of development batches are almost identical to those at full scale. Parallel filling heads and automated capsule manipulation provide the increased speed required to produce commercial volumes without the need for product or process change.
Finally, the four-step process for liquid filling contains a minimal number of processing steps to support rapid development and scale-up compared to equivalent solid oral technologies, such as an eight-step wet granulation process: dispense, dry blend, wet mass, sieve, dry, screen, granulate, compress. Streamlined processing is increasingly critical for meeting the industry’s need for simplified compound screening, rapid first-in-human studies and accelerated timelines to market.
The Four-Step Hard Capsule Liquid-Filling Process
Step One: Dispense
The first step of developing and commercializing a liquid-fill product with a highly potent API formulation is to isolate and dispense the active ingredient in appropriate amounts. Handling highly potent or toxic powder is a challenge at any scale, and in development there are many ways to contain small quantities of API while they are being evaluated. As the arriving container starts to get larger during scale-up, control may become less standard and it often becomes necessary to ensure that adaptable containment can be used. During development this may be as simple as having off-the-shelf isolators that the small containers and equipment can be moved into for the operations to take place.
However, during scale-up, the weight of materials for manual handling and physical constraints of entry for larger containers prevent usage of this type of isolator. Unless an appropriate isolator is available that already matches the containers and scale, it is not cost-effective to have a fixed isolator for irregular manufacturing. Two ways to approach this challenge include:
- The design and implementation of a permanent hard isolator that can cope with many different container sizes and types;
- The use of flexible isolators, allowing a huge range of options to deal with containers and processes, which are not routine, at a fraction of the cost of building or modifying a hard isolator.
Both approaches can be qualified to similar levels for short-term occupational exposure, but the hard isolator must be verifiably cleaned before re-use. In contrast, the flexible isolator is disposed of at the end of use, with its relatively short lifespan offsetting the need to both clean and verify cleanliness.
Step Two: Mix
The next stage of the process requires transferring the dispensed material into the mixing vessel and ensuring it is homogeneously mixed. This mixing depends on whether the API is solubilized in the excipients or is suspended in them, and during scale-up the ability to transfer the powder into the mixer becomes a significant control factor alongside the creation and maintenance of homogeneity.
When a solution is generated it is critical to understand if time and energy are required to dissolve the API. For a suspension formulation, homogeneous dispersion and stability of the dispersion are important to characterize. During small-scale manufacturing and development, this process can be fully contained within an isolator, at least for the first stage of wetting down any powder materials with liquid excipients. Often this is conducted as part of the same process as dispensing. Subsequent dilution for these small-scale processes can then be conducted in a less contained environment, as the initial liquid addition and mixing has removed the risk of dust generation. Visual assessment of solubilization and dispersion usually provides the first check of homogeneity, followed by analytical assessment over a period of time to check how quickly homogeneity is achieved and how readily it is maintained.
During scale-up to commercialization, the liquid-fill formulation provides several advantages for powder transference. Generally, the process starts with some, or all, of the liquid excipient in the mixing vessel. All liquids are degassed under vacuum to prevent bubbles from generating during the filling process. This vacuum over the liquid presents a means of transferring the powder from a dispensing isolator, which has a valve pipe connected directly to the underside of the mixer so it can be directly sucked into the underside of the liquid while mixing. This prevents any form of “blooming,” where the API would be dispersed over the surface of the vessel; instead the API is entrapped within the liquid and quickly wet. On the rare occasion when the powder properties preclude this type of transfer there are alternatives that can be used, such as direct powder pumps or pre-wetting the powder with liquid excipient and transferring the concentrated solution or slurry.
Once compounding in the mixer, several variables can affect the process, including homogeneity of solution/suspension, particle size of a suspended powder, viscosity of the mixture, moisture content and thermal degradation rate of the components. Liquid-fill products often utilize jacketed vessels as mixers, with heating and cooling, which are appropriate for vacuum degassing and contain both high shear mixer heads and paddle type agitator stirrers. If oxidation is a risk, nitrogen can be introduced into the mixing vessel at the end of the vacuum application, rather than air, to bring it back to ambient pressure.
Temperature can play a role. Elevated temperatures may be used during mixing to aid in the dissolution of the API if all the components are sufficiently thermally stable, but temperatures beyond 70°C may damage the capsules. The temperature may also be altered to control viscosity of the mixture: reduced viscosity to aid mixing and filling or increased viscosity to maintain homogeneity. Due to the broad range of rheological properties the mixers can handle, tight control limits are not usually required. The homogenizer (high shear mixer) is used to put energy into the system to aid dissolution or to disperse powder to a homogeneous suspension. It quickly creates heat in the system but also provides rapid dispersion and de-agglomeration without significant particle size reduction taking place. The homogenizer speed and continuous, or intermittent, time of application can also affect the outcome. The agitator is generally employed after the homogenizer is complete to maintain an even temperature throughout the bulk liquid and sometimes to assist with maintaining homogeneity. While these controls are required the window of control is usually not too tight.
Step Three: Filling
Once compounded, the mixture is pumped into the filling machine. At this stage, the high-potency risks from airborne powder have been completely removed and the operation can be conducted in a controlled but less contained environment. Production risks do remain: Fill accuracy and uniformity, prevention of external capsule contamination and minimizing pressurization are the key attributes to assess while filling the compounded mixture into hard capsules.
The accuracy of fill is achieved relatively easily, as precision pumps provide an accurate dosing capability over a broad range of viscosities, but it does entail two key challenges:
- The first challenge is to ensure the mixture is cleanly filled into the shells at as fast a rate as possible without it “squirting” out the other side, dripping, splashing or “tailing,” where the fill stream is not broken between capsules. This is achieved through a balance of nozzle selection, pump timing and drawback settings, designed to break the fill stream and set filling speed and temperature/viscosity control. Cleanly filling into capsules is critical to ensure that the external capsule does not become contaminated. Contamination on the outside of capsules could prevent sealing, and high-potency material on the outside of the shell presents a contamination risk to healthcare workers, patients and their families, in addition to a cosmetic impact.
- The second risk is pressurization of the two-piece capsule shells as the product is scaled up. Both the cap and body components of the capsule contain air, which is compressed as the capsule is closed at high speed. Impacts on the pressurization within the capsule at this stage include:
-
- the design of the capsule shell, to vent this air;
- the temperature of the fill mixture, which may further heat this air; and
- the quantity of fill material in the capsule body, which affects the distribution of the pressure.
In a worst-case scenario due to over-pressurization, the capsule can self-open prior to being sealed, or distort during the sealing process. Even some time later, an over-pressurized capsule could split as it re-equilibrates from the physical and chemical stresses applied to it during manufacture. Appropriate expertise and attention are required to ensure pressure is minimized to the point no longer presenting a risk to the product, and the result matches the sealing technique used.
Scale-up of the filling process is straightforward, contingent upon the potential risks having been worked out of the product during development. Small-scale filling equipment works on exactly the same mechanisms as larger scale equipment, with multiple pump heads and automated capsule handling providing most of the speed gain.
Some refinement, with additional controls to adapt to the impacts of high speed filling, is available on commercial-scale equipment. Unfortunately, many companies rely on inexperienced vendors who do not have familiarity of commercial processing to conduct their early work, and this is the stage of the process where those design errors can have the biggest impact. As a result, some scale-up operations of products transferred from an organization inexperienced with all scales of manufacture may require the correction of prior mistakes before the scale-up can take place.
Step Four: Sealing
Sealing of the capsules takes place when the formulation is already enclosed within the shells and presents little risk from potent material. Sealing prevents leakage from liquid-fill products, or thermo-softening materials that may be exposed to sufficient temperature to melt the components. In the case of banding, this seal also provides tamper evidence for individual capsules, which is increasingly required for certain compound classes. The main goals in the sealing process are to ensure the capsules have no leaks, bubbles or cosmetic problems.
When the previous scale-up filling development has been appropriately completed, ensuring the internal pressure is appropriate and the external capsule is not easily contaminated, then the sealing process is generally straightforward. Fusion sealing and banding are the two standard approaches to sealing capsules. Fusion sealing applies the seal between the body and cap using a micro-spray and banding applies a band of seal solution over the cap and body joint. The choice between the two is generally not for technical reasons but will impact the selection of capsule type being used.
For banding activities, the process of scaling up to commercialization rarely requires product-specific setup other than the shell selection already mentioned. To ensure robust sealing, the process must optimize several variables at commercial scale: banding solution composition and viscosity, banding speed, disc type and speed, disc height, band solution quantity applied, drying temperature and airflow.
Conclusion
In summary, liquid-fill capsule technology has long-established market precedence and a range of specialized applications – including providing a versatile solution for safe and effective handling of highly potent and other complex API. Scale-up is straightforward, contingent upon development that has been conducted appropriately, due to the consistency of liquid handling mechanisms. Powder containment measures are only required in the first few steps of the manufacturing process. Specialized CDMO partners exist in the marketplace with the prerequisite infrastructure, expertise and processing equipment in place to support effective and agile liquid-filled product development from feasibility studies through clinical trials and commercial manufacture.
References
- HPAPIs and Cytotoxic Drugs Manufacturing Market, Roots Analysis, August 2014, http://www.rootsanalysis.com/reports/view_document/hpapis-and-cytotoxic-drugsmanufacturing-market/64.html
- Grand View Research, High Potency Active Pharmaceutical Ingredients (APIs) Market Analysis By Product (Synthetic, Biotech), Manufacturer (In-house, Outsourced), Drug Type, Therapeutic Application (Oncology, Hormonal, Glaucoma, Others), And Segment Forecasts, 2018 – 2025
- S. Brown. “Why high potency drugs require a specialised approach.” European Pharmaceutical Manufacturer
- Geoff Rowley, “Filling of Liquids and Semi-solids into two piece hard capsules” Pharmaceutical Capsules, Pharmaceutical Press, 2004, pp. 169-194
- Feeney et al.,50 years of oral lipid-based formulations: provenance, progress and future perspectives, Adv. Drug Deliv. Rev., 101 (2016), pp. 167-194
- Lonza Pharma & Biotech, Internal Market Analysis, 2018.
- Matt Richardson and Sven Stegemann, Filling two-piece hard gelatin capsules with liquids, Tablets and Capsules, January 2007