Andrew Dixon

Commonly accepted convention within the pharmaceutical industry is that fewer blockbuster drugs will be developed in the foreseeable future as the human genome project takes effect and personalized medicine becomes more of a reality. Consequently, drug-discovery strategies have changed. More firms focus on developing new chemical entities that are targeted, have greater potency, and produce fewer side effects compared with conventional therapies. Many anticancer, antiviral, or central-nervous system drugs that are currently in clinical trials have these characteristics and will eventually require commercial production. 

Because the potency of these drugs is greater, the commercial quantities required are relatively small. Industry data suggest that around 20% of drugs in development pipelines may be classified as highly potent, up from about 5% in the 1990s (1). At the same time, high-volume manufacturing is shifting to lower-cost operations in India and the Far East, and Western manufacturers are refocusing their efforts by establishing high-potency manufacturing assets that provide multiple barriers to entry. Typically, these barriers are capital investment, production capabilities, technology, and regulatory compliance. Several Western producers of active pharmaceutical ingredients (APIs) have adopted this strategy by building or enhancing capabilities in manufacturing highly potent compounds (1). This shift is also occurring for secondary manufacturing of high-potency drugs (2).  

Liquid and semisolid encapsulation using two-piece hard-shell capsules is an ideal oral drug-delivery approach for poorly water-soluble compounds, compounds that exhibit poor bioavailability, and for highly potent drugs. From a manufacturing perspective, the production of two-piece hard-shell capsules provides an environment in which containment is easier and operates at a comparatively lower safety risk compared with powder filling or tablet manufacture that typically generate dust particulates. The authors review the challenges involved in the secondary manufacture of high-potency drugs. From their own experience, they further provide insight in designing and constructing a new high-potency secondary manufacturing facility for liquid and semisolid APIs and their manufacture into two-piece hard-shell capsules.  

High-potency APIs are classed according to their inherent toxicity characteristics and pharmacological potency, which are translated into an occupational exposure limit (OEL). Typically, APIs with OELs at or below 10 micrograms per cubic meter (μg/m

 ) of air as an 8-h time-weighted average are considered potent from an occupational health perspective. There is no universally accepted system of categorization, although most seem to use a four-category system (see Table I). The four categories range from Category I, low-potency compounds requiring conventional good manufacturing practices (GMPs), to Category IV, for which a high degree of containment is required (3). 

The quantification of OELs and category classification is typically defined by the end of Phase-II or during Phase-III clinical studies. This process, however, does not address the classification of preclinical and early-development compounds. For early-stage compounds, it is important to have all relevant toxicological or compound-comparative data available to ensure an appropriate analysis of the risk and level of containment required to maximize safety.  

Approximately 28% of the drugs currently on the market are considered potent by these criteria, according to SafeBridge Consultants. The same firm estimates that approximately 40–45% of the OELs that have been set by the pharmaceutical industry are at 10 μg/m

  or less. Supporting data relating to drug-development pipelines confirm a substantial and growing market (4). 

 Data published by management consultants Becker Associates suggest there are 300–400 highly potent compounds currently in production for either clinical evaluation or commercial manufacture (5). 

Many high-potency molecules such as cytotoxics, hormones, steroids, potential mutagenics, or ingredients that may produce toxic intermediates are frequently assigned OELs of less than 1 μg/m

 . Working to these levels requires more planning and risk analysis to ensure that every stage of manufacture and waste disposal is safe for workers and the local environment (4).  

The availability of integrated formulation and secondary manufacturing services for oral drug products is scarce within the pharmaceutical industry. There are several factors for this situation as follows:   

Capital costs for facilities and equipment

Product and waste-management containment and remediation. 

Bowtle has extensively reviewed the strategies for formulation development (6). These options have mushroomed during the past few years so that poorly water-soluble compounds are now the norm rather than the exception. The key objective is to scope out the most suitable liquid or semisolid formulation from which a final oral dose product can be produced. Liquid excipients may be used in this process and can involve the use of both off-the-shelf or proprietary excipients (see Figure 1). 

Risk-reduction in high-potency secondary manufacture

The exposure risks associated with handling solid, highly potent drug substances can be substantially reduced if a liquid or semisolid formulation can be developed. This situation is based on the reduced operator exposure through the removal of a potential dust hazard during the manufacturing process that further facilitates ease of API transfer during the formulation stage and cleaning of the production equipment. From the authors' experience, a liquid or semisolid formulation can also reduce processing time through easier handling and transportation and can drive down overall process control. 

There are several advantages to incorporating crystalline highly potent APIs into liquid, semisolid, or suspension formulations. These advantages are as follows:   

Increasing operator safety through reducing potential exposure 

Removing the potential risk of fire or explosion 

Substantially increasing the ease of handling, transfer and cleaning

Additional advantages of liquid-filled two-piece capsules are summarized in Figure 2. 

Containment, and most importantly, the safety of production and associated staff, is the key issue facing manufacturers of high-potency products. This focus means a higher level of investment is required that involves:  

Increased operator expertise through specialist training 

Validation of facility and equipment to meet target OELs. 

The construction of appropriate barrier isolation equipment such as glove boxes, isolator units, and manufacturing equipment represents a high capital investment, particularly if off-the-shelf equipment needs to be modified to meet the lower OEL target limits. 

Liquid-fill, two-piece capsules may be used in the delivery of high-potency drugs.  

Griffiths has produced a comprehensive review of safety as a design feature in secondary manufacturing that includes a "protection-cascade" approach (7). This approach involves multilevel containment by which the primary concern is the facility's ability to ensure product quality, worker safety, and protection of the external environment. It supports the concept that the project and operations teams must provide a clearly defined system of overlapping layers of protection and control throughout a facility and its operations (see Figure 3). 

The ability to efficiently clean through effective validation procedures is a critical design aspect in the construction of a general-purpose high-potency facility. The overall elements as part of the people, process, prefacility construction, and equipment planning process are as follows:   

Ensure that internal trainers are appropriately trained, and that training is maintained by using external expertise

Undertake regular training and maintain appropriate records for supervisory and operational staff

Increase the profile and importance of safety from the board down to operators

Review all and any relevant safety data and request toxicological and clinical data from the originator and evaluate the data against occupational health categories

Undertake an evaluation of the physical and chemical properties, particularly particle size, explosive or static- electricity potential

Undertake a thorough evaluation of the containment that will be required to carry out the specified processing and ensure that the processes are in place for further checking and validation

Articles

Liquid and semisolid encapsulation using two-piece hard capsules is an ideal drug delivery approach for highly potent compounds and poorly water-soluble drugs. The authors detail the factors to reduce risk when designing and operating a facility for secondary manufacturing of highly potent drugs.