Challenges in the Secondary Manufacture of Encapsulated High-Potency Drugs

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.

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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.

Classification of high-potency compounds

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/m³ ) 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/m³ or less. Supporting data relating to drug-development pipelines confirm a substantial and growing market (4).

Market size and growth

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/m³ . 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).

Strategies for formulation development

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:

• Safety and regulatory compliance

• Capital costs for facilities and equipment

• Segregation requirements

• Technical expertise

• 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).

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.

Table l

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

• Minimizing product cross-contamination

• Increasing operator safety through reducing potential exposure

• Reducing processing time

• Increased efficiencies of filling speeds

• Removing the potential risk of fire or explosion

• Substantially increasing the ease of handling, transfer and cleaning

• Reduced processing costs.

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

Figure 2

Safety as a design feature

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

• Facility design

• Equipment design and modification

• 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).

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:

• Training programs

• 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

• Safety evaluation

• 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

• OEL definition

• Using available data (or analogy to similar compounds), define the safe OEL limit

• Implement industrial-hygiene sampling and develop analytical methods for monitoring exposure

• Design-containment strategy

• Design and communicate the containment approach for actual and perceived potential hazards

• Define the isolation technology to be used, ventilation, and other processing equipment that will be required

• Standard operating procedures

• Develop appropriate procedures for handling and disposal of high-potency compounds, including cleaning and validation of all equipment

• Ensure that written procedures for all aspects of the process are fit for purpose and relate to the level of OEL for that compound

• Verification

• Validate performance of engineering controls by monitoring each step of the process being undertaken

• Undertake continuous health surveillance during the operation

• Environmental

• Assess the environmental impact, particularly in terms of waste disposal

• Undertake an environmental assessment.

Example of the manufacture of two-piece, hard-shell, liquid-fill capsules.

Elements of a containment solution

The authors' experience is that a comprehensive containment solution within a single manufacturing facility can address the varied and ever-increasing demands of potent-compound manufacturing and handling. This approach allows for highly efficient and safe processing that meets specific requirements for APIs and drug products from clinical-trials supply to commercial-scale manufacture. The authors' experience involves constructing a new high-potency facility with two validated Class 100,000 high-containment suites with barrier technology for CGMP manufacture of the final-dosage form for oral drug products. From this experience, the authors outline important design features of this type of facility:

• API material contained in specialized and antitamper containers

• Contained and direct-process transfer of APIs using barrier technology from isolator to vessel

• High-efficiency particulate air (HEPA) filtration

• Controlled access to high-potency processing areas for trained personnel only

• Personnel protection through strict gowning and control procedures

• Routine assessments of air particulates performed to ensure best-working practices and proper maintenance of OELs

• Clean-in-place and wash-in-place (WIP) processing equipment

• Epoxy-painted walls and welded sheet-vinyl flooring

• Argon- and nitrogen-gas capability for inert and dry environment control

• A clean dry-air system for automated equipment.

Other important features of the containment suite include 100% air extraction and 100% air makeup using the heating, ventilation, and air-conditioning systems. These elements ensure that there is no air recirculation within the high-potency manufacturing areas, thereby eliminating the opportunity of cross-contamination or risk to operator safety. High containment barrier isolators (glove-box technology) allows for dispensing, sampling, and charging highly potent or cytotoxic materials while providing operator and environmental protection to nanogram levels. A key feature is to meet an OEL target down to at least 0.1μg /m³ (100 nanograms); however, modification of working processes will allow even more potent compounds to be handled.

As part of an ongoing and integrated program, it is important to adopt the most efficient and safe working practices through operator training and ensure that barrier technology is optimized to reach its maximum potential. The isolator intakes air through a HEPA filter from the cleanroom. The internal conditions of the isolator, therefore, are classified again to Class 100,000. All air from the isolator is extracted to the environment after it has passed through a double HEPA extract filter. All parts of the high integrity glove-box isolator, which has potential product contact, will be constructed from certified 316L stainless steel. Further design features include incorporating a rapid-transfer port (RTP) and a continuous bag-lining system for safe introduction and removal of APIs and waste material. The RTP allows the transfer of highly potent APIs directly from the primary manufacturing site to the secondary production site in a safe and contained manner. To ensure ease of cleaning, the isolator is fitted with wash lances as part of a WIP system. Additionally, all waste material can be disposed by using environmentally sensitive procedures such as contracted offsite disposal services.

The inclusion of a P+AM F40 liquid filler (P+AM, Mumbai, India) and S70 Automatic Band Sealing machine (P+AM, Mumbai) meet requirements in producing small and commercial batches of liquid and semisolid two-piece hard-shell capsules. These two items of equipment are similar to the Bosch range of liquid-filling equipment and Qualiseal banders. The liquid-filling machine is capable of filling hard gelatin or hydroxypropylmethylcellulose capsules over a size range from zero to four, containing 90–850 mg of formulated dose. The system is compatible with various pharmaceutical liquids such as oils, thixotropic gels, or molten waxes.

Conclusion

Liquid and semisolid encapsulation using two-piece hard-shell capsule technologies is a useful approach to deliver highly potent compounds. A key benefit of using this type of encapsulation is that the containment in the secondary manufacturing environment is easier and provides a lower safety risk compared with powder capsule-filling or conventional tablet manufacturing.

Acknowledgements

We are grateful to Stephen Brown, PhD, director of research and development at Encap Drug Delivery, for his input in preparing this article.

Joe Carey*, PhD, is CEO, and Andrew Dixon is validation manager of Encap Drug Delivery, Units 4, 5 and 6, Oakbank Park Way, Livingston, West Lothian, Scotland, United Kingdom, EH53 0TH, tel. 44 150 644 8080, fax 44 150 644 8081, Joe.Carey@encapdrugdelivery.com

*To whom all correspondence should be addressed.

References

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2. P. Van Arnum, "Investing in High-Potency Manufacturing," Pharm. Technol. 31 (11), 54–58 (2007).

3. P. Van Arnum, "Contract Manufacturing Organizations Expand in High-Potency Manufacturing," Pharm. Technol. 30 (9), 62–68 (2006).

4. M. Greener, "Manufacturing Highly Potent Drugs: Reducing Risks," Pharmaceutical Visions sourced from SafeBridge Consultants (Mountain View, CA), wwwsafebridge.com, accessed Mar. 17, 2008.

5. S.Birks, "Building on New Strengths," Packaging Today, May 1, 2007.

6. W. Bowtle, "Materials, Process and Manufacturing Considerations for Lipid-based Hard Capsule Formats," in Lipid-based Formulations for Oral Drug Delivery D. Hauss, Ed. (Informa Healthcare, New York, 2007).

7. M.C. Griffiths, "Facility Design with Containment Chemistry in Mind," Pristine Processing (2003).