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Challenges in the Secondary Manufacture of Encapsulated High-Potency Drugs
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.
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).
Example of the manufacture of two-piece, hard-shell, liquid-fill capsules.
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
