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