Challenges in the Secondary Manufacture of Encapsulated High-Potency Drugs - Pharmaceutical Technology

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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.


Pharmaceutical Technology


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.


Figure 1
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


Table l
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.


Figure 2
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.


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


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