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


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,

*To whom all correspondence should be addressed.

References

1. K. Watkins, "Handle with Care," C&E News 79 (14), 31–34 (2001).

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), http://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).


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