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