CMOs specializing in secondary manufacturing are moving forward with expansion plans as well.
Ben Venue is building a new $139-million, 240,000-ft2 manufacturing plant for producing cytotoxic and genotoxic compounds. The facility will produce both commercial and clinical-trial
materials. Construction is scheduled to be completed by the end of 2008. Qualification activities are expected to be completed
in the first quarter of 2009, and facility approvals are anticipated for the second quarter 2009.
Patheon (Mississauga, Ontario) is investing $2.8 million to add a dedicated, 3386-ft2 high-potency and controlled-substance manufacturing area at its Manati, Puerto Rico, facility. The production area will
have capacity for high-potency (i.e., containment down to 1 μg/m3 OEL) and humidity-controlled solid-dosage form products. Construction is scheduled for completion by the end of September
2008. Last month, Patheon partnered with BSP Pharmaceuticals (Aarhus N, Denmark) to promote BSP's cytotoxic manufacturing
capacity and development services. The move provides Patheon the ability to provide high-potency manufacturing services.
In June 2008, Pharmatek (San Diego) completed construction of a new 18,000-ft2 facility for high-potency manufacturing of oral dosage forms. The facility includes analytical and formulation laboratories
and two certified and validated ISO Class 8, US Class 100,000 CGMP containment suites for the manufacturing of high-potency
and cytotoxic drug products for early-phase clinical trials. Certification and validation of the facility is scheduled to
be completed in mid-August. The facility will become fully operational in the fourth quarter of 2008.
With the expansion, Pharmatek will offer analytical-method development, preformulation testing, formulation development, CGMP
manufacturing for early-phase trials, release testing, stability testing and storage, and technical transfer for commercialization
for high-potency compounds.
Earlier this year, Catalent Pharma Solutions (Somerset, NJ) added a Phase I sterile vial-filling suite in its Research Triangle
Park, North Carolina, facility. The new suite can fill vials with most highly-potent compounds, traditional small-molecule
drugs and biologics, as well as DEA (Drug Enforcement Administration) Schedule 1–5 compounds.
Issues in high-potency manufacturing
For now, there is no official guidance from regulatory agencies regarding the production and handling of HPAPIs. "The industry
has been moving toward self-regulation, either via SafeBridge, or a five-tier system used by some pharmaceutical companies," says SAFC's Feldker.
SafeBridge Consultants (Mountain View, CA) provides third-party certification to evaluate a company's ability to handle and
manufacture potent compounds safely. SafeBridge offers the certification process for competency in the occupational-health
aspects of high-potency manufacturing. The "SafeBridge" potent-compound safety-certification program verifies performance
with set criteria in management, evaluation, containment, control, and communication elements of potent-compound production
operations. Elements of the program include onsite assessment of the potent compound manufacturing and laboratory areas and
equipment, training, toxicology, and industrial hygiene (1).
SAFC's Madison site is certified by SafeBridge for handling products up to Category IV. Its St. Louis facility is completing
the requirements for certification, notes Feldker. SAFC plans to seek certification for its new plant in Jerusalem after its
completion in early 2009.
Specialized equipment for containment, operator training, and safety practices are required for high-potency manufacturing.
"The concept to contain a product within a manufacturing suite is similar for both biologic and small-molecule HPAPIs as well
as conjugates," says Feldker. "The development and manufacture of HPAPIs requires significant planning, proper equipment,
and facility design, as well as implementation of the necessary procedures to safely handle the compounds. In addition to
containment systems for solid, powder, and liquids handling, secondary protection is provided by protection suits and supplied
air systems, customized for each particular project. Sound systems must be employed in all aspects of the HPAPI handling program,
from initial project evaluation, through equipment cleaning, to disposal of process waste."
Other CMOs emphasize the importance of facility design and operation when working with HPAPIs. "A site must carefully assess
each step of their operation for the risk of possible product cross-contamination, CGMP and regulatory compliance, and the
potential for employee exposure to potent compounds," says Ben Venue's Hansbury. "A multidisciplinary team should be involved
in this review, including personnel from production, engineering, quality, validations, and environmental health and safety.
Tools such as failure mode and effect analysis or fault-tree analysis are helpful in defining and ranking risks. Processes
need to be thoroughly understood and risks ranked to understand where to put forth the best investment to control risk. Using
data such as environmental, air, and wipe sampling from current processes shows where more control may be needed. This approach
was taken for the design and construction of our expansion," he says.
In its expansion, Pharmatek used a combination of facility-design elements and exposure-control systems. Key aspects included:
- Integration of clinical trial material storage, equipment storage, and equipment wash within the clean space
- Design of an alternating positive and negative pressure scheme to ensure containment and prevent cross contamination
- Design and integration of a development area to support GMP manufacturing
- Multiproduct suite design while controlling for unidirectional personnel and equipment flow
- Design and integration of soft-wall, barrier technology for process equipment.
Scott also outlines key issues to consider on an operational basis such as cleaning-method development and implementation,
cleaning verification, the cost associated with single-use containment technology and gowning items, and hazardous waste disposal.
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org
1. P. Van Arnum, "Investing in High-Potency Manufacturing," Pharm. Technol.
31 (11), 54–58 (2007).
2. PhRMA, "Medicines in Development for Cancer" (Washington, DC, 2008).