Examining High-Potency API Manufacturing

High-potency active pharmaceutical ingredients (HPAPIs) are a niche but growing area for pharmaceutical manufacturers and contract manufacturing organizations (CMOs). Specialized considerations in facility design, equipment, operation, and process safety are needed to achieve the desired level of containment of the drug substance or finished-drug product. For drug-substance manufacturing, the HPAPI may be a small-molecule, biologic, or a hybrid of the two such as an antibody–drug conjugate, which links a cytotoxic small-molecule to a monoclonal antibody.

Patricia Van Arnum

Assessing HPAPIs

The definition of an HPAPI varies depending on the literature, but generally is defined as (1):

• A pharmacologically active ingredient or intermediate with biological activity at approximately 150 µg/kg of body weight or below in humans (therapeutic daily dose at or below 10 mg)

• An API or intermediate with an occupational exposure limit (OEL) at or below 10 µg/m³ of air as an 8-h time-weighted average

• A pharmacologically active ingredient or intermediate with high selectivity (i.e., ability to bind to specific receptors or inhibit specific enzymes) and/or with the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses

• A novel compound of unknown potency and toxicity.

The potency of HPAPIs is characterized by OELs in µg/m³. The lower the value, the more potent the compound, and the greater the level of containment required (1). OELs and related criteria such as toxicity and carcinogenicity are used in determining the performance-based exposure control limits, which link compound toxicity and potency to procedures for safe-handling of HPAPIs (1). The industry generally uses two rating programs that categorize compounds based on performance-based exposure limits, a five-tiered system or a four-tiered system, which is similar to the one developed by SafeBridge Consultants (Mountain, View, CA) (1).

IMAGES COURTESY OF SAFC

Facility design, equipment, engineering controls, and the proper operation of facilities and equipment are needed to achieve the desired level of containment in HPAPI manufacturing. Operator safety is also critical and involves the use of personal protection equipment, related training in handling HPAPIs, and implementation of safe-handling practices and current good manufacturing practices (CGMPs) to prevent operator exposure and contamination (1).

A case study

Understanding the requirements for HPAPI manufacturing and related costs is critical for a CMO or pharmaceutical company interested in expanding or adding HPAPI capacity. The CMO SAFC (St. Louis, MO) went through this decision-making process in several recent expansions. The company has invested $75 million during the past 18 months to expand its HPAPI capacity. These investments include: a $4.5-million project to add a CGMP pilot plant and kilo-laboratory capacity at its Madison, Wisconsin, facility, completed in early 2008; a $29-million investment to expand bacterial and fungal fermentation-derived HPAPI capacity at its site in Jerusalem, Israel, due for completion in early 2010; and a $30-million investment to build a new commercial-scale HPAPI facility at Madison, due to be completed by year-end 2009. SAFC also commissioned a conjugation suite for HPAPIs in September 2008. It invested $12 million for expanding its viral manufacturing capacity (Biosafety Level 2-compliant at its facility in Carlsbad, California. This expansion is to become operational in the second half of 2009.

Small-molecule HPAPI manufacturing. SAFC is building a new commercial-scale HPAPI plant in Madison following several expansions at its facility there. "We made the decision to expand our services by building from scratch rather than acquiring another building or CMO since there would have inevitably have been a great deal of retrofitting necessary," says Dave Backer, director of business development and marketing at SAFC Pharma. "When it comes to HPAPI facility design, SAFC has always felt that it is better to build a facility with the type of products to be manufactured in that facility rather than to try and build into existing facilities, which may not have the containment principles in place already."

Growth in oncology drugs

SAFC made two previous expansions at its Madison HPAPI facility, but needed additional capacity for large-scale and commercial capabilities. Construction began in the fall of 2008 and will be completed by the end of 2009. The new facility will be capable of manufacturing, handling, and transferring large volumes of product up to 4000 L. This capacity will allow for batches of potent compounds to be manufactured in the range of hundreds of kilograms. The material-handling systems are being designed for full containment on a large scale. The company is adding a milling and micronization area in the facility for potent compounds. The facility is designed to adhere to Category IV standards, as defined by SafeBridge Consultants. SAFC's existing facility in Madison is certified by SafeBridge, and the company intends to seek certification for the new facility upon its completion. "Safety and consistency are paramount, and it is important to note that in addition to very careful facility design that SAFC has work processes and very experienced staff," which the company uses in its small- and large-scale HPAPI manufacturing, adds Backer.

Antibody–drug conjugates. SAFC recently received SafeBridge certification for its high-potency antibody–drug conjugation suite in St. Louis to complement such certification for its high-potency manufacturing facilities in Madison. "For the high-potency conjugation suite in St. Louis, we wanted to take the best practices that we had in facility design, operator training, and operator safety that has been in operation for years at our Madison plant, and marry it to the conjugation and biologics capabilities and expertise already employed at our St. Louis facility," continues Backer.

SAFC's high-potent conjugation facility was designed from its inception as a containment facility. Some key factors in designing such a facility are room-pressure differentials, with appropriate monitoring and verification, to ensure that the pressure of the major handling area is negative to its surrounding airlocks and vestibules. Single-pass air is used with temperature, humidity, and particulate controls. Misting showers are part of the degowning and exit process for operators and equipment. The suite also has filtration and capture equipment, both with the isolators and with the exhaust system of the heating, ventilation, and air-conditioning system. Isolators and fume hoods are used for certain operations as are biologic safety cabinets. Other facility designs such as unidirectional flow and restricted access are consistent with most recently built biologics facilities."

"Traditional biologics facilities that produce proteins and antibodies in mammalian-cell-culture or bacterial fermentation are designed to have the suites where purification occurs be positive to their surroundings. However, when working with potent products, such as viruses or biologics that are conjugated to highly potent APIs, processes are performed in a suite negative to the surrounding rooms to ensure the potent compounds are contained within the working environment," explains Backer. "Protection of the operators is also an absolute requirement. The operators are well trained in operating with protective garments and wear respirators," he adds. "Training in the handling of high-potent products is ongoing and essential. Changeover processes are validated and in place."

SAFC employs this negative-room-pressure concept at its facilities for viral-vaccine manufacturing in Carlsbad, its small-molecule HPAPI manufacturing facility in Madison, and its potent antibody–drug conjugation suite in St. Louis. The company is also including this approach at its fermentation facility in Jerusalem, which will target potent and cytotoxic molecules, and at the company's new large-scale, small-molecule HPAPI commercial manufacturing facility in Wisconsin.

As with all HPAPI facilities, operator safety is key. "Demonstrating that controls are in place to ensure the highest levels of safety to workers and the environment is an important consideration," says Backer. "The operators are well trained in operating with protective garments and wear respirators. Training in the handling of high-potent products is ongoing and essential. Changeover processes are validated and in place." He adds that SafeBridge certification adds assurance that there will not be interruptions in manufacture due to safety concerns.

Biologics high-potency manufacturing. SAFC is expanding bacterial and fungal fermentation-derived HPAPI capacity at its Jerusalem facility. The Jerusalem site has an existing API manufacturing plant using fermentation, and the $29-million expansion will add a new GMP HPAPI fermentation facility next to the existing plant. Requirements for both containment for HPAPI manufacturing and the scale-up and the purification of biologics through fermentation had to be factored into the new facility's design and operation.

"From a facility design aspect, one needs to have the ability to use solvents, so the design of blast-proof suites was an important consideration," says Backer. The scale of production, which will be more than 10 L in a Biosafety Level-2 environment, requires dedicated suites, airlocks, 100% single-pass air, and exit showers. "Since the facility will operate 4000-L fermenters, there are appropriate systems and procedures for cleaning and sterilizing of equipment as well as for the transfer of product and large volumes of liquid," he adds. Biohazard safety cabinets will be used for small-scale operations.

SAFC will seek SafeBridge certification for its HPAPI fermentation facility in Jerusalem, which includes implementation of operator safety procedures and practices. "For personnel, strict gowning procedures are implemented to protect the employees that are trained and qualified to perform these operations, including the manufacture of these potent products," says Backer. "Personnel, materials, and waste flows are kept unidirectional. All of these measures plus strict changeover procedures also ensures the prevention of cross contamination, which is the heart of GMP." The product becomes more potent as it moves downstream and is concentrated into a powder stage. At this point, operations occur in isolators, and operators use respirators, similar to equipment and protection offered in other HPAPI facilities.

A look forward

As in other areas of manufacturing, disposables or flexible containment technologies are becoming important in HPAPI manufacturing. "The manufacturing of potent products follows a trend in the industry of providing smaller lots and more potent products. The use of disposable equipment is being employed, where appropriate, though the use of various chemicals and solvents limits the use for certain HPAPI products. We also use dedicated equipment where appropriate," says Backer. Table I identifies the facilities in which SAFC uses disposable technologies.

Table I: Examples of technology and equipment in SAFCs high-potency active pharmaceutical ingredient (HPAPI) facilities.

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, pvanarnum@advanstar.com

Reference

1. D. Bornett, "High-Potency APIs: Containment and Handling Issues," Pharma Ingredients supp., Pharm. Technol. 32 (9), s12–s16 (2008).