Hans-Dieter Zeitz is Vice President, Heumann PCS 3rd Party Business, in Feucht, Germany; Heumann PCS is a business unit of Pfizer CentreSource.

Michael Tschöpe, Ph.D., is Head of Process Unit Pharma, Heumann PCS.

Carlos Fernandez is Marketing Manager, Pfizer CentreSource.

Outsourcing High Containment Operations

Criteria for contracting HCO

By Hans-Dieter Zeitz, Michael Tsch-pe, and Carlos Fernandez
Pfizer CentreSource

Today, pharmaceutical outsourcing has grown into a sizable industry in itself. The total global market for contract manufacturing, according to PharmSource, is roughly $30 billion per year, growing at 8-10% annually. API and dosage form outsourcing represent the largest segments; approximately 30% of API production (representing $9 billion) and 26% of dosage form and packaging activities ($7.8 billion) are currently being outsourced.

The reasons for the growth in contract manufacturing are certainly well established (see sidebar on p. 36 for more information), but what is not as broadly understood is the issue of outsourcing high containment operations (HCO), one of the industry’s most pressing topics.

The trend toward the development of more receptor-specific—and thus increasingly potent—compounds for therapeutic treatments has driven demand for HCO services to very high levels. These new drugs do not necessarily belong to the classes of cytotoxics and hormone-like oncological therapeutics, which have long dominated high containment operations. The press is on for the industry to fulfill demand in a competitive arena where HCO capacity is at a premium.

Against this challenging backdrop, companies that require HCO manufacturing will benefit from a deeper understanding of containment infrastructure, maintenance, testing, training and other issues. Thus armed, they can more accurately evaluate outsourcers that specialize in HCO production, and more confidently transition such projects for maximum success.

In its simplest terms, HCO has one primary objective: to prevent the release of active compounds that may present a hazard to employees, or to nearby human and animal populations. One approach is to build the entire process around containment, creating a sealed envelope around the critical areas where the active drug is handled and ensuring that manufacturing operations are conducted in the safest possible manner. This sounds simple. In reality, there are many potential pitfalls to high containment drug production. This awareness has prompted an increasing number of drug makers to outsource their HCO activities.

Infrastructure is one of the primary obstacles to handling high containment production in-house. The sheer investment required—in technology, engineering, construction, and expertise—deters many drug producers from handling HCO on their own. High containment dosage form production, in particular, offers a great illustration. Even companies with products in Phase II or Phase III still experience a high failure rate, making in-house capital investment in HCO production difficult to justify. Far too many major pharmaceutical manufacturers have facilities originally built around one particular product that now sit idle. With so much at stake, many pharmaceutical companies rightly ask themselves: Why not outsource HCO instead?

The increasing numbers that rely on contract manufacturers may not know what to look for with regard to evaluating a third-party supplier’s HCO infrastructure. Technology advancements that permit HCO facilities to handle highly potent compounds while ensuring maximum safety—for employees, and human and animal populations—continue to evolve. They include:

The increasing numbers that rely on contract manufacturers may not know what to look for with regard to evaluating a third-party supplier’s HCO infrastructure.

Why are more Pharma companies outsourcing dosage form manufacturing? The popularity of this practice hinges on four key factors:

HCO also places special demands on machines and equipment with regard to engineering details and materials used:

Another consideration is whether the HCO facility can handle the particular challenges of solid dosage forms. Solid dosage forms are more difficult to work with than liquids because of the particulate state of the material, not all
HCO facilities can meet the challenges they pose.

Like infrastructure, personal protective equipment (PPE) is another costly and involved element of high containment production units. PPE should be required only when isolation by engineering means cannot be made sufficient to protect workers from exposures above compound OELs. It is not acceptable to build an HCO manufacturing strategy solely based on PPE. Successful contract manufacturers must evaluate the PPE provided to employees to make sure it is suitable for the intended use. PPE used in the HCO include air-supplied “space suits” for critical operations, as well as powered air purifying respirators or P3 masks and Tyvek suits for less critical, more routine operations. Half-suits may also be employed as key components of isolators. Repeated use of the PPE require that it be routinely leak-tested using ammonium hydroxide or other accepted testing methods, to ensure maximum operator safety. In addition, cleaning validation needs to be employed in order to make sure that the PPE is adequately cleaned and does not pose a risk of cross-contamination to the manufacturing processes.

Return to top

In most cases, HCO facilities are multi-purpose facilities that generally focus on highly active or highly potent compounds, but handle more than one specific active drug—making the cleaning procedures and cleaning validation regimen critically important. In non-containment manufacturing, a general approach to cleaning validation is acceptable, for example, cleaning between lots using a regimen that has been demonstrated as suitable for multiple compounds. However, that is not the case with HCO operations. Each individual active compound needs to be evaluated on its own, including specific sampling procedures and analytical methods. Methods based on swabs are preferred over a rinse methodology. To further reduce cleaning problems in HCO environments, minimizing the surfaces that have direct contact with the product is another important practice.

HCO equipment or parts with direct exposure to potent compounds may be difficult to clean, or it may be difficult to validate this cleaning process. For this reason it is often desirable to dedicate equipment or parts to a specific active drug. Some facilities, such as the one we run in Feucht, Germany, make available customer- and product-specific tooling, a step designed to minimize possible contamination issues. The company has employed this practice for nearly a decade.

Waste disposal is an issue for HCO units. The contract manufacturing site needs to warrant that it complies with all applicable laws with respect to the environment, occupational health and safety, public health and safety, and waste disposal, and holds all current and applicable governmental licenses, approvals, permits and authorizations.

Waste from the isolator area should be placed into PE-bags fit on one of the ports, where they are sealed, separated and added to the plant’s hazardous waste stream. In addition, many other materials will need to be collected and discarded: used PPE, IPC material, material accumulated in dust control systems, and the wash water after cleaning. Waste handling must be done in a way that prevents rupturing of containment bags or otherwise releasing dusts. The waste must be either incinerated by specialized companies or decontaminated or detoxified by special techniques. Handling disposal of the wash water constitutes the biggest challenge in HCO operations, due to the large amount of cleaning that is required.

Return to top

Effectively training operators and other personnel on the specific requirements of running and maintaining the high containment facility is an absolute imperative. First and foremost, staff safety is the priority. All operators who have been issued PPE must be fit tested and trained in its proper selection, use and storage. Records of this training and the routine/regular inspection and testing of all PPE must be carefully maintained.

Specialized training programs may be needed for different job functions. For example, there are critical demands placed on operators working in high containment facilities. Failure to follow instructions may result in harm to the personnel and the environment. The following job functions/tasks are just a representative sample of issues requiring specialized training:

Personnel must be trained to achieve a balance in operator comfort and production work efficiency while keeping operator safety the highest priority. Highly detailed SOPs on training are an essential aspect of success in this area.

Another critical requirement for HCO facilities is sophisticated industrial hygiene monitoring. Many details (including sampling media, sample flow rate, optimum sample volume, and preferred analytical techniques) must be considered in setting up an effective air-sampling program. For maximum accuracy, the facility should collect personal samples for all operators in each production area. Ongoing monitoring should be conducted, with sample analysis performed by an accredited analytical laboratory.

Internal information sharing and discussion is paramount. At the end of each monitoring program, results should be reviewed with all relevant colleagues, including input from the occupational hygienists and occupational health physicians, when appropriate. Any areas of concern must be flagged for immediate action and follow up.

Global regulatory expertise is always a key factor when choosing a qualified partner for outsourced drug production. High containment production is no exception. Only HCO specialists with expertise in global regulatory environments can provide truly comprehensive support. Many pharmaceutical companies today have truly global requirements. For example, companies with products in the oncology market may need an HCO manufacturing facility with supply capabilities that span continents. Among contract manufacturers, it is uncommon to find one facility that has FDA, EU and Japanese approval for high containment operations.

A final consideration relating to outsourcer selection is the type of HCO manufacturer. “Pure-play” contract manufacturers are businesses whose sole activity involves contract manufacturing. Some pharmaceutical companies are attracted to the single-minded, “specialty” focus attributed to pure-play providers. Another option brings specific benefits that other pharma companies value just as highly. They opt to work with contract manufacturers that are owned and operated by larger pharmaceutical businesses that maintain their own research, marketing and production units. Companies that select this route may benefit in two ways. Substantial financial resources are at the provider’s disposal. This benefit can be significant, given the cost of developing HCO facilities. Contract manufacturers affiliated with major pharmaceutical firms can be expected to perform to “Major Phar-ma” quality standards. They are less likely to risk their own regulatory certifications by performing to less-than-stringent standards for their contract manufacturing customers.

There is little doubt that demand for high containment production will continue. The market is under-equipped to handle the current HCO demand, even as newer, more potent drugs continue to be developed. The high costs to build and maintain high containment infrastructures, manage the testing, conduct worker training, and manage local and global market regulatory requirements may result in more pharmaceutical companies outsourcing this important function.