Production of today's more potent drugs requires specialised facilities but volumes are often small, making in-house investment uneconomic. Hans-Dieter Zeitz and Michael Tschoepe of the Pfizer Centre consider the requirements when outsourcing high potency clinical trial material
As the pharmaceutical industry turns to more highly potent active ingredients for its drug products, manufacturers are increasingly confronting new challenges related to the safe handling of APIs even in the smaller volumes required for clinical trials. While many of the largest pharmaceutical firms have their own high containment operations (HCO) for these potent compounds, there is a more limited universe among the ranks of contract manufacturers. Because of the relative scarcity of available high containment services for clinical trials volumes, pharmaceutical companies that require HCO manufacturing will benefit from a deeper understanding of containment infrastructure, maintenance, testing, and training issues. With this information, they can more accurately identify and evaluate those outsourcers who specialise in HCO production for smaller volumes of material suitable for clinical trials activities.
The trend toward the development of more receptor-specific compounds for therapeutic treatments has driven demand for HCOs to high levels. These new drugs do not necessarily belong to the classes of cytotoxics and hormone-like oncological therapeutics that have long dominated HCOs, but are increasingly the result of more precise and focused targeting of receptors by chemists, thereby increasing the potency of many new drugs.
It is estimated that 25% of the new chemical entities coming out of development today are highly potent and require a high containment environment for manufacturing. This number may increase to about 50% in future.
While all this is good news for the industry and for patients awaiting important new treatments, it places some pressure on pharmaceutical businesses with formulations in the early stages of drug development, particularly for the clinical phases where full GMP requirements need to accompany adequate containment measures.
Producing clinical quantities of a highly potent drug ingredient in volumes as low as 5 to 15 kg - while retaining the stringent protocols entailed in HCO manufacturing - is a growing challenge that is likely to continue as the high potency trend progresses. Simply put, there are few contract manufacturers today that have tooled their manufacturing operations to handle the smaller volumes entailed in early clinical phases. Those that have are helping pharmaceutical companies build a kind of production "bridge" between the lower-than-one-kilo scale needed to develop a formulation and the typical commercial scale volumes of 200 kilos and more.
At its simplest, 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, particularly when manufacturing involves making the leap to smaller, clinical scale volumes.
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.
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, and generally include:
- Isolator technology for bulk manufacturing and packaging
- Remote control systems to allow operators to act from outside of the critical area
- Automated self-adjusting equipment that minimises potential operator interference and exposure to the active drug
- Process analytical technology (PAT), one of the hottest areas in pharmaceutical production today, to reduce the level of manual or automated sampling for in process control and to continually monitor critical steps of the manufacturing processes to make these processes more reliable
- Separate production areas that use pressure cascade to contain any contaminants within the critical area. This includes individual material and personnel locks that are controlled by HVAC systems designed to provide increasing negative pressure towards the critical area
- Separate air-handling systems with high-efficiency particulate air (HEPA) filters in inlets and outlets, and with secondary filters in outlets to prevent contamination of the HVAC system and ductwork and to act as a safeguard against environmental release of the active drug should the primary outlet HEPA filter leak
- Suitably engineered docking systems in the production process, for careful transfer of active ingredient blends from one closed system to the next in the production line
- Closed manufacturing systems with a capability of handling substances with an occupational exposure level (OEL) down to 0.1 µg/m3 or less
- The ability to integrate the high containment elements of a production line with those elements that do not require isolation
- The materials and construction of walls, ceilings, and floors designed to resist aggressive cleaning and prevent dust deposits in cracks or corners.
- Analytical testing labs - separated from the normal lab areas and with limited access - that are furnished with appropriate equipment, such as safety work benches for sample preparations, containment hoods or isolaters for testing samples.
HCO also places special demands on machines and equipment. All equipment/materials must be resistant to detergents. There must be no hidden or inaccessible areas where cleaning is not possible, as can occur in equipment with enclosed conveyor belts.
Dust-tight, closed control boxes and drive rooms (a separate part of the machine where equipment motors are located), with air supplied from the outside of the room, are required. Filter elements on isolators or machines must be constructed and designed to allow changing and disposal of used filter elements without exposure to workers.
Much the same as infrastructure, personal protective equipment (PPE) is another costly and complex element of high containment production units. 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. In addition, cleaning validation needs to be employed to make sure that the PPE is adequately cleaned and does not pose a risk of cross-contamination to the manufacturing processes.
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 regime 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, minimising 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. For this reason it is often desirable to dedicate equipment or parts to a specific active drug. Some facilities, such as the Pfizer CentreSource HCO facility in Feucht, Germany, make available customer- and product-specific tooling, a step designed to minimise 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 authorisations.
Waste from the isolator area should be placed into PE-bags fitted 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 specialised companies or decontaminated or detoxified by special techniques. Handling disposal of the wash water constitutes the biggest challenge in HCOs due to the large amount of cleaning that is required.
specialised training
Effectively training operators and other personnel on the specific requirements of running and maintaining the high containment facility is an 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.
Specialised training programmes 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 employees, the personnel and the environment. The following job functions/tasks are just a representative sample of issues requiring specialised training:
- Transfer of actives into the weighing isolator
- Description of docking steps or process steps with inherent risk of contamination
- Sampling procedures
- Cleaning procedures for equipment and area
- Line clearance
- Functional checks for equipment set-up
- Gowning procedures
- Decontamination and degowning procedures
- Waste handling and disposal procedures
- Emergency procedures in case of critical failures or machine break down
- Safety instructions for specific actives
At the end of each monitoring programme, results should be shared and discussed with all relevant colleagues, including input from the occupational hygienists and occupational health physicians, when appropriate. Areas of concern must be flagged for immediate action and follow up.
long-term considerations
Global regulatory expertise is always a key factor when choosing a qualified partner for outsourced drug production. Only HCO specialists with expertise in global regulatory environments can provide truly comprehensive support. Many pharmaceutical companies today have 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 HCO.
In selecting a contract manufacturer, pharmaceutical companies must also consider the post-clinical period. While many companies will require only contract manufacturing support for HCO production during early stage development, others will want to consider maintaining a smooth supply flow from Phase II to commercial production. In fact, the leap from Phase III to commercial scale is particularly important; changing the contract manufacturer, formulation, or batch size at this point may raise questions during the registration process. So, pharmaceutical companies would be well advised to select an HCO contract manufacturing partner capable of assisting and transitioning from the clinical studies right through to commercial volumes.
A final consideration relates to the type of HCO manufacturer being considered. So-called "pure play" contract manufacturers are businesses whose sole activity involves contract manufacturing. Some pharmaceutical companies are attracted to the "specialty" focus attributed to pure play providers. However, opting to work with contract manufacturers that are owned and operated by larger pharmaceutical businesses can bring other benefits. Substantially greater financial resources are at their disposal, which could be significant given the cost of developing and maintaining HCO facilities. Also, contract manufacturers affiliated with major pharmaceutical firms can be expected to perform to "Major Pharma" quality standards. They are less likely to risk their own regulatory certifications by performing to less-than-stringent standards for their contract manufacturing customers.
The current trend in the use of highly potent ingredients in new drugs is likely to continue. As it does, demand for clinical scale HCO production will remain strong. The high costs to build and maintain high containment infrastructures, manage the testing, conduct worker training, and manage local and global market regulatory requirements puts pressure on pharmaceutical companies to make wise contract manufacturing choices - both for their early clinical volume needs and, hopefully, for their longer term, commercial success as well.