API manufacturing facility has a long history of successfully implementing innovative solutions to ensure containment of Highly Potent Active Pharmaceutical Ingredients (HPAPI)
, designed to protect workers from the unique hazards presented by potent compound handling. While the success of CordenPharma’s programs requires effective Engineering Controls
, the critical aspect to a robust containment program is the strength of the softer elements, including a Containment Culture, Process Development
, Occupational Health Pre-Planning
, and an ongoing Containment Execution Cycle.
Without these supporting elements, even state-of-the-art containment equipment will not consistently and reliably contain HPAPI.
CordenPharma’s manufacturing facility in Boulder, Colorado is an Active Pharmaceutical Ingredient (API) contract development and manufacturing facility which focuses on the production of therapeutic peptides, highly potent compounds, and complex small molecules. The facility utilizes a full range of development and manufacturing equipment covering all scales, with proven containment systems in laboratory, mid-scale, and large-scale production areas. CordenPharma Colorado has over 30 years of experience handling some of the most potent compounds on the market. As a multi-purpose facility that handles small and large scale production of highly potent compounds, CordenPharma has encountered and solved many containment challenges over the years.
In order to ensure a robust system, CordenPharma utilizes the concept of a “Containment Puzzle
where all of the pieces must align. Not only does a successful containment program require the hard elements of robust containment equipment and Engineering Controls
, but equally important are the soft elements of the Containment Puzzle:
a Containment Culture, Process Development, Occupational Health Pre-Planning,
and an ongoing Containment Execution Cycle.
Figure 1 displays the key elements of the Containment Puzzle as utilized in CordenPharma Colorado.
Engineering controls represent the hard elements of the containment program. CordenPharma Colorado utilizes a variety of containment systems, including hard-sided and flexible isolators, drum containment systems with powder transfer systems, continuous liners, local exhaust ventilation, and others.
Engineering controls are designed according to a Design Exposure Limit (DEL) based on the Occupational Exposure Limit (OEL) for the most potent product for all operations less than 2 hours, or 50% of the OEL for the most potent product for operations greater than 2 hours. The equipment must support not only the manufacturing process operations, but also decontamination of equipment and tools as well as waste disposal. Additionally, the equipment must be ergonomically friendly and easy for the operators to use. If a containment device is uncomfortable to operate, operators are less likely to do it properly, risking a loss of containment. Whenever possible, consistent types of containment systems are employed across the plant site to ensure that operators can move throughout the facility and effectively use all systems.
Engineering control selection and design includes setting a Design Exposure Limit and benchmarking, while the qualification process ensures the containment target is met. A mock-up exercise with input from the full project team and real-end user is an effective way to ensure all of these important design considerations are met. In Figure 2 below, a mock-up technique was used to design a rigid isolator. On the left is the exterior of the mock-up, in the center is the inside, where end-users were able to simulate the process flow and make final detailed design changes, which were implemented in the design of the final isolator, shown on the right.
Often existing systems are adaptable and can be modified to meet the needs of a specific process, and retrofit can be the most economical and effective means to address a containment need.
The expansion of containment levels of existing technology through continuous improvements has demonstrated that technique and personnel experience can vastly improve the levels to which equipment can contain. Once a facility has established and utilized a successful containment program for many years, their personnel at all levels (Industrial Hygienists, Engineers, Operators, Mechanics, etc.) become experts in the design, installation, verification and use of effective containment systems. These people are critical to the success of the program.
Soft elements, such as a containment culture, are also vital to the success of the program. Individuals at all levels of the organization must understand their personal roles and responsibilities to safely contain HPAPI. Top management must also be committed to and lead the program. This means that the appropriate resources are provided for containment systems, from design and ongoing maintenance to monitoring, and that employees are accountable for themselves and for their co-workers to ensure that containment systems are used properly. The end-user operators must also feel empowered to continuously identify and implement improvements to containment systems. Supporting this containment culture is a top-down process, where site-wide goals are set at the management level to maintain and improve containment and HPAPI handling capabilities, while at the operations level safety observations are openly discussed with management.
Containment culture is the product of the individual and group values, attitudes, competencies and patterns of behavior that determine the commitment to, and the style and proficiency of, an organization's Industrial Hygiene program.
During process development, essential activities are done to understand, mitigate, and possibly eliminate the hazards of the process. This includes selecting the right reagents and combinations, obtaining chemical hazard data and the Occupational Exposure Limits, as well as also designing the process to address these hazards.
Many approaches can be used to refine processes during the development phase to reduce exposure risk. Some examples include keeping the product in slurry, ensuring isolation and drying equipment is coupled, eliminating steps in the process, and optimizing the process flow to keep it inside the isolator as much as possible. In one process, CordenPharma chemists and engineers were able to significantly improve a process reducing the number of chemical steps from six to two, which eliminated four intermediate isolations and their associated exposure risk. Additionally, a highly toxic solvent was eliminated from the process. The developed process was not only more efficient, but it significantly reduced the employee exposure potential. While these types of significant process improvements are not always possible, they should be considered during the process development stage when thinking of a commercially safe process.
Process development includes not only obtaining product hazard data with Occupational Exposure Limits, but also addressing these hazards. The following data are important to process development, among others:
Product Hazard data
Physio-chemical – Minimum Ignition Energy (MIE), reaction calorimetry, flammability, flash point
Toxicity – acute, chronic, mutagenicity, sensitization
Ecotoxicity – biodegradation, toxicity to aquatic life
Product Categorization and Occupational Exposure Limits (OELs)
As a CDMO, CordenPharma Colorado works with customers to ensure that the most current data is obtained. The information that is available depends heavily on the phase at which the product is in the drug lifecycle. This information is crucial to ensuring that process hazards are mitigated and containment systems are able to contain to the appropriate level. Additionally, after a process is further developed and more data is available, initial assumptions should be re-assessed and operational refinements made as necessary.
OCCUPATIONAL HEALTH PRE-PLANNING
Occupational health pre-planning is the work done during process development to ensure that once a containment system is implemented, ongoing containment can be proven. This includes the development of the following:
OEL development or placing the product into a control band (for early-phase products)
Acceptable Surface Limits (ASL)
Industrial Hygiene (IH) sampling and analytical methods
Medical surveillance protocols
Deactivation and/or decontamination methods
As a CDMO, obtaining this information from customers can sometimes prove to be difficult due to a number of reasons. For example, “virtual companies” with limited manufacturing experience may have significant process knowledge but do not have the full understanding of the information needed to ensure a safe routine process. Similarly, the disconnect between the manufacturing side (cGMP) and the clinical side (cGCP) of the organization, although both sides need information to ensure worker and patient safety, often creates ineffective lines of communication between each other to ensure data is available to those who need it. As a drug progresses through its lifecycle, more data becomes available. CDMOs need to be aware of what data is available at each phase. Table 1 presents the phases of the drug lifecycle and the correlating information that can be obtained from the data acquired at each phase of the lifecycle (1).
CONTAINMENT EXECUTION CYCLE
The containment execution cycle is the on-going work that continues long after a new manufacturing process has been implemented. It includes aggressive Industrial Hygiene monitoring to collect enough data to confirm that containment has been achieved and is maintained. This includes task observation, equipment and operational refinement, as well as investigations into deviations from procedures to foster continuous improvement.
The requirements for success with this piece of the Containment Puzzle are trained and motivated Industrial Hygiene staff, availability of monitoring equipment and instrumentation, and resources for Industrial Hygiene analytical methods. The Industrial Hygiene staff and management must ensure that operational procedures (PJTs and OJTs) and batch records are adhered to, that consultation is readily available to operations personnel, and that deviations, departures and digressions are investigated and mitigated in a timely manner. Without this critical piece, a containment system that was qualified upon initial commissioning may develop a loss of containment that is not identified, putting personnel at risk for exposure.
At CordenPharma Colorado, all containment systems are placed on a monitoring schedule whereby observations, real-time screening, and integrated sampling are performed to ensure the containment target for the equipment is continually being met.
A robust HPAPI containment program recognizes that it takes an alignment of all of the pieces of the Containment Puzzle to ensure continued success, where there is no such thing as a “done stamp” on containment. Once containment is achieved it must be periodically observed, critiqued and monitored, because operational qualifications are not just for the initial installation. Finally, once a system is qualified and respiratory protection is removed, Industrial Hygiene monitoring becomes even more critical and should be completed more often.
The integration of the hard elements of Engineering Controls and the soft elements of the Containment Puzzle has proven enhanced and repeatable containment for specific installations and is vital for the success of a robust Industrial Hygiene program. Maximizing engineering control investment success allows continued alignment to a company’s commitment to providing a workplace free of recognized health and safety hazards.
Read the full online article in Chimica Oggi, Sept 2015, here.