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Patricia Van Arnum was executive editor of Pharmaceutical Technology.
An industry roundtable representing Metrics, Cambrex, Carbogen Amcis, Euticals, Ferro Pfanstiehl, and SAFC.
High-potency manufacturing is a niche, but specialized area that requires proper facility design, equipment selection, production processes, and operator knowledge to safely handle and produce highly potent APIs (HPAPIs) and finished drug products containing HPAPIs. Pharmaceutical Technology conducted an industry roundtable to gain a perspective of these issues. Participating were: Joe Cascone, director of potent product pharmaceutical development at Metrics; Joe Nettleton, vice-president and director of operations at Cambrex's Charles City, Iowa, facility; Peter Müller, delegate of the Dishman board and member of the Carbogen Amcis' management team; Theodore Iliopoulos, chief scientific officer at Euticals; Paul Doherty, chemical engineer, Sigma Black Belt, and plant manager at Ferro Pfanstiehl Laboratories; and David Bormett director of operations at SAFC.
Facility design and equipment selection
PharmTech: A key challenge in high-potency manufacturing is to maintain the level of containment throughout the manufacturing process. What are the key considerations in designing a high-potency manufacturing facility and in selecting equipment?
Iliopoulos (Euticals): High-potency containment structures address both cross-contamination requirements targeting patient safety, and at the same time, worker safety by maintaining occupational exposure limits (OELs) below 10 mcg (Band III) or 10 ng (Band IV) per cubic meter of air for an eight-hour weighted average. Exposure to just a small quantity of a highly potent HPAPI or highly potent compound can pose significant health risks.
The challenge in designing a high-potency containment facility is to find the appropriate level of containment that should manage the exposure risk at a reasonable cost. It also is crucial that the operators and the production staff understand the need and proper use of engineering controls. Enclosed reactors, centrifuges, dryers, and highly dusty mills are key manufacturing assets in an API production line and, together with product-transfer systems, are key elements in a high-containment design. The most crucial issues in selecting the proper equipment are the containment of the process itself. In other words, one must ensure that no airborne particles are released to the ambient air and that product remains in the process piping used. Equipment and facility-engineering controls apply to all areas handling such compounds, not just manufacturing. It also refers to process-development and quality-control laboratories.
Manufacturing chemist in personal protective equipment handling material in fully contained glovebox isolator at SAFC's facility in Verona, Wisconsin.
Bormett (SAFC): Proper initial design and engineering of a potent-compound handling facility is crucial to achieve the desired levels of containment. Consideration must be given for containment of the entire process, from weighing and charging of raw materials, to packaging of the final material. Key facility-design criteria include single-pass heating, ventilation, and air-conditioning (HVAC) systems, controlled access to areas, airlocks around potent-compound handling rooms for segregated gowning/degowning, proper room-pressure differentials for containment, degown misting showers, bag-in/bag-out filtration components, sufficient support utilities (such as supplied air), and proper waste-handling capabilities.
SAFC uses an overall potent-compound handling system that incorporates five levels of cascading protection, with the first two being the primary methods of material isolation/containment:
Nettleton (Cambrex): In pharmaceutical manufacturing, there are two primary objectives for containment: to protect product quality and prevent worker exposure. There are underlying design principles that apply to all pharmaceutical manufacturing and analytical facilities at Cambrex. The operational goal is to maintain process isolation using isolators, sealed process vessels, dedicated piping, and single-pass, high-efficiency particulate air (HEPA)-filtered airflow. It also is crucial to design the ventilation system so that potentially contaminated air will flow downstream and away from the process area. Ingress and egress also are controlled to ensure both air and worker traffic moves in a single direction with minimal turbulence. Gowning/degowning vestibules, material pass-throughs, and misting showers also are integrated into the flow. Upon ingress, disposable garments are donned, and upon egress, workers are misted with water to tack particulates to disposable garments, which are then discarded before exiting.
With respect to exposure prevention, in many instances, the design strategy for quality protection is the same as exposure prevention. Process isolation using isolators, sealed reactors and dryers, and HEPA-filtered airflows all are important. In some cases, however, pressure differentials that protect pharmaceutical quality may not be protective of worker exposure. For example, when opening an isolator, positive pressure in the isolator will prevent cross-contamination, but the pressure release will potentially expel particulate material toward the worker. In these cases, the engineering strategy may include a bag in/out system. It also may be appropriate to include extra personal protective equipment when transferring toxic or potent compounds.
Manufacturing chemist in personal protective equipment attaching a hose to the powder-transfer system below a glovebox on a Nutsche filter dryer at SAFC's facility in Verona, Wisconsin.
Mockups, training, and verification also are key. Because all manufacturing processes are different, it is important to verify that a given process design will function correctly and that operators are familiar with the process before a pharmaceutical product is actually manufactured. At Cambrex, it is common for the manufacturing team to develop and conduct mock handling exercises. These mock exercises may include the handling of surrogate pharmaceutical compounds followed by an assessment of potential releases and cross-contamination using wipes, air sampling, and appropriate analytical detection. Naproxen is typically used as a surrogate because it has an extremely low detection limit and is easy to clean. At completion, mock exercises will demonstrate that process and containment equipment performs as expected, provide process ownership and training for operators, and identify potential need for design modifications to prevent cross-contamination or worker exposure. Cambrex routinely conducts equipment maintenance and equipment performance verification to ensure isolators, hoods, balance enclosures, airlocks, and HEPA systems are working properly.
Müller (Carbogen Amcis): Carbogen Amcis has more than one site and has more than one production facility at its headquarters site in Bubendorf, Switzerland, but the concepts pursued with regard to containment are governed by one common philosophy regarding the handling of HPAPIs: the risks to be controlled regard the patient, the worker, and the environment. Therefore, we are analyzing the whole lifecycle from the purchasing of raw materials (which may eventually be highly potent compounds) to the delivery of products and to the creation of waste, the whole set of buildings and installations involved, and the whole series of applicable procedures and measures.
The containment requirements are defined in view of the toxicological category (performance-based exposure control limit [PBCEL], OEL, or acceptable daily exposure [ADE], respectively), whereby Carbogen Amcis is working with a four-categories approach, and strict requirements are applied in case of Categories 3 and 4. They involve with regard to production separation of the ventilation (room and/or reactor exhaust, i.e. systems), HEPA-filtration of exhaust air, separation of the room (airlocks), pressure cascades, partial dedication of specific equipment to HPAPIs, completely closed processing, and separation of the wastestreams. The focus is on avoiding carryover as well as contamination of the workers and the environment through production equipment (cleaning), through space, and through infrastructure systems. The respective considerations are applied along the whole sequence of activities (i.e., the lifecycle). The details cannot be outlined here, but it can be said in a summary that they include gloveboxes or isolators, respectively, barrier isolation benches, laminar flows, and flexible containment with all the activities subjected to their specific risk analysis. Personal protective equipment is eventually used as a safety backup during critical operations.
Cascone (Metrics): The facility and equipment constitute the barriers between the high-potent active agents and their surroundings. A facility designed with one-pass air and multiple airlocks with cascading negative pressure differentials will, in conjunction with other controls, mitigate cross-contamination. Hard- and soft-wall isolation technology demonstrates sufficient containment for the manufacture of solid-oral dosage forms containing compounds deemed to fall within an occupational exposure band of 10 mcg /m3 to 30 ng/m3 (TWA). These systems may be verified by recognized industrial hygiene practices, such as the ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment (1).
Enclosing a particular process or unit operation is reasonably well-established by most equipment manufacturers and isolation specialists. A key challenge is linking the unit operations together with the proper conveyance technology. This is particularly daunting if there is a wide variety of equipment makes and models. It is generally easy to contain powders within a bowl or vessel. Charging and discharging those powders and transporting them to other pieces of equipment is more complex. Examples of conveyance technology that may offer solutions include vacuum conveyance and continuous-liner 'bag-out' systems.
Another challenge related to isolation and containment centers on powder sampling. Process intermediates (e.g., blends and granules) need to be sampled to characterize in-process attributes and/or comply with prescribed regulations. Access to the product via properly designed and contained sample ports is essential.
Doherty (Ferro): First and foremost is the principle to not rely on 'moon suits' for the operators and instead have a strategy and philosophy to use engineering controls to provide proper containment. The key considerations are the OEL of the substance to be handled and, particularly for a CRO/CMO, the stage of the API and the scale of operation. The organization should have a system in place that uses the OEL to establish the acceptable options available for facility design and equipment selection. For a CRO/CMO, the best and most economical means to handle a potent substance depend significantly on the stage (preclinical, clinical, or commercial) and scale. For example, the best means of producing a preclinical small-scale API might be a combination of dedicated laboratory-scale equipment, disposables, and a small isolator. In contrast, a commercial product produced at a 50-kg scale might require plant-scale equipment with validated cleaning procedures and test methods.
Risk assessment, evaluation, and mitigation
PharmTech: What are key considerations in risk assessment, revaluation, and mitigation in high-potency manufacturing, including the metrics used to monitor risk?
Cascone (Metrics): Conducting a thorough risk assessment is the best practice to achieve a desired level of containment. It is important to note that 'more' containment may not be a 'desired level' of containment. Rather, the desired level of containment is derived from the need to protect employees and mitigate cross-contamination of drug products. The level of containment required in any instance should be technical and quantifiable. It is not speculative or derived from interpretation or opinion.
A comprehensive risk assessment will determine what engineering, facility, and administrative controls are required. A risk matrix may be developed for each step of the process. Each matrix will identify associated potential adverse events. Each potential adverse event should be quantified by calculating the product of its probability of occurrence by its severity. Risks cannot be monitored during a process, but actual events and exposures can. Proper feedback tools are essential to ensure the 'desired level' is appropriate and effective.
Bormett (SAFC): Utilization of properly designed engineering controls is the primary means for achieving the desired level of containment. It is important to understand the OELs or potential OEL of development compounds, for the product to be handled in the facility, and then design and test to meet 50% of the lowest OEL. Planning for containment at 50% of the OEL allows for variability that may occur due to different operators, process scales, material densities, and/or equipment use. Proper containment should be confirmed by obtaining industrial hygiene air/surface samples and conducting testing for the specific compound being handled, or using a representative surrogate product. Data generated during industrial hygiene testing should be used to assess areas of greatest potential risk for exposure to allow for improvements and changes to be implemented to minimize the risk. Testing must be repeated over time to evaluate containment systems and processes and to ensure that equipment continues to operate at expected levels.
Another key area for consideration is equipment cleaning following use with potent compounds. An effective and verified cleaning program is critical to prevent potential cross-contamination, especially in a multi-use facility. Equipment cleaning also can be an activity for potential employee exposure. Therefore, CIP systems should be employed when possible, and monitoring should be performed during cleaning activities to verify that the OEL requirements are being met.
Facilities handling highly potent compounds should have a compound evaluation and categorization system in place in order to conduct appropriate risk assessments and communicate hazards. This is especially critical when working on developmental compounds that may not have an established OEL. The categorization can be used to determine proper handling and containment requirements for the compound based on the systems in place within the facility.
Iliopoulos (Euticals): A proper facility to handle HPAPIs should be designed considering technologies such as isolators, laminar flow hoods, and local exhaust ventilation systems with air filtered before released to the ambient air. The air supplied to the rooms should be single-pass with proper air-pressure differentials to keep product-exposed areas negative to all adjacent areas or airlocks. Appropriately validated cleaning procedures should secure no cross contamination with the next compound to be produced using same equipment or piping. ISPE launched the Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) Baseline Guide, which provides a scientific risk-based approach, based on ICH Q9, to manage the risk of cross-contamination (2, 3). EMA followed with a concept paper, published in Oct. 2011, and suggests using "a more scientific approach...to establish threshold values" (4).
In instances when the toxicity of a compound is not known, it must be treated as Band IV compound. Obviously, the best would be to determine the toxicity of a given compound prior to embarking in high-cost production set-ups. To minimize the risk and for extra safety purposes even if engineering controls are in place, personnel working with highly potent compounds should wear suitable personal protective equipment, including respiration equipment. Best practices in dealing with HAPIs are the availability and checking of material safety data sheet (MSDS) data for any compound used in the process, process-hazard analysis, start-up, safety review, training, change control, emergency planning and response. Measurement of the dust during operation in the production areas is a key parameter in defining and checking the safety level at the operational level.
Nettleton (Cambrex): Risk management at Cambrex begins with training. All Cambrex employees granted access to areas that manufacture potent or toxic APIs must participate in training and become certified. Training follows a detailed risk assessment and risk-management framework that was developed in collaboration with the Cambrex toxicologist who is board certified and has extensive experience in risk assessment and with the Cambrex occupational nurse. Project-specific risk management recommendations are formalized by the toxicologist into a document known as a Project Safety Dossier (PSD). PSDs are formally reviewed by the manufacturing team before beginning work. In high-containment areas, new process designs are evaluated by certified Cambrex manufacturing teams in mock exercises that verify and document containment. Cambrex is guided by a four-band occupational exposure band (OEB) framework. Every molecule used to synthesize the API is evaluated separately and assigned an OEB. In some cases, where data are unavailable for a particular synthetic intermediate, Cambrex may conduct in silico assessment and in vitro toxicity testing (5).
When making risk-management recommendations and decisions, Cambrex is cognizant that safeguards must balance the conflicting goals of mitigating exposure risk, minimizing the ergonomic hazards imposed by unnecessarily conservative exposure controls, and quality considerations. Safeguards include integration of API-specific toxicodynamic factors into risk-management decisions, appropriate use of personal protective equipment, and containment verification with good hygiene practices.
Müller (Carbogen Amcis): The best practices to be applied depend on the category and amount of the material handled and on the frequency and complexity of the operation in question. For Carbogen Amcis, we are working with dedicated equipment that is firmly installed in many instances and working with flexible containment approaches in others (e.g., when having to dismantle equipment in the context of cleaning or when having to be sure that eventual leakage could be controlled). A realistic assessment of the risk in question is important.
Key practices in analytical monitoring involve swabbing surfaces (e.g., in the laboratory) as well as air-sampling during critical operations. Thereby, we are normally working with a combination of IOM samplers carried by the worker and of stationary samplers adequately placed to provide an idea of the eventual emission's distribution in space. We use surrogates right after installing new equipment and periodically perform analogous sampling and analyzing (i.e., high-performance liquid chromatography) of the true highly potent materials to control routine operations later on. The key parameter to be realistically determined is the exposed person's potential daily up-take in micrograms
Doherty (Ferro): Before moving forward with any project work, a process hazard analysis (PHA) should be conducted. This PHA will evaluate all aspects of the technical challenge and incorporate information, such as safety data sheets, product use, OELs, short-term exposure limits, odor threshold, industrial-hygiene monitoring method and analysis, irritant or sensitizer, toxicological data, primary toxic effect, route/mechanism of exposure, warning signs of exposure, treatment for exposure, cleaning procedures, acceptable surface residual levels, deactivation procedures, flammability/combustability, applicability of transportation regulations, waste disposal consideration, and other regulatory impacts.
Even with the best facility design and equipment selection, the level of containment can be largely determined by operational practices. Therefore, a considerable amount of effort needs to be devoted to writing solid operating procedures, and providing operator training. The organization should have a system in place that uses the OEL to establish the acceptable options for handling procedures and practices. In addition, industrial-hygiene monitoring should be used to verify that the combination of facility design, equipment selection, and operational practices is providing the expected level of containment. Medical monitoring of employees should be included as a verification of the adequacy of the industrial-hygiene sampling program.
PharmTech: What are some recent technological advances in facility and equipment design for high-potency manufacturing?
Cascone (Metrics): Many equipment vendors are pre-engineering their equipment to be contained whereas in the past this was considered an optional upgrade. New equipment is more modular in nature. Product-contact modules can be cleanly removed from drive units and disassembled and cleaned in remote washing areas. This reduces downtime and exposure risks.
Bormett (SAFC): There has been an increasing interest idisposable containment options for potent-compound handling, especially for larger-scale operations. Disposable systems reduce the time for cleaning and can eliminate the potential for cross-contamination. They also may be used as secondary isolation around fixed equipment to improve overall containment of the process to meet lower OELs. Improvements in local exhaust systems, with proper filtration for potent-compound capture, also have been implemented to further reduce potential exposure to employees or the facility. The integration of two types of equipment, in some instances by two different equipment vendors, also is an area that has seen improvement. This could include engineering glovebox isolation equipment onto Nutsche filter/dryers or lyophilizers to allow for containment during discharge of potent compounds.
Iliopoulos (Euticals): There is a growing trend in powder processing. Closed systems for powder handling and special valves are being developed along with engineering advances in the equipment used to contain the highly potent APIs or hazardous compounds. The term containment itself directs engineers in developing methodologies and structures to isolate the highly potent compounds. Charging materials to reactors, discharging a centrifuge, charging of a mill and packaging in closed systems are becoming popular practices in dealing with highly hazardous substances produced in multipurpose facilities. Traditional technologies are not easy to clean, and the risk of material remaining on the surfaces is too high. Disposables used in the closed system solve these problems, but have limitations with some solvents. Some examples of currently used isolation technologies using disposables are drum-sampling, dispensing, transfer sleeves, filter-change containment, decontamination, and cleaning containment. The benefit is that with low investment, one can achieve the desired containment level. I am sure that the future development will be focused in the development of isolation technologies at the level of dust generation.
Nettleton (Cambrex): With improved awareness and hazard recognition related to high-potency API development and manufacturing, there is a greater appreciation of proper risk management associated with HPAPI handling in general. Industry leaders are working to move away from administrative containment strategies to more robust engineering conrols. Specifically in regards to micronization of HPAPIs, Cambrex maintains GMP micronization suites equipped with high-level containment engineering controls. These containment systems units have demonstrated performance to 1 ng/m3.
Doherty (Ferro): What I am seeing is a lot of small improvements to potent-handling equipment, such as better means of cleaning split butterfly valves that provide continuous improvement in containment. These small improvements should not be underestimated in their beneficial impact.
1. ISPE, ISPE Good Practice Guide: Assessing the Particulate Containment Performance of Pharmaceutical Equipment (2nd Edition, Tampa, FL, May 2012).
2. ISPE, Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) (Tampa, FL, Sept. 2010).
3. ICH Q9, Quality Risk Management (Nov. 2005).
4. EMA, Concept Paper on the Development of Toxicological Guidance for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities (London, Oct. 2011).
5. M.S. Maier, Toxicol.Mech.Methods 21 (2), 76–85 (2011).