The advent of Highly Potent Active Pharmaceutical Intermediates (or HPAPIs) has required a rethinking of pharmaceutical production operations. These small molecules, usually produced in smaller batches, have greater potency and are able to target and eliminate specific maladies, often taking patient-specific genetic information into account. Nowhere has this trend been greater than in the research, development and production of anti-cancer drugs, bringing to the fore not just the researchers’ ability to use genetic information to match drugs to certain biological “markers” for specific types of cancers, but also the drug’s potential for side effects from accidental contact during the manufacturing process. This has required specialized equipment for their production, handling and packaging. This article focuses on some of these advances that process equipment manufacturers have made in response to the challenges faced by the industry.
According to the National Center for Health Statistics, cancer is the second leading cause of death in the U.S., accounting for about 30% of all deaths. Since mapping the human genome, the war on cancer has seen a major shift, with there being potentially a different drug to be used not only for different cancers, but also for different patients. With the pipeline of major “blockbuster” drugs dwindling, the biopharma industry has shifted gears and is currently in various stages of development of some 800 cancer drugs. For even a fraction of these to benefit humanity by making it to the market in a safe and timely manner, it will require changes not only in regulatory policy, but also how we think of drug development and production.
While in the past anti-cancer drugs targeted only cells in the cell-cycle and did not take into account the uniqueness of every type of cancer, advanced clinical research is shedding light on the specific therapeutic targets. As such, pharmacological research is entering into a new era of targeted molecules with selective cytotoxicity. These bio-conjugates combine the highly specific delivery of an HPAPI to targeted cells, with significantly reduced side effects to non-targeted cells — a “smart bomb” of drugs known as antibody drug conjugates, or ADCs.
Anti-cancer drugs are generally referred to as ‘highly potent.’ Some of the drugs are complex molecules of natural origin that are purified and then subjected to chemical synthesis. Usually, the production process has to be performed in a controlled environment; presence of minute amounts of these in their final form in a roomful of air has the potential to cause immense harm if inhaled or otherwise ingested/contacted.
Production of API and HPAPI — Worlds Apart
Conjugation of highly potent cytotoxic molecules creates an environment significantly more challenging than that needed for handling bio-molecules, as in API manufacturing. For bio-molecules, the key is avoiding contamination from people involved in the production process, and as such, a positive pressure is always maintained in and around the production area so as to preclude any contaminants from entering the product. However, in HPAPI production, due to the agent’s potential for harm if workers were to come in contact with it, worker protection takes on a whole new meaning. Complex air-handling requirements are carried out under negative pressure to prevent the material from entering the environment, and workers are required to wear full protective gear. The major difference between API and HPAPI manufacturing facilities is the specialized containment that ensures both the employees and the environment are protected. This requires investment of millions of dollars over and above what a GMP facility may entail, especially in the potent compound handling and biologics processing capabilities.
HPAPI production challenges may broadly be divided into three categories, namely:
- Handling requirements: worker protection is key, requiring complex air and material handling systems
- Personnel considerations: highly skilled and trained personnel are required, with regular training programs and standard operating procedures (SOP), full personal protective equipment (PPE), etc.
- Plant and equipment: specialized and multi-functional equipment for both the handling of the HPAPI as well as air-handling, to include fully contained sampling and testing methods with engineering controls as the primary source for containment and isolation.
HPAPI handling systems should incorporate primary and secondary containment on five levels, starting with process isolation (such as barrier isolation techniques and α/β valves), to the use of the proper containment equipment (such as active isolators and globe boxes), to the overall facility design (such as restricted access, air-locks, misting showers, etc.), to personnel training, and finally PPE. The key factor in all this is the people: their experience and expertise combined with their work-culture — thinking and training — will make all the difference between success — and very costly failures.
HPAPI levels of containment are based upon potency categories. In the absence of any governmental guideline, the industry has self-policed itself by developing its own standards. A four-category index developed by Safebridge Consultants has been expanded and customized to a five-tiered system used by Merck, and a Class one-to-six System used by Lonza (among others). These systems are all inherently based upon the active ingredient’s toxicity and pharmacological potency, as well as their occupational exposure limits (OELs). Typically, APIs with OELs <10 micrograms per cubic meter of air over an eight-hour time-weighted average (TWA) are considered “potent” from an occupational health standpoint.
HPAPI uses Process Analytical Technology (or PAT) tools to a much greater extent than API does, by identifying critical process parameters (CPP) and measuring in real-time, using what’s most appropriate in automation, sampling, multivariate data acquisition and data storage, among others, so as to control critical quality attributes (CQA). The use of PAT reduces unnecessary sampling, thereby reducing the risk of contamination. Also, since PAT uses mostly non-destructive methods, there is reduced sampling and testing that would otherwise lead to waste in production of these very high-value products.
Specialized Equipment for HPAPIs
In response to the demands of HPAPI production, equipment manufacturers have stepped up with many adaptations and enhancements in product design with innovations in barrier isolation technologies, split-valve design, dewatering/drying systems, among others. Some of these advances in the area of dewatering (or filtering) and drying are described below.
Pressure Nutsche Filter-Dryer with Multiple Chamber Active Isolators
Multiple chamber isolators are used where the pack-off is to be performed in a contained environment. Active isolators with separate air handling systems for the upper and lower chambers are typically used to provide optimum operator protection. In addition to the equipment provided with active isolators, multiple chamber isolators offer the following additional features:
- Optional pack-off using continuous liners
- Optional pack-off using in-line mills
- Optional detachable lower chamber
- Optional separate container entry/exiting chamber
Containment devices (such as glove boxes) not only allow for contained sampling, product discharge and pack-off into lined drums or other containers, but also heel removal for total product recovery and filter cloth disposal, while fully protecting the operating personnel and preventing contamination of the product. The isolator is installed on the filter-dryer using an adaptor flange around the discharge plug. Depending on the degree of containment specified, passive or active, single chamber or multiple chamber isolators are required.
Passive isolators, used for less demanding containment requirements, are operated under ambient pressure and are vented to the exterior using HEPA filters. Active isolators operate under a slight vacuum to prevent powder or gas exiting the containment. Air is extracted from the interior using a fan and double HEPA filters, with air or nitrogen purging through an inlet HEPA filter. The isolator interior pressure is monitored, and the extraction rate is raised if a pressure drop indicates containment breach, e.g. by a damaged glove. The HEPA exhaust filter differential pressure is also monitored to alarm the onset of filter blockage. From the isolator, product is discharged through a bag-out port, continuous liner, active valve, etc. into drums or other types of containers.
Side bag-in/bag-out ports or side RTPs are provided to move items such as sample bottles, tools, etc. in and out of the isolator. A wash gun permits cleaning the isolator interior, and CIP spray balls may also be installed. Other accessories could include a rake for heel removal, a glove port barrier to prevent the operator from reaching into the unit unless it is safe to do so, hinged front doors, and interior lighting. All filter dryer and isolator functions are monitored and interlocked to assure their safe functioning.
Vented Barrel Adaptor with Inflatable Seal and RTP
A single chamber passive isolator for sampling, product discharge, pack-off and heel removal installed on a 200-liter filter-dryer is shown. For pack-off, this isolator is equipped with a vented barrel adaptor with inflatable seal and a manually operated butterfly valve. A 105 mm RTP is installed to move sample bottles in and out of the isolator. Separate HEPA filters are installed for the venting of the isolator as well as of the barrel.
Another variation is a single chamber active isolator for sampling, product discharge, pack-off, heel removal and filter cloth disposal installed on a smaller filter/dryer with just 0.20 m² filtration area. The 270 mm side RTP permits moving sample bottles in and out of the isolator as well as to dispose of the used filter cloth. Pressure gauges permit monitoring chamber pressure and the differential pressure across the HEPA filters. A separate control panel contains the required controls and indicators for the operation and monitoring of the isolator.
Pressure Nutsche Filter-dryer Contained inside a Chamber Isolator
Shown here is a pressure nutsche filter-dryer installed inside a chamber isolator. Separate chambers are available within the isolator for a reactor, solvent containers, the filter-dryer itself, pack-off and discharge. The lower filter-dryer vessel section can be tilted for emptying and for cleaning.
Through-the-Wall Mounted Fully-Contained Centrifuge-Dryer System
Due to their ability to provide greater containment, filter-dryers have been overwhelmingly preferred for dewatering (or filtering) and drying applications over centrifuges in HPAPI production operations. Even so, the inverting filter centrifuge has evolved into a compact and sealed system with a footprint that is a fraction that of a filter-dryer of comparable throughput. This is a major advantage, given the HPAPI facility’s high cost of construction per square foot. Combined with higher G-forces and a feature known as Pressure Added Centrifugation (or PAC), which uses heated nitrogen to extract the final moisture, this centrifuge produces a cake that approaches the final moisture levels of a filter-dryer, in a fraction of the cycle time and cost. With its relatively low profile and available through-the-wall mounting, this centrifuge minimizes the need for valuable clean-room space. Available docking stations can be used at the solids discharge opening to make this a fully contained system.
The Challenge Ahead
HPAPI production, with its estimated compounded annual growth rates of 15%, represents a second wind to many CMOs, but there is still a learning curve even for long-established API manufacturers. Thanks to the eroding pharmaceutical chemicals manufacturing base here in the U.S. over recent decades, the kind of expertise and experienced personnel (a key requirement of a HPAPI facility) to draw from and train in order to establish a safe HPAPI production operation, has gotten more difficult to find. For now, the advantage lies in other markets, such as Switzerland and Germany, where the manufacturing base has remained intact and, in fact, has evolved in the direction of greater value addition. However, some U.S. manufacturers have taken strides in this direction. Most notably, Sigma Aldrich (SAFC) has opened a $30+ million state-of-the-art HPAPI facility in Verona, WI, and we can hope that other domestic CMOs will soon follow.
Tom Patnaik serves as director of sales & marketing at Heinkel Filtering Systems, a Swedesboro, NJ-based manufacturer of dewatering and drying equipment, specifically centrifuges, pressure-nutsche filter-dryers, vacuum dryers & mixers, among others, designed for the biopharmaceuticals, fine chemicals, chemicals, and other industries. He can be reached at email@example.com.