Contained but not constrained
The pilot plant at SAFC’s high potency API production site in Madison, US
Highly potent drugs require specialised manufacturing facilities to ensure they do not escape into the environment. SAFC’s Trevor Calkins describes how the company designed its multipurpose manufacturing plants to meet the complex containment requirements
The number of marketed drugs that are highly potent is growing, with much of this increase driven by cytotoxic agents. As only tiny amounts of these drugs are required to have a biological effect, they cannot be made in a standard active pharmaceutical ingredient (API) manufacturing plant because of the potential danger to operators, the environment and the general public in the event of exposure.
Instead, they are manufactured in dedicated facilities where enhanced containment has been designed in from the outset.
When a project first comes to us, the potency, toxicity and relative hazards of the molecule are evaluated to determine what level of containment it requires. Each molecule is put into one of four categories (see Table 1 on p18), based on toxicity data that comes from the customer, and also from our own internal evaluation using databases of known molecules of a similar class.
They are categorised in terms of performance-based exposure control limits that link both the toxicity and potency of the compound, and it is this classification that determines precise procedural handling considerations. This system was first established in the late 1980s by some of the big pharma companies for handling development projects where insufficient data were available about a product’s properties during the first production runs.
The category into which a compound falls determines the handling procedures required; our default position for a new chemical entity with unknown properties is to treat it as a category 3 compound. Categories 1 and 2 do not require highly potent manufacturing techniques, but the more hazardous category 3 and 4 compounds need to be manufactured using full containment.
Table 1: Categorisation of compounds
|Category 1: Low potency, higher dosage levels, minimal reversible acute or chronic health effects, good warning properties, no genic effects, not a sensitiser, slow absorption, no medical intervention required following exposure|
|Category 2: Moderate acute or chronic toxicity, reversible effects, weak sensitiser, fair warning properties, moderate absorption rate, no genic effects, may require medical intervention|
|Category 3: Elevated potency, high acute or chronic toxicity, effects may not be reversible, moderate sensitiser, poor or no warning properties, quick absorption rate, suspected or known genic effects, moderate to immediate medical intervention required|
|Category 4: High potency, extreme acute and chronic toxicity, irreversible effects, strong sensitiser, poor or no warning properties, quick absorption rate, known genic effects, higher degree of medical intervention required, may affect sensitive subpopulations.|
SAFC has two sites in the US where highly potent actives can be manufactured. The former Tetrionics facility in Madison, Wisconsin was opened in 1989, and a second, larger-scale facility is currently being brought online in nearby Verona. Both are able to manufacture bulk highly potent compounds. In addition, there is a facility in St Louis, Missouri where highly potent small molecules made in Madison can be conjugated to biologics, and the Jerusalem, Israel facility can make highly potent actives using fermentation.
The Madison and Verona facilities use a cascade of controls to ensure full containment. Five levels of safe handling help the company to put in the correct engineering and procedural controls for manufacturing highly potent compounds. These are: process isolation; containment equipment; facility design; personnel protective equipment; and personnel procedures.
First and foremost, the primary form of containment is process isolation. When manufacturing highly potent APIs (HPAPIs), closed system glassware and reactors are key. All powder transfers are carried out in closed systems and, on a large scale, we will use closed powder transfers such as the DDPS powder transfer system and/or a/b valve technology in conjunction with isolators. Further engineering controls are also in place, with containment equipment such as gloveboxes, weighing hoods and rapid transfer ports, as well as local exhaust ventilation and closed-system cleaning.
This all enables us to keep highly potent molecules inside the reactor and prevent them from being emitted into the common areas of the facility.
The third level of control is facility design. Both facilities are designed with dedicated project suites. Room pressure differentials are used to enhance containment and these are constantly monitored and verified. Airlocks and vestibules are used on all entries and exits to the manufacturing and lab spaces, with access restricted only to designated operators, and there are misting showers in the degowning and exit vestibules. The air is single pass, being changed 15 to 25 times an hour, with temperature and humidity control. Contaminants are filtered and captured using safe-change filters on both point source and the HVAC system. Preventative maintenance is essential, as are carefully implemented change control procedures.
Our operators also wear appropriate personal protective equipment, with Saranex coveralls and hoods, and either a powered air-purifying respirator (PAPR) or supplied air. It is important that the correct type of glove is selected for the chemicals that are being used, and chemical suits are used when the solvents or reagents deem it necessary. Protecting the operator in this way is purely a failsafe system in case there is a failure of the containment; if every-thing is working as it should then none of the highly potent compound should be in the atmosphere.
Coveralls, respirators and gloves provide a safety back-up
Finally, we have a very sound personnel training programme, educating our employees in safety and the carefully designed procedures that have been put in place to ensure their protection. We also monitor their health on a routine basis to ensure we can work on the most potent compounds without risking the safety of our operators.
Looking more closely at the engineering, the isolator is the first line of defence, as it keeps powders and solutions inside the reactors. Some other manufacturers consider the containment system sufficient, but we believe it is important for our operators to suit up as well for secondary precaution.
The isolator is more negatively pressured than the lab, and has a safe-change removable HEPA filter through which the air moves up into the facility’s ventilation system. The front of the isolator can be completely opened when clean in order to introduce large items of equipment that will not fit through the normal antichamber on the side. Obviously, this is carried out between operations and after decontamination, when no dangerous material is present. Also, our isolators are equipped with drying ovens for the removal of residual volatiles without exposing the HPAPI to the operating environment. These isolators are custom-made to our specifications.
Powder transfers into reactors are carried out using PSL’s a/b valve technology. One half of the valve is connected to the reactor and the second to a charging bottle, which is filled in an isolator; the two halves are connected and both opened to allow the addition of material to the reactor under containment. They are then closed and disengaged. This ensures that no material is present on the outer surface of either reactor or charging vessel.
When moving solids around, the drying process is also critical. The typical industry standards for drying bulk solids are tumble dryers, cone dryers and tray dryers, but with highly potent compounds drying also has to be carried out in a contained way. This is achieved using Nutsche filter dryer technology, where the discharge is also isolated to move material out of the filter dryer and into packaging without exposing it to the environment.
Packaging highly potent powders also poses problems. We overcome this by using PSL valves that marry to product charge bags, which enables us to close off the bag before disconnecting from the isolator. Within the glovebox itself is a discharge port that allows material to be removed from the filter dryer and dropped through a hopper at the bottom of the glovebox into contained packaging.
While some of the equipment is off-the-shelf, further customisation is often needed. For example, the Nutsche filter dryer is married to the isolator, so the two engineering companies worked together to make the equipment that meets our requirements. Industry is now beginning to identify what is necessary in equipment for manufacturing highly potent compounds, but in most instances it still requires several equipment companies to make a piece of equipment that meets HP manufacturing requirements per our design specifications.
We also test and verify our containment equipment and cleaning methods (project specific verification) to ensure that they perform as they should. This includes surrogate testing, using a model compound such as naproxen sodium or lactose. In addition, the facility is audited and certified by a third party, Safebridge Consultants, every two years; in the intervening years we carry out our own assessment. While there are no formal certification requirements for working on highly potent compounds, we believe it is important to involve an outside organisation to give both our customers and our employees confidence that SAFC manufactures with high containment and industry standards.
The cut-off point for manufacture within the Madison facility is about 50kg, depending on volumetrics and particle density. Any larger runs, up to about 400kg, will be carried out at the new Verona facility, where we have a 2,000 litre Hastelloy reactor, 2,000–4,000 litre glass lined reactors, and 4,000–8,000 litre glass lined work-up vessels. These are used in conjunction with two Hastelloy Nutsche filter dryers, one 1m3 and the second 2m3.
The concepts are the same in both, although the engineering controls are slightly different. However, the quantities create additional complications, such as the logistics of introducing hundreds of kilograms of a potentially potent solid into a reactor.
The kilo lab. The cut-off point for manufacture within the Madison facility is about 50kg
Up to about 50kg, it is straightforward to fill a charge bag or bottle and then connect it to the reactor through an a/b valve. But this becomes cumbersome with larger quantities; either the charge bottle would be far too heavy to manoeuvre safely or, more realistically, the reagent would have to be added in numerous smaller batches. However, the more times something is done, the more the inherent risk increases for a breach of containment. As a result, we designed the solids handling process for Verona slightly differently.
The solution was equipment that enables isolated drum discharge. The isolator within the facility looks like any normal isolator, but at the back there is a coupling interface that allows connection of a drum. The connection system is put on the drum before it is opened; the drum is then raised and connected to the isolator so the contents can be discharged into the isolator without any material being released into the operating environment. The isolator contains a hopper connected to a delumper, which then discharges into a peristaltic powder handling system from De Dietrich. This allows the solid to be moved over a long distance, thus safely introduced into the reactor. The same system can be used in conjunction with our filter dryers to transport the materials back into the reactors for further processing. After transfer, the system is washed and verified for cleanliness before it is used in the next process.
After the reaction is completed, the product is transferred from the reactor into the isolated filter dryer, and from there is packaged using a Dover continuous liner packaging system. The bottom of the packaging material is sealed, the finished product added via contained discharge from an isolator, and the bag sealed, cinched and cut, ready to start the next drum. This ensures the powder is contained at all times.
It is not only the production area where great care is taken over containment – in both Madison and Verona our analytical QC laboratories are also equipped with isolators and/or laminar flow weighing hoods that allow small samples of highly potent compounds to be weighed out in a contained environment. This work is performed in a segregated area from the rest of the laboratory.
Validation and verification
Finally, in multipurpose facilities like ours, it is important that we can verify to our customers that a rigorous cleaning process has taken place to ensure there is no carryover from one batch and product to the next. The procedures are laid out in OPs and protocols, and include equipment description and design, materials of construction and product contact materials, product contact surface area calculations, identification of difficult-to-clean areas on equipment, cleaning procedures, who performs what, and acceptance criteria.
Cleaning method verification procedures are critical when working in a multipurpose facility and must be performed for all projects, along with recovery studies. Maximum allowable carryover calculations have to be used to determine system cleaning limit requirements; this is process train specific and requires detection and cleaning limit of <10ppm.
Systems and equipment that cannot be verified clean, such as product contact process hoses, are considered project/use dedicated. Like any standard cGMP manufacturing facility, the equipment is quarantined until it is verified clean.
Setting up a facility to manufacture highly potent compounds is an expensive and painstaking operation. However, the growing number of APIs that are classed as highly potent has led to an increase in demand for capacity from contract manufacturers. Commissioning a highly potent API facility is a significant investment, particularly with the number of failsafes we have built in, but we believe it is important that safety of our operators and the environment is assured.
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