By Monica Colberg and Terrence Fay
Today’s pharmaceutical markets involve the development of highly potent active ingredients where small quantities of product cause pharmacological effects on humans. These new products can be manufactured in small scale manufacturing suites which in turn reduce operational and capital costs among others. However, operator exposure during the manufacture of this product has to be controlled. This article reviews design considerations for tablet containment facilities integrated with process containment technologies that will provide the owner with a facility that is flexible, cost effective and will meet the containment requirements of the product.
During the past five to ten years, pharmaceutical industries have been producing an increasing amount of potent drugs where the active pharmaceutical ingredient(s) (API) is part of the incipient composition. Potent drugs have the capability of achieving a pharmacological effect with very small amounts of active ingredients. Airborne particles can present risks to the operator if released into the room environment. Potent drugs can enter the bloodstream through the respiratory airways and skin, among others.
Potent drugs are classified in different containment bands defined by operational exposure limits (OEL) and peak exposure limits (PEL) also called short term exposure level (STEL). While an OEL is based on an average amount over an eight- or twelve-hour period, the PEL considers a maximum amount of exposure at any given time (typically 15 minutes). Often, it is simpler to meet the OEL than it is the PEL requirements. In general, these limits are product dependent and are determined by the manufacturer’s Industrial Hygenist / Toxicologist based on potent ingredient testing.
OELs have been divided into several exposure bands or categories. These bands are set by the manufacturer and vary from one company to the next. A typical set of bands is defined as follows: While dust and exposure control should be a part of all designs involving powder processing, as a general guideline, active ingredients in the exposure bands of 3, 4 and 5 in the above table should consider operator protection with different levels of containment according to their bands when designing a facility for their handling.
Contained Tablet Press Facility Design Considerations
The design of tablet press rooms with containment are a source of debate throughout the pharmaceutical industry. What will be the design basis OEL of the tablet press room? What level of containment should be used in the powder feeding section and tablet discharge sections? Typically, the containment level in a compression room is lower than in those areas where the pure potent drug is handled because the active ingredient is mixed with other inactive ingredients rendering the mixed product a diluted mix.
Dilution should, in theory, allow the operator to be exposed to larger amounts of the processed material without any adverse pharmacological effect. However, powders tend to segregate based on particle size and density. Most process equipment is designed to minimize this behavior but any product that is outside the process equipment could segregate if the material shows these characteristics. Segregation causes the mixed product to separate by raw material type, therefore pockets of concentrated API could be found. This behavior is highly product dependent but has been seen in many processes and should be considered in the design and selection of equipment and facilities. In general, product entering the tablet press room has gone through a granulation process via wet granulation, oscillators, roller compactors, etc. followed by a milling step. Granulated powder typically has the active ingredient better distributed through the granules formed on this step. Segregation may not be much of a problem since particle size and density of the granules has been controlled. Processes that do not incorporate granulation steps prior to compression have to be analyzed for potential exposure due to API segregation. In order to put levels of containment into perspective, one sugar crystal weighs approximately 3 milligrams. One microgram is 3,000 times less than that single crystal.
When designing a contained tablet press room, the designer must establish how this facility will be used based on containment category. Considerations regarding the facility being single or multi-product will impact the design of the facility which affects room layout and pressurization. In contained facilities, pressurization of the room should be negative with respect to the surrounding environment provided that the air entering the facility meets the room classification. However, in a multi-product facility, this might create cross contamination so a different scheme is required- typically still negative pressure relative to the connecting room but usually an airlock is provided. The airlock would be positively pressurized relative to the process room and also to the common corridor. In some cases, for even lower chance of migration, a cascaded airlock configuration would be designed. Further, gowning, de-gowning, mist showers and material airlocks within each compression room will be required to avoid cross contamination. The drawing below depicts a layout and room pressurization design for a high containment multi-product facility. It is important to note that HVAC pressurization for containment facilities varies depending on the type of facility, adjacencies, production and containment requirements
Spatial restrictions: Contained systems usually feed product through bins or stainless steel drums via a containment valve or flexible bags for specialized applications. Typical room heights require 15-20 feet which may not be available in the room. Should there be available space on the floor above the tablet press, a docking station with a containment valve could be installed. If enough ceiling height is available, a post hoist and frame may be used to position the charging bin, drum or flexible bag above the press feed. Other alternatives include dense phase conveying and material conveyors such as vibrating feeders. Containment features may require additional floor space. For example, a double-sided tablet press with tablet discharge on both sides may require isolators on both sides of the machine requiring a larger room. Some tablet press manufacturers offer single-sided discharge for double-sided presses. This significantly reduces the floor space requirements and ancillary equipment with containment costs. Ancillary equipment such as dedusters, reject collection and tablet testing (automatic or manual) should also be considered when planning for contained spaces.
Cleaning requirements: Tablet presses go through periodic cleanings as well as product changeovers. The use of personal protection equipment (PPE) cannot be used as the primary method of containment per OSHA, FDA and European Commission Guidelines. Contained operations must use engineering solutions. Closed systems are the best approach to containment, in particular those within Bands 4 and 5. A contained tablet press should provide systems to perform both. Personal protection equipment can be used as a secondary protection. The owner must determine if the system will be washed in place or washed out of place followed by a manual cleaning after the equipment has been decontaminated. Some clean in place (CIP) designs have proven very difficult to validate and a careful analysis of the different types of tablet presses is recommended. Though many tablet press manufacturers have tried to simplify the product contact areas in such way that they are easier to clean, some machines still have a lot of corners and parts that are not easy to clean and may require manual cleaning. If the system will be washed out of place, a facility for contained cleaning must be provided as well as means of getting the parts out of the machine and transferring them to the cleaning station in a contained manner. Tablet press cleaning nozzles (in place and out of place) must be placed in strategic locations in the compression zone to insure full wetting of all product contact surfaces (note: some tablet presses require that the feeder be removed prior to cleaning). Cleaning is validated using several methods including riboflavin testing and swab tests for detergent and active ingredient.
Wastes: The designer must determine if the product is water soluble or not and if it is deactivated by water. Most potent products have a toxicity level in concentrations on the parts per billion range. While some are inactivated by water exposure or are quickly biologically degraded, allowing their discharge to waste treatment, others require special treatment to deactivate and/or remove the product from the water. Deactivation can be thermal or a chemical reaction with a caustic, acid or oxidizing solution depending on the chemical nature of the active. Removal can be achieved through carbon filters, reverse osmosis, or pH adjustments or a combination of any of them but again disposal of the active must still be addressed. Laboratory testing of the wastewater will determine the best treatment process for the wastewater. As a general practice, independent wastewater collection and treatment systems should be provided.
Maintenance requirements: Equipment maintenance without having to clean the area is preferable. Ease of access, assembly and disassembly of equipment must be considered. Any product chutes, ductwork, filters, and dust collectors must be analyzed for potential operator exposure. Often, this is an area that is neglected in containment designs. Some tablet presses provide through the wall design. In this type of design, the production compartments can be reached from the cleanroom or production area while the drives and other mechanical parts can be accessed from the mechanical room behind a tablet press room. Maintenance access in all tablet presses should be studied for the optimal fit with the maintenance philosophy of the facility.
Dust Collection: Tablet presses require dust collection. An independent dust collection unit per tablet press is recommended versus a centralized unit. Potential ductwork contamination and difficulties with balancing of the tablet presses air handling in high containment presses might occur. Bag-in/bag-out HEPA filters are recommended. These units should come with a spray nozzle for wetting the unit and removing airborne contaminants prior to opening them for maintenance. The dust collection unit must be designed to allow for connection and disconnection of powder drums in a contained manner (i.e. continuous liners, glove boxes, and/or containment valves among others). If the dust collection system to be used is a central unit, cleaning of the ductwork must be designed into the system via sprayballs and low point collection drains. Further, balancing of the press isolator, press dust collection and other facility pick up points is difficult to achieve and will result in a high risk of product release within the facility should a power failure or other event occur that impacts system balance. Ductwork design must consider dust explosion potential and should not be seamed or spiral ducting in order to ensure conductivity throughout the line. Some containment facilities use smaller portable dust collectors with HEPA filtration, containment and electrical classification instead of the centralized units. These smaller units can be dedicated to the tablet press, allow for system balancing and meet containment requirements without the need for installing, operating and cleaning ductwork throughout the facility.
Powder Feed Containment Technologies
Contained tablet press room equipment must consider all activities within that room. An analysis of materials into and out of the press as well as connections and disconnections must be performed. Once the equipment is setup and ready for processing, the typical first step is powder charging. The connections to the tablet press must be closed connections such as containment valves or contained flexible liner connections from bulk bags. In either option, the product is placed on a post hoist, lifted and docked above the bin or it is docked in a station on the floor above.
The connection method must be integrated with the tablet press controls and wash-in-place sequence. It must receive signals from the containment valve indicating that the bin has docked properly as well as signals to open and close the valves. Spray nozzles and washing routines must be incorporated into the powder chute. Containment valve vendors supply a wash hood for cleaning-in-place of the active valve, while other designs include the removal of the powder feed chute and cleaning out of place. If connections are made by using flexible liners, there are two methods of disconnecting the chute from the tablet press, one is by double tie and clip, and the other method is by heat sealing the plastic liner. Once the systems are disconnected from each other, the separate systems can be washed with spray nozzles at the designated location.
Some powders segregate easily. Freefall of product exacerbates this characteristic. Powder decelerators are used as a means of preventing segregation. Many of these technologies meet dust tight requirements but may not meet all bands of containment requirements.
Air Deceleration Unit: The Air Deceleration Unit consists of a product chute, with inflatable flexible membrane or membranes run internally through the length of the chute. The membrane is inflated and deflated to control the descent of material to the inlet of the press. Some units insert lay-flat tubing inside the membrane. This prevents product from contacting the flexible membrane in the decelerator. It also allows for an improved containment strategy where the lay-flat tubing is connected to the feed hopper of the tablet press and disconnected by heat sealing of the tube. Once heat sealed, the lay-flat tube is removed and another inserted.
Tablet Press Containment Technologies
Different manufactures have approached the containment design in their presses using different strategies as described below.
WIP approach: The WIP approach consists of a tablet press with an enclosed compression zone such as integrated isolator or sealed doors that are washed without having to remove the turret to a different location. The wash in-place system utilizes a design that wets any airborne particulates and most of the dust on surfaces, and then removes them from the system through drainage ports. The next step performs an automated cleaning with multiple cleaning zones for removal of most and in some cases all product contamination. The manual cleaning process of the machine begins after the completion of this decontamination. Some disassembly may be required such as punch removal or feeders prior to the start of the wash-in-place. An analysis of how these parts are going to be removed must be performed to allow for operator access. Some tablet presses provide glove ports and rapid transfer ports for removal of these parts while others depend on wetting the machine prior to opening it. Some tablet presses have experienced water leakage into the mechanical space which is undesirable because of potential damage to the press and release of potent drug into an uncontrolled environment.
Some tablet presses are supplied with glove ports that are ergonomically designed to access the equipment during all phases of operation including start-up, breakdowns, equipment changeover and cleaning. The glove port design must be provided with internal and external covers that maintain it between the covers during operation. Prior to accessing the tablet press, the outlet cover is removed, followed by the inlet cover. The inlet cover is provided with sensors that stop the press when opened as safety interlock to prevent operators from accessing moving equipment parts.
Tablet press access by the operator without use of glove ports for product changeover and major cleaning is achieved by performing a wash-in-place. Tablet presses have installed spraying devices in strategic locations to clean and wet the compression zone. Dust is wetted down before the press is opened and the majority is flushed out before opening. Depending on the type of tablet press, some parts may have to be removed from the press prior to the wash-in-place process. Some presses are equipped with contained rapid transfer ports for tool access and contaminated parts removal without generating any operator exposure Manual dust collection for minor cleaning and manual spray wands for dust wetting are additional features that have been incorporated in some tablet press designs. These two systems are used with the closed machine via glove ports.
Some manufacturers compartmentalize the turret from the upper punches and lower punches from the lower machine part by providing shrouds, covers, bellows and silicone bands. The latter design reduces the amount of product contact parts to be cleaned thus reducing the amount of cleaning agents to be used. These types of machines have been validated for CIP processes.
Exchangeable modules: This approach encapsulates all product contact parts including the product feed, turret, and tablet discharge into modules. The module within the tablet press is designed in such a manner that connections to the different parts of the tablet press such as powder feed, tablet discharge, and dust collection among others are performed in a contained manner. For example the powder feed system and dust collection systemsare connected by using lay-flat tubing. Connections between the powder feed and the product bin are performed using containment valves. As discussed before, the lay-flat tubing connection is removed by using a heat seal system that splits the tube into two sealed sections thus maintaining the integrity of the system. The module can be removed from the machine in a contained manner, placed in a cart and washed off line in an appropriate contained washing system. Once washing is completed, the module parts can then be manually cleaned. The remainder of the equipment left in the tablet press room is the mechanical equipment which makes up the bulk of the tablet press. While the contaminated module is cleaned off-line, production with another module can be resumed on the machine, which does not require any cleaning. Washing of the module within the room is also possible provided that the proper cleaning connections are supplied. The modules can be designed for different levels of containment.
Tablet press retrofit: There are several factors such as schedule, cost and validation requirements that lead the owner to decide that a press retrofit is the most adequate option. Several isolator manufacturers are able to build an isolator that retrofits around a tablet press. Containment levels of less than 10mg /m3 have been achieved in some designs. The retrofit provides for bin docking, operator access through glove ports, parts removal, sampling, rejects, and tablet discharge. They come with air handling units to maintain the pressurization requirements. Cleaning is manual and may require PPE based on the tablet press design and wet down capabilities. Manual cleaning will occur via the glove ports that have been retrofitted to the tablet press. There may be some parts that are not accessible therefore an isolator window may have to be opened. In those cases PPE is required and a higher inflow rate through the open window is recommended to prevent contaminating the area outside the isolator.
Air Handling Units: Most tablet presses with containment operate under negative pressure in order to prevent any potential leaks from becoming sources of contamination. As the levels of containment approach Band 5 and frequently Band 4 as described in the table above, the tablet presses are supplied with air handling systems that control the pressurization of the tablet press isolator while in operation, dust extraction for machine cleaning and containment breach. The air handling system must meet the following requirements:
* Pressure level inside the equipment needs to be at least 0.5 KPa (2 in H2O) below the surrounding environmental pressure. * Negative pressure needs to be maintained until wash fluid has moistened all dust or flushed the majority of the product cake from surfaces before opening. * System must ensure negative pressure in emergency cases.
Tablet handling systems containment
Once the powder has been compressed into a tablet and dedusted, the release level of airborne contaminants is lower. Nevertheless, for Band 4 and 5 products as described in the table above, these systems must be considered as contaminant sources especially during product changeover and major cleaning. Band 3 designs should include, at a minimum, closed connections between the tablet press, a closed de-duster, and a metal check.
Closed deduster/metal detector with wash-in-place: This technology is appropriate for Band 3 and 4 as described in the table above types of containment and sometimes Band 5 depending upon the connection and WIP design. If the equipment is going to be washed and disassembled in a wash room, connection and disconnection of these systems have to be closed connections such as sealed layflat tubing or containment valves with flexible hoses. Contained equipment cleaning procedures and equipment such as cleaning isolators and WIP systems must be provided. These connections may not be necessary if the system is designed so that the WIP system can wet them prior to product changeover and manual cleaning.
Deduster/metal detectors inside isolator: This technology is most typically used for Band 5 containment levels. In effect, the de-duster and metal detector are placed inside a rigid isolator. This isolator is provided with a rapid transfer port for connecting to the press tablet discharge chute. Further, it is attached to a tablet receiver via rigid connections with containment valves. The isolator must have a rapid transfer port to allow for entrance of testing material and sampling as needed. The de-duster and metal detector are wet-in-place prior to product changeover and then cleaned manually. Most of the cleaning takes place through the glove ports that have been provided for operator access. Once the bulk of the product has been removed and dust wetted, the window of the isolator can be opened for disassembly and cleaning of the equipment. Though airborne contaminants and dust have been removed, the operator should wear PPE while performing this task.
Sampling: Consideration must be given to what type of sampling and testing (i.e. hardness, weight, friability) will take place and the location where it must be performed. A sampling isolator may be required based on the sampling protocols. The operator must be able to obtain the sample from the tablet press in a contained manner and dock the sample to the sampling isolator. Some tablet presses have automated sampling devices which must also be isolated. Note that design of the contained disposal of the tablet remnants is required as well. Tablet receiver: There are several types of tablet receiver technologies. Some include the use of a continuous liner which is double-tied and clipped once the liner is filled. Some manufactures use 200L-500L bulk bags with double tie and clip connections to reduce the amount of handling. Most common are stainless steel tablet bins or stainless steel drums with containment valves. Due to the amount of changeover time that any of these options have, some vendors have incorporated a double valve system where one drum is being fed with tablets while the other is being disconnected from the system. The bins and stainless steel drums must be cleaned in the contained manufacturing area wash room.
Design of tablet press rooms with containment are often a source of controversy since the active ingredients have been diluted with other incipients. Product mix characteristics, facility considerations regarding space and use, as well as equipment design and operation must be considered in the design of these facilities. These parameters will impact project scope, cost and schedule and must be determined early on in the design of the process.