Rational approaches to containment implementation for pharmaceutical actives processing: Part 3

Paper presented at Reed Exhibitions Interphex 2000 Workshop WS-15March 22, 2000

By Nick Phillips and Terry FayLockwood Greene Engineers

Part three of a three-part article (click here to read Part 1 or Part 2

Table of ContentsBlendingTablet compression and capsule fillingCoatingCleaning of equipmentPackagingPotential for liquid leakageOptions for leakage containmentSummary

BlendingThere are many types of blending operations, "V", Double Cone, Planetary, Bin, etc. For products, which require containment, processing of materials using bin blending is currently the preferred method. Since it reduces the amount of material transfers and equipment transfers.

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Tablet compression and capsule fillingContained tablet compression machines are making their way into the marketplace, but at this point the long-term results are still being established. To meet Category 3 & 4 OEL using standard equipment a uniflow operation with separate gowning procedures is required. An operator should enter a gowning suite carrying a clean Personal Respirator (PR). The operator will don a disposable bunny suit and enter their specific compression room through an airlock, once they have done so and the machine is in operation they should not return to the clean corridor.

It is recommended that the equipment be charged from the floor above through drop stations. The operator will open the valve remotely on the IBC discharge station and the material will be fed into the equipment on the level below. To insure that product separation does not occur, a pinch roll transfer system can be used (drawing below supplied by Lockwood Greene Engineers (LGE)).

Current contained compression units are being fully enclosed with glove port access panels for adjustment, and maintenance. The upper half of the machine is maintained under a negative air pressure relative to the room. All tooling replacement and cleaning is done using the glove ports. A house vacuum connection is available inside the cabinet. Tooling to be removed from the machine is passed out of the machine through an RTP and into a plastic bag. As yet there are no specific designs for capsule filling containment. Fette has a glove box accessed tableting area and IMA has a "Wash In Place" design for their new presses.

It is recommended to reduce operator handling that compressed tablets be lifted via tablet dedusters and fed into enclosed stainless steel bins.

Operators leaving this area must first pass through an air shower, misting shower or full water spray in the personnel airlock. They can then manually clean their PAPR and place the unit in a pass through locker. They will then remove their outer garment, dispose of it, and exit the room.

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CoatingIn new operations coaters with top and bottom discharge should be used. This will allow charging directly from enclosed bins or by vacuum transfer. If front loading units are required, the material should be picked up with a post hoist and mated to an adapter flange, which will cover the charging port of the coater. The coater air handling unit will be turned on to reduce air born particulate, and the tablets will be fed by gravity into the coater. Discharge from the coater will make use of the plow with an adapter flange and chute being required to feed the coated tablets into the enclosed container.

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Cleaning of equipmentIn order to reduce the level of employee exposure, where applicable, equipment should use Clean In Place (CIP) Technology. This should include the isolation booths in Sampling, the isolation dispensing units in Central Weigh, the Formulation operations, Coaters, Compression Equipment, if so equipped, and Bin Washing. These systems are usually multi-tank units with PLC for creating different cleaning profiles based on specific equipment and material cleaning requirements.

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PackagingStudies done to date have shown low exposure levels for most tableted and capsuled materials. Particularly coated tablets. Care should be taken when handling fragile uncoated tablets, which may require better machine enclosures then are normally supplied.

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Potential for liquid leakageLeakage of liquids containing dissolved or suspended actives must be addressed. There are two sources of this leakage.

Leakage through equipment/vessel/piping wallFailure of metallic equipment and piping walls is unusual for batch operations if pressure/vacuum checks are done between runs, safety venting is properly considered, and testing for corrosion/erosion is done for maintenance. Therefore, double walled containment of vessels and mechanical equipment to protect from wall rupture is not commonly implemented for pharmaceutical containment.

Double walled containment systems are available for piping systems. (For example: Conley and Fibercast make FRP systems; Asahi and Rovanco make plastic piping systems). This is done on hazardous materials, especially if the piping is a non-metallic system, the piping is header piping always in operation, there are corrosion/erosion potential problems, the piping is buried, and/or if there is a risk of mechanical damage (from fork lifts, trucks hitting pipe bridges, etc). In pharmaceuticals, these risks are not very high and double wall piping is usually limited to plastic acid headers, etc and piping passing through open access, non process areas.

Leakage/spray through mechanical or packed seal, or gasket of agitator, rotating equipment, valve or flangeMechanical seals are commonly used on agitators, pumps, and other rotating equipment. A single mechanical seal presents a high risk factor. A double mechanical seal should be used with a flush which is compatible with the process but which has a non-interruptible supply (such as a pressured reservoir of sufficient capacity) to prevent leakage outside. If this cannot be implemented, secondary containment on the unit must be considered.

In pharmaceuticals, the use of a wide variety of chemicals leads to the common usage of Teflon as a gasket material. Teflon is not an elastomer and it presents specific problems with leakage, which is only exacerbated by the batch nature of the operations and the heating and sub-freezing cooling cycles that are common. The use of elastomers as gaskets improves the reliability of the gasketed joint but this is still an area of risk for leaks and sprays. There are several options for containment of this problem.

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Options for leakage containment

Double sealed flanged systemsThe use of a double seal allows continuous monitoring of the primary seal and containment of leakage within the system. The only manufacturer of double containment flange systems, that LGE is aware of, is Asahi Chemical. They market these flanges for their line of thermoplastic containment piping. These consist of a double O-ring seal with the annulus space between them being an extension of the double pipe's annulus space. Key High Vacuum Products makes a single O-ring sealed stainless flange for high vacuum purposes and they have made double seals for custom orders. The space between the O-rings could be tapped top and bottom in the external faces of the flanges for tubing fittings. The bottom fitting would allow a collection tube to a 0.2-micron hydrophobic filtered vented container and the second tubing fitting would allow flushing with a killing solution. The flange could also be equipped with a pressure sensor to detect leakage between seals, as an alternate.

When the active is in the liquid phase (dissolved or itself a liquid) this will not provide sufficient barrier protection. Vapors containing actives will penetrate the filter and can be inhaled; they will deposit actives on surfaces. Therefore, in these applications a carbon bed filter should be used for absorption or the unit must be vented to a scrubber or Thermal Oxidizer.

The use of these techniques provide additional protection if a good seal is originally established, but can still lead to a single mode of failure since it can potentially leak out if a bolt on the flange fails. They cannot be retrofitted—flanges must be changed out.

Double gasketed systemsDouble Gasketed Systems are found primarily on valves designed to meet EPA "zero emissions" standards. They consist of a set of packing on the valve stems, a spacer in the valve bonnet, followed by a second set of packing. The space between the packing is tapped and can be equipped with purge and drain tubing, and leakage detection (see picture at right). These systems are reliable, but their major disadvantage is cost and the fact that it only protects from valve stem leakage (which is the primary but not the only source of leakage for valves). In some cases, this approach can be retrofitted to existing valves (Jamesbury and Xomox make retrofit kits for their ball valves). It should be considered for all new installations. Worcester makes a model 94 ball valve of this type in standard stainless ASME flanged design and in a 3-piece tri-clamp sanitary tubing design. Xomox makes butterfly, ball, and plug valve double gasketed system. Consideration should still be given to containing the body of the valve to assure control of leakage at the piping connections and at the body joints. LGE is unaware of any diaphragm valves with secondary stem seals.

Sealed enclosed containmentAnother approach is to totally enclose the gasketed/packed area in a sealed enclosure, which is typically capable of withstanding some pressure or vacuum, and assuring control of leakage.

Ramco Manufacturing Co. makes a flange containment system consisting of gasketed clamshells made of Noryl/FRP or ABS/PVC that is rated up to 300°F and 20 psig (see picture above supplied by Ramco). These are put around the flange and held in place with stainless steel bands. The limitation of this system is that it is only available for ¾ to 1" piping, cannot handle non-round cross-sections (such as the neck of some diaphragm valves), and cannot fit into tight spaces due to dimensional limitations. They can be equipped (at an additional cost) with purge and drain tubing, and leakage detection and they can be retrofitted over existing flanges.

Conley Corp. makes custom FRP double containment valve enclosures and Asahi makes custom plastic double containment valve enclosures which will fit around valves, flanges, etc. They are also subject to dimensional limitations. Conley's designs will handle a pressure of 10 psig. They can be equipped (at an additional cost) with purge and drain tubing, and leakage detection and they can be retrofitted over existing fittings and valves.

Atmospheric closed containment, and "splash guards" and drip pansThese are sealed fabric or sheeting " aprons" that can be installed around flanges and valves. Tie cords or metal clamps attach them. These units vary from simple shields, which break up sprays but do not contain them (they will leak) to units that have moderate containment and are available with flush and drainage connections. They are low cost and fit in most locations; their weakness lies in cleaning them after a leak and the potential for them to leak themselves.

Ramco makes both flanges and valve covers out of Teflon material and use stainless bands to hold them in place (see pictures above supplied by Ramco). They are rated to 300°F and have been adapted to flush bottom Strahman valve containment in the past, but the design used did not allow operation of the valve with the shield in place unless the valve is automated. These units provide a low cost approach, which can be used in low level containment requirements and, for higher containment requirements where other systems will not fit, or used with secondary systems. Dripping from under the cover, and residual wetted piping and material (since it is not sealed) must be addressed in the system design. A simple drip pan under the unit will collect the drainage and can direct it elsewhere, but this provides additional exposed surface. The best solution to this problem is to enclose the covered units in an enclosure. Since there is no spray shielding concern, the covered units need only be contained to control dripping and residual if a leak occurs. A simple box with access ports, negative pressure differential to the room and connections to a drainage system, can be used to accomplish this. The inside of the box can be flushed with decontaminates through a fixed CIP system or by using a portable pressurized spray can. Operation of the valves is either automated or done by reaching into the ports with appropriate gloves. This is not a problem since the inside of the box is not contaminated during normal operation but only during a system failure.

Leakage/spray/residual coating from making and breaking connectionsWhen lines are connected to valves, flanges, etc, there is a potential that they will leak when put into operation. Once they start to leak, the line has to drain down before leakage stops and there are pockets of liquid in the piping, tubing, or hose that is removed. All this represents exposure problems for the personnel. The best method of making and breaking these type connections is a double valved system that stops flow at both ends. These also should be contained since there is a potential for leakage and spray during operation. A simple box with access ports, a negative pressure differential to the room and connections to a drainage system, can be used to accomplish this. The main disadvantage of this approach is cost and space requirements. All lines that can be fixed in place should be and the need for flexibility should be accomplished in the piping and valving. Temporary connections during operations should only be used when implementation of the above approach has been exhausted.

Victualic provides a double butterfly valve design for making and breaking connections. It is simple to operate but has a larger exposed area to clean when the units are disconnected. They are available from 1" up to 3" with working pressure of 210 to 120 psig respectively. They have an operating temperature range of 20°F to 230°F with Teflon seals and stainless steel or Hastalloy parts. Aeroquip makes a double ball valve system (see picture at right supplied by Aeroquip). One ball is scooped out to accommodate the other and provides very good interlocks to prevent opening while the ball valves are not together. They are rated for up to 250°F and 600 psig (3/4" & 1", 300psig 1-1/2, 2 &3") with Teflon seals and stainless steel or Hastalloy parts.

For hoses and tubing ½" and under, Swagelock or Parker self-closing fittings are commonly used but they have a tendency to "gum up" and leak or become difficult to disassemble when processing materials that are tacky or have solids.

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SummaryAs we have seen suppliers to the pharmaceutical industry have made great strides to reduce operator exposure through modification to their equipment designs. New equipment is constantly being designed, and implemented. The focus has clearly shifted to replace Personal Protective Equipment with Engineering Controls.

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For more information: Nick Phillips ([email protected]) or Terry Fay ([email protected]), Lockwood Greene, The Tower, 270 Davidson Ave., Somerset, NJ 08873-4140. Tel: 732-560-5700.

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