Rational approaches to containment implementation for pharmaceutical actives processing: Part 2

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

By Nick Phillips and Terry FayLockwood Greene Engineers

Part two of a three-part article (click here for Part 1)

Table of ContentsSamplingCentral weighFormulationReactor chargingMilling

SamplingThe sampling area should be comprised of multiple suites, which are accessed from an airlock through interlocked doors. These doors cannot be opened if an exterior door is opened or if one of the sampling room doors is open.

Samples from non active ingredients, containers of actives shipped with sample bags, and packaging materials, will be taken into sampling rooms, which are equipped with laminar flow booths. Active ingredients, supplied with sample bags in the container must be opened under controlled conditions to insure that if the inner liner is damaged there will be minimal exposure. In some cases, such as Category 3 & 4 actives not supplied with sample bags, direct sampling is required.

Sampling of highly potent actives should take place in a room equipped with specifically designed sampling isolators, typically a three chambered isolation unit capable of maintaining OEL to below 1 µg/m3. The operator will place a drum of material into the first chamber (C1) and close the port. Using a glove box the operator will open the port from C1 to the second chamber (C2) and the drum will be conveyed into the second chamber. The operator will close the port, and remove the cover of the drum. If the inner double poly liners are damaged, the operator will close the drum, manually clean the outside of the drum and the drum will be removed through C2 and either the drum will be returned to the supplier or a double bagging procedure will be used. C2 will be automatically CIP. If the liner is intact, the operator will press a button which will lift the drum up and seal it with a gasket against the bottom of the third chamber (C3). In the bottom of C3 is a cover which when opened allows access to the poly liners. The first liner is opened and wrapped around a flange in the floor of C3, then the second liner is opened and the sample is manually taken and placed in a sealed container. The procedure is reversed and C3 is automatically Cleaned In Place (CIP).

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Central weighDispensing operations are usually comprised of multiple suites, some of the rooms can be equipped with glove box isolators to eliminate employee exposure to Category 3 & 4 active ingredients. Multiple rooms are required to assure that one room is always available while the other is being CIP.

The other rooms should be equipped with laminar flow booths and bag and drum dump stations for handling bulk ingredients (see picture above supplied by Extract Technology (ET). These rooms can be set up to handle Intermediate Bulk Containers (IBC) that will be used to load equipment such as Fluid Bed Granulator Dryers, Microwave Dryers, or Reactors.

Bulk Material Weighing—Bulk raw materials such as starch and lactose can be delivered to the upper level, bulk dispensing rooms which will contain a bag dump station with dust collection and bag compactor, a pallet lift for raising bags of material to the ergonomically correct height for the operator, a portable drum inverter capable of handling containers of various height and diameter, and a laminar flow booth. The laminar flow booth (see drawing at right supplied by ET) can be equipped with floor, bench, and analytical scales for weighing of minors prior to dispensing into the dump station and a sifter for materials, which need to be sieved before weighing. The bag dump station can include a discharge hopper, mounted on load cells to insure each material is weighed correctly before it is mixed with the other ingredients already in the IBC.

An operator will place a clean IBC in the charge station on the lower level, and material will then be dispensed from the charge hopper. Connections to the IBC will be made through a standard butterfly valve or if the bin will contain potent materials a Split Butterfly Valve (SBV) (a.k.a. High Containment Transfer Coupling (HCTC)). When the valve is in contact it can be automatically locked in place and open. The material dispensed from above will pass through the sieve and the SBV, into the IBC. SBVs are made by PSL/SerckAudco, Buck, and Glatt. Matcon makes a "cone valve" and Totes makes a spool piece which are other types of contained couplings.

Addition of Actives—In the weighing area, all actives are in their most concentrated state, therefore addition of these ingredients particularly those which have an OEL of < 5µg/m3 must be handled using isolation technology. To preclude the use of PPE in this environment, materials should be dispensed in glove box isolators (see picture at left supplied by Powder Systems Limited (PSL)). A dispensary/subdivision glove box should be designed such that all make/break connections for raw material additions loading, sampling, and product unloading are minimized and cleanable to reduce contamination risk.

An IBC will be placed below the isolator. A sealed drum of active ingredient is placed into the drum lift, the system will lift the drum into a chamber which is then sealed off from the external room. The operator, using a glove box, will open the drum and dispense the material into a charge hopper mounted on load cells. Upon completion of the weighing, the drum will be resealed. If the drum is metal or plastic the outside surface will be spray washed, and blown dry, the drum will be removed and the system will be CIP. If the use of fiber drums is still required a bag out procedure will be used, wherein the drum is placed in a plastic bag and sealed for reuse or disposal. The IBC will automatically be disconnected and a dust collector will insure that minimal material will become airborne at the valve interface. The isolator will then be CIP.

If the quantity required is a small amount the material will be weighed out into a Transfer Container (TC), on a bench scale inside the glove box. The TC can be used for quantities of < 10 kg and have an SBV. The booth will be fitted with a glove box isolator on top and a second GBI below (see drawing above supplied by ET). Depending upon how the material is received the different means of material handling can be accomplished. The GBI will be equipped with an RTP for receiving Beta Bags and bottles. It will also have a port for bag in and bag out of drummed and bagged material, which can be equipped with a drum tipper. Waste and samples will also use the sausage or continuous bag technique for removal. The material can be brought to the vessel and charged manually with the assistance of a vibrator attached to the wall of the plastic container.

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FormulationThe weighed material in the IBC's for charging of the process equipment are moved into the specified bin discharge room. When placed into position on the bin discharge station, the operator will leave the room. The bins should be equipped with SBV (see picture at right supplied by PSL) for the bottom discharge. The SBV it will lock it place and then will be opened automatically. When charging of the equipment is complete the valve will close, the SBV will unlock, and the bin will be raised separating valve. A dust collector around the interface will insure that room exposure will be at a minimum.

The control room operator can monitor the process, by sampling material from the reactor through a Sampling Port. Samples of compounds taken from the reactor can be accomplished using a sampling adapter through the SBV or an AlphaBeta port in a glove box. Using an SBV system the operator will open the GBI and place the sampling unit on the docking station. The GBI is closed and the valve is docked, locked, and opened. The operator then inserts the sample extraction wand through the valve and draws a sample into the bag (see drawing at left supplied by PSL). The valve is closed and the unit is undocked. The operator will then clean the exterior surfaces and bag out the unit for testing.

When the process cycle is complete, the batch load will be discharged and the batch will pass directly into an IBC.

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Reactor chargingPBECL-4—For small scale operations the TC can be brought to the reactor, which will have a laminar flow charge booth with the glove port face plate mounted on the front (see drawing at right supplied by ET). The booths could be portable or permanently mounted to each reactor. The operator will open the access panel to the booth and place the TC on the docking station and mate the slave half of the valve with the master half on the reactor. The operator will then close the booth and use the glove ports to manually lock and open the valve. The SBV will provide the primary containment and the glove box will provide secondary containment.

When the bottle is empty the process is reversed with the addition of a cleaning step. The SBV will contain down to 5 µg/m3; the reason for this is the mating surface of the two valve halves. This is the primary point of contamination. Therefore it will be necessary to clean this surface prior to removing the bottle. Since the internal surface of the glove box must be cleaned both operations can be accomplished by the operator with a spray wand. Wash water is drained to a collection point. The fan for the box is turned up to a higher speed to dry the surfaces, when this is complete the bottle is removed.

PBECL-3—This and lower levels can be met using TC with SBVs and laminar flow booths without the need for glove ports. The operator will bring the TC to the reactor, which will have a laminar flow charge booth. The booths would be portable or permanently mounted to each reactor. The operator will place the TC on the docking station and mate the slave half of the valve with the master half on the reactor. The valve will be manually locked and opened. The SBV will provide the primary containment and the laminar flow booth will provide secondary containment.

In addition to closed reaction systems, filter dryers are made by PSL, Rosemund, and Cogeim. PSL supplies two specially designed high containment models. One has split butterfly discharge, sampling, and sight glass on the filter cake side as well as internal CIP loop. The other combines a glove box, and sausage bag or RTP for cake access for higher levels of containment (see picture at left supplied by PSL).

Fluid Bed Granulator Dryers are now being made by Glatt and Aeromatic for contained charging and discharging of their units. A basket centrifuge with a more contained cake discharge system is being provided by Heinkel or Ferrum.

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MillingMilling is required to create a batch of material with a more uniform particle size. There are four typical types of mills; Frewit Turboseive, Fitzpatrick Mill, Stokes Oscillator, and Quadro Comil. The operator will move a bin of material into position above the mill and the SBV discharge valve will be mated to the mill. Below the mill a clean IBC will be placed on the lifting platform for mating to the SBV on the discharge port of the mill. The milling will take place with material passing by gravity to the clean bin.

Sweco and other sieve and grinder manufacturers are now making closed systems but cleaning is still not totally contained. Since many mills cannot be adequately contained, nor can they be CIP the operators will require PPE in this operation, particularly during cleaning.

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End of Part 2. Click here to read Part 3.

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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