RTP system ensures biosafety

The IDC (France) BioSafe 110 double-door rapid transfer port was developed with aseptic transfer in mind and has been successfully applied to the supply of stoppers and machine parts to vial filling lines.

However, a transfer system that can maintain sterility is likely to be equally successful in containing hazardous materials. Thus when a requirement for the aseptic loading of a reactor with highly active material arose, containment performance was devised and checked. Using a protocol broadly written to conform to SMEPAC guidelines, air samples were taken during multiple transfers of micronised powder to a dummy reactor. The results indicated that the port performed well in containing the material and when modified for exterior opening will be suitable for charging the reactor while protecting both product and operator. The double door transfer port is a well-known device extensively developed by French company La Calhène in the 1970s for the movement of highly toxic nuclear materials between process gloveboxes and cells. It has subsequently found application in the pharmaceutical industry, particularly in aseptic transfers. La Calhène refers to this port as a DPTE (double port, transfert étanche) but it is also known as a rapid transfer port (RTP). Figures 1a, 1b and 1c illustrate the mode of operation.

Specific problems Several versions of the RTP are available and IDC (France) has developed a system that employs a non-rotative docking action, combined with single-use, disposable containers. This is known as the BioSafe 110 port. The non-rotative action is easier to operate and does not "smear" any adventitious contamination around the seal, while the single-use containers eliminate the need for cleaning and all that this entails. Figures 2a and 2b show the cleanroom side and isolator side of a standard IDC BioSafe 110 port. IDC designed this port with aseptic pharmaceutical applications in mind, and if the port worked well in aseptic operation it seemed reasonable to suppose that it might work equally well in containment applications. Until recently, IDC had not seriously explored this possibility, other than in the disposal of medical waste from hospitals. Janssen Pharmaceutical Ireland approached IDC with a specific problem. It needed to load an industrial-scale reactor vessel with a small volume of a highly active product while maintaining both operator safety and the aseptic status of the product. Since the reactor was to be CIP/SIP there could be no sleeves or gloves fitted to open the port door. Thus the port would not only have to withstand the CIP/SIP process but also operate from outside the vessel. IDC first designed a special shallow stainless steel "false container" to be docked onto the open port during CIP/SIP. This was successfully tested at 6 Bar, allowing a good safety margin on the 3 Bar normally required. After this, an outside opening system was devised, with the client specifying that a John Crane seal should be utilised for the shaft used to move the port door from outside the vessel. However, before the port was built Janssen needed to check the containment level that the port could achieve during the transfer process. A maximum airborne concentration of 370 ng/m3 was set as the target, this figure being based on the known characteristics of the product.The following test was designed to conform to Protocol 1 of Assessing the Particulate Containment Performance of Pharmaceutical Equipment (reference Smepac9_101703). The test rig and protocol were provided by IDC while the air sampling and reporting were carried out by an independent industrial hygienist.

Simulate conditions A simple isolator was constructed from flexible film, in the form of a 500mm cube, supported by a framework of tubing, to represent the reactor. The isolator was fitted with a standard IDC female port in the centre of the top face and a single glove sleeve on one of the walls, to be used for opening the port. A line filter was fitted to the isolator canopy to allow it to "breathe" and thus maintain neutral pressure during the transfer operations. This isolator was set up in one of the lobbies of the production building to simulate conditions within the production areas as closely as practical. This lobby was maintained at positive pressure, with the room air inlet directly above the test rig and the air exit located at floor level beside the rig.

Air samplers Ten double-ended IDC containers were prepared the previous day in a separate area, each of them filled with about 6kg of micronised lactose. The containers were filled by docking the containers in turn to a further IDC port, which was mounted in a horizontal table. Extreme care was taken to avoid contaminating the outside of the containers and each was washed down with water after filling, as a further precaution. These particular containers were fitted with semi-rigid delivery chutes housed within the neck of the bag, designed to aid the direct delivery of the powder with the minimum of fly. Double-ended containers (i.e. with a "male" container flange at each end) were of course required, since the docking process can be carried out only once for each container flange. The containers were finally placed in the lobby near to the isolator. Figure 3 illustrates the isolator and containers. The next stage of the operation was to set up air samplers at a series of sites as follows: A, B, C and D: Equally spaced around the IDC port, at a radius of about 200mm, on the top face of the isolator. These sites were designed to check airborne levels of lactose close to the transfer process. P: Fitted to the lapel of the lab coat worn by the operator during the transfers. This site was designed to represent the breathing air of the operator. R: Remote site about 2 metres from the port, used to monitor background levels of lactose. These air samplers were fitted with glass fibre filters and the flow rate of each air pump was verified before and after the test period. A series of transfers was then made using the IDC port, simply dumping the lactose from the containers into a conical heap on the floor of the isolator. The first two transfers were control "blanks" in which the container was docked to the port, but the port was not opened and the container was removed again. This was designed to establish an initial baseline or background level, should any lactose be randomly present in the environment. Six true transfers were then made, manipulating the semi-rigid chutes in each container to deliver the powder below the level of the port seal. Containment performance The chutes were carefully withdrawn back into the container after each transfer, to minimise fly. Finally, two more blank transfers were made to establish the background level at the end of the transfer process. During the transfer operations, air samplers A, B, C, P and R were run continuously for the 150 minutes of the test work. In the case of air sampler D, however, the filter was changed for each transfer, running for 15 minutes each time. This was designed to test the consistency of port containment performance through the series of transfers. At the end of the tests, the 15 resulting air filters were sent for independent analysis. The lactose burden for all 15 filters proved to be below the detection level of 5ng, for the analytical method used. Thus for the filters which operated for the full 150 minutes of the transfer operations, the airborne level of lactose could be calculated as being <17ng/m³. For those filters which ran for the 15 minute individual transfers, the level could be calculated as being <170ng/m3. This places all samples well below the required level of <370ng/m³. These results suggest that the standard IDC transfer port system is capable of reaching very high containment levels when used for the transfer of micronised solid APIs from one contained volume to another. On the strength of the results, Janseen has placed an order for the specialised IDC port needed for the reactor-loading operation. Further extensive containment tests will be carried out on the new port as fitted to the reactor vessel, under operational conditions, before using the system with active materials for production. It is hoped that the results of these further tests will be published in due course.