INTRODUCTION: ISOLATORS AND TRANSFER SYSTEMS FOR HANDLING APIs
Within the pharmaceutical and biopharmaceutical manufacturing space, isolators are often the preferred engineering solution used to allow potent and highly potent active pharmaceutical ingredients (APIs) to be handled safely. These isolators are built with the sole purpose of protecting the operator by providing a reliable barrier between the person and the hazard. The containment performance of well-designed isolators has been shown to be in the low nanogram/metre cubed range (airborne concentration outside the isolator) and therefore these devices are well suited for protecting operators from exposure to potent and highly potent APIs. Within the pharmaceutical industry it is generally accepted that a potent API has an occupational exposure limit (OEL) at or below 10 μg/m3 and highly potent API as having an OEL below 1 μg/m3 (2).
Pharmaceutical grade isolators traditionally employ a negative pressure interior chamber to improve the containment of APIs. This feature is particularly advantageous in enhancing the integrity of the seals between the metal frame and glass windows that commonly make up their design. However, some applications require aseptic handling of APIs which involves operating the isolator under positive pressure. These two variants of the isolator, i.e. positive and negative pressure, are both reliably engineered devices which may differ somewhat in design and features, but both possess a solution to the basic need to transfer items (product, containers, cleaning materials, etc.) into and out of the isolator in a contained manner.
The most common device used to transfer items into an isolator is a transfer chamber. This integrated chamber typically consists of an external access door for placing items inside the transfer chamber and an internal access door for passing items from the transfer chamber into the main chamber of the isolator. This simple but effective method of transfer is not without its restrictions; the most significant being the contamination of this chamber when opening the inner door and the limitation on how many times this transfer chamber can therefore be used in quick succession.
Continuous liners are one of the most common transfer devices used for removal of items from isolators. These cost-effective devices are versatile in their application, often used for direct filling of products or for “bagging out” of specific items. There are limitations associated with these devices. They are normally used only for transferring items or API out of isolators and their performance is affected by operator technique and the need to handle them carefully to avoid punctures, tears or leaks. However, the main limitation with these devices is often associated with the cutting of the liner and the manual interaction required with this process. There are a range of associated crimping and cutting devices available on the market all requiring manual operation.
Getinge’s DPTE® Alpha port combined with a DPTE® Beta Container or DPTE-BetaBag® is an alternative transfer device which allows contained transfers of items into and out of isolators. However, its individual containment capability and performance had yet to be formally assessed and documented. This is the basis on which Getinge asked SafeBridge to perform this work and write this article.
DPTE® TECHNOLOGY
The first secure transfer system was developed in 1963 by La Calhene (now Getinge) and was named “DPTE®” Double Porte pour Transfert Étanche (Double Door for Sealed Transfer). This type of rapid transfer port (RTP) was developed initially for use in the French nuclear industry for the safe transfer of radio-active materials. However, its potential as an effective containment device was quickly realised and it was adapted to facilitate the safe transfer into and out of isolators for various sterile and toxic applications. It is recognised as a successful industry standard for transfer systems with around 40, 000 units in use around the world (Getinge) (1).
CONTAINMENT PERFORMANCE ASSESSMENT OF DPTE – OVERVIEW
Getinge’s DPTE Alpha ports (Figure 1) represent a well-known, respected and widely used containment device within the pharmaceutical industry. However, there is little substantial data available in the public domain indicating the containment performance of these devices to demonstrate their suitability for making contained transfers, into and out of isolators, when handling potent, or highly potent API’s. SafeBridge were commissioned by Getinge to conduct a containment performance assessment of the four available DPTE Alpha ports. Each of the different sized Getinge DPTE Alpha ports available were assessed; 105 mm, 190 mm, 270 mm and 350 mm diameter.
Depending on the specific pharmaceutical application, the DPTE Alpha port could be subjected to consecutive connections and disconnections. Determining whether repeated connections and disconnections to a DPTE Alpha port affected its containment performance was therefore included as part of the assessment criteria. The containment performance of each of the four DPTE Alpha ports was therefore assessed after one connection and disconnection of a DPTE- BetaBag or DPTE Beta Container, then after five and then ten connections and disconnections, carried out in succession.
The purpose of the containment performance assessment was to quantify the effectiveness of the DPTE Alpha transfer device in preventing emissions of powdered API during a transfer task. This was assessed on an isolator while handling a low toxicity (surrogate) powder, using proximate area samples (primarily) and personal samples. Proximate samples were positioned around the equipment at close proximity to the target area, at locations that are considered potential leakage points. Personal samples were positioned within 30 cm of the operator’s breathing zone, to reflect the concentration of API around the equipment during the range of individual tasks carried out during the process. The airborne concentrations recorded were averaged over the task period and used to indicate the containment performance of the devices.
This is different than assessing employee personal exposures in the workplace against occupational exposure limits (OELs) (2). Personal samples are taken within the breathing zone of the employee and are the primary indicator for assessing personal exposure. In that case, the airborne concentrations recorded are normally averaged over eight hours before a comparison is made to the limit value.
The challenge was to assess the effectiveness of the DPTE Alpha port alone when removing the DPTE-BetaBag or DPTE Beta Container, as well as ensuring that the necessary opening of the isolator to change between different sized Alpha ports did not result in emissions of API.
RESULTS ANALYSIS AND INTERPRETATION
For this assessment airborne acetaminophen that might be released during the DPTE use was quantified by drawing air into sampling heads with volumetric flow of 2.0 litres per minute. The IOM filter cassette samples were analysed by the SafeBridge AIHA accredited analytical laboratory, applying the validated method, using HPLC and electrochemical detection.
Surface samples were collected using polyester swabs. Samples were also analysed using this internal method. This extremely sensitive analytical method allowed detection down to less than 1 ng/m3 per sample for air samples and less than 1 ng per cm2 for surface samples.
PRELIMINARY WORK: CONTAINMENT VERIFICATION OF PROPOSED ISOLATOR
This complex assessment required extensive preliminary work to assess whether external sources of airborne surrogate would interfere with the DPTE Alpha port containment performance assessment. The preliminary work had two main objectives; the first was to assess the likelihood of external airborne contamination affecting the containment performance assessment of the DPTE Alpha ports, the second was to assess the potential for airborne and surface contamination to occur when changing the diameter of the DPTE Alpha port aperture prior to undertaking the next assessment scenario.
The first objective was achieved by assessing the effectiveness of the containment provided by the left chamber of the test isolator (Figure 2) to verify there were no inherent weak points with the isolator. The task used to challenge the containment of the left chamber involved transferring a small quantity (500 g) of surrogate powder (acetaminophen), from one container to another, using a spoon. Proximate samples were placed around the outside of the left chamber at potential weak points, for example at glove ports and isolator seals. Proximate samples were also placed inside the right chamber adjacent to the hinged stainless-steel plate that housed the DPTE Alpha port. The assessment consisted of three test runs; each test run was identical in nature except for the size of the DPTE Alpha port apertures fitted to the right side of the left chamber. A different port aperture was used for each of the three test runs to verify that changing of the DPTE diameter would not affect the containment performance of the isolator.
The likelihood of surrogate emissions migrating from the left chamber through the hinged stainless-steel plate and DPTE Alpha port was concluded to be extremely low. During the preliminary containment verification of the proposed isolator, twelve air samples were taken from positions adjacent to the stainless-steel plate and DPTE Alpha port and only 3 samples returned values at detectable concentrations, the highest recorded value was 3 ng/m3.
PRELIMINARY WORK: CLEANING VALIDATION
Assessing the potential for airborne and surface contamination to occur when changing the size of the DPTE Alpha port aperture (objective two) was fundamental in allowing the comparison of containment performance data between each of the DPTE Alpha port apertures. When reviewing the proposed isolator setup it was apparent that changing the aperture of the DPTE Alpha port (ready for the next containment performance assessment) could lead to an unwanted release of acetaminophen from the potentially contaminated and open left chamber and the surface of the stainless-steel plate which housed the DPTE Alpha port (Figure 3).
The methodology developed for limiting the impact of this potential contamination when changing the DPTE Alpha port aperture focused on adequately cleaning the internal surfaces of the left chamber and preventing any transfer of surface contamination to the right chamber. This was achieved by developing a robust cleaning method and verifying the effectiveness of the cleaning by quantitative air and surface sampling. The following operations occurred during the cleaning validation:
After the cleaning of the left chamber of the isolator, the isolator was left running overnight (at least 12 hours) at -100 pa.
Surface samples from 5 positions were then taken inside the left chamber.
The DPTE Alpha port was then replaced with a different sized DPTE alpha port.
The right chamber of the isolator was then cleaned.
Surface samples from 4 positions were taken inside the right chamber.
Two air samples were taken inside the right chamber close to the DPTE Alpha port.
The surface sample results inside the left chamber (for all three test runs) ranged between 0.0034 -0.15 µg per cm2, with the surface concentrations decreasing per test run, indicating that the level of cleaning was improving with practice. The surface concentrations recorded in the right chamber (for all three test runs) after changing of the DPTE and cleaning the surfaces ranged from 0.0016 – 0.12 ng per cm2. The air samples taken inside the right chamber after at least 12 hours following the DPTE Alpha port change over, were all below the limit of quantification for the analytical method. These results provided confidence that any residual surface contamination present was unlikely to become airborne and interfere with the next assessment.
CONDUCTING CONTAINMENT PERFORMANCE ASSESSMENTS ON DPTE ALPHA PORTS
To assess the containment performance of the DPTE Alpha port, a suitable and easily repeatable task was required to challenge the device. This was achieved by subjecting one chamber of a two-chamber isolator, which housed a DPTE Alpha port on the dividing wall to an internal airborne concentration of surrogate. This was accomplished by transferring a small quantity (500 g) of surrogate powder (acetaminophen), from one container to another using a spoon.
The left chamber had an approximate internal volume of 0.5 m3, it was closed and operated at -120 Pa. The right chamber had an approximate internal volume of 0.8 m3, its front window was left open for access purposes. In between the left and right chamber was a hinged stainless-steel door that housed the DPTE Alpha port. This retractable stainless-steel door was secured in place by an inflatable seal. The middle section of the door featured an interchangeable steel plate which accommodated specific sizes of DPTE Alpha port (105, 190, 270 and 350 mm).
To quantify airborne emissions of surrogate from the DPTE Alpha port after disconnection of a DPTE- BetaBag or DPTE Beta Container, three air samples were placed at close proximity around the DPTE Alpha port (right chamber); one at the top center, one at the bottom right position and one at the bottom left position. Two personal air samples were also taken to assess personal exposures during the containment performance assessment, one during surrogate manipulation in the left chamber and any connections and disconnections of the DPTE- BetaBag® or DPTE Beta Container (all samples ran for approximately 25 minutes) and one during the final disconnection to help identify when and where any exposure might be occurring (all these samples ran for 15 minutes). The sample positions were chosen based on guidance available in Appendix 1, Protocol 1 of the ISPE guide (2).
For each of the four different diameter DPTE Alpha ports assessed, three scenarios were performed:
containment performance during one connection and disconnection (Figure 4)
containment performance following five connections and disconnections
containment performance following ten connections and disconnections
When a DPTE Alpha ports was being assessed after ten connections and disconnections for example, the DPTE- BetaBag or DPTE Beta Container, was connected and disconnected nine times in quick succession to the DPTE Alpha port (opening the internal Alpha door each time). Finally, the DPTE- BetaBag® was connected for the fifth time or tenth time and then left in position (with the internal Alpha door open) during the transferring of 500 g of surrogate powder, from one container to another.
Three test runs were performed to assess each of these three separate connection and disconnection scenarios. Therefore, nine test runs were performed for each size DPTE Alpha port and thirty-six test runs were performed over a ten-day period, with a total of 270 air samples collected.
After each DPTE Alpha port had been subjected to the three scenarios, the DPTE Alpha port was changed to the next aperture size using the validated methodology explained previously in the preliminary work section.
SURFACE SAMPLING AND RING OF CONCERN
The “ring of concern” is the generic term used to describe the area where an Alpha port door and the Beta assembly meet. This very small circular band on the lip seal is approximately 0.1 – 0.5 mm wide and is exposed to the inside of the isolator when the alpha door is opened. It can therefore potentially become contaminated with whatever is present inside the isolator chamber at the time of use, which in this case was the acetaminophen surrogate.
Surface samples were collected from the ring of concern prior to and immediately after the first test run of the containment performance assessment for each of the four different sized DPTE Alpha ports, after one, five and ten connections and disconnections. Samples were collected before each test run to quantify the contamination present, if any, on the ring of concern prior to the DPTE containment performance assessment.
RESULTS SUMMARY FOR AIR CONCENTRATIONS
The results of the assessments, conducted during connection and disconnection of the various DPTE devices, demonstrated excellent containment performance, and based on the parameters adopted in this assessment indicated that the containment performance of each of the four DPTE Alpha ports does not significantly change after one, five and ten connections of a DPTE-BetaBag or DPTE Beta Container.
The concentrations recorded on all samples were all averaged over the task period and used to determine the DPTE Alpha port containment performance.
The airborne concentrations recorded on the proximate area samples adjacent to the DPTE Alpha ports were all less than 1.2 ng/m3, and of the 108 proximate area samples, 96% were below the limit of quantification for the analytical method used.
The airborne concentrations recorded on the personal samples during the final disconnection of the DPTE Alpha port was between <1.5 – 36 ng/m3, the other detectable value recorded was 2.5 ng/m3. Out of the 36 personal samples, 94% were below the limit of quantification for the analytical method used.
These results demonstrate the suitability of all the different sized Getinge DPTE transfer devices when working with highly potent pharmaceutical active ingredients.
RESULTS SUMMARY FOR SURFACE CONCENTRATIONS
The surface concentrations recorded on the ring of concern of the DPTE Alpha ports were all between <0.1– 72 ng per cm2, and of the surface samples taken, 75% (9 out of 12) were below the value of 10 ng per cm2.
CONCLUSIONS
The containment performance of four different sized Getinge DPTE Alpha ports has been reliably assessed and the data indicates their suitability as contained transfer devices when handling potent and highly potent pharmaceuticals. In addition, the containment performance of each of the four DPTE Alpha ports does not significantly change after one, five and ten connections and disconnections of a DPTE- BetaBag or DPTE Beta Container.
It appears that very small quantities of powder are being transferred onto the peripheral band on the lip seal (ring of concern) of the DPTE Alpha port during connection and disconnection of a DPTE- BetaBag or DPTE Beta Container. Cleaning the ring of concern following removal of the device, is therefore essential to maximize the performance of these devices and should be considered part of the end user’s operating procedure.
LIMITATIONS
Due to the inherent variability of airborne particulate data generated when assessing the containment capabilities of pharmaceutical equipment, it is recommended that a statistical approach is applied to data interpretation prior to comparison with limit values.
Figure 1. Getinge DPTE® Alpha port.
Figure 2. Test isolator used for containment performance assessment of DPTE Alpha port.
Figure 3. Stainless-steel plate housing the DPTE Alpha port.
Figure 4. Connection and disconnection of DPTE- BetaBag®.
REFERENCES AND NOTES
- Getinge, DPTE Alpha Port.
M. W. Axon, J. Ball, and E. V. Strijdonck.,” Containment Performance of Semi-continuous Tablet Coating Equipment ”, Chemistry Today, Vol. 38 (6), 2020, pp 45-49. - International Society for Pharmaceutical Engineering, “Assessing the Particulate Containment Performance of Pharmaceutical Equipment”, ISPE Good Practice Guide, ISPE, 2nd Edition (2012).
