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September 5, 2016

Flexible Film Isolators for Single Use HP-API Manufacture

The Pharmaceutical manufacturing sector faces many challenges with the growth of ADC (antibody drug conjugates) manufacture and the adoption of Strictly Controlled Conditions (REACH Regulations) in manufacturing facilities. To provide the necessary personnel protection for HP-API’s (high potency active pharmaceutical ingredients) the adoption of flexible film containment technology seems to offer the perfect solution able to meet both the need for personnel protection system in the workplace and by disposal on a campaign basis – eliminate the need for cleaning validation.
Let’s look at the steps needed to make this popular containment solution suitable for Single Use HP-API manufacture:

Development of Flexible Film Containment Systems:
Since their inception and adoption by the Pharmaceutical industry in the early 1990’s flexible film containment systems have seen much technological development. Early “Glove-Bag” and flexible isolator systems were focussed on minimal technology and minimal cost. These early systems are easily recognisable by their basic set up often suspended on elastic (bungee) cords to permit stretch and movement of the enclosure. Early systems were often designed to operate at ambient / room air pressure and with basic low cost filtration systems, often simply a P3 breather filter disc. Whilst P3 filters are functional in their ability to permit airflow into or out of the contained space of the flexible isolator let’s remember P3 filters are by and large a mass produced and un-certified filtration product. This raises issues with IQ/OQ validation of the containment system and from a regulatory perspective is not as satisfactory as a manufacturers certified H14 HEPA filter with full traceability.
As flexible film containment technologies developed for handling more potent compounds some manufacturers have extended their flexible systems to incorporate certified HEPA filter systems. These compact cartridge HEPA filters typically purchased from Camfil or similar HEPA vendors provide a compact solution for enhanced filtration performance and are easy to integrate into a flexible film enclosure. However, due to the design constraints of elasticated support cords these more advanced glove-bag type containment systems are limited to ambient air pressure in the API contaminated enclosures. Typically to maintain ambient air pressure with H14 inlet/outlet HEPA filters dual fan airflow systems are employed to provide both a supply air and exhaust air flow and thus generate air movement within the flexible isolator enclosure – through the H14 HEPA filter systems.
In the field of hard shell API containment isolator technology the use of “ambient air pressure” within the isolated (API contaminated) chamber is totally unknown. Typically with hard shell API containment isolators a negative pressure cascade and the ability to create a “Breech Velocity” is a common if not mandatory requirement. Breech velocity is the inward airflow into a glove sleeve in the event of a glove failure. For Solo Containment applications this inward airflow velocity is set at 0.5M/Sec over a 105mm Dia. Open glove port. The velocity rated is sufficient to prevent egress of airborne particulate from the contained chamber back out into the processing facility. Breech velocity and therefore negative pressure operation is seen as a major safety benefit especially when considering the extremely low occupational exposure limits associate with ADC’s and associated HP-API’s.
By using negative pressure airflow within flexible film isolators a more engineered approach than supporting the enclosure with elastic cord is needed. Negative pressure flexible film isolators can have operating pressures at up to 100pa below the surrounding processing room. Hence, at these duties the deflection of the thin wall isolator enclosure panels can be very significant. As a result for negative pressure operation the flexible film isolator designer must add additional frame members and securely attach the enclosure using tight fitting press stud attaching tabs. With effective design deflection may be limited to 20 or 30 mm movement on enclosure sidewalls.

Flexible Isolator Performance with Negative Pressure Operation:
So can a flexible film isolator operating at negative air pressure and fitted with multi stage H14 HEPA filtration deliver equivalent containment performance as a stainless steel hard shell isolator?
Recent test data obtained through independent third party testing certainly demonstrates that containment performance is HP-API compatible.
On 13 & 14th July 2015 a negative pressure Solo isolator was tested by Vega Environmental Consultants using protocols set by the International Society of Pharmaceutical Engineering (ISPE) Good Practice Guide ‘Assessing the Particulate Containment Performance of Pharmaceutical Equipment’. In this application the target OEL for personal exposures was less than (<) 0.1 μg.m-3, as an 8-hour Time Weighted Average (8h TWA). In accordance with BS EN 689:1996 it was also desirable to control personal exposures to ≤ 25% of this value i.e. ≤ 0.025 μg.m-3, 8h TWA.

Personal sampling was carried out over three identical 10Kg powder dispensing runs and one cleaning run. Vega set up both dynamic operating personnel sampling and static sampling at five locations on or near the flexible isolator. In dispensing each run a complete continuous liner cycle (API batch removal) was included using the Solo Containment 6-Step SOP. The HPLC (high pressure liquid chromatography) assay detected low levels of naproxen sodium in each of the personal samples. The graph below was constructed to visually represent the range of these results
in direct comparison with the target OEL. (Samples were analysed by Bureau Veritas Laboratories in the United States).

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Clearly from the above data the containment performance of a negative air pressure flexible film isolator makes these devices suitable for ADC manufacture – however the next challenge is to combine high containment performance with true “single use” functionality.

Single Use Functionality:

Again if we look back at the development of flexible film containment systems we have seen these have evolved from basic glove bag systems with elastic support cords and un-specified filtration systems to ambient air pressure dual fan systems – often with HEPA filters sealed using Chem-Tape. Such systems are for reasons of economy shipped with an Installation Kit whereby the user is expected to attach the enclosure cords to the support frame and possibly tape attach HEPA filters to capture API particles. Solo Containment have taken this a stage further by supplying screw mounting as well as Push-Push safe change HEPA filters that are fitted by the client during set up. But these stay attached to the contaminated flexible enclosure during disposal. The unit above tested by Vega Environmental Consultants fell into this category.
Where continuous liner ports for contaminated item exit are required Solo have traditionally been offering a stainless steel or economy plastic continuous liner holder protected by a plug cap and 6 stage SOP when HP-API containment performance is required. The protection of the liner port has typically been effected by carrying the flexible film sleeve through the rigid port and back under the liner cassette. This in theory permits a changeover of the contaminated flexible film enclosure with no loss of containment – but the sequence is seen as complex and can be time consuming.

For true “Single-Use” functionality the engineering team at Solo Containment are now supplying fully pre-assembled / pre-tested flexible enclosure with these key features:
• Pre mounted – air inlet / air exhaust H14 HEPA cells permanently bonded to the flexible enclosure side wall. These are disposed of totally at each flexible enclosure change over.
• Gas tight fully welded zips on loading airlock + SOP for through glove decontamination prior to reaching through into the airlock chamber
• Push-Push instant change glove cuffs with cytotoxic rated gloves
• Pre- installed single use continuous liner port with gas tight protection zip. This is bonded to the flexible film enclosure side wall and is carried by a yoke bracket. This permits the complete continuous liner system to be disposed of without separation of the carrier port and film sleeve – greatly reducing change over time and the risk of API aerosol escape.
• Segmented isolator base trays: To protect the delicate base panel in their flexible film isolators Solo Containment have for many years offered a disposable plastic base tray system. Now for single use functionality these trays are offered at “tiles” that may exit through the continuous liner port.
• Analytical balance recovery sleeve: Whilst some of Solo’s clients have elected to use a single use (disposable) balance in the enclosure – other clients are looking recover the electronic balance for future campaigns. Here Solo are able to offer a secure one time system for contained balance exit – with no loss of containment.
• Complete system subjected to detailed PDI with pressure decay testing.

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In offering the isolator enclosure as a pre populated kit the time burden of set-up has transferred from the user in the pharmaceutical manufacturing facility to the flexible film isolator provider. Early trials are suggesting that the pre-assembled / pre-tested system as described here may be set up as a ready to operate enclosure within 30 to 40 minutes. This is compared to typical set up time of 1 to 1.5 days for a conventional “client build” system. Similarly with enclosure disposal – all key components of the isolator system including the continuous liner port may be lifted off their carrier yolk and placed into the incineration bin.
Conclusions:
By operating flexible film containment devices at negative pressure and using multi stage certified H14 HEPA filters a step change in containment performance can be seen. However, the short operational campaigns typical of ADC manufacture combined with the highly potent nature of these materials requires the isolator technology to be delivered as a ready to operate – safe to dispose of package to reduce both risk to personnel and cycle times.
END
The Author:
Martyn Ryder – Managing Director of Solo Containment has been involved with flexible film isolation systems since 1995. For further information please contact www.solocontainment.com