In spite of a tried and true method for safely detaching glovebag sleeves which has been in use by the Nuclear Industry since the 1950’s and the Pharmaceutical Industry since the early 1990’s, questions often arise challenging the efficacy of the procedure. The issue commonly arises due the lack of consideration of materials compatibility. The more rigid films do present a challenge because they do not readily conform to extreme folds and will result in air by-pass leakage channels. Elastomeric films are compliant with the surfaces more readily reshaping under stress of the tie, while surface tack further enhances the formation of an airtight seal:
Performance properties of polymer films
- Linear low density polyethylene (LLDPE) film as typically used in the Pharmaceutical Industry:
The film is formulated using a catalyst and further modified by addition of blocking agents.
Additional modification occurs when anti-stat agents are incorporated. Both the virgin film and film with additives are relatively stiff at room temperature, with stiffness increasing as temperature decreases, e.g. chill room storage and trans-shipment. Tensile strength is moderately low, decreasing as temperatures both increase and decrease. The seams will tear readily unless the thermal seals are properly tempered. Transport in the holds of aircraft at both decreased temperature and pressure present even more likelihood of embrittlement. When folded using a bag-tie for closure, higher tension is required when compared to other films, to minimize air by-pass leakage due to channeling caused by the film crenellating rather than folding.
- Polyvinyl chloride (PVC):
PVC also incorporates a catalyst, blocking agents, etc. Although commonly used prior to 1995, it has become less common since it was declared a hazardous waste. PVC has a characteristic odor due to the plasticizers (usually phthalate esters) vaporizing out of the film resulting in the formerly flexible film becoming more brittle over time. This phenomenon also reduces the shelf life of PVC. A drop in temperature causes PVC to embrittle and, at temperatures below 0°F, PVC will fragment. Tie closure is considerably better than LLDPE at room temperature due to the film being both flexible and collapsible with a surface tack adding to the air-seal efficiency. Temperature decrease will weaken the seal, which will ultimately fail as the film stiffens.
- Polyurethane (PU)
Urethane formulations do not require a catalyst for polymerization. Blooming and anti-stat agents are the most common additives to the formulation. Formulations used in the Pharmaceutical Industry are pliable across a wide temperature range. The film is elastomeric and will easily fold and compress when tied, with the surface tack adding to the air-seal resulting in an effective air-lock. The compressibility, the elasticity, and the surface tack all add to the stability of a tie minimizing the tendency of a tie to slide during handling.
Bag tie selections are restricted both by Quality demands and temperature restraints. Much stability testing is conducted using Nylon 6,6 (a co-polymer of hexamethylene diamine and adipic acid using only a catalyst additive) bag ties. The reason is obvious, the absence of conditioning additives means less potential for vapor emission, aging, and enhanced temperature stability. Raw, intermediate, and final API materials are often subjected to decreased temperature conditions, e.g. storage in a chill room and shipping. Hence, polypropylene and similar materials frequently fail when subjected to decreased temperatures and the shock of handling, while the pliability of Nylon 6,6 is well suited to such conditions.
History
The closure method dates back to the 1950’s when the Nuclear Industry (following on from the original Manhattan Project) developed the technique of twisting and tying the neck of polyethylene bags before detaching from a rigid glovebox. Two ties are spaced about 2 – 4 inches apart to secure both cut ends before cutting between the ties. The result is two cut ends extending beyond each tie-point (image below).
The closure method has long been approved by Health Physicists as an alternative approach to using interlocking Glovebox pass-throughs. The waste stub is secured within a waste containment drum for disposal. Health Physicists sample procedures using instantaneous readout methods having a sensitivity several orders of magnitude better than sampling and analysis for chemicals (>100,000 fold more sensitivity). The methodology involves sampling around the twist, tie, cut operation using a calibrated radiation-monitoring instrument to observe spontaneous events. Testing repeatedly showed the approach to be permissible for coping with minute waste particles encountered by the nuclear industry. In this way both experienced operators, during routine retraining, and new operators, in initial training, master the appropriate technique based on immediate feedback. The procedure is:
TWIST, TIE, CUT
The original Twist, Tie, Cut (TTC) method has evolved to incorporate the use of Military Specification steel ties in place of conventional bag ties for more secure long-term storage. Bag-out using this procedure remains the primary method of removing waste radioactive materials from gloveboxes.
The TTC method has been enhanced for the Pharmaceutical Industry by affixing a second tie above the security tie, taping over the twisted film stub to keep it compressed, and finally securing the resulting stub ends with more adhesive tape. These additions improve the containment performance of the original method. The resulting process (below) has become:
TWIST, TIE, TAPE, CUT, SECURE (TTTCS or T3CS)
An improvement over the double tie closure is the J-clamp. In this procedure two additional ties are used, allowing for increased space between the original ties. This also creates two additional airlock seals either side of each of the existing tie-points (images below). The resulting procedure (below) has become:
TWIST, TIE, TAPE, FOLD, TIE, CUT, AND SECURE (TTTFTCS or T3FTCS)
Additional methods have been developed as alternatives to using bag/cable ties. One such method comprised of stretching the neck flat and tight, and then creating a wide heat seal, which is separated using a cutting tool down the middle of the heat seal. This requires tests to ensure that heat damaged material is unable to contact product within the bag. Airtight closure via the heat seal is essential.
Materials Compatibility
The Pharmaceutical Industry has adopted three primary materials that require contained detachment: polyethylene (PE), polyvinyl chloride (PVC), and polyurethane (PU). Each comes in several flavors using ‘Agency’-approved additives to attain conductivity. PE and PVC formulations also include a catalyst, several possible anti-blooming agents, plasticizers, and other materials to extend stability over time. Their stability to temperature change follows the order:
PVC << PE < PU
At normal user temperatures their pliability follows the order:
PE << PVC < PU
Pliability relates to the force required to ensure an airtight seal for twisted material, and also to the ease with which a tie will slide off a closure.
Being less pliable, it is quite difficult to compress a PE neck to prevent air bypass through the resulting air channels. When placed under tension, the rigidity encourages formation of a ‘floret’, which when cut can spring open and release any entrapped materials as a small dust emission.
PVC is more pliable and conforms more readily to folding tight during twisting of a neck and compressing tightly at the tie point, resulting in more force to accidentally dislodge the tie when the cut twist is released. The ‘floret’ effect is less prone to happen when cutting compressed PVC.
PU displays the best-case scenario due to the inherent ‘tack’ of the material. Even when anti-stat material is added, this property is retained. The advantage lies in the fact that PU has a tendency to fold in flat layers in intimate contact even before compressed with a tie. The resulting compressed neck requires more force to accidentally dislodge the tie, indeed removal of a tie requires cutting. The ‘floret’ effect is reduced to a minimum due to the inherent ‘tack’ of clear PU. Frosty finish PU has slightly less tack than virgin PU.
The added requirement of “product contact integrity” requires the use of Nylon 6,6 formulated bag/cable ties for some users, especially when used for final product packaging and storage. The tie point defines the boundary between usable, i.e. below the tie, and unusable, anything above the tie is waste.
The subsequent user cuts below the tie when preparing the contents for discharge.
The closure method has been further modified for the Pharmaceutical Industry to ensure no releases occur after the detachment is complete. The method involves a sequence of:
TWIST, TAPE, TIE, CUT, SECURE
Taping prior to cutting secures the twist before and during the cutting procedure, which minimizes potential for releasing dust, i.e. the ‘floret’ effect is compressed significantly.
Since the twisted neck is in close proximity to product, the tape is required to have no animal-related components in its formulation. 3M-brand tape #8884 meets this criterion. All materials used on closure of a stub piece should have comparable formulation.
The heat-seal method required that the heat seal be subjected to stress testing using standard procedures. In the initial trial, the heat seal was formed with a selection of contaminant materials sealed within the heat seal boundary. The seal was subjected to stress at elevated temperatures, and a peel test was also performed. The heat seal withstood both challenges. Additional uses would require similar testing for the API, intermediates, and anticipated contaminants to validate the seal integrity.
Performing a TTTCS stub detachment
The images depict the sequence of events for the two most common techniques:
STEP 1 Tightly twist the neck between the two security ties
STEP 2 Tape neck tightly between the security ties using 3M #8884 tape
STEP 3 Place two ties over the taped area allowing room for cutting and separation.
STEP 4 Cut cleanly.
STEP 5 The finished product. Two stubs secured with 3M #8884 tape ready for further handling.
TTTCS performance
Many records of testing and continuing performance of closure and detachment using the TTTCS method of closure and detachment have been generated since the method was first applied showing consistent performance to ~0.2 ng/m³. The results were achieved for all films used for containment purposes, including virgin LLDPE, virgin PU, conductive PE, conductive PU, PVC, and ILC Dover Armorflex specialty film products, and special film formulations from Lormac (UK and Ireland), all of which meet acceptance criteria. We recognize that operator awareness of testing was a dominant factor in performance.
Nevertheless, a long-term study provided routine confirmation of the absence of measurable levels of material in the production environment. In addition to individual testing, long-term use has been documented for a facility using the TTTCS method exclusively for both PE and PU containment films in 4 of the said facility’s 17 containment zones on a daily basis. This facility was monitored 24 hrs/day, 7 days/week, for over 6 years with no evidence of release excursions traceable to the TTTCS practice. One event was observed when a release of 0.11 µg/m³ occurred, which was traced back to a screw feeder during a packaging operation, with no evidence for release at the actual TTTCS usage point. The incident only lasted for 20 minutes total as traced by continuous reading particle counters, which confirmed the reliability and sensitivity of the testing protocol.
Operator training when using the TTTCS method for packaging both an endocrine disruptor and an oncolytic drug using Lormac film bags was performed while monitoring with conventional methods for both personal and area exposures. In addition, two CLiMET 6-channel particle counters were located at the charging and packaging cut-off points to immediately alert when spontaneous releases occurred. Knowing this, the operators were diligent during their first training/qualification and no releases were observed even with our ability to detect spontaneous minute quantities of released powder (<0.1ng would have been observed above the background noise level of the particle counter).
Alternative TTTCS stub detachment
An alternative procedure results in a shorter stub having less potential for forming a ‘floret’ after the cut has been made. It differs by reversing the order of the 2nd and 3rd event in the sequence of TTTCS, i.e. the Tie and Tape:
STEP 1 The first step is taping the length between the security ties
STEP 2 Affix the 2 cut-point ties close together
STEP 3 Cut cleanly between the two ties
The cut ends are very close to the actual cut, reducing the probability of the ‘floret’ opening and releasing material.
STEP 4 Seal the cut ends using 3M#8884 tape to complete the procedure
Performing a J-Clamp (TTTFTCS) detachment
This procedure requires that a longer neck be created between the initial tie-points to allow folding into a loop proceeding as follows:
STEPS 1, 2, & 3 When creating the security closure, leave a long length (>12 inches) of neck between them, tightly twist the length, and apply the cut-point ties ~8 inches apart
STEP 4 Coil the extended length of neck such that the two additional fold ties are enclosed within the lower loop of the coil
STEP 5A Tie one end of the coil to enclose the previous tie within the new tie
STEP 5B Both ends of the coil are tied enclosing the previous Ties
STEP 6 Cut through the remaining loop of the coil
STEP 7 It remains for the stub ends to be secured using 3M #8884 tape
The released component can be transported safely either for storage or disposal depending on the purpose of the detachment.
All methods are dependent on operators following the procedure with diligence. By creating two additional air lock seals, the TTTFTCS method is considerably more foolproof in ensuring the utmost containment capability, performing far below the lowest measurable concentrations. Procedural failings are minimized.