Quality organizations in the Pharmaceutical Industry are rightly concerned with any issues that may affect product integrity. Any solids, liquids, or vapors that may be released in close proximity to a product are suspect. The presence of any of these places additional burden on Quality laboratories.
Film Cleanliness
There is considerable confusion about what can happen when you don’t use the correct film for containment devices. In reality, all films are prone to the same concerns or lack thereof! All films start their life at the time they are first drawn from a molten pool of polymer. To prevent the film from crystallizing and becoming exceedingly fragile it is shock cooled. The film is drawn upwards out of the molten polymer. To keep it from collapsing on itself it is blown into a large bubble shape with copious quantities of air. The air used is cool ambient air. The moment cool air contacts the skin of the bubble immediately above the molten polymer pool the film is shock cooled. This prevents the film, which is now a solid solution, from annealing to form an crystalline matrix. Annealing is a common occurrence when a simple strip heater is used to seal a polyethylene bag creating a crystalline edge along the heat seal that is more fragile than the bulk film. The effect is more pronounced when a thick film, e.g. 20 mil thick, is heat sealed without shock cooling. Even holding the film on either side of the heat seal will cause parting along the sides of the seal.
The film bubble is drawn up to the cutting and folding mechanism where it is collapsed upon itself. The air inside and outside the bubble is room air. The technology for most film formulations has not changed radically over the years. Blowing is not done in a clean room or with purified air.
The friction due to airflow causes the film to become statically charged. As a result it is capable of attracting small airborne particles from the air surrounding the bubble on both the inside and outside surface. The supplier makes no attempt to clean the film before shipping the rolled material to a user.
The good news is that the dust does not readily release from the film surface because of residual static charge. Accrued dust remains stable on the surface of the film under normal conditions due to this residual charge – which is enhanced during handling. However use of copious quantities of liquid, or use for materials packaging, can result in extraction or abrasion of particles from the film surface.
Film cleanliness can be tested empirically
In a customer study, vendors were asked to submit film for cleanliness testing. Swatches measuring 100 sq.cm were aggressively treated with purified water and the resulting suspension filtered for comparison with standard part-per-million (ppm) filters. While most films showed a low level of staining (~4 ppm) there were two exceptions:
One film showed no observable staining. This was traced to the vendor pre-cleaning the sample on the understanding that cleaned film was to be provided.
The second exception was a film that produced a stain so black that it could not be quantified.
This was traced to vendor use of a third party fabricator.
A second request was made for film without disclosing the purpose. The results were the same except that the stain created by the previously clean film was in line with the others.
In a follow-up study a variety of polymeric films were cleaned using alcohol swabs resulting in stain free filters.
Most vendors of flexible containment perform tempering, cutting, assembly, inspection, and packaging under clean conditions. To use actual clean room conditions for these operations is meaningless when the stock film is not certifiably clean in the first place.
If a particle free film is desired, no degree of assurance is achieved when clean room fabrication is used. The accrued dust from film blowing, storage, and shipping will still be present on the film surface.
However, a clean product can be delivered by requesting post-production cleaning of the inside surfaces of the fabricated product. At FabOhio, Inc. this is performed by qualified operators in a clean environment using isopropyl alcohol swabs.
The learning point is that sub-contracted fabricators need to be audited as carefully as the primary vendor. FabOhio Inc. does not use sub-contractors, however we do fabricate products for other vendors under the same stringent quality requirements as our own products. Every product that leaves our loading dock in Uhrichsville, OH is manufactured, inspected, overpacked, and documented to the same standards that have been approved by independent industry auditors. FabOhio Inc. stands firmly behind all products leaving our only fabrication site whether provided for our customers or for other vendors.
FabOhio Inc. is pleased to deliver products which have been swab cleaned when requested. The same products can also be radiation conditioned after sealing for shipment in an overpack. Materials data sheets for our commonly used film are available at our website.
Film Composition
Linear Low Density Polyethylene (LLDPE) film was established as the Regulatory Agency standard reference material against which all other film formulations are compared. LLDPE bulk material used for blown film is a homogeneous polymer consisting of reacted monomer and the catalyst fully integrated into the final melt. LLDPE film shows poor long term resistance to some low molecular weight solvents in both the liquid and vapor states, e.g. methylene chloride and methyl alcohol. These are also solvents to which most polymeric films show poor resistance.
The European Medicines Agency (EMA) has established criteria for conductance of polymeric materials involved in intimate product contact that places serious constraints on formulation by allowing only a limited number of approved additives. They also list a battery of solvents against which a polymer film intended for product contact must be tested.
Any additive to LLDPE, or any film polymer formulation, raises concern about the integrity of the film material. While such polymer films may show stability to liquid solvents, this is not a predictor of solvent vapor stability.
Modifier additives to the formulation do not incorporate into the film matrix by reaction, but rather in a state of solid solution within the polymer. The additives physical characteristics remain virtually unchanged. Additives on the approved list are all volatile. The vapor pressure of the additive is a consideration. For example plasticizers added to Polyvinyl Chloride (PVC) can be identified by the characteristic smell emanating from PVC film. For this reason PVC is not used to contain product or intermediate when other alternatives are available.
Polymer films not involved in intimate product contact, e.g. glove bags, flexible enclosures, and flexible room barriers are not subject to the same criteria as product contact films. There is no justification for using a specialty film for such applications.
A polymeric film is only approved for product contact once short and long term stability tests with product contact have been completed. Short term accelerated stability testing occurs at elevated temperatures and requires 90 or more days. Long term stability testing takes 2 or more years, with the actual product storage requirements determining the maximum duration. The user, or a sub-contract, laboratory conducts stability tests. Vendors of flexible containment products rarely become involved in such testing. Refer to our earlier blog for details on a user experience.
The user is ultimately responsible for selection of a flexible film for use in their application. FabOhio Inc. does not claim superior qualities for the multiple film choices that we use to make glove bags, flexible enclosures, flexible room enclosures, glove sleeves, and other products that leave our site.
FabOhio Inc. will be pleased to advise you on the optimum film and conditioning requirements for your containment project. We give due consideration to the physical and chemical environments in which they are to be used, based on our extensive database of comparable applications. We consider both application requirements and cost efficiency for your benefit. We make available a number of film formulations. Our products are made by qualified personnel under clean conditions. Fabricated products are available pre-swabbed for cleanliness. Radiation conditioned products are conditioned in their sealed overpacks with the radiation tags still attached when shipped to the customer.
Summary
- Any raw material used as an additive for blown film complicates the product contact matrix
- Vendor claims of an approved film formulation do not implicitly guarantee that the film is an acceptable or superior product for use in your application
- A blown film is only approved for your use in extended product contact applications after you have completed and documented both short term accelerated and long term stability studies
- Containment barrier products fabricated from blown film in a clean room are intrinsically no improvement over products fabricated using clean manufacturing practices
- With current technology for blowing film, the only assurance of a film surface having lower than currently measurable surface contamination is to require the final product be cleaned with alcohol swabs immediately before sealing in a similarly cleaned overpack
- Product materials used for stability studies should be actual production materials, not stored reserve materials
- Flexible film applications not involving product storage do not benefit from the use of custom film formulations
- When auditing a provider of flexible film containment products, all manufacturing sources should be audited, including sub-contract providers