1.4 Stability and Compatibility
1.4.4 Material Contact Compatibility
The compatibility of the drug product with the materials with which it comes into contact must not only be assessed in relation to the primary packaging (e.g., a rub-ber stopper, a glass vial, or a plastic container), but it must also be assessed in rela-tion to the materials to which the formularela-tion will be exposed during manufacturing.
For example, the formulation will likely be compounded in a steel tank, so the for-mulation’s sensitivity to the appropriate grade of stainless steel must be evaluated.
In addition, the fi lling system may have diaphragms or gaskets in the pumps, and the fi ltration system will include tubing and various fi lter materials and components.
Is the operation being carried out in a disposal bag system? If so, the compatibility with the disposable bag system should be addressed. In all cases, appropriate stud-ies must be conducted to assure product integrity.
1.4.4.1 Primary Packaging
The selection of an optimum closure system is critical. Ideally, a vial/stopper com-bination must be found that will provide both a sterile closure system and long-term
stability for the product. Some products require glass ampoules, which avoids any leachables or extractables from a vial’s elastomeric closure system; however, a stop-pered vial is the fi rst choice. Stopper screening consists of exposing under stress conditions a series of potential elastomeric formulations to the lead formulation. For example, exposure of the lead drug product formulation to the elastomeric formula-tions at temperatures from 40 to 60 °C might be performed. The major stopper manufacturers can provide some guidance on elastomer selection and the require-ments for meeting compendial standards, such as USP <381>. Nonetheless, it is still the obligation of the formulator to demonstrate that any manufacturer-recommended closure system is acceptable.
Once the elastomer has been selected, it must be qualifi ed for use. Qualifi cation includes confi rming sterility assurance by demonstrating container closure integrity as well as by confi rming physicochemical compatibility. Testing for container clo-sure integrity can be done using either a dye ingress or a microbial ingress method (FDA Guidance for Industry 1999 , 2008a ).
Determining compatibility of a solution with an elastomer entails both assuring physical compatibility and chemical compatibility. Stopper elastomers can interact with the active ingredient, which causes degradation of the API, shifts in pH, intro-duction of undesirable materials, precipitation of material, and loss of material due to absorption or adsorption. In some cases, the product is so sensitive that a barrier is needed between the elastomer and the solution. Barrier options range from Tefl on to polymeric coatings. In cases where a barrier is used, understanding the interac-tion of the base elastomer with the product is helpful because if the barrier is ever compromised, the resultant effect can be explained. USP <381> lists a series of tests, conditions, and specifi cations. This USP monograph also specifi es who is responsible for the testing—the vendor, the user, or both.
USP Type I glass is the primary material for injection vials or ampoules; how-ever, the use of plastic containers is increasing. A host of other packaging presenta-tions are also common. For example, prefi lled IV bags and prefi lled syringes are more and more prevalent. Containers fi lled via blow/fi ll/seal technology are also on the rise. Pen injectors often have multiple components, including the glass cartridge, the needle assemblies that deliver the product, and the internal and external stoppers within the cartridge. Other products, such as implants, ophthalmics, and inhaled products, must also be shown to be compatible with the plastics, metals, and lining materials used for packaging.
Care must be taken with each of these materials, even with glass, to understand any potential interactions between the container and the product. Considerations such as oxygen migration, label adhesive migration, leachable material, extractable material, sterilization, and clarity are all issues to be examined.
1.4.4.2 Equipment Materials of Construction Compatibility
During the manufacturing process, the product will come in contact with a variety of equipment made from a variety of materials. Vessels, tubing, pumps, and fi lters
can be made out of steel, silicon, elastomers, and plastics. Federal regulations require the formulator to show that each of these materials does not interact deleteri-ously with the drug product ( Code of Federal Regulations ).
Stainless steel is the material of choice for compounding and storage of product, pump housings, fi xed piping, and fi lter cartridge housings. To assess the compati-bility of the product with stainless steel, coupons or strips of stainless steel that are of the same quality and fi nish as the manufacturing equipment are placed into contact with the formulation for extended periods of time, which depend on the estimated time of exposure during the overall process. Samples of the formulation are taken and tested in order to determine if any potency losses or increases in degradation are observed. Such studies should be performed at the temperature at which the process is expected to be run. Testing duration should exceed the expected process time in order to allow for the inevitable delays that will be expe-rienced during manufacturing.
Platinum-cured tubing is often used for pumping and fi lling product. Tygon tub-ing may also be used; however, platinum-cured silicon tubtub-ing is typically more compatible with a wider variety of products.
Tubing does not usually cause degradation, but it can cause a loss of critical materials because both the active ingredients and the excipients can be removed from solution by adsorption onto the tubing surface. To assess tubing and formula-tion compatibility, lengths of tubing adequate to hold enough of the formulaformula-tion for testing are sterilized or otherwise prepared as they would be in the production envi-ronment. One end of the tubing is sealed, either with a clamp or a glass stopper. The tubing is fi lled, and the other end is likewise sealed. The tubing is then held at the process temperature for a number of predetermined periods of time that are linked to the manufacturing conditions. At each time period, a length of tubing is emptied and tested for the potency of the active ingredient and/or excipients. If a loss of material is observed, loss data must be shared with the production personnel so that they can establish the period of time after which the equipment must be fl ushed if a line stoppage occurs. This fl ushing ensures that the low potency product is removed from the line and that the product will be fully potent during fi lling.
When testing the compatibility of the tubing, the question of potential leachable and extractable material may also be raised. In this case, the materials stored in the tubing are tested for the appropriate leachate. Often, the tubing vendor can assist with putting into place the appropriate test methods.
Filters are another source of potential interaction (PDA Technical Report No 26 2008 ). Solutions that contain surfactants, organic cosolvents, or all organic vehicles are of special concern because they can leach, or even dissolve, material from the membrane and/or housing, which sometimes ruins the product as well as the fi lter.
To assess these effects, small-scale fi lters are fi lled with solution and held at the processing temperature for an extended period of time. These fi lters are then placed into a water bath, pressurized, and observed. Streams of bubbles may indicate leaks in the housings. In addition, the membrane is tested by performing a standard integ-rity test in order to confi rm that the porosity of the membrane has not been affected by the prolonged presence of the formulation vehicle. An integrity test is typically
a bubble point test using either the fi lter wetted with the bulk solution product or the fi lter fl ushed with water to remove the bulk solution product.
Just as the vehicle can affect the fi lter, the fi lter has the potential to contaminate the formulation vehicle with leachable or extractable material. Again, working with the vendor can help address this, typically as part of the fi lter validation study.
Finally, similar to some of the studies previously described, the propensity of the drug and/or critical excipients to adsorb onto the fi lter must be addressed. Two types of studies can be performed—a static study and a dynamic study. In the static study, the bulk drug product solution is placed into the fi lter and held for extended periods of time. In the dynamic study, a specifi ed volume of bulk solution is recirculated repeatedly through the fi lter. During each study, samples are taken at specifi ed time intervals. For each sample, measurements of the concentration of the drug/excipient are made in order to determine drug and excipient losses. When losses are too great for the product to be fi ltered and fi lled in parallel, the fi ltration may be performed completely into a bulk receiving tank prior to fi lling so that losses are minimized. If a bulk receiving tank is not available, the bulk vehicle may be fl ushed through the fi lter system until the drug/excipient adsorption reaches saturation and the level of the drug/excipient in the bulk solution is at label strength. If neither of these approaches are an option, then alternative fi lter systems should be explored.