Formulation & Delivery of Protein and Peptide Biopharmaceuticals:Multidose Formulations

Formulation & Delivery of Protein and Peptide Biopharmaceuticals:Multidose Formulations
2005
Integrity Biosolution
Multidose Formulations Multidose formulation should be used when dose adjustment, dose-pooling, and/or dose-splitting becomes a necessary practice. In general, the addition of preservative(s), regardless of the type and amount utilized, significantly changes the stability profiles of proteins. In some extreme cases, visible precipitation and aggregation have been reported from the introduction of these materials. Therefore, the effect of various preservatives on the stability of protein should be carefully examined. Other experiments are also required to qualify a protein product for multidose formulation capabilities. The most notable tests include analyses for antimicrobial preservative effectiveness and stopper resealing. As proteins have limited stability in the presence of preservatives, dual chamber syringes or dual chamber cartridges containing bacteriostatic diluents are routinely used.
Example of Integrity Biosolution's Multidose Formulation Development Study (lyophilized formulation & multidose diluent combo study**)
Both lyophilized formulation and the diluent will be optimized for storage stability of the product and antimicrobial preservative effectiveness suitable for the targeted market. Stability results from lyophilized vials, reconstituted vials, lyophilized dual-chamber cartridges or equivalent container-closure packages, and reconstituted dual-chamber cartridges or equivalent container-closure packages will be provided.
Key objectives
Optimization of lyophilized formulation for storage stability and convenient reconstitution
Optimization of diluent for effective multidose formulation
Real-time stability data for reconstituted formulations
Antimicrobial preservative effectiveness test results for selected formulation(s)
Recommendation of both lyophilized formulation and diluent formulation candidates
Recommendation of crude lyophilization process(es) for selected formulations
Results from container-closure system which can be adapted to more advanced delivery device(s)
Lyophilized formulation optimization
The formulation will be optimized for suitable stability, good cake appearance, and easy reconstitution. Both vials and dual chamber cartridges (or glass cartridges with equivalent product contact surfaces) will be tested. The following formulation components will be optimized.
Bulking agent
Stabilizer(s)
pH and buffer
Protein/peptide concentration bracket (higher concentration for lyophilization followed by larger volume reconstitution will significantly reduce the lyophilization time)
The following parameters will be used for the optimization.
Storage stability based on accelerated stability data at 37 and 50 degree C
Stability to light exposure
Preservation of native structure as demonstrated by FTIR analysis
Glass transition temperature of lyophilized powder as determined by DSC (should be higher than room temperature).
Good cake formation and efficient lyophilization cycle as determined by subambient DSC analysis (formulation suitable for lyophilization in dual chamber cartridge)
Good compatibility with at least one tested diluent
Sufficient stability for manufacturing, handling and delivery
Rapid reconstitution time (< 1 minute)
Good syringeability
Diluent formulation optimization
A diluent that demonstrates suitable stability and compatibility with the lyophilized formulation will be developed. A desirable diluent will have the following attributes:
Preservative(s) complying with antimicrobial preservative effectiveness criteria
Acceptable stability during terminal sterilization process or reasonable justification for sterile filtration -
Storage stability as a diluent
Suitable stability after reconstitution
Isotonicity or isoosmolality and/or minimal injection site irritation
Selection of preservative(s)
As most preservatives render proteins unstable, thorough research is required to evaluate the feasibility of developing a multi-dose formulation with compatible preservative(s). As the effectiveness of each preservative is highly influenced by both the pH and the composition of formulations, it should be incorporated into the formulation optimization process. For European products, if antimicrobial preservative effectiveness criteria A cannot be achieved with tested samples, justification for criteria B will be generated by demonstrating that tested preservatives will significantly increase the rate of aggregation when their concentration is increased to meet the criteria A. The best preservative or combination of preservatives will be selected for the protein/peptide. This will require information about protein-preservative interaction, preservative-excipient interaction, stability indicating assays, and a stress condition to accelerate any preservative-induced degradation. The source of GMP (or equivalent) quality preservative will also be evaluated as a minor impurity can cause significant degradation of the protein. If necessary, a convenient assay will be developed for the quality control of preservative raw material.
Bridging the multidose formulation with convenient delivery devices
For the lyophilized formulation with multidose diluent combo package, we recommend an easy to use auto-injector/pen device that is capable of variable and multi-dosing from a dual-chambered, lyophilized cartridge. Pen systems are most noted for their flexible dosing abilities. Insulin pen systems for diabetes treatment are the most well known examples of pen injection systems.
Some specific benefits with pen injection systems are:
Simple, often intuitive, self administration (2-4 steps for a disposable system, 3-6 steps for a reusable system)
Utilizes existing industry standard cartridge container closure systems
Can offer needle-stick and sharps protection post injection
The ability to multi-dose from the same primary container (usually cartridges) given a properly preserved and suitable formulation
The ability to offer variable dosing or dose titration
The ability to offer an intuitive and seamless reconstitution and subsequent delivery of lyophilized formulations when utilizing dual-chambered cartridges
The ability to utilize very fine needles to contribute to the minimization of injection pain (up to 31 gauge vs. 27 gauge with pre-filled syringes)
The disadvantages of pen systems:
Most disposable auto-injection systems are considered combination drug/devices and must pursue approval as a drug product candidate versus a device only candidate
Patient initial training is often more time consuming due to the inherent increased complexity of these devices
Auto-injectors and pen systems have been historically and generally utilized for both acute and chronic therapies. For acute therapies, the industry has gravitated toward the use of disposable systems primarily due to their ease of use attributes. Conversely, for more chronic conditions, reusable systems have been more popular due to the ability to amortize initial capital costs over a longer term period and minimize the recurring expenses for an overall reduced program cost. For pharmaceutical companies considering these systems, the choice between reusable versus disposable systems becomes an important factor and careful consideration should be applied to assess and maximize the overall economic benefit of each option to the company. In summary, we believe that an appropriately selected and implemented injection delivery system can offer many potential benefits to the pharmaceutical company. It not only offers convenience to the patients, but it also offers unique advantages to the company itself through brand loyalty, market share capture and retention and the erection of larger barriers to entry for any existing or potential competition. Integrity Biosolution can assist in the development of device if customer wants to launch an injection device for the multidose formulation.
** Potential risks associated with aggressive formulation development timeline
Considering that long-term stability is predicted based upon results obtained from a limited time frame, there is always the possibility that some unexpected issues will arise at later time points. The degradation of proteins follows very complex reaction pathways where both activation energy and the reaction order of each reaction is different from others. Therefore, a dominant reaction at one temperature may turn out to be insignificant at another temperature. In addition, the contribution of external factors like impurities from excipients and head space oxygen may be a dominant factor at one condition while other competing factors can be more important at other conditions. The state-of-the-art analytical methods that are available today may not disclose all physicochemical changes occurring in the formulation. While we employ as many analytical methods as possible to minimize undesirable degradations, there always remain risks associated with today's limited analytical capability. There are numerous intellectual property and trade secrets which can potentially prevent the commercialization of formulation candidates. While we run comprehensive patent searches to make sure that there are no competing patents, the potential for undiscovered blocking patent information always exists. The availability of a desired delivery device can be dependent on timing. There are a limited number of delivery device companies and the availability of their technology can and do change periodically.