De-Risking Biologic Drugs and Injectable Drug-Device Combination Products
RISK CONSIDERATIONS SPECIFIC TO COMBINATION PRODUCTS
Growth in biologic drugs in the development pipeline of products has led to growth in the use of injectable drug-device combination products. A combination product is a product comprised of two or more differently regulated constituent parts – for example a drug and a device. Looking at history, there are several clear examples that justify why special considerations must be given to biologics and combination products. Risks specific to each component must be understood because a system is only as strong as its weakest link, however, typically issues occur at the intersection of various components of a system. Several examples are: 1. Leachables from an elastomeric component interacting with polysorbate 80 was one of the factors in the Eprex® drug product to lead to the increased occurrence of pure red cell aplasia in patients as reported in The Increased Incidence of Pure Red Cell Aplasia with an Eprex® Formulation in Uncoated Rubber Stopper Syringes. Kidney International, Vol 67 (2005). 2. Silicone oil distribution issues that led to the autoinjector stalling and delivering an incomplete dose of Enbrel® (etanercept). Recalls occurred in various geographic regions of the globe due to the potential of the glass syringe breaking within the autoinjector.1 The root cause was the poor silicone oil distribution within the glass syringe used within the autoinjector – resulting in higherthan-expected syringe extrusion forces. 3. Tungsten residuals from the staked needle insertion process used in glass forming of prefilled syringe (PFS) barrels led to protein aggregation in Neupogen® (filgrastim) and several other biologic drugs.2 Research conducted has shown that due to the presence of certain tungsten residuals, their concentration and the pH of the drug solution, aggregation formation can occur. It was determined that this protein aggregation mainly occurred through electrostatic interactions where the conformation of the proteins remained unchanged.2 It is clearly evident through an assortment of examples that there are various challenges that must be considered and overcome throughout the component selection and system characterization and optimization processes. This is why a holistic understanding that considers the uniqueness of the molecule and drug formulation, the primary package and its delivery device, the patient/user, and the manufacturing process to make it all happen is critical.
UNIQUE CONSIDERATIONS FOR BIOLOGIC-BASED DRUG PRODUCTS
There are sets of risks that must be considered based on the fact that protein-based drug products have unique challenges that are different from traditional small molecule chemical drug products. Understanding this allows appropriate de-risking measures to be taken. Risks such as incorrect folding, aggregation, amino acid modification, and proteolytic cleavage can affect the bioactivity of the protein itself. In addition to this, drugs based on proteins are typically a higher viscosity because they are larger in physical size (25,000 atoms versus 100 atoms) compared to chemically derived
drug products. This leads to higher milligram per milliliter (mg/mL) concentrations. As the concentration increases so does the viscosity which leads to additional challenges, especially in relationship to packaging and delivering the drug product. The interface of the biologic, delivery device, and the patient brings together all of the risk considerations. An example of this that may not routinely be considered is the bioavailability of a drug. Bioavailability is defined as the proportion of a drug that enters the circulation when introduced into the body, so it can have an active effect.3 When a drug is administered intravenously, its bioavailability is 100%. When an injectable combination product is being used the drug is typically administered subcutaneously or intramuscularly, so the bioavailability is critical and can depend on aspects such as the depth of needle injection, etc.
DEVELOPMENT PROCESS
A development process for a combination product always starts by defining the end targets that need to be met. This means combining the drug target product profile (TPP) and the device/system user requirements (URS). A methodical process to identify risks and causes of failures should occur. Tools such as Ishikawa diagrams and failure modes and effects analysis (FMEAs) are commonly used in this process. It is critical that cross functional teams work together to identify and prioritize the risks of not only the final combination product, but its constituent parts and critical components. The physical characteristics of the drug will play a major role in delivery performance. Aspects such as viscosity, inherent particle size and thermal sensitivity, among others of the drug along with characteristics such as the injection time, activation forces, physical discomfort, and dose accuracy must be understood and managed.4 Part of this development process is the work to identify the essential performance of the combination product.
ESSENTIAL PERFORMANCE REQUIREMENTS (EPRS)
EPRs are intended to be a subset of design controls related to assuring that clinical performance of the device meets the combination product’s intended use and be proven safe and effective. The FDA generally considers EPRs as being the performance attributes responsible for the clinical performance of the device at the point of use (dosing/administering) and include the device’s performance attributes relating to the user interactions required to administer the dose.5 These EPRs are identified within the combination products market application to the regulatory agency, therefore, any change that may occur that could have an impact to the EPRs must be communicated to the regulatory agency.
MANUFACTURING PROCESS
Processing steps can impact certain characteristics of the biologic leading to issues such as aggregation and particle generation. Steps such as fermentation/ expression, unfolding/refolding, purification, freeze– thaw, filtration, pumping, pressurization and drying, among other processes, can lead to aggregation. Many of these steps may lead to shaking and shearing of the protein during production or distribution. This can induce protein aggregation although the extent of impact depends both on the intensity and duration of exposure to such stresses. Shaking can create air/water interfaces. The hydrophobic property of air relative to water induces protein alignment at the interface, maximizes exposure of the hydrophobic residues to the air, and initiates aggregation. Shearing can also potentially expose the hydrophobic areas of proteins and may cause aggregation.6 All significant risks must be considered and mitigated in process development.
RISK IDENTIFICATION FOR PACKAGE/DEVICE
Once the individual risks in these areas are understood, there must be consideration taken for the interactions of all these aspects. An example of this type of risk is the fact that proteins will have different affinities for various surfaces. Adsorption can be affected by solution pH, salt concentration, and temperature. Container closure systems have been shown to induce surface-related protein aggregation. This has been exhibited with contact of metal containers/surfaces or the indirect effect of a leachable or process aid from the container closure system.6 Extractable and leachable studies should be performed to evaluate the potential for the container closure materials to interact with and modify the biologic product. Change in product quality attributes should be realized in respect to component extractability, physicochemical compatibility and safety. Reactive species present at levels lower than the analytical evaluation threshold (AET) could have a negative impact on biological product quality or lead to a potential patient safety issue. The amount of work completed for these studies should be commensurate with the phase of development.7 Over time, knowledge and understanding will build, and this should continue through active lifecycle management. An understanding of the potential risks of the package and delivery system is critical as they will form the basis for potential issues with the final combination product. It is thought that a prefilled syringe system is a relatively straight forward product to develop. In Figure 1 below, there is a visual example of some of the risks that should be considered early in the combination product development process.
PATIENT/USER CONSIDERATION
All drug and device work is important and ultimately benefits the patient. The FDA has made it clear that human factors considerations are a must in developing any combination product. Ultimately, the design validation testing (DVT) that occurs at the end of development is completed to assure that the right product was developed. The objective of human factors is to consider the users, their environment, and the interface with the device to assure safe and effective use. Formative human factors work should be conducted while the combination product is still under development – including misuse considerations. This process is iterative and should provide feedback into the design so that improvements can be applied. A risk mitigation strategy should be documented to de-risk the identified hazards to an acceptable level. Retesting should occur to demonstrate effectiveness.8 The design verification and validation processes at the end of combination product development should assure the correct product has been developed for the targeted user and therapeutic need.
BIOLOGIC FORMULATION AND PATIENT/USER CHALLENGES CAN BE MITIGATED THROUGH INNOVATIVE DEVICE PLATFORMS
As mentioned, these biologics are sensitive to their environment and formulations may come with physical challenges such as larger volumes and higher viscosities with a broader range in injection rates. An alternative way of addressing some of these challenges is through the use of on-body injector systems. These systems can typically hold a larger volume that can be delivered over a period of minutes versus “seconds,” which are typical of autoinjector systems. Wearable injectors adhere to the body to deliver larger volumes of drugs subcutaneously. Several pharmaceutical and medical device companies have developed wearable injectors. The device consists of a reservoir for medicine, a cannula for substance delivery to tissues, and a drive system to deliver the appropriate drug volume. An adhesive is used to attach the device to the patient’s skin. The benefits to the patient can be many because of the ability to deliver greater drug volume by a subcutaneous injection over extended time periods. This type of product provides an avenue to move treatment from a hospital/clinical environment to the home. It can enable self-administration in a safe and effective manner.
SUMMARY
As the many benefits of biologic drugs being delivered as part of a combination product platform are realized, this trend toward self-administration will continue to grow. Understanding the various risks and being positioned to mitigate those risks is not an option but a must in development and commercialization. The use of a risk-based approach is foundational from a regulatory perspective and should be at the center of all work that is being conducted. It is imperative that the unique challenges of biologic drugs and the intersection of various components of the system be considered at the center of these programs for them to be successful.
REFERENCES
1. Government of Canada Recalls and Safety Alerts. Enbrel SureClick Autoinjector (September 18, 2009). https://healthycanadians.gc.ca/recall-alert-rappelavis/hc-sc/2009/9736r-eng.php 2. Jiang Y., et.al. Tungsten-Induced Protein Aggregation: Solution Behavior. J Pharm Sci, Vol. 98 No. 12, (2009), pp 4695-4710. https://doi.org/10.1002/jps.21778 3. National Center for Biotechnology Information (NCBI). https://www.ncbi.nlm.nih.gov/books/NBK557852/ 4. DeGrazio F, Paskiet D. Injectable Combination Product Development: Facilitating Risk-Based Assessments for Efficiency and Patient Centric Outcomes. J Pharm Sci, Vol. 109 No. 7, (2020), pp 2101-2115. https://doi. org/10.1016/j.xphs.2020.03.020 5. Lipman J, Stevens A. Essential Performance Requirements – Latest FDA and Industry Insights on Identification and Control Strategies. Xavier Health Combination Products Summit (September 13, 2019) 6. Wang W, Nema S, Teagarden D. Protein Aggregation – Pathways and Influencing Factors. International Journal of Pharmaceutics Vol 390, Issue 2 (2010), pp 8999. https://doi.org/10.1016/j.ijpharm.2010.02.025 7. Paskiet D. Safety Thresholds and Best Demonstrated Practices for Extractables and Leachables in Parenteral Drug Products. PharmEd Extractables and Leachables Virtual Summit. (June 2021) 8. Follette Story M. Human Factors Considerations for Combination Products. RAPS. (2011) https://www.fda. gov/media/81986/download
Eprex is a registered trademark of Johnson & Johnson Corporation. Enbrel is a registered trademark of Immunex Corporation. Neupogen is a registered trademark of Amgen Inc.