Stuart R. Gallant, MD, PhD
Drug substance and drug product release specifications have numerous uses throughout the product lifecycle. They guide process development and provide a framework for risk assessment, stability testing, and shelf-life determination. Today’s post provides examples of release specifications for small molecule and for antibody drugs and discusses common issues that arise in specification setting.
Small Molecule Release Specifications
Example specifications for small molecule drug substance and drug product are provided below:
Some common issues to think about in the development and application of these specifications include:
- HPLC Assay Development: The heart of any small molecule release specification is the HPLC method, as such it carries the weight of characterization and stability assessment of the API and the drug product. Ensuring that the method is robust and stability predictive is critical. Think about issues like reagent quality early on. As an example, trace impurities in reagents can create unwanted interfering peaks; even reagents marked specifically for HPLC use, must be evaluated to guarantee lack of interference; preferably several lots of each reagent should be trialed.
- Sterility: Sterility testing should be free of interference from the active and from excipients. Consider carefully the possibility that the active could suppress growth as the sterility testing is planned and executed.
- Stability: Consider carefully the drug substance and drug product storage conditions. Ideally, a long shelf life will be achieved—during early clinical work, the number of manufacturing campaigns will be small, leading to a drug product supply crisis if the drug product has a shorter real time shelf life than predicted.
Antibody Release Specifications
Example specifications for antibody drug substance and drug product are provided below:
Some common issues to think about in the development and application of these specifications include:
- pH: Seemingly a simple issue, pH can be a vexing problem. As protein solutions are concentrated during UF/DF operations, the pH of the final solution can deviate from the diafiltration buffer. Great care should be taken to ensure that the drug substance starts out in the center of the specified pH range to prevent the product from drifting out of acceptance over time.
- Stability Data: For a biologic, 6 months of real-time stability is required for the IND; this contrasts with small molecule drugs. For that reason, early development stability studies are even more critical in order to de-risk the stability testing and shelf-life condition selection for the initial GMP lot. Negotiate the timeline for stability testing prior to signing any contract with your CMO/analytical testing laboratory to ensure that there are no painful surprises.
- Biosimilarity: Biosimilarity is a complex concept; additional characterization beyond the assays listed in the release specifications is required to fully understand product comparability.
- Evolution of the Specification: As additional manufacturing experience is obtained, the characterization space of the drug will be more fully understood. By analyzing and trending manufacturing data, the specification can be tightened in order to more accurately express what is acceptable and non-acceptable drug substance and drug product.
- Complex Mechanisms: Biological molecules have even more complex interactions with the body than small molecules. Make sure that you understand how your molecule performs in the clinic through relatively cheaper and lower risk early trials before pushing all the companies chips onto the table in a Phase 3 trial. Many companies have failed to recover from a badly planned Phase 3 trial.
Conclusions
Careful thought and collaboration applied to drafting the release specifications allows the entire project team to focus attention on the important properties of a drug. As living documents, they are revised throughout the product lifecycle to incorporate new manufacturing knowledge about the drug. Through this process, these documents become tools in assessing risk, planning stability studies, and claiming shelf life.
Disclaimer: This post is reprinted from PharmaTopoTM. This post is reprinted from PharmaTopoTM. PharmaTopoTM provides commentary on topics related to drugs. The content on this website does not constitute technical, medical, legal, or financial advice. Consult an appropriately skilled professional, such as an engineer, doctor, lawyer, or investment counselor, prior to undertaking any action related to the topics discussed on PharmaTopo.com.