Aaron Moulin, Field Application Specialist at Purolite, explores the need for a straightforward, quality-by-design (QbD) led approach to switching chromatography resin suppliers so that when new antibody types are developed, novel purification challenges can be overcome.
Chromatography is a crucial component of downstream processing, removing or reducing contaminants to acceptable levels and achieving a highly pure end product. For monoclonal antibody (mAb) therapies, Protein A affinity chromatography is typically employed as a critical step in purification, with the target molecule generally eluted under acidic conditions, between pH 3 and 3.5. As antibody-based therapies continue to progress and antibody properties become increasingly diverse and complex, a wider operational window for elution is sometimes necessary to maintain high yields. Access to alternative Protein A resins that allow for elution at higher pH levels can maintain high yields and retain the use of a classic Protein A and Ion Exchange mAb purification. However, established Regulatory frameworks and best practices for optimal evaluation and selection of alternative Protein A resins are lacking.
Removal of unwanted impurities and contaminants is crucial for producing a high-quality drug product. For biologics like mAbs, affinity chromatography is used to preferentially bind the target molecule and separate it from unwanted materials before a change in conditions releases it. In mAb purification, it is common to use chromatography resins composed of cross-linked agarose, glass, or polymer-derived beads bound to a Protein A ligand via a linker. Protein A specifically attaches to antibody-based materials and forms a complex at pH 5 to 8. The bound antibody is eluted upon a change in pH to acidic conditions. This method is generally adopted early during the development stage and carried through to commercial production.
As we move towards an era of novel antibody-based products, such as Fc-fusion proteins and bispecifics, common Protein A resins may no longer be a viable option for purifying pH-sensitive molecules. Instead, an innovative solution is required: a resin that doesn’t rely on acidic pH for elution. While maintaining easy access, these resins provide manufacturing advantages as they are chosen specifically based on the characteristics of the biologic in question.
Regrettably, there is currently no standardised approach for implementing a new resin into a pre-approved process. The current regulatory framework also means switching to these alternatives cannot occur without notifying the relevant regulatory agencies. If a new resin is adopted, it can lead to the entire manufacturing process requiring revalidation for regulatory approval, which can be costly and time-consuming. With this in mind, the biopharmaceutical industry has come together through BioPhorum to outline a regulatory- acceptable solution.
Using a QbD approach for regulatory acceptable CMA solution
Accessing alternative materials is currently a significant challenge and that prevents the incorporation of innovative resins into downstream processes. Despite the manufacturing advantages in antibody downstream processing, current regulatory frameworks mean switching to these alternatives cannot occur without regulatory notification, which can result in having to re-evaluate the process for approval.
This inflexibility has prompted the biopharmaceutical industry to come up with a regulatory-recognised solution for implementing materials from an alternative supplier or source based on a QbD approach, in the form of BioPhorum. Adopting the BioPhorum convention of defining a material by its function and critical material attributes (CMAs) could allow materials to undergo an equivalency investigation instead of manufacturing revalidation.
Aligned with the latest ICH guidelines, ICH Q12, the regulatory-approved process consists of four steps:
Step 1: Target material profile
Summarising the raw material characteristics to ensure drug product and process, quality, and safety.
Step 2: Material attributes
Defining the raw material attributes, including chemical, physical, microbial, and other safety attributes.
Step 3: Summary control strategy
Defining controls derived from the understanding of current products and processes to assure performance and quality.
Step 4: Bringing it all together
Collating the information from the three steps above to define the CMAs.
Using these four steps, this solution aims to increase supplier flexibility and ease regulatory approval. Applied to the pH Protein A challenge, the BioPhorum approach sets a precedent for incorporating resins compatible with pH-sensitive materials into existing processes.
A supportive supplier partnership provides Protein A solutions
Forming a fluid and comprehensive partnership can assist in implementing innovative resins for pH-sensitive antibody testing. Following the BioPhorum guidelines, providing detailed documentation on CMA enables interchangeability, making manufacturing integration and regulatory approval easier.
When applied to Protein A resin, the BioPhorum approach deems the resins interchangeable if the same process and critical quality attribute outputs are achieved. To ensure consistent product quality and safety when alternative Protein A resins are used, the following controls are required:
● Testing of specific attributes of Protein A by the supplier, providing a corresponding statement certificate.
● An accompanying manufacturing study with defined parameters completed.
● Verification of the viral control strategy.
● Assessment of downstream process capacity to remove unwanted materials, leaving a high-quality product that is safe and efficacious at release.
● Conformation of the extractable and leachable profile of the resin with a risk assessment.
● Validation of the lifetime, cleaning, sanitisation, and storage conditions used to maintain the quality of the resin.
● A detailed and comprehensive regulatory support file for the resin, which contains the defined content.
● A statement on freedom from materials of animal origin for the Protein A resin.
With all the necessary documentation in place, the interchangeability of Protein A resin is enabled. As a result, BioPhorum has set a precedent for delivering flexibility into the manufacturing process.
Looking ahead
By using the BioPhorum convention to replace the traditional Protein A affinity chromatography with innovative resin solutions, we can now explore the use of this process for other manufacturing challenges currently facing the industry. Moving toward new and complex biologics that often have unique handling requirements opens new possibilities for tailored downstream processing without hindering regulatory approval timelines.
Working with a resin supplier with the BioPhorum QbD approach in place allows for manufacturing flexibility and eases process optimisation.