Characterization and Validation for Biologics

Monoclonal antibodies and next-generation therapeutics need a more complex manufacturing process than a simple enzyme. For those molecules you need to assure their quality attributes and safety profile. In this article, we are going to explain how this validation process is done. 


Understanding Process Risks 

Even during the early drug discovery process, there are valuable opportunities to simplify the path to commercialization.  At this stage, multiple candidate molecules may be screened for their ability to bind a specific biological target and demonstrate the desired clinical effect. Often, there are multiple candidates that meet these criteria. When selecting a candidate to advance into development, it is neccesary to understand the unique properties impacting its activity and safety. 

From this phase to commercialization Quality by Design (QbD) concepts should be applied. QbD is a systematic approach, applied throughout the entire drug development process, linking process design and control to critical product quality attributes.   


 You can also read our article: Quality By Design in Biologic Drug Development 


Process parameters are evaluated during process development, with respect to their effect on important product quality attributes. From this evaluation, key process parameters (KPPs) and critical process parameters (CPPs) are identified, as well as their effects on critical quality attributes (CQAs) that are physical, chemical, biological, or microbiological properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality. 

When you are approaching the initial risk assessment, it is very important to have a team with strong experience and expertise that has worked with a diverse set of molecule types at different phases of development from clinical through commercialization. An experienced team can predict potential risks that may affect your process and product quality.  


53Biologics has a multidisciplinary team with a strong experience and expertise in implementing QbD 


Experiments that are well executed and performed by a skilled and experienced team will result in a reliable dataset with the appropriate amount of information to create a control strategy for manufacturing and process validation.  Once the initial risk assessment is complete, the team will begin process characterization studies.  


Process characterization 

Process characterization is a thorough, experimental and statistical evaluation of a manufacturing process. This evaluation defines and confirms process parameters and ranges that can be controlled to assure product quality, safety, and efficacy.  

An important element of process characterization is the development and qualification of a scale down model, which is used to represent and model the manufacturing process at a small scale.  

Larger biopharmaceutical companies may have the capabilities to develop a scale-down model and perform a thorough process characterization in-house but it is more recommended to work with an experimented CDMO that will understand the risks and liabilities of the process and the molecule, ensuring a complete thorough and accurate assessment.  


53Biologics has great expertise in process characterization due to its team’s experties in biologics production


A valuable tool in process development, and especially in process characterization, is the use of design-of-experiment (DoE) statistical methodologies with high-through process and analytical methods. This approach allows for multiple process parameters to be studied in parallel in order to rapidly identify their effects on product CQAs.  

Depending on the specific design used for your project, these studies can screen for the parameters that have the greatest impact on CQAs, provide insights on multivariate interactions between parameters, and even identify optimal process set-points.   

Today, more and more, these studies are being included in clinical-phase process development activities to limit the process changes needed for commercial readiness. These study results can then be leveraged to eliminate low-risk parameters from in-depth process characterization studies and greatly reduce the timelines and resources needed for process characterization studies. 

After the process characterization studies are completed, you have to conduct a Failure Mode and Effects Analysis (FMEA) that is a risk assessment that reviews the entire product and process history of a molecule, including data from early development, manufacturing, and process characterization. This assessment is used to determine a robust in-process control (IPC) strategy that will be used to validate an at scale manufacturing process. 


You can also read our article: How to Improve Efficiency in Biopharmaceutical Process Development


Evaluate and Control Product Quality 

As we mentioned before, the results of process characterization are used to develop the final risk assessment and an in-process control (IPC) strategy. For example, if the CDMO team determined in the FMEA that cell culture pH is a process parameter that might have a critical impact on product quality, process characterization results will be used to determine what pH range the bioreactor must operate within during manufacturing to safely maintain product quality. Operating ranges are then defined for all KPPs and CPPs and built into the control strategy. This IPC strategy thereby establishes guidelines and limits for process parameters and operation.  

Following development of the IPC strategy, process validation is executed in the form of process performance qualification (PPQ) where the process is run multiple times at manufacturing scale using the IPC strategy to confirm robust and reproducible performance resulting in consistently acceptable product quality.  

It is important to say that process validation is not the same for all biologic molecules. Although traditionally relied on using three batches during the PPQ phase for mAbs, this is not always the case for today’s new drugs. The number of batches used for validation should depend on the complexity of the molecule and the process, the risks anticipated in manufacturing, and any potential impacts on the safety and efficacy of the product. If a large number of risks are identified, or if the risks that do exist are high, more than three batches may be required to ensure that the process is well controlled. 


You can also read our article: Consider cGMP to Minimize the Risks and Accelerate Your Development Milestones  

Regulatory Agencies 

Once process characterization is complete, a control strategy is confirmed, and the process is validated with a sufficient number of PPQ runs, the following step is to file for regulatory approval of its manufacturing process.  

The regulatory agencies will determine whether the process is appropriately and sufficiently controlled. For example, if the process is deemed to have been incompletely characterized during process characterization or insufficiently validated with too few PPQ runs, the manufacturing strategy might not be accepted, potentially delaying the commercial release of the biopharmaceutical product at a significant cost to the company. 



While process characterization and validation can be challenging, using a risk-based approach to generate an appropriate control strategy will help assure that your product meets the regulatory agencies requirements, enabling timely approval and launch to market. 

53Biologics has the expertise and the capabilities to improve the efficiency of your biologics development and manufacturing project. 

Let´s Talk! Arrange a meeting with our expert team to discuss your biologic manufacturing project. 

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