Putting the “Process” into Process Characterization
By Daniel Sayut, Senior Scientist I, Lisa Rives, Senior Scientist II, and Evan Pasenello, Account Manager, Biologics, at AbbVie Contract Manufacturing
Before you can validate your process, receive regulatory approval, and manufacture a biopharmaceutical for commercial distribution, the critical step of Process Characterization provides the in-depth understanding of the drug product to establish effective process control strategies. The experiments and studies performed during Process Characterization help define the critical product and process parameters and determine the proven acceptable ranges for efficient manufacturing.
Done correctly, Process Characterization reduces the risk of manufacturing failures and regulatory delays. Though it requires a significant investment of time and resources, it provides a level of confidence in the successful manufacture of complex biologic products.
Currently, there are no industry standards or firm guidelines around Process Characterization. Pharmaceutical companies and CMOs establish their own processes based on experience and benchmarking against industry peers.
It is important to understand that the US FDA and other regulatory bodies pay close attention to the manufacturing process, not just drug product and manufacturing facilities, when approving biologics. According to the FDA, “Because of the complexity of manufacturing and characterizing a biologic, the Public Health Service (PHS) Act emphasizes the importance of appropriate manufacturing control for products.”
Starting at least a year prior to validation, Process Characterization is a many-months-long effort to test and evaluate processes used to develop and manufacture the biologic to determine acceptable ranges for hundreds of parameters. Because it is inefficient to test every parameter, statistical modeling is used in some instances.
Scientists at the AbbVie Bioresearch Center (ABC) have established a platform approach to Process Characterization that has been proven effective as it has been used to support the approval of several marketed products. AbbVie has mapped out a five-step process that results in a thorough understanding of the biologic and process control strategies to ensure drug safety, purity, and potency at the commercial scale. Process Characterization efforts continue throughout commercial manufacturing, to continually assess, refine, and improve processes.
Step 1: Draft a Master Plan
A Master Plan is one of the most important steps to ensure a well thought-out, justified, and complete Process Characterization. The plan should contemplate strategy and rational for approaches to small-scale characterization and full-scale validation for the product, describing the efforts to implement and complete the various activities required by current Good Manufacturing Practices (cGMP).
Step 2: Perform Risk Assessments
These assessments are performed on process parameters and product quality attributes to generate a prioritized list of parameters to be evaluated in Process Characterization studies.
Step 3: Characterize the Cell Culture and Downstream Processes
This breaks down into the development of five activities:
- Laboratory scale-down models: Laboratory bioreactors, chromatography columns, and, where feasible, filtration steps, are run under conditions that simulate manufacturing as closely as possible. Scale-down model performance is compared with manufacturing process performance to determine if the model is suitable for conducting the Process Characterization studies described next (II-IV).
- Process mapping: Quality attributes of the in-process material and Bulk Drug Substance (BDS) will be measured and tracked using appropriate analytical methods.
- Proven acceptable range (PAR): Studies are performed to determine the impact of deliberate variations in relevant operating parameters on unit operation performance (e.g., the effect of the bioreactor temperature on cell growth). Most PAR data is generated in bench-scale experiments, but in some cases it is derived from analysis of historical manufacturing data. PAR data provides documented evidence for justification of manufacturing operating conditions.
- In-process sample stability: The stability of in-process samples at anticipated holding steps during the process is investigated to determine the impact of extended hold time on product yield and quality, using relevant in-process assays.
- Impurity clearance: In-process mapping of impurities, such as DNA, host cell protein, and process chemicals, are conducted to assess the impurity clearance capability of the process.
Step 4: Post-Characterization Risk Assessment
A second round of risk assessments is performed on the process parameters, based on the data generated from Process Characterization studies. The outcome is a listing of critical and non-critical parameters, as well as a ranking of the critical process parameters.
Step 5: Process Justification Report
This report summarizes and provides justification of the proven acceptable ranges for manufacturing operating parameters. It also provides a basis for process validation. This report is written using historical manufacturing data and Process Characterization data.
CMOs as Process Characterization Partners
While some major pharmaceutical companies have the expertise, resources, and facilities to handle Process Characterization, some stakeholders involved in clinical trials of a biologic are wise to partner with an experienced CMO to handle this important stage of the drug’s lifecycle.
Experienced CMOs offer many advantages, from equipment to expertise. For example, a CMO with a suite of bioreactors can significantly reduce testing time by running multiple experiments simultaneously. CMOs that have performed Process Characterization studies previously can provide the established platform for planning, assessment, analytical studies, data analysis, and review to support market approval. Leveraging the expertise and services of a CMO can reduce the cost and time of Process Characterization, moving you faster to regulatory approval and market.
The cost of not getting Process Characterization right is too high. Issues with regulatory compliance or manufacturing performance can set you back and force costly re-work and delays in getting to market. Perhaps even worse, Process Characterization that cannot fully justify the ranges of a process can result in tight tolerances for the proven acceptable ranges, greatly restricting manufacturing. When executed with the right planning, foresight, and statistical and analytical support, Process Characterization helps both the biologics manufacturer and the regulatory agencies fully understand the biopharmaceutical to be manufactured and the processes under which it can be efficiently, compliantly manufactured for safety, purity, and potency.
Contact us to talk about Process Characterization for your biologic drug. As a division of AbbVie, a leading biopharmaceutical company, AbbVie Contract Manufacturing has performed nearly a dozen Process Characterization projects and offers expertise in biologics manufacturing, cold chain, and packaging.