Batch Definition and Traceability in Continuous Bioprocessing

July 31, 2020

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What Is a Batch?


A batch is defined in FDA’s Code of Federal Regulations 21 CFR 210.31 as a certain amount of a drug or other material that is intended to have a uniform character and quality within defined limits and is manufactured according to a single production order during the same manufacturing cycle.


The European Medicines Agency’s EMA ICH Q72 defines the batch as a homogeneous material within certain limits. EMA ICH Q7 specifies that in the case of continuous production, a batch can correspond to a defined proportion of the production. The batch size can be defined both on a fixed quantity and on a fixed time interval.


The FDA has stated3 that the batch and batch definitions from 21 CFR 210.3 apply to continuous manufacturing, where a batch can be based on a fixed amount of product or raw material, a fixed time interval or a timeframe in production.


Regulatory expectations regarding batch definition for continuous bioprocessing (CBP) may include establishing start-up and shutdown procedures with defined criteria for the start and end production of products. It is also stated that a batch can be flexible but must be defined in any case before production. A batch definition based on time constants of the process could include the cyclic behaviour of multi-column chromatography or steps to inactivate by low pH viruses in the process.


Industry examples have used both time-based and volume-based strategies in biologics platforms that use continuous upstream or downstream processing: Alvotech (Iceland) presented the definition of a batch of biologics based on the time with 15 days as one batch. A similar approach has been described by Sanofi Genzyme (USA) for a monoclonal antibody from a 31-day continuous process in which a batch is defined as an operating day. BiosanaPharma (Netherlands) uses a volume-based approach for a biosimilar antibody from the CBP.


A rationale based on a risk assessment can be considered and mapping the batch definition to the highest risks on the platform can minimize the business impact in the event of a batch refusal.


Batch Traceability and Variance Management


For batches in continuous production, especially if they are based on a fixed time interval, it is important to establish a connection between material and batch in order to identify and track material in the dynamic process. Since the material is not normally stored in surge tanks between unit operations to the same extent as in batch operation, the material quickly spreads through the cascade of unit operations. A one-step discrepancy can spread to subsequent unit operations before any action can be taken. It is therefore important to understand how quickly material flows through the cascade of unit operations.


The FDA asked for a scientific approach to characterize the material flow, for example by characterizing the residence time distribution (RTD). By characterizing the RTD of each unit operation and the combination thereof in the integrated cascade, it is possible to identify the product in every phase of the process train. This also makes it possible to subsequently determine which batch or batches are affected by a process deviation, or even specify at which stage of the cascade the product should be isolated or redirected. Designing redirection points allows you to take action and redirect the product to interim vessels or storage bags.


An RTD can be determined a) experimentally by tracer experiments, in which a representative non-reactive tracer is introduced into the system and changes in concentration over time are measured, b) by online process monitoring of certain products and their attributes or c) by modeling the process steps.


Learn more about batch certificates in the Biotech Regulatory Support Portal.




1 FDA: Code of Federal Regulations, Part 210 — Current Good Manufacturing Practice in Manufacturing, Processing, Packing, Or Holding of Drugs

2 EMA: ICH Topic Q 7: Good Manufacturing Practice for Active Pharmaceutical Ingredients. Note for Guidance on Good Manufacturing Practice for Active Pharmaceutical Ingredients (Cpmp/Ich/4106/00)

3 FDA: Quality Considerations for Continuous Manufacturing Guidance for Industry, Draft Guidance


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Martin Glenz – Principal Scientist, SLS

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