ABSTRACT: This paper shows the definition of batch in continuous manufacturing, its importance from a regulatory perspective, the importance of linking it to control strategies and why continuous manufacturing presents a major shift for quality systems. It also reviews the global regulatory landscape associated with continuous manufacturing.
BATCH SIZE AND CONTROL STRATEGIES
USFDA 21 CFR 210.3 defines the important terms of batch and lot as follows:
Batch: A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits and is produced according to a single manufacturing order during the same cycle of manufacture”.
Lot: A batch, or a specific identified portion of a batch, that has uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures it having uniform character and quality within specified limits.”
The concept of batch is very important in GMP due to the following reasons
1.Laboratory determination of final specifications for release are linked to batch. 21 CFR 211.165(a) states that for each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product prior to release
2.Documentation of Manufacturing is linked to batch. 21 CFR 211.188 state that batch product and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch
3.Extended investigations of unexplained discrepancies are linked to batch. 21 CFR 211.192 state that the investigation shall extend to other batches that may have been associated with the specific failure of discrepancy.
4.Recall situation are linked to batch and lot. 21 CFR 211.150(b) state that distribution procedures shall include a system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary
Thus, as summarized above, the definition of a batch for continuous processes is critical to material traceability and has implications for product recalls and other regulatory actions.
The concept of batch size is one of the concerns that many companies may have when considering whether to move from batch manufacturing to continuous manufacturing. On Feb. 26, 2019, the FDA issued a draft guidance entitled “Quality Considerations for Continuous Manufacturing”3 in an effort to advance greater predictability for companies adopting CM technology. The guidance explains that a batch can be defined “based on the production period, quantity of material processed, quantity of material produced, or production variation (e.g., different lots of incoming raw material), and can be flexible in size to meet variable market demands by leveraging the advantage of operating continuously over different periods of time”1.
Hence, using an appropriate control strategy and ensuring a continued state of control, it could be possible to designate large quantities of manufactured product to be of uniform character and quality, even if different batches of excipients or processing may have been used during the production run. In this context, a batch can be defined based on the production time period, quantity of material processed, equipment capability, or production variations (e.g., different batches of in-coming materials)
According to ICH Q8(R2) and Q10, the control strategy is a planned set of controls, derived from current product and process understanding that ensures process and product quality.2,3 A comprehensive control strategy should cover the material attributes of drug substance and drug product components, the facility and equipment operating conditions, in-process controls, and finished product specifications.
Key elements of control strategy for continuous manufacturing include process understanding which includes impact and interactions of process parameters and material attributes over time, characterization of process dynamics including development of methods for detection and control and batch definition as it relates to a “state of con...
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