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 control” and verification of control strategy.
CONTINOUS MANUFACTURING- MAJOR SHIFT FOR QUALITY SYSTEMS
In case of batch manufacturing process, the unit operations are discrete. During the process of manufacturing, in-process materials are collected and tested at the end of each unit operation and appropriate hold time studies allow time for investigation for any deviations from the defined manufacturing process.
However, in case of continuous manufacturing, different unit operations are integrated, and material is constantly generated in the manufacturing process due to the nature of the continuous manufacturing and moving ahead. Given the nature of controls for the manufacturing process, the manufacturing environment is highly data rich. As a result, QC oversight must be built into the process of decision-making
The regulatory expectation for assurance of product quality is the same for batch and continuous manufacturing. However, the risks associated with continuous manufacturing processes, can be different as compared to batch manufacturing processes given the nature of the continuous manufacturing processes. Hence, the quality risk management of continuous manufacturing demands special considerations in risk assessment, risk communication and risk mitigation. For risk assessment, characterizing process dynamics with respect to material properties, equipment design, and process conditions is inherent to understanding potential risks of continuous manufacturing to product quality. Data generated at risk assessment stage aids the formulation and regulatory evaluation of a control strategy proposed for a continuous manufacturing process design. An enhanced control strategy is required to ensure a continued state of control throughout the entire operation and collection of materials. Data from continuous manufacturing needs to be analyzed, utilized, and communicated appropriately to link elements of the proposed control strategy with specific risks to product quality, enable real-time quality decisions during manufacture and aid continual improvement of the process.4
GLOBAL REGULATORY LANDSCAPE FOR CONTINOUS MANUFACTURING
On Feb. 26, 2019, the FDA issued a draft guidance entitled “Quality Considerations for Continuous Manufacturing”3 to advance greater predictability for companies adopting CM technology 1.
In this guidance, firstly, the FDA outlines key concepts of continuous manufacturing by defining process dynamics and batches for continuous manufacturing processes. Next, the FDA defines and discusses control strategies and offers guidance on input material control, process monitoring control, material diversion, real-time release testing, specifications, equipment and systems integration, and data processing and management. The draft guidance also explores the three stages of process validation: process design, process qualification, and continued process verification. Since continuous manufacturing is a variable system, these three steps are the key to maintaining an effective process. It offers additional pharmaceutical quality system considerations (PQS) for potential adopters. Specifically, for those implementing continuous manufacturing in an existing manufacturing facility, the FDA recommends the site evaluate its PQS and associated elements to determine if the design of and programs within the PQS should be modified. It includes information on the different modes and methods of scale-up and the risks associated with each and recommends communication with the agency to determine the complexity of a change and potential impacts on the finished product. The FDA includes recommendations for post-approval filing strategies for scale-up in the draft guidance. In the section on stability, the FDA points out that regulatory expectations for demonstrating stability over the finished product’s shelf life do not change between batch and continuous processing. The FDA also offers guidance on bridging existing batch to continuous manufacturing operations. Finally, the guidance offers specific instructions on where to include information within a submission to the FDA using the Common Technical Document format (CTD).
In the EU, no specific regulatory guideline is currently available for continuous manufacturing, but existing guidance are supportive. Some of them are mentioned below.
-EU guideline on Chemistry of new active substances- In this, continuous manufacturing is not specifically addressed, but it is not in contradiction – applicable to Chemistry.
-EU Guideline on Use of NIR: principles applicable to other chemometric models
-Ph. Eur: chapter on Chemometrics (5.21), NIR (2.2.40), Raman (2.2.48), Large sample sizes (UDU 2.9.47)
-GMP Annex 15 (Qualification and Validation) & Annex 17 RTRT
-EMA Guideline on process validation for finished products - information and data to be provided in regulatory submissions
Other major countries like Japan and China also do not have any specific regulatory guidelines issued yet however considering the volume of initiatives on continuous manufacturing in both these countries, it is a matter of time, before such guidelines are issued.
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1.FDA, Draft Guidance for Industry, Quality Considerations for Continuous Manufacturing (CDER, February 2019).
2.International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Expert Working Group (CH). Pharmaceutical Quality System Q10 Step 4 [Internet]. Geneva: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Expert Working Group; 2008. p 22. Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ Quality/Q10/Step4 /Q10_Guideline.pdf.
3.International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Expert Working Group (CH). Pharmaceutical Development Q8(R2) Step 4 [Internet]. Geneva: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Expert Working Group; 2009. p 28. Available at: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ Quality/Q8_R1/ Step4/Q8_R2_Guideline.pdf.
4.Moheb M. Nasr, Markus Krumme, Yoshihiro Matsuda, Bernhardt L. Trout, Clive Badman, Salvatore Mascia, Charles L. Cooney, Keith D. Jensen, Alastair Florence, Craig Johnston, Konstantin Konstantinov, Sau L. Lee; Regulatory Perspectives on Continuous Pharmaceutical Manufacturing: Moving from Theory to Practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals; Journal of Pharmaceutical Sciences, (2017) 1-8.
ABOUT THE AUTHOR
Deepak Hegde, Ph.D., M.F.M, is an industrial pharmacist by training. He has a been involved in development and commercialization of both innovative and generic drugs from a very early phase of development to technical transfers for commercial manufacturing sites, for the past 25 years. During his career, he has worked Rhone Poulenc, Novartis (Sandoz), USV Ltd., WuXi AppTec and GSK. He is currently working with EOC Pharma. as Chief Technology officer.
Since the promulgation of the Hatch-Waxman Act in 1984, in order to promote drug competition and improve public drug availability, FDA has formulated a number of policies aimed at accelerating the marketing of generic drugs.
According to statistics, the market size of China’s oncology treatment industry reached RMB387.6 billion in 2020, with a compound annual growth rate of 10.3% in the past five years as compared to RMB261.4 billion in 2016, and this market size is expected