Switching from Batch to Continuous: Don’t Forget about Formulations

When pharma companies consider making the switch from batch processing to continuous manufacturing (CM), they often first think about machinery. But they shouldn’t forget about formulation. 

CM requires more insight into excipient variability, especially where process control depends on process analytical technology (PAT) signals from the excipients. In addition, CM provides an opportunity to develop and introduce further co-processed excipient combinations. The development of drug products and processes for CM will require a thorough investigation of excipient properties and identification of Critical Material Attributes (CMAs) using Quality by Design (QbD) principles to develop robust formulations and processes. Engineering expediency should not take precedence over rational formulation and process design and development. Pharmaceutical companies have found it necessary to develop additional understanding and management of the impact of excipient variability on CM. This is especially important because as more companies make the switch to CM, there are sure to be new regulatory concerns as well as manufacturing questions.

As stated in the ICH Q13 Continuous Manufacturing Concept Paper, 

Focus Areas for Understanding Impact of Material Variability on Product Quality 

CM has unique challenges for excipients beyond what is required for typical batch manufacturing. CM typically has a limited number of feeders (usually 4-6), which means that formulators do not have the flexibility to use many different individual excipients as they do with batch manufacturing. Also, the excipients used need to have good flow properties to facilitate the feeding process as well as provide the performance needed in the finished drug product. Examples of other excipient-related problems unique to CM are buildup on equipment surfaces (fouling) and traceability of excipient batches. Due to CM process constraints, the importance of the raw material properties and their variability on process performance must be considered. To properly assess the impact of excipient variability on a CM process, it is critical to use appropriate process analytical technologies at multiple stages to monitor the stability of the operation. 

Control of Material Properties 

CM may require additional raw material control, especially if multiple lots of a raw material are used in a run. The type and frequency of controls used in batch processing may not suffice for CM. In addition, the material and process design should be optimized to handle material variability and include some sort of safety buffer for diversion of nonconforming material(s). 

Manufacturers planning to switch from batch to CM should re-evaluate existing raw material specification(s). Consider multivariate analysis in reviewing historical excipient values, then link excipients’ quality to both the process need as well as the drug product’s critical quality attributes. 

CM-Specific Excipient Opportunities

Due to the challenges identified above, excipient selection requires greater focus on physical and functional characteristics than may be necessary with batch processes. For oral solid dosage forms, powder flow must be understood to ensure uniform feed into the process to assure content and weight uniformities. CM will drive the need for more multifunctional excipients that address the constraints caused by limited ingredient addition ports. Particle engineering, and coprocessing in particular, may provide several characteristics in a single ingredient. 

Some “engineered” excipients already exist and are well suited to CM; however, the need for continued innovation in material science and improved functional performance persists. Through proper design and development, excipients engineered at the particle level (for example, integrating several individual excipients at the particle level through co-processing) offers other benefits and solutions to such issues as equipment fouling and process fatigue. Further, such excipients incorporate multiple functional characteristics needed for dosage form manufacture. In tablets, flow, compaction, and disintegration may be combined by co-processing binder, flow aid, and disintegrant, integrating the functional performance of each at the particle level, thus reducing the number of feed ports from three to one. Similarly, particle engineering—either through co-processing or other means—benefits other dosage forms manufactured using CM, particularly when powders are involved. 

Variation and Complexity 

Excipients contribute to unpredictable special cause variation (SCV) due to their complexity, which can adversely affect finished product quality. CM by itself will not eliminate SCV but has several mitigating advantages: 

Elimination of scale-up 

Batch processes require scale-up, which increases uncertainty due to inhomogeneity of processing and composition. Additional processing time is required to render the batch homogenous. This confounds the data from small-scale development, especially as the number of experimental batches decreases with increasing scale. 

Small-volume pharma 

CM processes can be run for longer times to increase output without changing the working volume, thus avoiding the confounding associated with traditional batch scale-up. Development data is essentially production data. Better correlation of process response and excipient variability Due to the smaller working volume, there is greater spatial certainty in CM, which affords better correlation of process response to excipient variability in real time. In traditional batch manufacturing, sensor signals have to reach stability over time. This helps establish homogeneity but is too little too late to afford meaningful process control. CM affords more frequent in-process monitoring by sensors, which facilitates Quality by Control. Using feed forward from excipient-related signals— or feedback from downstream processing—allows the CM process to compensate in real time for excipient variability. The greater the understanding of impact from excipient variability, the better the real-time process control.

Insight on excipients from metering control and other process analytical technologies 

Excipient feeders in CM can be regarded as “soft sensors.” If feeder settings can be correlated with finished product quality, especially using multivariate analysis, this may give warning of system drift in advance of SCV-related failure. 

CM will not Compensate for Irrational Product and Process Design 

With the move to CM of compressed tablets, there appears to be a preference for direct compression and an unfortunate parallel trend to over-simplify formulations due to the limited number of powder feeders that can be located at the inlet to a continuous blending unit. This formulation over-simplification runs contrary to basic understanding of formulation science whereby sufficient excipients, and types of excipients, are included in the formulation to provide for a robust formulation and process, which can accommodate the typical variability seen in excipients, and may provide some defense against certain unforeseen changes (SCV), for example an unanticipated change in polymorph after launch. 

Oversimplification of formulations is a disaster waiting to happen. There are solutions to this dilemma. For example, incorporating a further blending unit could allow inclusion of other necessary excipients. Or using a coprocessed excipient could combine functions, like filler and disintegrant. Avoid sacrificing a rationally designed, robust formulation and process for engineering expediency to maintain finished product robustness. 

CM – A Regulatory Perspective

To address emerging concerns from technical and regulatory challenges associated with adopting innovative approaches to manufacturing, in 2014 the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) created the Emerging Technology Program (ETP). Early technologies accepted into the program included CM of drug substances and drug products, model-based control strategies for CM and continuous aseptic spray drying. 

Examples of CDER progress with CM include FDA approvals utilizing CM for solid oral dosage forms as well as utilizing hybrid CM for small molecule APIs, sterile products, and biotechnology products. In addition, CDER continues to collaborate on research to support CM application assessment and policy development.

In addition, in 2018, the ICH Assembly endorsed development of a Guideline for CM of Drug Substances and Drug Products (ICH Q13). Objectives of the Guidelines included: 

• Capture key technical and regulatory considerations, including certain CGMP elements specific to CM 
• Allow drug manufacturers to employ flexible approaches to develop, implement, or integrate CM to manufacture small molecules and therapeutic proteins for new and existing products, and
• Provide guidance to industry and regulatory agencies regarding regulatory expectations on the development, implementation, and assessment of CM technologies used in the manufacture of drug substances and drug products. 

The first draft (Step 2) of ICH Q13 Guideline was endorsed and published in mid-2021. Currently the ICH Q13 working group is reviewing/addressing comments received and developing a training and education package. 

In February 2019, the FDA issued a Draft Guidance for Industry entitled “Quality Considerations for Continuous Manufacturing.” The guidance focused on scientific and regulatory considerations specific or unique to continuous manufacturing including process dynamics, batch definition, control strategy, pharmaceutical quality system, scale-up, stability, and bridging of existing batch manufacturing to continuous manufacturing. 

In 2020 IPEC published a QbD Guide, which emphasizes understanding the impact of product variability on drug product performance. This guide becomes particularly relevant given the additional insights afforded by CM and PAT. 

Conclusion 

CM could help reduce operating costs, increase sustainability, enhance product quality and thereby improve patient safety. However, without robust formulations (designed with CM in mind), these benefits may not be realized. Scientifically based formulation design should never be sacrificed for engineering expediency. Enhanced understanding, relevant to CM, of the excipients used in a particular drug product, and their limitations in the particular application, will be key considerations in the move to CM. As with any manufacturing approach, the process should never sacrifice product robustness. 

References or Further Reading 

• Thomas O’Connor, Understanding Impact of Material Attributes on Product Quality for Continuous Manufacturing, Excipient World Conference and Expo Workshop, March 6, March 6, 2019. 

• Brian Carlin, Excipient Impact on Continuous Manufacturing, and vice-versa, Excipient World Conference and Expo Workshop, March 6, 2019. 

• Role of Excipients in Continuous Manufacturing of Solid Oral Dosage Forms, Excipient World Academy Webinar, Wednesday, April 21, 2021. https://education.ipecamericas. org/courses/30889# 

• ICH Harmonised Tripartite Guideline: Continuous Manufacturing for Drug Substances and Drug Products, Q13, Step 2, July 2021. 

• US Food and Drug Administration, CDER, DRAFT Guidance for Industry, Quality Considerations for Continuous Manufacturing Guidance for Industry, February 2019. 

• The International Pharmaceutical Excipient Council Incorporation of Pharmaceutical Excipients into Product Development using Quality-by-Design (QbD), 2020.