The U.S. Food and Drug Administration (FDA) recently updated its pharmaceutical manufacturing guidance on Continuous Manufacturing (CM), including elaborating on established industry best practices.
Examples of new insights provided by FDA include clarification of the differences between CM modes and manufacturing approaches. The intended purpose behind the guidance is to continue industry harmonization efforts between ICH guidance and FDA regulatory & statutory requirements.
CM involves the process of uninterrupted materials being steadily added into the manufacturing process. The in-process ingredients are then manufactured and simultaneous developed into output materials during manufacturing. The updated FDA guidance focuses on facets of a CM system where multiple steps of the operation are connected as continuous flow manufacturing.
The intended seamless procedure is considered by many industry experts as more efficient and helps reduce human error. By comparison, batch manufacturing lines may not use the same types of automated monitoring nor leverage as many predictive maintenance data points.
Factors of Production
The FDA guidance provides a deeper explanation into the underlying CM factors of production. A description of these characteristics by the Agency expands upon continuous flow production themes, including types of technology, options for dosage form, or molecule type.
Topics that are broadly applicable to a continuous production system and batch manufacturing are not included the updated guidance scope. FDA recommends to the reader to revisit other existing ICH Q7 guidance as needed and appropriate for the medical manufacturer.
Continued process performance and product quality are two primary elements describe in the scientific approach to continuous manufacturing. State of control relies on the continuous production process and unique parameters (e.g. process parameters, quality attributes, etc.) that are designed to stay within an appropriate pre-set range.
Further, the guidance specifically calls out the importance of identifying the root cause of drift. FDA continuous manufacturing examples highlighted for employees to closely monitor include variation of inputs, equipment fatigue, and aging of materials.
Understanding transient events and various impacts they can have on the continuous production system is a critical facet of FDA Control Strategy. Further, the FDA guidance elaborates that this includes transient events that are both planned (e.g., process start-up, process shutdown or a manufacturing pause) and unplanned (e.g. production disturbance).
Residence Time Distribution (RTD)
One key takeaway from the FDA guidance for industry is understanding how process dynamics are characterized when output material quality is affected. Additionally, using measures like residence time distribution can help medical manufacturers differentiate between the time available for material transport and transformation.
This type of quality metric strategy is specific to the manufacturing process an often includes:
- Product composition
- Product formulation
- Material properties
- Equipment design
- Equipment configuration
Each planned operating range should be based around the process dynamics and characterized by the planned over the planned ranges and anticipated input. Further, the FDA clearly states the material variability should use scientifically justified approaches for measuring quality against process dynamics that illustrate the variation during material transport and transformation.
The FDA guidance goes on to list material feeding, process dynamics and output material quality as crucial elements that negatively impact material characterization. The FDA guidance lists a materials characterization facility as important to increasing production quality. Finally, realizing the predictability of material attribute variability on process performance and product quality is significant to control strategy.
Solid Dosage Form
While analyzing the material flow process in a solid dosage form, the FDA guidance lists the following considerations that can impact powder feeding:
- Particle size
- Static charge
- Surface area of drug substances and excipients
While analyzing material flow process in a chemically synthesized drug substance, the FDA guidance lists the following considerations that can impact flow properties:
- Multi-phase feed
While analyzing material flow process in a therapeutic protein (e.g. monoclonal antibody) substance, the FDA guidance lists the following considerations that can impact cell culture performance, process performance, or process consistency:
- Lot-to-lot variability
- Cell culture media
- Different types of feed components
The FDA guidance goes into depth about integrated systems characteristics and how equipment design can influence continuous manufacturing performance:
- Design configuration
- Maximum run time compatibility
- Parts geometry impacting transformation
- Integration and transfer steps
- Design interface
- Surge tanks
- Mass flow rate
- Material diversion and sampling
- Diverter valve
- Sampling probe
- Material flow
- Material transformation
The guidance continues to elaborate on equipment selection and how the equipment design, if executed properly, can help with process simplification.
Process monitoring and maintaining a state of control during production increases the understanding of real-time system performance. The FDA guidance states that these common approaches to process monitoring and control are also applicable to continuous manufacturing:
- Established target setpoints
- Established control limits
- Design space
- Measurement specifications
Process Analytical Technology
The FDA guidance also elaborates on why process analytical technology is suitable for continuous manufacturing. Examples provided by the agency for industry employees include:
- In-line ultraviolet (UV) flow cells
- Monitoring therapeutic protein concentration
- In-line near-infrared spectroscopy
- Assessing blend uniformity or water content
- High-performance liquid chromatography
- Monitoring the conversion of chemical reactions
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