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 continuous manufacturing modes and manufacturing approaches. The intended purpose behind the guidance is to continue industry harmonization efforts between ICH guidance and FDA regulatory & statutory requirements.
Continuous Manufacturing
Continuous manufacturing involves the process of uninterrupted materials being steadily added into the manufacturing process. The in-process ingredients are then manufactured and simultaneously developed into output materials during manufacturing. The updated FDA guidance focuses on facets of a continuous manufacturing system where multiple steps of 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 of the underlying continuous manufacturing 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 in the updated guidance scope. FDA recommends to the reader to revisit other existing ICH Q7 guidance as needed and appropriate for the medical manufacturer.
Control Strategy
Continued process performance and product quality are two primary elements described 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.
Process Dynamics
Understanding transient events and the 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 continuous manufacturing process an often includes:
- Product composition
- Product formulation
- Material properties
- Equipment design
- Equipment configuration
Operating Range
Each planned operating range should be based on the process dynamics and characterized by the planned over the planned ranges and anticipated input. Further, the FDA clearly states that material variability should use scientifically justified approaches for measuring quality against process dynamics that illustrate the variation during material transport and transformation.
Material Characterization
The FDA guidance goes on to list material feeding, process dynamics and output material quality as crucial continuous manufacturing 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 the control strategy.
Solid Dosage Form
While analyzing the continuous manufacturing material flow process in a solid dosage form, the FDA guidance lists the following considerations that can impact powder feeding:
- Particle size
- Cohesiveness
- Adhesiveness
- Hygroscopicity
- Static charge
- Surface area of drug substances and excipients
Chemically Synthesized
While analyzing the material flow process in a chemically synthesized drug substance, the continuous manufacturing FDA guidance lists the following considerations that can impact flow properties:
- Viscosity
- Concentration
- Multi-phase feed
Monoclonal Antibody
While analyzing the material flow process in a therapeutic protein (e.g. monoclonal antibody) substance, the FDA guidance lists the following continuous manufacturing considerations that can impact cell culture performance, process performance, or process consistency:
- Lot-to-lot variability
- Cell culture media
- Different types of feed components
System Integration
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
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
About RCA’s Pharmaceutical Consulting Services
Regulatory Compliance Associates (RCA) has helped thousands of pharmaceutical companies meet regulatory, compliance, quality assurance, and remediation challenges. With more than 20 years of experience with FDA, Health Canada, EU and global regulatory agencies worldwide, Regulatory Compliance Associates® offers leading pharmaceutical consultants. We’re one of the few pharma consulting companies that can help you navigate the challenges associated with industry regulations.
Our pharmaceutical consulting firm includes over 500 seasoned FDA, Health Canada & EU compliance consultants and regulatory affairs experts who understand industry complexities. It’s a pharma consultancy founded by regulatory compliance executives from the pharmaceutical industry. Every pharmaceutical industry consultant on the Regulatory Compliance Associates team knows the unique inner workings of the regulatory process.
Client Solutions
Whether you’re in the product planning, development or pharmaceutical lifecycle management stage or need a remediation strategy for a compliance crisis, Regulatory Compliance Associates will guide you through every pharmaceutical consulting step of the regulatory process. Our pharmaceutical consulting Experts will create a customized approach depending on your product and company’s individual needs. Our regulatory compliance clients include:
- Companies new to FDA, Health Canada or EU regulations and regulatory compliance
- Start-up organizations with novel submissions to 510(k) submissions from multi-national corporations
- Investment firms seeking private equity due diligence for pre-acquisition and post-deal research
- Law firms seeking pharmaceutical consulting firm expertise in the remediation of warning letters, consent decrees, 483’s or import bans
Regulatory Affairs
Regulatory affairs is Regulatory Compliance Associates backbone. We exceed other pharma consulting companies with industry experts experienced in complexities of the pharmaceutical and biopharmaceutical industries. Our pharma consulting expertise spans all facets and levels of Regulatory Affairs. Additionally, we specialize in Regulatory Support for New Products to Life Cycle Management, Outsourced Regulatory Affairs, Submissions, Training, and more.
As your partner, we can negotiate the potential assessment minefield of regulatory compliance services with insight, hindsight, and the clear advantage of our breadth and depth of knowledge and regulatory compliance consulting. We offer the following pharma consulting regulatory affairs services for pharmaceutical companies.
- New Product Support
- Product Lifecycle
- Other Regulatory Services
- Combination Products
Compliance Assurance
The regulations process surrounding pharmaceutical companies can be tricky for even the most experienced industry veteran to understand. Just one misstep could mean significant and lasting consequences for your business. At Regulatory Compliance Associates, we offer the pharma consulting experience and pharma consultants necessary to guide you through the quality compliance process.
- Assessments
- Audits
- Regulatory Agency Response
- Preparation and Training
- Inspection Readiness
- Data Integrity
Quality Assurance
Regulatory Compliance Associates Quality consulting includes assessments, strategy, implementations, staff augmentations, and identification of quality metrics to ensure continuous improvement. Our pharma consultants understand the strategic thinking needed to align your business needs and goals. Regulatory Compliance Associates quality assurance services include quality experts with experience spanning major corporations and start-ups. Our pharmaceutical consulting firm knows firsthand how to achieve, maintain, and improve quality. Finally, our regulatory compliance services team excels in transferring continuous improvement knowledge to your organization.
- 21 CFR Part 11
- Data Integrity
- Manufacturing Support
- Facility Support
- Quality Metrics
Remediation Services
Regulatory Compliance Associates has a proven remediation services approach to managing FDA Warning Letters, Consent Decrees, Remediation and other serious regulatory situations. Our pharma consultants know how to partner with executive, legal, and communication teams. Each RCA pharma consulting Expert will develop a response that will be accepted by the regulatory agency and be realistic to execute.
Regulatory Compliance Associates pharma regulatory consultants will develop a comprehensive proof book of documented evidence demonstrating the corrective action taken to remediate non-compliant issues. In addition, each Regulatory Compliance Associates pharma consulting Expert understands compliance enforcement. We’ll prepare a comprehensive pharma consulting strategy to assist in your remediation efforts, drive continuous improvement, and maintain regulatory compliance with the regulations.
- Regulatory Action
- Regulatory Compliance
- Regulatory Enforcement
- Warning Letter
- 483 Observation
- Oversight Services
- Risk Management Plan
About Regulatory Compliance Associates
Regulatory Compliance Associates® (RCA) provides pharmaceutical consulting to the following industries for resolution of life science challenges:
- Life Sciences
- Pharmaceutical
- Biologic & Biotechnology
- Sterile compounding
- Medical device
- Lab Testing
We understand the complexities of running a life science business and possess areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. We are used to working on the front lines and thriving in the scrutiny of FDA, Health Canada, MHRA and globally-regulated companies.
As your partners, Regulatory Compliance Associates can negotiate the potential minefield of regulatory compliance and regulatory due diligence with insight, hindsight, and the clear advantage of our unique expertise and experience.
- Founded in 2000
- Headquartered in Wisconsin (USA)
- Expertise backed by over 500 industry subject matter experts
- Acquired by Sotera Health in 2021
About Sotera Health
The name Sotera Health was inspired by Soteria, the Greek goddess of safety, and reflects the Company’s unwavering commitment to its mission, Safeguarding Global Health®.
Sotera Health Company, along with its three best-in-class businesses – Sterigenics®, Nordion® and Nelson Labs®, is a leading global provider of mission-critical end-to-end sterilization solutions and lab testing and advisory services for the healthcare industry. With a combined tenure across our businesses of nearly 200 years and our industry-recognized scientific and technological expertise, we help to ensure the safety of over 190 million patients and healthcare practitioners around the world every year.
We are a trusted partner to 5,800+ customers in over 50 countries, including 40 of the top 50 medical device companies and 9 of the top 10 pharmaceutical companies.
Commitment to Quality
Our Certificate of Registration demonstrates that our Quality Management System meets the requirements of ISO 9001:2015, an internationally recognized standard of quality.
Regulatory Compliance Associates® (