New Trends in Guidelines for Continuous Process Manufacturing

by: Lidia Cecilia Cadena Casas, CQV Advisor & Auditor, Associate Partner @PQE

What's NEW in the guidelines world? 

2023 did not just give us the chance to accomplish our New Year’s resolutions and supersede the low pace caused by two previous years of living under a pandemic. It also provided new purposes and challenges for those in the field of continuous manufacturing of pharmaceuticals, drug substances and biologicals. After two years of analysis and comments from the first draft publication, on January 6th, 2023 the final guidance document, ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products, was published and will be legally effective from July 10th, 2023.   

But, what does Continuous Manufacturing (CM) mean? 

According to ICH Q13, Continuous Manufacturing (CM) involves the continuous feeding of materials into the transformation of in-process materials, and the concomitant removal of output materials from a manufacturing process. What it is very interesting from this description is that now, we have a guideline that embraces the key concepts of CM not only for pharmaceuticals or drug substances but which may also apply to other biological/biotechnological entities. 

It is important to understand that within CM there are different approaches. While some manufacturers can decide to do unit operations following batch mode and then combining them with continuous mode, some others have processes where the materials are continuously formed and processed through integrated unit operations.  

But being very simplistic, in CM one of the main paradigms is the change of the concept of batch as we traditionally know it. While standard manufacturing in batches implies stops at different steps during the process and defined quantities of inputs and output materials, in CM essentially the product is created without needing to stop until the very end of the process, and management of input and outputs normally involve continuous feeding.  

Continuous Manufacturing ICH_Site PQE

State of the Art, which are the new guidelines? 

Q13 Continuous Manufacturing of Drug Substances and Drug Products is the new guidance that describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing. This guidance provides clarification on CM concepts and describes scientific approaches and regulatory considerations specific to CM of drug substances and drug products. 

Consideration points on CM 

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In this guideline, fundamentals for being able to meet the main aspects of the Food and Drug Administration (FDA) and other regulation expectations, good manufacturing practices and key aspects for successful CM are provided with the premise that the output materials from the batch and continuous processes should have comparable quality. 

Manufacturers who want to convert the approved batch process to a continuous manufacturing process look must always first obtain regulatory approval.  

Regulatory Considerations 

Regulatory Considerations 

Focus Area 

Key aspects for submission of the Common Technical Document (CTD) 

Description of manufacturing process and process controls 

  • Process flow diagrams and summarized process stages (including start-up, shutdown, pause, restart, etc.) 
  • How the materials will be collected and transported 
  • Process parameters related to continuous flow with location of control points 
  • Critical aspects of selected equipment design, configuration and system integration 

Control strategy 

Must ensure that output materials made over time are of the desired quality. Must consider:  

  • Variability impacts of input materials 
  • Process monitoring description including controls, sampling, data evaluation 
  • How systems are operated 
  • Strategy for triggering material diversion 

Batch description and batch size  

  • The approach to define batch size or range for commercial batch based on a suitable quantitative metric 

Process models  

  • Detail of model development, validation and maintenance over the lifecycle  


Drug substance and drug product stability   

  • Stability fundamentals related to other guideline requirements 

Conversion of a batch process to CM 

  • A risk-based approach should be used for establishing product comparability and assessing the need of bioequivalence, clinical vs. non-clinical studies, and stability data   

Process validation   

  • Requirements for process validation established by region are similar for CM and batch manufacturing processes and also can follow the same standard approach of a fixed number of validation batches  

Pharmaceutical Quality System  (PQS) 

  • The expectations for the PQS are the same for batch and CM processes, following pertinent ICH guidance. The strategy for the diversion of non-conforming materials must be clearly defined.


Diversion of non – conforming materials

For batch-sized manufacturing processes, the segregation of non–conforming products can be clearly defined. Procedures are normally in place to describe how to define the frontiers between a good product and a bad product. CM expectations are not different from this, however, now the diversion concepts become relevant. Diversion is the procedure in which materials are isolated and separated from the product stream in the manufacturing process, therefore, based on the control strategy and the sampling procedures, diverse products can be approached in different ways.   


Essentially, two aspects are relevant to this new ICH Q13 Guideline. The first is that it has a wider scope than others, covering not only pharmaceuticals and APIs that can commonly be put under the same umbrella but also takes into account biotechnological/biological processes with the non-clear boundaries of what those types of processes include.  

The second aspect is that Continuous Manufacturing basically has the same requirements that batched size manufacturing processes. What makes total sense and includes enforcing consistent good manufacturing practices, making robust quality assurance for pre- and post-production tasks, ensuring robust control strategies and warranty of stability of products, are the key points in CM.  

A really interesting point is how to explain all of the previous aspects as clearly as possible in the CTD, following a risk-based approach and making it clear for those that need to approve it is the real first challenge. Then, how to sustain a lifecycle of these types of products and processes will be the next endeavor.  We now have been given the directions.   


Want to know more?

PQE Group has been supporting computer system and software validation for more than 24 years. Our experts are prepared to help medical device manufacturers understand how this guidance impacts their facilities and support the transition to this Risk-based manufacturing methodology. 

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