Pharmaceutical groups want more clarity on continuous manufacturing guideline

Regulatory NewsRegulatory News | 17 December 2021 |  By 

Several industry trade associations are asking for more clarity on the International Council for Harmonisation’s (ICH) Q13 guideline on continuous manufacturing, including what constitutes a state of control for a continuous manufacturing process, the scope of the guideline, and the definition of a batch size. One manufacturer said the guideline places too much emphasis on non-conforming material, which has not been a significant issue in continuous manufacturing.
The ICH Q13 guideline, released on 27 July, “describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing (CM).” The guideline covers continuous manufacturing of drug substances and drug products, including chemical entities and therapeutic proteins. (RELATED: ICH releases widely anticipated guidance on continuous manufacturing, Regulatory Focus, 27 July)
The guideline also covers new drugs, generic drugs, and biosimilars, as well as the conversion of batch manufacturing to continuous manufacturing for existing products. The principles in the guideline “may also apply to other biological/biotechnological entities.”
The US Food and Drug Administration (FDA) released the guideline for comment on 14 October as a draft guidance; the deadline for receiving comments was 13 December. Nine respondents representing a mix of pharmaceutical trade groups, pharmaceutical companies, and non-profit organizations commented on the guideline.
Clarity on scope
The Biotechnology Industry Organization (BIO) said more clarity is needed on whether the principles in the guideline also apply to advanced therapy medicinal products (ATMPs).
BIO said that “some ATMP manufacturing processes can fall into the definition of CM [continuous manufacturing]. Although not explicitly excluded from this guidance, it is not clear if they would be understood as part of biological/biotechnological entities.”
State of control example
BIO also suggested the guideline provide an example of a continuous manufacturing process being in a “state of control.” The group writes that providing such an example “would be helpful for demonstrating when a state of control has been achieved.”
The guideline defines a state of control as “a condition that provides assurance of continued process performance and product quality.” Further, it is “important” for manufacturers to have mechanisms in place to ensure that a process is in a state of control.
Related to this, the International Pharmaceutical Excipients Council of the Americas (IPEC-Americas) wants more clarity on what is meant by the term “steady state” showing that a manufacturing process is in a state of control. The group writes that “people often get confused by the term ‘steady state.’ It is important to clarify what is meant here by steady state.”
The guideline says that “a state of control can be demonstrated for some CM processes when a set of parameters (e.g., process parameters, quality attributes) are within specified ranges, but the processes are not necessarily in a steady state condition.”
Definition of ‘batch’ needs revision
In other areas, BIO suggested that the definition of a batch should be expanded to include additional examples.
The guideline specifies that the size of a batch produced by continuous manufacturing can be defined by one of the following: quantity of output material, quantity of input material, or run time at a defined mass flow rate. It also states that “other approaches to define batch size can also be considered, if scientifically justified based on the characteristics of the CM process.”
BIO writes that “the need to ‘define’ a batch is not questioned …. However, there may be situations where defining it by ‘size’ may not always be the most relevant, e.g., yield/productivity or flow rate may not always be constant leading to a fairly wide range of ‘batch sizes.’“
Over-emphasis on waste
Eli Lilly says the guideline places too much emphasis on non-conforming material, or waste, in continuous manufacturing, when this has not been a significant issue.
The guideline says that “CM processes may include periods when non-conforming materials are produced, for example, during system start-up and shutdown and when disturbances are not appropriately managed and mitigated. The ability to divert potential non-conforming material from the product stream during production is an important characteristic of CM and should be considered in developing the control strategy.”
Lilly said that this “sentence implies that all CM processes have startup or shutdown transition waste, which has not been the industrial experience with continuous unit operations, such as CSTRs [continuous stirred tank reactor], mixer/settler extractors, evaporators, crystallizers and filters, and some drug product CM operations. This statement should not leave the impression that material must be diverted unnecessarily, when the unit operations have demonstrated lack of transition waste.”
The firm argued in its comment that the provision should be revised to downplay the prevalence of manufacturing waste. The sentence should state that “CM processes may include periods when non-conforming materials are produced, for example, during system start-up and shutdown for some CM unit operations, and when disturbances are not appropriately managed and mitigated.”
Distinction between small molecules and biologics
The National institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) said the guideline should make a clearer distinction between continuous manufacturing of small molecule drugs and biologics.
“While many technical matters are no different between these two classes of pharmaceuticals; regulatory review, inspection, and management of post-launch process changes can be quite different due to complexity of the products and residual uncertainty associated with first principle understanding of critical quality attributes,” said NIIMBL. “Rather than being silent on these differences, we suggest the document be explicit about differences in quality assurance and regulatory oversight between biologics and small molecule drugs. Being clear about these differences mitigates unintended outcomes and facilitates regulatory convergence.”
Comments on ICH Q13
ICH Q13 guideline


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