Friday, 28 April 2023 / Published in News, NMPA Registration in China, Pharmaceuticals & DMF

Oral solid dosage continuous manufacturing introduced in China

Oral solid dosage continuous manufacturing technical guidelines have been issued (No.19-2023) by the China Center for Drug Evaluation (CDE) for trial implementation from March 21, 2023, onwards.

Background

As an advanced production process, continuous manufacturing involves continuous feeding and conversion of input materials during the production process, accompanied by continuous output of materials. Unlike the traditional batch production process, the continuous manufacturing process is characterized by continuous production steps without interruptions, high production efficiency, small equipment footprint, real-time product quality monitoring, and easily adjustable production batches, which help improve the quality of pharmaceuticals.

This guideline applies to the continuous manufacturing of oral solid dosage forms of chemical drugs and describes the basic ideas and regulatory considerations for the continuous manufacturing batch definition, control strategy development, process validation and stability studies, batch changes, etc. The relevant requirements are consistent with the basic principles and concepts of ICH Q13.

In the existing traditional batch production process, one of the biggest drawbacks is that if a production process deviates, the whole batch will be scrapped, but continuous manufacturing avoids this phenomenon, the guidelines require the applicant to study the process, together with ICH Q13, to establish an effective control strategy to ensure that the process is always maintained in a controlled state during continuous operation, to detect transient disturbances and reject possible non-conforming materials in a timely manner, to ensure that the output material meets the expected quality requirements.

In 2018, ICH opened the Continuous Guidance Program, which aims to advance regulatory evaluation and monitor consistency of continuous manufacturing technologies across regions. The National Medical Products Administration (NMPA), as a member of ICH, also participated in the drafting of the guidance. The CDE, under the NMPA, published an exposure draft of the ICH Guideline Q13: Continuous Manufacturing of APIs and Formulations in October 2021 and, in response to the Guideline, held an expert workshop in August 2022 to address the guidance.

The guideline is a trial preparation for the implementation of ICH Q13 in China.

Summary of the guideline

The continuous manufacturing processes described in these guidelines are generally applicable to integrated processes consisting of two or more unit operations directly connected.
Continuous manufacturing process can be applied to some or all unit operations in the production process. The continuous manufacturing mode of chemical oral solid dosage form can be divided into:
- Partially continuous production mode – This production mode, part of the unit operation for the batch production mode, the other two or more unit operations directly connected to the continuous mode.
- Whole process continuous production mode – In this production mode, all unit operations of the production process are in continuous mode.
In continuous production, the definition of batch size is critical. The guidelines suggest that the applicant can use the output material volume to define the production batch, or the input material volume, or the run time at a specified mass flow rate, and the applicant can choose one of these three approaches based on the actual production process.
Unlike batch production processes, continuous manufacturing processes are dynamic systems. During normal operation, the properties of input materials, process conditions or environmental factors may lead to transient disturbances in the system. Applicants should develop effective control strategies to maintain the process in a controlled state, detect transient process disturbances, divert potentially unqualified materials from the system, and reduce the risk of potential disturbances to product quality.
Continuous manufacturing requires the study of process model for dynamic control of the circle process (intelligent system). A scientifically sound method should be used to characterize the material flow in the process. A common approach is the residence time distribution (RTD) characterization for each unit operation and/or integrated system, which is a probabilistic distribution describing the residence time of the material in the process depending on several factors (e.g. input material properties, mass flow rate, process parameters, equipment design and operation, etc.) and can be achieved through tracer experiments, on-line measurements of product quality properties and/or process models, RTD can be used to determine material traceability as well as diversion strategies.