New FDA Guideline: Quality Aspects for Continuous Manufacturing

In February 2019, the FDA published a new draft guideline that addresses quality aspects in the continuous manufacturing of medicinal products. It covers topics related to development, process validation, marketing authorisation and routine production.

The FDA sees continuous production as the most important tool in the modernisation of the pharmaceutical industry. In a statement released at the same time by FDA Commissioner Scott Gottlieb and CDER Director Janet Woodcock, there is meanwhile mention of five continuously manufactured products (from four companies) that have already been authorised. Four years ago it was only one authorised product. In total, twenty companies are working with the FDA on continuous manufacturing. These are both original and generic manufacturers. In order to further support the pharmaceutical industry, the present guideline has been developed. The development of an ICH guideline for continuous manufacturing of medicinal products was also initiated and its completion is planned for 2021.

The draft guideline entitled "Quality Considerations for Continuous Manufacturing" is primarily aimed at manufacturers of solid medicinal products or small molecule medicinal products. Basically, the guidelines can also be used for the production of biologics, but these are not the focus of the paper.

The FDA defines a continuous process as a process consisting of at least two connected Unit Operations to which material is continuously fed and from which material (product) is continuously removed. According to the FDA, conventional batch processes consist of a sequence of individual process steps. Since the integrated, continuous procedure is new for the pharmaceutical industry, the new guideline describes the key elements that must be considered in continuous processes. Those elements are covered in the individual chapters:

A. Key Concepts of Continuous Manufacturing
1. Process Dynamics
2. Defining Batches for Continuous Manufacturing Processes

B. Control Strategy
1. Input Material Control
2. Process Monitoring and Control
3. Material Diversion
4. Real Time Release Testing
5. Specification
6. Equipment
7. System Integration, Data Processing, and Management

C. Process Validation
D. Additional Pharmaceutical Quality System Considerations
E. Scale-Up
F. Stability
G. Bridging Existing Batch to Continuous Manufacturing

In contrast to conventional batch processes, continuous processes are dynamic. In order to be able to characterize the process flow, it is necessary to determine the residence-time distribution (RTD). RTD is a probability distribution that describes how long a mass remains in the process. It can be determined by tracer studies, by online measurement of certain product properties and/or by mathematical methods (Process Modelling).

A very important aspect of the continuous process is the control strategy. The key elements for this are: control of input materials, process monitoring, material diversion, real-time release testing (RTRT), specification and process equipment.

Since continuous processes must be continuously "fed" with input materials, their flow behaviour plays a much greater role. This can lead to additional material properties having to be specified, e.g. particle size distribution or density of APIs or excipients.

Ideally, a continuous process is in the so-called "state-of-control". However, there will always be situations where this is not the case, e.g. due to incidents, start-up or shut-down of the process. Here, it has to be ensured that non-compliant material is diverted depending on the severity and duration of the failure and the process dynamics. Unexpected defects that lead to the diversion of product should be investigated before the batch continues to be used.

Through the use of PAT and the associated collection of in-process data, the establishment of a real-time release is possible (RTRT). According to the FDA, this is a "can" and not a "must" for continuous processes, but it is recommended.

According to FDA CFR, a specification is required for finished medicinal products. The establishment of specifications for continuously manufactured products should follow the requirements of ICH Q6A and B. The FDA considers the data generated within the scope of an RTRT to be more meaningful than data determined within the scope of a final and offline testing of the product. Nevertheless, the specification should include offline test methods and acceptance criteria in order to be able to perform stability tests at a later time.

The FDA expects the performance of equipment used for continuous production to decline over time. To prevent this, additional aspects of qualification, maintenance and cleaning must be considered. The qualification of equipment must cover both individual manufacturing steps and the integrated overall process. Qualification should consider expected conditions (flow rates, pressures, speeds, duration). The diversion of non-compliant material should also be checked during qualification. The Quality Unit should establish acceptance criteria for the performance of equipment.

The cleaning procedure should be developed by monitoring materials during and after manufacturing. Residues in the equipment (in pipes, filters, etc.) must be evaluated.

Since continuous processes must be controlled in real time, a great amount of data is generated in a very short time, which must be evaluated in real time in order to make process decisions. According to the FDA, this should be done by an automated system. The FDA considers the design and validation of this system to be particularly critical. The Quality Unit should define in advance which alarms require which actions. The system must also meet the requirements of 21 CFR Part 11.

For the validation of a continuous process, the FDA names the following guidelines: Process Validation: General Principles and Practices as well as ICH Q8, Q9, and Q10. The FDA's three-phase model is also applicable (1 Process Design; 2 Process Qualification; 3 Continued Process Verification), whereby certain qualification steps can shift from phase 2 or 3 to phase 1.

Since the introduction of continuous processes is so fundamental, the manufacturer should evaluate its pharmaceutical quality assurance system and ensure that new issues are covered, such as handling process failures in real time, review of raw materials & in-process materials, change management, CAPA as well as qualification and maintenance for continuous processes.

A chapter is also dedicated to scale-up. Scale-up is possible in three ways: extending process time, increasing flow rates, or increasing both. The FDA sees the lowest risk if the process time alone is increased. In this case, and if other parameters remain unchanged, it may be possible for the manufacturer to map the scale-up within his QA system without sending a supplement to the FDA.

The transition from a conventional batch process to a continuous process is also intended by the FDA as a Prior Approval Supplement (PAS),  usually associated with inspection. In addition, the annex contains a list of definitions and a table indicating where specific information for continuous manufacturing can be provided in a submission (CTD format).

The draft guideline "Quality Considerations for Continuous Manufacturing" can be found on the FDA website.

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