Do you know what will change regarding the FDA’s quality considerations for continuous man


Did you review the FDA’s quality considerations for continuous manufacturing and how it will enable a new way of working in companies compared to the batch manufacturing? Get up to speed quickly by reading the highlights in this blog.



The FDA describes:




Continuous versus batch manufacturing


The main difference between both terms is not necessarily the quantity of produced materials, but the setup of the process. While continuous manufacturing combines all units in a single process flow, batch manufacturing uses the same units but in separate process steps.



Reference: “A comparison of continuous manufacturing and batch manufacturing. Image courtesy of Sau Lee. J. Pharm Innov (2015) 10:191-199.



Advantages of continuous manufacturing


As continuous manufacturing processes are set up as integrated systems combining a series of different units of operation, several advantages are linked to this method.

  • The amount of required production steps for the manufacturing activity can be reduced as every unit is linked. In batch processes intermediate collection and storage steps are required. Consequently, the processing time can be reduced.

  • Another advantage linked to the reduced amount of process steps is that less human actions are required which results in a reduction of human errors. Real-time product quality monitoring is possible, which allows monitoring of the process and the produced materials at all times. The reduced human errors and real time monitoring result in a reduction of the drug product quality issues.

  • The throughput time of continuous manufacturing processes is lower as no intermediate hold times are required, the production speed will consequently increase causing the drug shortage to reduce. A higher guarantee for the availability of high quality drug products will be assured.

  • The equipment can be operated for longer periods resulting in a higher quantity of produced materials to respond to differing market requests.

  • The used equipment can be smaller because of the continuous in- and outflow of materials, resulting in a smaller equipment footprint.

The flexible operation, the reduced amount of process steps, and the smaller equipment footprint all result in a reduction of manufacturing costs.



Production process


Batch manufacturing is a static production method, a well-known amount of raw materials is used, and a fixed set of parameters is applied which creates a roughly known amount of finished products (in case of no issues). The process dynamics are less important as the process is not monitored and controlled in real-time.

On the other hand, continuous manufacturing is a dynamic process, production materials are fed and finished products are removed constantly. A range of parameters is predetermined in which the process is being monitored and controlled in real-time. As transient disturbances occur, it is very important to know the process dynamics in order to be able to adapt parameters to control the process. Material identity verifications of raw, intermediate and finished products allow to monitor the process closely.

While the risk assessment for batch manufacturing focusses on the process understanding of each unit of operation separately, the risk assessment of the continuous manufacturing should focus on the process understanding of the integrated system including the interrelations of all units of operation.

For batch manufacturing, one campaign is defined as one batch. However, for continuous manufacturing a batch has to be defined by production period, or quantity of materials fed, or quantity of products produced. For both methods the batch has to guarantee that all products within the batch are within the limits of their specifications.



Control strategies


Controlling the process is essential for assuring the production of high-quality products. For continuous manufacturing it also has the additional function of monitoring and controlling the process in case of transient disturbances.


Input material control

In batch processes the input materials are only verified against a standard and approved if they correspond to the specifications. In continuous manufacturing additional characterization of the raw materials (particle size distribution, density, material flow …) is necessary. The material characteristics are used to set up models in order to be able to monitor the material inlet flow and to observe disturbances early.

When changing from batch to continuous manufacturing, it is necessary to re-evaluate the existing product specifications of the raw materials to ensure all required characteristics are known.


Material diversion

In batch processes no material diversion is required as the materials are homogeneously mixed, and no fractions are out of specification. In continuous processes, however, materials can be temporarily non-conforming, a process should be in place for diversion of the out of spec materials without impacting the rest of the batch. The monitoring of the process is an important aid for separating the in and out of spec materials.


Equipment

The production periods of continuous manufacturing can be much longer than those of batch processes, causing an increased chance of fouling and wear and tear of the equipment. Therefore, the equipment for both methods should suit the requirements:

  • Additional measures are required regarding the qualification, maintenance and cleaning of the equipment used in continuous processes.

  • As all units are linked in the continuous process, the inter-equipment functionalities should be verified as well.

  • The qualification should be performed for a longer period in which the parameter variations and drift should be verified.

Maintenance of continuous processes cannot be performed with fixed periods as it is the case with batch processes because campaigns can have a wide variety of production periods. The maintenance will mainly be carried out based on indicators of the well-functioning of the system and by using preventive maintenance time tables.

Also, the cleaning cannot be performed with a fixed periodicity, instead, it will be based on elapsed operating time, quantity of materials processed, history of process conditions or deviations. The maximum operating time can be determined by examining the equipment for material hold and build up, film formation and microbial growth.



Process validation


Besides the qualification of equipment, utilities, computerized systems, etc. used in batch manufacturing, the ability to evaluate real-time data of the integrated system should be qualified as well.

For batch processes mainly prospective validation is applied as first test materials are used and afterwards commercial materials. In continuous manufacturing, concurrent validation is applied for example process design combined with equipment qualification because the equipment used in the development phase will be upscaled later for commercial production.


In stage 1 (process design), not only the equipment and automation system is designed like in batch manufacturing, but also the complete process and control strategies are designed. Stage 1 includes design of equipment, automation systems, input material attributes, process dynamics and variability, material diversion, process monitoring, process control and the control strategies discussed earlier in this document. Well-designing all of the above provides foundational understanding of manufacturing processes and quality expectations which enables the verification of process robustness in stage 2.


In stage 2 (Process qualification), the focus on assuring process performance is even higher as it is important to have reliable performing equipment and automation systems as all steps are linked to each other. One failing unit stops the complete process.

The qualification of the equipment of batch processes is based on the worst case setpoints, however for continuous processes a range of parameters is defined. Therefore, the robustness of the system is verified with respect to the known sources of variability, acceptance criteria are defined for parameter stability or variance and yield.

The initial process performance qualification (PPQ) is representative for the intended commercial run times. For commercial processes unforeseen sources of variability (process drift, equipment fatigue, material build-up) can cause extended run time. If the initial qualification is no longer representative for the commercial run times, new PPQ should be performed.

In batch processes the number of samples is higher during PPQ-runs to have a stricter verification of the process, however for continuous processes this is not required due to the high-frequency monitoring.


Stage 3 (continued process verification) is performed for batch processes by carrying out periodic reviews. However, for continuous processes it is evaluated by continuous data analysis and trending.



Transitioning from batch to continuous manufacturing


It is possible that a company wants to transition their existing registered batch process to a continuous process. This transition, however, requires a lot of effort as it is linked to changes in product and process design (equipment, process parameters, control strategy) and it is recommended to file a prior approval supplement (PAS) after discussing the proposed changes with the agency to gain feedback prior to conducting the required studies.


The evaluation of the transition should include a comparison of individual unit operations, process parameters, equipment, control quality attributes and the control strategy. When the risk of the changes to the product quality is low, demonstration of in vivo equivalency may be sufficient by using batch data (e.g. physiochemical properties, impurity profiles). When the risk is expected to be high, additional in vivo bioequivalence studies might be required.


When implementing continuous manufacturing into an existing facility, the existing pharmaceutical quality system (PQS) should be evaluated and adapted. The evaluation should include:

  • Handling of planned and unplanned process disturbances

  • Raw and in-process material investigations

  • In-process material diversion

  • Change and CAPA management

  • Performance qualification and continued process verification approach

  • Equipment qualification and maintenance

  • Application of formal and informal risk management principles


Conclusion


Both batch and continuous manufacturing can be applied for producing high-quality materials. The continuous process however has a higher throughput time, a lower risk of product quality issues and a lower manufacturing cost.

As the continuous manufacturing process is a dynamic process, it is very important to know the process dynamics and to define additional controls. Both are required in order to be able to monitor and control the integrated system, so all parameters remain within their predefined ranges.

A more extensive qualification approach is required to assure a well-functioning, robust and representative continuous process.

When the intention of making the transition from batch to continuous manufacturing exists, first discuss the change with the FDA to gain feedback before performing all required studies. When a positive response is obtained a prior approval supplement can be issued.

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