Continuous manufacturing affects the way processes are developed, certified and validated in the pharmaceutical industry. Instead of manufacturing pharmaceutical products in batches, which means a fixed amount of material produced until it is stopped, continuous manufacturing refers to uninterrupted or semi-constant processing of materials through the interconnected processes involved in the manufacturing.
Through a batch process, researchers will view any given batch broadly, identifying its information and making sense of its history and testing outcomes. Meanwhile, in continuous manufacturing, products entering the system at one end may not exit it at the same time, as various materials may not experience the same processing conditions throughout their flow through equipment.
What this means is that validation cannot just rely on a simple adoption of traditional batch validation methods. Here, the validation approach should indicate the process is controlled consistently, after which traceability of materials as it goes through the processing stage should be demonstrated.
Most importantly, the paradigm shift should occur whereby the focus changes from "three successful batches" notion to deep understanding of the entire process, control and traceability of materials throughout the processing steps.
- Feeding
- Mixing
- Granulation
- Drying
- Grinding
- Compression
- Coating
- Packaging
In this type of process, raw materials enter the line and finished products leave the line for several hours. This creates a few challenges for validation, while many of them are not significant in batch manufacturing.
For example, if the feeder changes its performance, it may change the composition of the mixture downstream. The effect of the feeder remains unnoticed for a certain period of time until the mixture gets out from the equipment.
This time is called residence time and it should be known when conducting validation in continuous manufacturing.
The development team must ensure:
What impact does a change in one parameter have on the process and when does this change show in the product?
This question is critical to continuous manufacturing, rather than just describing the normal conditions of operation.
Some CQAs are:
RTD is a method for calculating how long certain amount of material stays within the process or section of the equipment, along with how it moves around.
Picture a disturbance which happens at one point of a continuous manufacturing line. The effects of this will not be felt instantly when the product comes out.
Thus, the validation team needs to estimate the following:
- average residence time
- residence time distribution
- residence time minimums and maximums
- dead volumes
- material hold-up
- transfer delays between steps of the process
RTD statistics are useful for the creation of sampling plans, diversion plans, carrying out process monitoring and investigation of transitory phenomena.
The monitoring strategy should account for:
For example, when the variability of the feeder rises, the monitoring system will notice the situation and change the operation parameters accordingly before it affects the operations that come next.
The use of PAT helps in finding out attributes like:
However, the PAT systems should also be verified and validated.
Aspects of verification include:
What are the goals of the development studies?
Establishing:
It is also important to develop a validation strategy that would prove the reliability of the continuous processes in a certain range of business activity.
During the start-up process, there can be variations in the material properties and process parameters since:
Validation process should, therefore, provide:
Some examples include:
- An interruption of the feeding process for a short time
- A change in the feed rate
- A change in the equipment speed
- A temporary disturbance in the utilities
- A failed sensor
- A variation in the raw materials
- Small disturbances in the parameters of the process
The purpose should not be to create problems without reason but rather to be able to see how the process works under changed conditions.
The investigation should provide answers concerning:
- How fast is the response of the process?
- How long does the disturbance affect the product?
- Is it possible to identify the product affected by the disturbance?
- Is the process back to normal automatic mode?
- Is it necessary to divert the affected product?
So far, distinguishing between batches in the classic batch process is safe and straightforward, where the batch number will identify the batches and assist the manufacturer in distinguishing what batch has been impacted.
Continuous manufacturing requires more dynamic approaches in reference to batch identification.
An effective control strategy consists of the following elements:
The key factors when sampling are as follows.
A common error is to take many samples without checking for scientific necessity in the collection. The goal should be to gain the information showing that the process is controlled rather than taking samples for the sake of that.
To that end, the protocol must define:
Thus, cleaning validation must look at:
The systems may involve:
This data should be exploited through Continuous Process Verification (CPV) methods.
The trends may include:
Key topics include:
This approach is much more suitable than treating validation as one event.
Validation of continuous manufacturing technology should not be thought of in the same way as traditional batch validation. The aim is not to prove that a certain number of batches fulfill regulations but rather to prove that the continuous process is under control in a continuous way and that the flow and residence of the resources is monitored and that any variation can be detected and tracked.
The best continuous manufacturing concepts do not isolate process development, risk assessment, equipment validation or PAT from each other but develop them all in coordination and as a result, a very stable and data-rich continuous manufacturing environment is created.
A very important takeaway is that process dynamics should drive the validation process. Sampling, diversion, acceptance criteria and monitoring should analyze how the material moves through manufacturing. When the validation process understands these dynamics, it can provide evidence of the true state of control.
What this means is that validation cannot just rely on a simple adoption of traditional batch validation methods. Here, the validation approach should indicate the process is controlled consistently, after which traceability of materials as it goes through the processing stage should be demonstrated.
Most importantly, the paradigm shift should occur whereby the focus changes from "three successful batches" notion to deep understanding of the entire process, control and traceability of materials throughout the processing steps.
What Makes Continuous Manufacturing Different?
Continuous manufacturing can consist of multiple functions, including:- Feeding
- Mixing
- Granulation
- Drying
- Grinding
- Compression
- Coating
- Packaging
In this type of process, raw materials enter the line and finished products leave the line for several hours. This creates a few challenges for validation, while many of them are not significant in batch manufacturing.
For example, if the feeder changes its performance, it may change the composition of the mixture downstream. The effect of the feeder remains unnoticed for a certain period of time until the mixture gets out from the equipment.
This time is called residence time and it should be known when conducting validation in continuous manufacturing.
Start Validation with Process Understanding
Validation in continuous manufacturing should start during the development phase, not after the commercial process is complete.The development team must ensure:
- Properties of materials
- Behavior of processes
- Interactions of equipment
- Distribution of residence time
- Relationships of process parameters
- Quality attributes of processes
- Parameters of processes
- Traceability of materials
- Range of normal operations
- Behavior of disturbances in the process
What impact does a change in one parameter have on the process and when does this change show in the product?
This question is critical to continuous manufacturing, rather than just describing the normal conditions of operation.
Define CQAs and CPPs
Critical Quality Attributes (CQAs) and Critical Process Parameters (CPPs) are very important in continuous manufacturing.Some CQAs are:
- Assay
- Content Uniformity
- Dissolution
- Blend Uniformity
- Moisture
- Impurity levels
- Hardness of Tablets
- Particle Size
- Feeder Weight
- Speed of the Screw
- Speed of Mixing
- Conditions of Granulation
- Drying Temperature
- Compression Force
- Spraying Rate for Coating
Residence Time Distribution Is a Critical Consideration
Residence Time Distribution (RTD) is a highly relevant thought in continuous manufacturing validation.RTD is a method for calculating how long certain amount of material stays within the process or section of the equipment, along with how it moves around.
Picture a disturbance which happens at one point of a continuous manufacturing line. The effects of this will not be felt instantly when the product comes out.
Thus, the validation team needs to estimate the following:
- average residence time
- residence time distribution
- residence time minimums and maximums
- dead volumes
- material hold-up
- transfer delays between steps of the process
RTD statistics are useful for the creation of sampling plans, diversion plans, carrying out process monitoring and investigation of transitory phenomena.
Develop a Strong Control Strategy
Continuous manufacturing relies on a robust monitoring strategy.The monitoring strategy should account for:
- Characteristics of raw materials
- Platform properties
- Method parameters
- Method quality tests results
- Results from applying PAT technology
- Automatic management technology
- Maximum allowable values
- Change of raw material
- Cessation criteria
For example, when the variability of the feeder rises, the monitoring system will notice the situation and change the operation parameters accordingly before it affects the operations that come next.
Process Analytical Technology in Continuous Manufacturing
The utilization of Process Analytical Technology (PAT) has particular importance in continuous manufacturing.The use of PAT helps in finding out attributes like:
- Quality of blending
- Moisture content
- Chemical composition
- Properties of particles
- Properties of tablets
However, the PAT systems should also be verified and validated.
Aspects of verification include:
- Compatibility of the sensors
- Calibration
- Accuracy of the measurements
- Precision of the measurements
- Sampling
- Integrity of data
- Functionality of software
- Chemometric models if required
Define Normal Operating and Proven Acceptable Ranges
With respect to the continuous processes, the operating ranges should be grounded on scientific knowledge.What are the goals of the development studies?
Establishing:
- Normal Operating Range (NOR)
- Proven Acceptable Range (PAR)
- Alarm limits
- Action limits
- Process shutdown limits
It is also important to develop a validation strategy that would prove the reliability of the continuous processes in a certain range of business activity.
Validation of Start-Up and Shutdown Conditions
Start-up and shutdown are both critical aspects of continuous manufacturing as they may not initially be at the desired steady-state.During the start-up process, there can be variations in the material properties and process parameters since:
- Feeders are stabilizing
- Equipment assumes operational conditions
- Temperature profile is getting stabilized
- Materials start filling the equipment train
Validation process should, therefore, provide:
- The procedure for start-up
- Steady-state criteria
- The procedure for shutdown
- Requirements for segregation of materials
- The diversion criteria
- The transition periods that could be allowed
Handling Process Disturbances
The validation process must include disturbances that help test the process.Some examples include:
- An interruption of the feeding process for a short time
- A change in the feed rate
- A change in the equipment speed
- A temporary disturbance in the utilities
- A failed sensor
- A variation in the raw materials
- Small disturbances in the parameters of the process
The purpose should not be to create problems without reason but rather to be able to see how the process works under changed conditions.
The investigation should provide answers concerning:
- How fast is the response of the process?
- How long does the disturbance affect the product?
- Is it possible to identify the product affected by the disturbance?
- Is the process back to normal automatic mode?
- Is it necessary to divert the affected product?
Material Traceability and Diversion Strategy
Of all longstanding manufacturing troubles, determining which material has been impacted by process perturbation is possibly considered the hardest one.So far, distinguishing between batches in the classic batch process is safe and straightforward, where the batch number will identify the batches and assist the manufacturer in distinguishing what batch has been impacted.
Continuous manufacturing requires more dynamic approaches in reference to batch identification.
An effective control strategy consists of the following elements:
- Material tracking arrangements
- Time-based tracing
- Equipment location tracing
- Residence-time calculations
- Diversion logic
- Material specifications
Sampling Strategy for Continuous Processes
Sampling plans must take into account the variability inherent in this type of process.The key factors when sampling are as follows.
- Start-up of the operation
- Stable process operation
- Discontinuation of operations
- Disturbances of the process
- Changing parameters
- Sampling in various process locations
- Sampling at different times
A common error is to take many samples without checking for scientific necessity in the collection. The goal should be to gain the information showing that the process is controlled rather than taking samples for the sake of that.
Process Validation Studies
Validation studies must establish reproducibility in an actual commercial environment.To that end, the protocol must define:
- The duration of the manufacturing process
- Operating conditions
- The batch of raw materials
- The configuration of the equipment
- The sites of sampling
- The frequency of sampling.
- Ranges of critical process parameters
- Tests of critical quality attributes
- Monitoring of the process
- Requirements for starting and stopping the process
- The challenges of process disruptions
- Acceptance criteria
Cleaning and Equipment Considerations
Continuous equipment can be complicated. It can include numerous interconnected devices and places where substances can build up.Thus, cleaning validation must look at:
- Contact surfaces of the product
- Holds of the equipment
- Transfer points
- Screw and filler components
- Difficult places to clean
- Product change-over conditions
- Worst-case products
Computerized Systems and Data Integrity
Automated systems play an essential role in controlling and observing the continuous manufacturing process.The systems may involve:
- PLC systems
- SCADA systems
- Distributed control systems
- PAT application
- Historian databases
- Electronic batch records
- Automated diversion system
- Data integrity
- User access rights
- Audit trail
- Electronic record keeping
- System interfacing
- Alarm management
- Backup and recovery
Continued Process Verification
Continuous manufacturing enables the collection of substantial amounts of process data during normal operations.This data should be exploited through Continuous Process Verification (CPV) methods.
The trends may include:
- The performance of CPP
- The results regarding CQA
- PAT measurements
- Feeder fluctuations
- Process capability
- Alarm occurrences
- Diversion events
- Equipment actions
- Yield
- Deviations
What Regulators will Expect
Regulatory reviewers look at whether the company knows its process and whether it can show that it can keep things in control all the way through the process.Key topics include:
- Justification of the control plan
- Understanding of process dynamics
- Residence time
- Traceability
- Dealing with disturbances
- PAT approach
- Automated control
- Data integrity
- Validating the process
- Ongoing process verification
A Practical Validation Strategy
A practical validation approach can be based on six steps.1. Process understanding
Identify CQAs, CPPs, material attributes, process dynamics and equipment interaction with CQAs and CPPs.2. Risk identification
Find out the failure modes and determine the areas where the risk should be controlled or enhanced.3. Process characterization
Calculate the operational range, RTD, process capability and response to disturbances.4. Development of control strategy
Define the aspects such as PAT, automated controls, alarms, diversion logic and sampling.5. Process performance qualification
Prove the reproducibility of the process under commercial conditions.6. Process verification
Use the manufacturing statistics to confirm the process control.This approach is much more suitable than treating validation as one event.
Validation of continuous manufacturing technology should not be thought of in the same way as traditional batch validation. The aim is not to prove that a certain number of batches fulfill regulations but rather to prove that the continuous process is under control in a continuous way and that the flow and residence of the resources is monitored and that any variation can be detected and tracked.
The best continuous manufacturing concepts do not isolate process development, risk assessment, equipment validation or PAT from each other but develop them all in coordination and as a result, a very stable and data-rich continuous manufacturing environment is created.
A very important takeaway is that process dynamics should drive the validation process. Sampling, diversion, acceptance criteria and monitoring should analyze how the material moves through manufacturing. When the validation process understands these dynamics, it can provide evidence of the true state of control.
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