Quality Considerations for Continuous Manufacturing in the Pharmaceutical Industry
The FDA issued a draft guidance document in February 2019 titled “Quality Considerations for Continuous Manufacturing, Guidance for Industry”. This guidance document contains information regarding the FDA’s current thinking on the quality considerations for continuous manufacturing of small-molecule and solid oral drug products. It is important to understand that this draft guidance document is currently in the ninety day consultation and review period. It has not yet been approved for implementation.
It outlines that the benefits associated with continuous manufacturing mean that the manufacturing process will ultimately result in an integrated manufacturing process with fewer steps and shorter processing times. If implemented correctly a continuous manufacturing process would provide the following benefits:
- Smaller equipment footprint
- Supporting an enhanced development approach (e.g., Quality by Design (QbD), use of Process Analytical Technology (PAT) and models)
- Real-time product quality monitoring
- Flexible operation to allow scale-up, scale-down, and scale-out to accommodate changing supply demands
The output of these improvements would ultimately reduce the number of drug product quality issues, lower manufacturing costs, and improve availability of quality medicines to patients.
Some key concepts of a continuous manufacturing process include the following:
An understanding of process dynamics is essential for the identification and mitigation of risks to product quality. The different elements associated with process dynamics range from the input material attributes to process conditions to equipment design elements both during and after production. As a result of the dynamic nature of a continuous manufacturing process the risk assessment should consider process understanding of the integrated system in addition to each unit operation.
A Control Strategy is a key quality aspect to the successful implementation of continuous manufacturing. Establishing, maintaining, and refining a control strategy is a life cycle activity – from development to technology transfer to ongoing verification during the commercial manufacturing phase. An effective PQS strengthens the links across the stages of a product’s life cycle and enables the development and continuous improvement of the control strategy. Key elements of a control strategy include;
- Control of input materials
- Process Monitoring and Control
- Material Diversion
- Real Time release testing
- System Integration, Data Processing and Management
The ability to evaluate real time data to maintain operations within established criteria to produce drug products with a high degree of assurance of meeting all the attributes they are intended to possess is an integral element of process validation. For the successful validation of a continuous manufacturing process, the FDA recommends that the following guidelines are incorporated:
- Process Validation: General Principles and Practices
- ICH Q8 Pharmaceutical Development
- ICH Q9Quality Risk Management
- ICH Q10Pharmaceutical Quality System
- FDA’s three-phase model (1 Process Design; 2 Process Qualification; 3 Continued Process Verification)
Additional Pharmaceutical Quality System Considerations:
The guidance document also recommends that manufacturers should re-examine their quality management systems to ensure that is robust enough and covers the new challenges that continuous manufacturing presents such as handling process failures in real time, review of raw materials, change management and CAPA. An appropriate level of continuous manufacturing expertise in area such as quality, manufacturing operations and regulatory affairs should also be established, and training plans put in place where appropriate.
Scale up is possible in three ways – increasing run time with no change to mass flow rate, increasing the mass flow rate or increasing both. Each method of scale up should be carefully examined to identify and assess risks. An advantage of continuous manufacturing is that the equipment used for process development can also be used for commercial manufacturing. Any scale up activities must be appropriately evaluated in the company’s change management process.
As outlined in guidance for industry ICH Q1A(R2) Stability Testing of New Drug Substances and Products (https://www.ema.europa.eu/en/ich-q1a-r2-stability-testing-new-drug-substances-drug-products), data from stability studies should be provided on at least three primary batches of the drug product, and where possible, these should be manufactured by using different batches of the drug substance. Alternatively, stability samples could be obtained from a single continuous manufacturing campaign where manufacturing variability is captured (e.g., by introducing different batches of input material(s) in a sequential manner).
Bridging existing batch to continuous manufacturing:
As a change from batch to continuous manufacturing would result in a change in the scientific operating principle, the most appropriate filing strategy would be a Prior Approval Supplement (PAS). The FDA encourage any Manufacturers wishing to implement Continuous Manufacturing to discuss changes and bridging strategies to gain feedback prior to conducting any studies.
The continuous manufacturing draft guideline can be found on the FDA website: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM632033.pdf
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