Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms
Abstract
:1. Introduction
2. Background
- For investment in pharmaceutical manufacturing innovation, including CM in R&D and production.
- For the manufacturing of products using CM processes.
- Expedited approvals (similar to break-through designations) for products using CM for new products, generics or those moving from batch processes.
- Some form of certification for companies where the increased rigour and control in CM process allows simpler and faster regulatory approvals.
3. Regulatory Aspects of CM
3.1. International Conference on Harmonisation (ICH)
3.2. Major Regulatory Agencies
3.2.1. FDA
3.2.2. MHRA
3.2.3. EMA
3.2.4. PMDA
3.3. Other Regulatory Considerations
4. Quality Considerations of CM Processes
4.1. Control Strategy
4.2. Batch and Lot Definitions
- The amount of material produced within a specified period of time (the most common definition);
- A fixed quantity of raw material processed.
- Or by operational considerations such as:
- The input API batch size;
- The length of an operator’s shift.
- Increasing the run time (within validated limits). Consideration needs to be given to issues such as the build-up of material during longer runs (in transfer lines, filters, granulator barrel walls, punch surfaces, etc.), equipment overheating, etc.
- Parallel operation of multiple items of kit. Need to assure the uniformity of output from each process.
- Increasing the throughput of the process. This has an impact on the process dynamics and may affect aspects such as sampling frequency and size for PAT equipment, Residence Time Distribution (RTD) and material diversion (see Section 4.3) and will likely require that the control strategy is rebuilt.
- Change of size of equipment. Also, likely to require a completely different control strategy and complete re-validation
4.3. Traceability and Residence Time Distribution (RTD)
4.4. Process Disturbances and Diversion of Material
- Deviations that fall outside pre-set ranges of material attributes and process parameters as determined by development studies (e.g., response surfaces, design spaces);
- Prediction of quality attributes from process modelling with real-time inputs of process parameters and measurements;
- Direct measurement of quality attributes in real-time (use of PAT).
4.5. Real Time Release Testing (RTRT)
4.5.1. Blend Mixing and Tablet Content Uniformity
4.5.2. Moisture Content
4.5.3. Solid State Chemistry
4.5.4. Drug Release (Dissolution)
4.5.5. Related Impurities
4.6. Process Validation and Verification
4.7. Models Used in CM
4.8. Data Requirements
4.9. Summary
5. CM Equipment
5.1. Unit Operations
5.1.1. Feeders
5.1.2. Powder Blenders/Mixers
5.1.3. Granulators
5.1.4. Dryers
5.1.5. Coaters
5.2. Integrated Continuous and End-to-End (E2E) Manufacturing
5.3. Alternative Continuous Manufacturing Approaches
6. Process Analytical Technology (PAT)
- Direct measurement of the CQA;
- Prediction of the CQA based on a first-principles model that is fed measurements of related variables and is running in parallel with CM unit operations;
- Prediction of the CQA based on an empirical or semi-empirical model (e.g., response surface map, chemometrics model) that is fed measurements of other variables;
- Operation of the CPPs to lie within a design space (ie a specified set shown in offline studies to provide assurance) [97].
- At-line: measurement where the sample is removed, isolated from and analysed near the process stream.
- On-line: measurement where the sample is diverted from the manufacturing process and may be returned to the process stream.
- In-line: measurement where the sample is not removed from the process stream and can be invasive or non-invasive.
7. Material Property Requirements for Continuous Manufacturing
8. Industry/Academia/Government Collaborations to Progress Continuous Manufacturing
8.1. International Symposia for Continuous Manufacture of Pharmaceuticals (ISCMP)
8.2. Consortia Working to Progress CM
8.2.1. Novartis—MIT Center for Continuous Manufacturing
8.2.2. CMAC
8.2.3. C-SOPS
8.2.4. RCPE
8.2.5. IIAPM
8.2.6. MMIP/MMIC
- To create a ‘digital twin’ of the CM process and via virtual formulation experiments to select equipment and initial processing conditions for CM and thereby give confidence that CM DC process will work. This will be useful evidence that a company might use to justify an investment in CM.
- To enhance understanding of raw materials to build a CM control strategy to allow RTRT and develop robust formulation processes on a modular flexible CM DC platform.
- To de-risk and accelerate CM DC technology by modularising equipment and standardising control systems moving away from supplier-specific approaches [120].
8.2.7. SSPC
8.2.8. NIIMBL
8.2.9. UK-CPI National Formulation Centre, National Industrial Biotechnology Centre and National Biologics Manufacturing Centre
8.2.10. AMED
8.3. Other Supportive Organisations and Guidance
8.3.1. United States Pharmacopeia
8.3.2. ASTM
8.3.3. ISPE
8.3.4. NIPTE
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
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Drug Product | Indication | Company | Year of First Approval | Regulatory Body |
---|---|---|---|---|
Orkambi® | Cystic fibrosis | Vertex | 2015 | EMA, FDA |
Prezista® * | HIV | Janssen (J&J) | 2016 | EMA, FDA |
Verzenio® | Breast cancer | Eli Lilly | 2017 | EMA, FDA, PDMA |
Lorbrena® | Lung cancer | Pfizer | 2018 | ** |
Daurismo® | Myeloid leukaemia | Pfizer | 2018 | FDA |
Symkevi®/Symdeko® | Cystic fibrosis | Vertex | 2018 | EMA/FDA |
Tramacet® | Pain | J&J | ** | PMDA |
Faster and leaner transition from development to commercial scale | Same equipment used during development, clinical supply manufacture and commercial production with batch sizes accommodated by changing run times Shorter cycle times More rapid development |
Shorter supply chains | All operations conducted on one piece of equipment in one location without hold-ups and inter-site transfers between manufacturing stages Improved stability as no intermediate holding periods |
Supply chain security | Enhanced domestic manufacture with reliance on high technology rather than low-cost labour Shorter manufacturing times meaning longer product shelf lives |
Improved product quality | Domestic manufacture In-process monitoring, feedback and feed-forward controls. Maintenance of a state-of-control Reduced dependence on end-product testing Decreased regulatory oversight—frees resources for other higher-risk areas Fully aligned with principles of Quality by Design (QbD) |
Cost benefits (after initial investment) | Lower production costs Improved utilisation of equipment Lower personnel requirements Smaller footprint |
Supply chain responsiveness | Batch sizes tailored to requirements by adjusting run times Ability to respond rapidly to demands |
Patient benefits | More suited to niche/personalised products Alternative manufacturing technologies (e.g., active pharmaceutical ingredient (API) printed or sprayed onto a dosage form) Lower risk of stock-outs |
Societal benefits | Less environmental impact (less use of solvents, lower energy costs) Less waste/improved yields. Lowered risk that a whole batch will need to be rejected if it fails end-product testing Higher process intensification (less use of space, energy and raw materials) Improved safety (reduced handling and exposure to materials, easier cleaning) Source of high-tech jobs |
Existing equipment and facilities are geared to batch processes | Initial investment cost to implement CM (albeit with lower subsequent costs) Existing equipment likely depreciated so may be less of an issue |
Facilities not located to achieve end-to-end processing | API and drug product facilities may be in different countries (perhaps driven by tax benefits) or locations within a country |
Different expertise requirements | CM requires experts in statistics, process control, modelling, QbD processes, PAT (Process Analytical Technology), etc. Requirement to better understand material attributes |
CM process | Limited possibilities for re-work (but also less likely a need to do so) Limited opportunities to halt the process part way through |
Maintenance | Control algorithms and models require adjustment to accommodate changes in raw materials. May have regulatory implications Sophisticated PAT equipment |
Submission requirements | New submissions required to switch batch to CM No globally recognised harmonised CM approval process Concern that regulators will baulk at CM processes Limited expertise in non-FDA, EMA, MHRA, PMDA regulated countries Longer approval times for global registration |
Equipment | Lack of appropriate bench and pilot-scale equipment Not all unit operations can currently be included in a CM process Handling of dry solids and solid laden fluids can be difficult |
Experience | Lack of examples of end-to-end processes Limited company experience of CM submissions Limited experience in regulators (in particular EMA, MHRA and PMDA) |
Number | Date | Title | Contents of Relevance to CM |
---|---|---|---|
ICH Q8(R2) | 2009 | Pharmaceutical Development | Control strategy, continuous process verification |
ICH Q9 | 2015 | Quality Risk Management | Risk assessment and control |
ICH Q10 | 2008 | Pharmaceutical Quality System | Continual improvement of process performance and product quality |
Quality-IWG | 2012 | Points to consider for ICH Q8/Q9/Q10 guidelines | Models in QbD, continuous process verification |
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Wahlich, J. Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. Pharmaceutics 2021, 13, 1311. https://doi.org/10.3390/pharmaceutics13081311
Wahlich J. Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. Pharmaceutics. 2021; 13(8):1311. https://doi.org/10.3390/pharmaceutics13081311
Chicago/Turabian StyleWahlich, John. 2021. "Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms" Pharmaceutics 13, no. 8: 1311. https://doi.org/10.3390/pharmaceutics13081311