The variability of materials such as reagents and consumables, paired with supply chain challenges need to be considered.
What Scales Up Must Scale Down
At AbbVie, our research and development teams discover chemical processes that create molecules, treating multiple diseases. Do you ever wonder how we take these processes born in the lab and transform them into tangible products millions of patients can use? Engineers and scientists at AbbVie work together to scale-up processes scaling-up is to scale-down!
Challenges of Scaling-Up New Processes
Variability in the process and establishing method understanding can be difficult first steps to scale up.
Building Process Robustness
One of the first stages to building process robustness or troubleshooting is scaling down and understanding critical aspects of the process such as:
Critical Quality Attributes (CQAs) which are quantifiable properties that are considered for purity, efficacy, and safety of the product.
Critical Process Parameters (CPPs) are factors that have a direct impact on a CQA when varied beyond a limited range.
Understanding Scaled-Down Models
Understanding scaled-down models is critical for complete scale up. Design of experiments (DOE) is vital in scaled down models to understand how parameters need to be tested, how they are interconnected, and then be used to communicate the driving factors of the process.
Identify CQAs and CPPs
Analyze data to understand the correlation between CPP and CQAs
Use a scaled down models with known parameters
Early Development
In early development, process research and development groups focus on:
- Choosing a path for scale-up
- Considering process safety
- Availability of materials
- Models and simulations used at this stage
Scale-Up
In full development, the compound has passed milestones in clinical response and efficacy:
- Development continues focusing on a robust and efficient process
- Evaluate yield and cycle time
- Process tested on pilot plant this stage scale equipment
Final Development
In the final stage of development, the goal is to attain a comprehensive understanding of the chemistry, manufacturing, and controls (CMC). Defining process parameter ranges and key unit operations is essential to support process validation
Scaling Up an Active Pharmaceutical Ingredient (API)
The active pharmaceutical ingredient (API) is the component in a drug that is biologically active or has direct effect in the treatment, mitigation, diagnosis, prevention, or cure of disease. It can take multiple stages and processes to create an API. APIs can be generated via a chemical reaction or biological process and once expressed they are isolated through separation and purification unit operations. Understanding these unit operations on the small-scale is the first step in large-scale production.
Focal Points for Scale-Up
Safety
Process safety is one of the main chemical engineering concerns throughout process development. Examining reaction issues in relation to mixing, rate, and corrosivity and evaluating thermal and chemical stability and hazards is necessary.
Quality
For APIs, CQAs must meet specifications and these attributes may include overall purity, levels of impurities, form, color, metals, solvent content, and powder properties.
Optimization
Improving productivity metrics such as yield, reaction time, chemical transformations, material usage, and waste generation are also drivers when developing and optimizing processes.
Examples of Scale Changes
| Factor | Pilot Plant | Large Scale |
| Equipment Setup | Utilizes unique equipment with flexible setup | Utilizes standardized equipment; parallel operations |
| Operating Hours | 5 days (24 h/day) | 7 days (24 h/day) |
| Automation | Manual to fully automated | More likely automated |
| Analytical Support | Short turnaround time | Limited testing and longer turnaround times |
Scale-Up Factors for Reactions
These factors can vary significantly from the lab to scale equipment:
- Time to Charge Reagents
- Charge Method
- Charge Port
- Sequence of Addition
- Mixing Time
- Mass Transfer
- Heat Transfer
Example of Scale-Up at AbbVie
The North Chicago F3 pilot plant has many small reactors (55L to 750L) where experiments for scaled down models can be executed.
The North Chicago Fermentation site scales up processes in their fermenters which range from 30,000 to 100,000 L!
