Process Development in the Pharmaceutical Industry: Engineer’s Guide to Scale-Up

Key Takeaways

• Process development is a technical workflow that designs the detailed manufacturing scheme required to take a lab-tested product into commercial production. 
• During process development in the pharmaceutical industry, challenges often arise based on the fundamental differences between lab and full production operations. 
• By using a well-defined engineering strategy, process development can overcome these challenges and drive successful scale-up across quality, regulatory compliance and financial fronts. 

When a pharmaceutical company aims to launch a new drug or medical device, they have two separate development workflows to follow: an FDA-approval workflow and an industrial process development workflow. Of the two, process development in pharmaceutical industry is often the more complex workflow as it must simultaneously satisfy technical, operational, regulatory and commercial objectives.

Pharmaceutical process development is the industrial process engineering activity that designs and specifies how a pharma product will be manufactured. As a product completes laboratory trials and is deemed viable for scaling, it then goes through process development to specify how it will be manufactured. In this way, pharma process development is typically the first step in full-scale commercialization. 

During process development, engineers cover multiple steps. They: 

• Evaluate production methods.
• Establish operating parameters.
• Select appropriate equipment. 
• Determine how key product attributes will be protected throughout the manufacturing process. 

This is where scaling challenges often arise, as naturally, lab conditions do not map onto production conditions identically. Many products don’t make it past this step, but those that do are only successful because engineers found reliable ways to overcome these concerns. 

Common Scale-Up Challenges Found in Pharma Manufacturing  

There are more than a few potential issues that engineers must solve for in developing their product’s production means and methods, including:   

• Reaction kinetics variations: Reaction rates and yields often change when process volumes, mixing dynamics and transfer rates increase.
• Process consistency and repeatability: Process conditions that are easily controlled in development can become more difficult to maintain at scale.
• Product quality changes: Product attributes such as purity, particle size, density or potency can shift during scale-up.
• Thermal and mass transfer effects: Heating, cooling, drying and material handling often perform differently in larger equipment.
• Equipment design differences: Industrial equipment rarely matches lab development systems exactly, creating unforeseen process behavior.
• Raw material variations: Ingredient specifications and quality can vary (sometimes greatly) when purchased in bulk versus lab quantities. 
• cGMP and regulatory compliance: Industrial processes must satisfy validation, documentation and regulatory requirements not yet defined during lab testing. 
• Quality control and analytics: Testing methods must remain accurate, practical and statistically representative at industrial scales. 

An Engineering Strategy for Pharma Process Development

From a purely technical standpoint, process development in the pharmaceutical industry is mainly about maximizing batch volumes, repeatability and efficacy at appropriate cost and complexity levels. In other words, this is an engineering equation in need of a solution. We’ve crafted an engineering strategy to work towards such solutions. The strategy includes:

• Process characterization: Start by specifying all product transformations and unit operations including raw, mid-process and final states.   
• Critical process parameter identification: Next, specify critical parameters for all materials, utilities, operator actions and environmental conditions.
• Equipment selection: Specify manufacturing equipment and components to satisfy all requirements at scale, including governing regulatory requirements. 
• Experimental scaling: Iif not performed prior, experimentally determine all optimal operating ranges and interactions approaching mass scale. 
• Raw material qualification: Perform physical testing of raw materials to confirm that bulk material sources fall within expected parameters. 
• Formulation: Assemble the above decisions into a master formulation or “recipe,” which proceduralizes and standardizes all process steps.    
• Pilot-scale testing: Optionally, perform pilot-scale testing of the above formulation on similar equipment to prove out full batch performance. 
• Quality alignment: Add quality assurance requirements over the above formulation and testing, ensuring cGMP, BPE, HAACP, etc, alignment.   
• Risk assessment/HazOp: Perform appropriate safety and risk assessments (HazOp, HazComm, etc) to identify any remaining scale-up deficiencies. 
• Process simulation/mock validation: Perform computational process simulations and validations to assess manufacturing performance.
• Documentation preparation: Prepare all drawings, SOPs, protocols, operational parameters, quality metrics and other documentation ahead of manufacturing. 

Matching Process Development to Commercial Objectives

As we touched on earlier, process development in the pharmaceutical industry is half technical, half commercial in nature. Broadly speaking, pharma products are extremely costly and resource-intensive to scale up. Sadly, not every otherwise viable product will make it to market due to barriers in developing a financially sound process.  

Aside from financials, there are other commercial objectives that process development must consider, too: workforce availability, yields and throughput, time, and so on. 

We like to say that as far as process development is concerned, commercial and technical objectives are equally important. If you’re interested in learning more about how we meld all these goals together in our own pharma engineering efforts, contact us here.