Scale-Up in Pharmaceutical Manufacturing: Challenges and Best Practices

Last week, I read an article that Glenmark Pharma and Cipla were planning to scale-up their manufacturing units in the United States. As a regular reader of pharma news, I of course, know what this means from an economic perspective. But what does this mean from an operational perspective? What exactly does a company do when they’re “scaling-up” their manufacturing?

The question quite intrigued me, and I went down a rabbit hole to find out what scale-up in pharma manufacturing actually entails. So, here’s a brief summary of what I’ve found. In this article, you’ll learn how pharma companies scale-up their manufacturing, what challenges they face, and which technologies are simplifying scale-up! So, let’s begin!

Stages of scale-up in pharma manufacturing

Scale-up generally refers to the entire transition from the laboratory to commercial production. Hence, here are the key stages of scale-up pharma manufacturing:

From laboratory scale to pilot scale

At the laboratory scale, the initial formulation is developed; hence, the manufacturing process is at a very small scale, typically involving milligrams or kilograms. By contrast, at the pilot scale, 10-100 kg of the formulation is manufactured. Hence, the first scale-up involves transitioning the manufacturing process from the lab to a pilot plant. This involves refining the critical parameters and product attributes.

From pilot scale to production scale 

At the pilot scale, 10-100 kgs of the formulation are manufactured per day. By contrast, at the production scale, 1000s of kgs or more of the formulation is manufactured per day. Hence, this scale-up stage involves integrating larger equipment and accordingly adjusting process parameters. Furthermore, operators are trained to work on these upgraded equipment, and standard operating procedures are established.

From production scale to commercial production

At the commercial stage, the company may need to manufacture more quantities of the product. Hence, this involves either shifting from batch manufacturing to continuous manufacturing OR designing and setting up new manufacturing facilities to meet the demand. Accordingly, the standard operating procedures, process parameters, and product attributes are adjusted and the involved personnel are trained or re-trained on operating procedures.

While it sounds like a relatively straightforward process, in reality, companies often face many challenges. Here are a few key challenges that make scale-up difficult.

Challenges of scale-up in pharmaceutical manufacturing

Ensuring regulatory compliance

During the research phase, formulations are often manufactured in small test quantities, and it is easy to follow regulatory guidelines and current good manufacturing practices (cGMPs) for small batch sizes. However, during scale-up, cGMPs and regulatory guidelines may be breached as the company focuses on ensuring the production is according to requirements rather than compliance. For example, stringent product purity and quality guidelines may be breached by failing to implement appropriate quality controls. This regulatory non-compliance during scale-up in pharmaceutical manufacturing can have consequences later on.

Inadequate funding

Setting up new facilities includes the procurement of numerous equipment. In India, setting up a Schedule M-compliant formulation manufacturing facility costs approximately Rs. 91.8 million. Setting up a compliant pharmaceutical manufacturing facility costs approximately USD 2 million in the USA. In addition to these setting-up costs, companies must pay fees to get their facilities and processes approved by regulatory bodies. These high costs are often a massive hurdle for scale-up in pharmaceutical manufacturing. Companies have to procure funds from external investors or banks or reserve funds from their profit to set up such facilities, both of which are time-consuming.

Maintaining quality

During the research stage, it is relatively easy to maintain the product quality because only small batches are manufactured. However, maintaining this quality is a huge challenge of scale-up in pharmaceutical manufacturing because the batch size is significantly larger. The process, raw material ratios, raw material quality, temperatures, pressures, humidity, and several other reaction parameters must be re-optimised according to the batch size. The equipment may also create challenges of scale-up in pharmaceutical manufacturing because it may not support the required conditions or may support it but not afford the desired product quality.

However, because the global pharmaceutical industry amounts to USD 1.48 trillion, several best practices for scale-up in pharmaceutical manufacturing have already been established.

Best practices for scale-up in pharmaceutical manufacturing

Work with experienced partners.

Pharmaceutical companies can hire experts or consultants to guide them during the scale-up process. Successful scale-up projects depend on various factors, which can only sometimes be understood from textbook knowledge. Therefore, hiring experts and consultants will help identify potential roadblocks beforehand and develop solutions. To this end, companies can employ contract development and manufacturing organisations (CDMOs) that specialise in scale-up in pharmaceutical manufacturing.

Determine regulatory compliance at every step.

Regulatory compliance should be determined beforehand by analyzing the process to find potential risks. If the facility is first set up and then the compliance is checked, there is a chance of errors. These errors may result in fines, legal issues, regulatory warnings, or even demolition – all of which lead to financial loss. Therefore, regulatory requirements and compliance should be checked at every step.

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Design the facility for scalability.

When scaling up from laboratory-level research to manufacturing, it is also necessary to consider future growth. The designed facility should accommodate the company's growth for several years, if not decades. If the facility can only support the initial demand, it may become necessary to build a second facility. Setting up a second facility will be as time-consuming and expensive as the first.

Be prepared for changes.

Scale-up in pharmaceutical manufacturing comes with many hurdles, especially regulatory ones. Companies must get process approvals from regulatory bodies, who may request changes or reject projects if they are non-compliant with rules. Therefore, companies should be ready to make changes in decided plans. These changes will likely affect the project budget and timeline, but the alternative is going against guidelines, which will be just as expensive.

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Naturally, scale-up involves some level of risk, depending on the batch size. However, it’s critical to efficiently manage this risk.

Risk management during scale-up

Here are a few tips that will help you effectively manage risk during scale-up:

1. Understand and use the right principles: Use the principles of ICH Q9: Quality Risk Management to identify, assess, and control risks during scale-up. Identify critical quality attributes and process parameters. Use quality by design principles to design a space where these attributes and parameters can be varied without compromising quality.
2. Test before trying: Conduct pilot-scale risk assessments to test the scalability of the process before implementing full-scale processes. Doing so will allow you to validate the equipment performance before full-fledged operations. Furthermore, this can help mitigate risks that may arise due to potential process failures.
3. Use technology: It goes without saying, but technology can be used to simplify scale-up. For example, process analytical technology can facilitate real-time monitoring, which will help you identify deviations early on and resolve them without compromising the operations. Many new and upcoming technologies can facilitate the scale-up process. (Don’t worry, we’ve provided a complete list later in the article!)
4. Plan. Plan. Plan: Scale-up isn’t as simple as getting up one day and purchasing new shoes. It requires extensive planning at all stages of the operation. All possibilities need to be comprehensively exhausted. The best way to mitigate or avoid risk is to ensure you’ve planned for every possible bad scenario.
5. Use a Twin: Digital twins are an excellent untapped opportunity that can help you identify the risks of set up. Want to understand how? We’ve written a comprehensive article on the use of digital twins for pharma!

New technologies facilitating scale-up

Machine learning (ML)

ML is one of the prime technologies expected to shape scale-up in pharmaceutical manufacturing. ML models can be trained using historical data from factory setups, internally and from competitors. Then, the model can be used to design factories and predict the associated costs.

Generative artificial intelligence (AI)

Generative AI, like ChatGPT, can decode complex regulatory requirements. The regulatory guidelines, documents, warnings, notifications, and other documents can be input into the AI model, which can then provide directions for setting up facilities. The model can provide detailed equipment information, raw material requirements, facility specifications, etc. This will increase the chances of successful scale-up projects.

Deep learning algorithms

Deep learning algorithms can be used to simulate the factory and identify risks associated with the operations. For example, safety failures and hazards can be simulated, and safety measures can be implemented accordingly. Doing this before setup will allow the company to mitigate operational risks, resulting in successful scale-up projects.

Conclusion

Scale-up in pharmaceutical manufacturing requires a lot of planning and financial investment. Companies often face several challenges, such as regulatory non-compliance, inadequate funding, loss in product quality, etc. However, hiring experienced partners or consultants is an excellent way to get ahead of the various challenges faced during scale-up. These partners are experienced in regulatory requirements and can recommend solutions before problems arise. Despite the involvement of experienced partners, pharma leaders should never forget that scale-up is a lengthy process subject to regulatory guidelines. Therefore, even the best-made plans may need to be changed. Hence, flexibility is the key to successful scale-up projects.

FAQs

1. Why is scale-up in pharmaceutical manufacturing necessary?

Scale-up bridges the gap between laboratory-scale research and commercial manufacturing. The scale-up allows companies to manufacture their product in large quantities and then sell it.

2. Which costs are associated with scale-up in pharmaceutical manufacturing?

Costs generally include land lease/purchase costs, equipment purchase/leasing costs, raw material procurement costs, facility setup costs (e.g., setting up clean rooms and HVAC systems), hiring/training costs, regulatory documentation and approval costs, legal fees, and other small costs.

3. What are some examples of successful scale-up projects?

Most medications and pharmaceutical products available in the market are examples of successful scale-up projects. These projects started as laboratory research, and only after appropriate clinical trials were successful and regulatory approval were they scaled up for manufacturing.