Scale-Up in Pharmaceutical Manufacturing: Challenges and Best Practices

Scale-up is an essential step that usually happens in the phase III of drug development. This complex process often requires several changes to the manufacturing process and even the equipment. At times, it is also necessary to re-optimize ratios, temperatures, pressures, and other parameters to get the same product quality. Here, we discuss several challenges in terms of scale-up in manufacturing and share some of the best practices along with the emerging technologies to enhance the process. Let’s keep reading to learn more!

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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Emerging technologies for improved 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.