Paving the Way for Modernized Drug-Product Manufacturing Through Excipients

Patient safety is a top priority at each stage of the manufacturing process and requires an increased attention to detail. There are a number of hurdles to clear when implementing any new initiatives or process changes. Historically, these challenges mean the pharmaceutical industry is slower to innovate and hesitant to adopt new strategies that could improve manufacturing productivity.

Continuous manufacturing has garnered global attention in its ability to alleviate costs, while simultaneously increasing productivity and quality. Thus far, the full potential it offers remains relatively untapped as only two continuous-processed drug products have been submitted and approved. Despite slow adoption, the benefits of continuous manufacturing are clear to manufacturers, and the industry seems optimistic based on drug-product development using continuous manufacturing. As the concept matures and both innovative and generic-drug companies express interest, the question to implement continuous processes will continue to transition from a question of “why” to “how.”

Understanding the “why”

Lower pharmaceutical manufacturing costs mean drug products will be more globally accessible and available to patients who need them. Direct-compression tableting is a form of continuous manufacturing that can eliminate expensive and energy-intensive granulation steps to offer a cost-effective solution. In addition, using less process steps removes potential sources of variability in the final drug product. 

As demonstrated in Table I, switching to continuous processes that enable direct-compression tableting can help reduce total operating costs by up to 60% and cut time by more than 50% to streamline manufacturing and gain efficiencies (1). Shortened development time and lowered manufacturing costs offer both short- and long-term benefits for drug-product manufacturers as the freed-up resources and time will allow them to focus on other life-saving innovations. 

The push for a more sustainable planet has also gained continuous manufacturing popularity as companies become increasingly conscious to have a smaller environmental footprint.  For the drug-product manufacturer, continuous manufacturing offers the additional benefits of implementing process analytical technology, consequently improving process control and enabling real-time release. It offers the additional benefit of smaller, more flexible manufacturing footprints that are more easily transferrable across manufacturing sites.

Continuous manufacturing can significantly save time and energy associated with wet granulation and thus reduce the environmental impact of drug-product manufacturing. Table II reflects the amount of energy and water used in wet-granulation operations. For high-volume drug products (roughly 400 million tablets per year), nearly 50 metric tons of water and 31 megawatt hours of energy per year could be saved through direct compression. 

Companies that move away from batch-by-batch processing to create more reliable and affordable drug products at a faster rate are at a significant competitive advantage. The need for drug products to be more readily available to patients will only continue to rise.  One facet of this demand increase is driven by the rise in aging population.  Predictions indicate that in 2050, the number of people aged 80 years or over will reach 434 million globally, having more than tripled in number since 2015 (2). As people are living longer, it will be vital for drug products to be more accessible to ensure quality of life in the aging population. 

Understanding the “how”

Companies want to find a way to incorporate new processes without hindering productivity and disrupting processes that have been in place for decades. For many manufacturers, the answer to this challenge is to incorporate excipients in formulations for improved flowability and processability. 

Dow Pharma Solutions has responded to the industry-wide trend in switching from batch production to continuous processing with Methocel DC2 hydroxypropyl methylcellulose (HPMC). The technology is engineered to improve dry-powder flow for streamlined matrix-tablet manufacture and improved drug content uniformity.  This also helps shorten development time and reduce manufacturing costs by up to 60%.

When choosing excipients, drug-product manufacturers should consider additional attributes of excipients such as particle size, particle morphology, density in relation to impact on powder flowability, compactibility, and the critical quality attributes of excipients impacting performance of the final drug product.  To successfully do this, drug manufacturers must partner with suppliers who have rigorously tested their excipients against industry standards and have available data. Drug-product manufacturers who partner with trusted suppliers will have the support needed to ensure they are choosing the strongest fit for their formulation. 

By choosing the right technologies and suppliers that have the expertise and experience needed, drug product manufacturers are equipped with the tools necessary to tackle the “how.” 

Uptick of excipients in drug formulations 

There has been an increased focus on excipients as drug makers continue to explore new ways to take pharmaceutical manufacturing to the next level. Formulations will require new excipients to support evolving continuous-manufacturing processes, and thus it is imperative for drug-product manufacturers to have better understanding of excipient properties and variability. 

The dependence on excipients has prompted drug manufacturers to work with their suppliers more closely than ever before to ensure their current supply of excipients is consistent and quality is being upheld to control variability. Drug-product manufacturers must partner with trusted suppliers to ensure current excipients are still applicable when transitioning to continuous processing as well as for customization or creation of new excipients to better fit their evolving formulation and manufacturing needs.  

The new concept “designed for purpose” has gained popularity amongst drug-product manufacturers and reflects the need for individualized solutions to optimize each manufacturer’s processes. Currently, drug makers are hesitant to use novel excipients. Therefore, industry leaders and regulatory bodies are working together to explore regulatory pathways that would enable the use of novel excipients and ensure new and modified excipients can more readily move through approvals.  Knowledgeable suppliers can assist in overcoming this hurdle by developing novel excipients within existing pharmacopeia standards as well as innovating completely new-to-the-world functional polymers.

These factors have the potential to impact current regulatory standards and pave the way for a new approval process for novel excipients. 

Roadblocks in continuous manufacturing 

The pharmaceutical industry transition to continuous manufacturing will be challenging and time-consuming, but the long-term benefits will outweigh the time and money invested.  

The first hurdle drug-product manufacturers must clear is the initial startup cost. This cost can include old batch equipment retirement, new technology purchases, new processes implementations that adhere to quality-by-design principles, and staff retraining. To justify the large expenditure, drug-product manufacturers must focus on the long-term benefits of this investment and how continuous manufacturing will eventually be imperative to maintain a competitive edge.

Lengthy approval times and inconsistent regulatory requirements across borders create the need for increased collaboration between manufacturer and supplier. The drive for harmonized regulatory standards across country lines and the updating of current approval processes will allow drug-product manufacturers to enjoy a more connected industry landscape. These efforts will revamp industry infrastructure and alleviate some of the challenges associated with adopting continuous technologies.   

Lasting legacies of continuous manufacturing 

The implementation of continuous manufacturing will bring about many changes that will likely have lasting positive effects on the pharmaceutical industry. Recognizing change at this scale can be time-consuming but manufacturers recognize the positive impact it could have on their business. Many collaborations will be formed between drug-product manufacturers and suppliers to help navigate the complexity of continuous manufacturing. 

Regulatory agencies are actively engaged in the modernization of drug manufacturing to better facilitate implementation of new technology. The collaboration between industry leaders and regulatory agencies will play a vital role in pharmaceutical advancement. 

The nature of continuous manufacturing is an example of the opportunity to thrive with the combination of business- and science-driven approaches. Manufacturers will become increasingly business savvy to maintain a competitive edge.  Continuous manufacturing will help satisfy both sides of the spectrum by improving the overall product for formulation ease, patient safety, manufacturing flexibility, while also reducing costs and mitigating risks. 

References

1. Dow Pharma & Food Solutions, “Methocel DC2 Premium Excipients”, pg. 4, accessed May 12, 2018.
2. United Nations, Department of Economic and Social Affairs, Population Division (2015), “World Population Ageing 2015,” pg. viii, accessed May 12, 2018.

Article Details

Pharmaceutical Technology
Supplement: APIs, Excipients, & Manufacturing2018
September 2018
Pages: s14, s16, s30

Citation

When referring to this article, please cite it as A. Faham, K. Hewlett, and T. Rogers, "Paving the Way for Modernized Drug-Product Manufacturing Through Excipients," Pharmaceutical Technology APIs, Excipients, & Manufacturing 2018 (September 2018).

About the Authors

Amina Faham is global associate director, Pharma Application Development & Innovation; Kathryn Hewlett is an Application Development & Innovation scientist; and True Rogers is R&D Technologies leader-all at The Dow Chemical Company.