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Flexible Manufacturing Environments are Vital for Today’s Potent Oral Dose Forms

Driven by advances in oncology treatments and personalised precision medicine, two trends are converging to increasingly challenge pharma’s developers and their external contract manufacturing suppliers: highly potent active pharmaceutical ingredients (HPAPIs) and small batch manufacturing.

Currently, approximately 25% of drugs on the market today contain HPAPIs.1 As of 2022, the global market for these drugs was worth $21 billion.2 Finished HPAPI drug products range from anti-cancer therapies containing small molecule cytotoxic compounds to potent large molecule biologic compounds, to antibody-drug conjugates (ADCs) and hormonal therapies.

Spending on cancer medicine, which includes small molecules, biologics, and emerging modalities, such as cell and gene therapies, rose to $164 billion globally in 2020 increased by an average of 14.3% over the past five years (2015 to 2020), according to IQVIA.3

Even though IQVIA projects that the overall oncology market will slow slightly, with a compound annual growth rate projected at 8.7%, Market Data Forecast analysts predict the market for HPAPIs will climb to more than $31 billion by 2027.2 With this demand on the horizon, drug sponsors will increasingly be challenged to source effective specialist HPAPI manufacturing capabilities, as well as expertise to formulate and finish them into patient-ready drug products.3

Development of Biologic Molecules for Oral Drug Delivery

Oral biologics are another emerging market segment of highly potent API drugs requiring highly specialised development and manufacturing capabilities. Oral biologics already on the market mostly target chronic disease treatments to eliminate the need or provide a substitute for repeated, frequent injections. Targeted indications in this segment include diabetes (e.g., similitude), irritable bowel syndrome (e.g., linaclotide) and diseases requiring immunosuppressants (e.g., cyclosporin A).

Even if at present, there is only a very limited number of drugs in the market, an estimated 4% of ongoing oral clinical trials are biologics, some of them potential blockbusters (e.g., oral insulin). There is still a way to go in these clinical trials and there is a risk that they will never come to market, as development trends and oral biologics begin to attract substantial investment. This said, should the efficacy of oral biologics in the medium term be proven in existing ongoing clinical trials these developers will have to secure the specialised capacity to manufacture these drug products safely and compliantly.

Tackling the Challenges of Small Batch Manufacturing Flexibly

Manufacturing large and small molecule HPAPIs compliantly demands manufacturing under high-containment conditions and processing operational controls. Specialised operator training with a level of containment based on occupational exposure limits is another prerequisite. While HPAPIs have the potential to treat many medical conditions and therefore represent a lucrative business opportunity, sponsors with promising formulations can face significant challenges in developing these innovative medicines and bringing them to market safely and cost-effectively.

From ensuring the environmental health and safety (EHS) of operators to demonstrating to regulators the presence of adequate controls to mitigate cross-contamination risk, pharma manufacturers will always be challenged to deliver compliant HPAPI capacity cost-effectively. Market trends for HPAPIs, notes IQVIA, suggest that CDMOs will be tasked with handling even more demand for HPAPI manufacturing services in the near future. However, emerging drug development trends are raising the bar on all manufacturers to deliver such high-demand capacity cost-efficiently because HPAPI batch volumes are trending lower, not higher.4

Trends in personalised medicine and patient-centred drug design have turned pharmaceutical manufacturing economics and business models on their heads. Drugs in the blockbuster era of development used to justify enormous capital investment into large-scale dedicated facilities. However, the rise in the number of orphan-drug approvals and an increase in the development of more targeted therapies with smaller patient populations is resulting in lower-volume drugs entering the market.4

The development of these and similar modalities will require strong adaptations by drug manufacturers, as it both affects economies of scale and containment controls at a given site. Small batch manufacturing implies exponential complexity at an operational level, to deal with multiple substances and products as well as the consequent need to shift production between batches. The emphasis on processing smaller batches more efficiently represents significant institutional change. In response, the industry’s contract manufacturers are investing heavily in engineering flexible small-volume HPAPI operations with flexible facilities configured to meet the high demand for low-volume batch manufacturing services.