1. Trends come and go in our industry, as is the case in every industry. What would you say is currently the single largest trend in active pharmaceutical ingredient (API) development and manufacturing?
DS:Targeted therapies in oncology API development and manufacturing continues to be a growing trend. The pipeline of antibody-drug conjugates is expansive, and the ability to handle the diverse manufacturing requirements will be a differentiator in the CDMO industry. The emergence of biosimilars into the biologics sector of the oncology market will also be a key development to watch, to track how the industry manages the competitive landscape unique to each region.
GE:The single largest trend is the move to increasingly complex API’s, Highly Potent API’s (HPAPI), cytotoxics, Anti-body Drug conjugated (ADC) warheads, and increasingly complex syntheses with multiple chiral centers. Given the regulatory emphasis, a larger portion of the industry pipeline is now dedicated to orphan and cancer indications with niche requirements. The synthetic challenges from this trend have placed further weight on the importance of analytical technology and in 2010, Alphora further invested in isolator technology for HPAPI’s and cytotoxics for R&D, Analytical and cGMP scale-up. The use of these capabilities continues to grow as does the pipeline for such API’s within the sector.
KH:We believe the single largest trend is a significant increase in placement of API development and manufacturing programs with North American-based suppliers. A few drivers for this increase would include: 1) More efficient and collaborative project management, particularly with respect to process chemistry, analytical and Quality Assurance. 2) Greater number of entities offering full service or one-stop shop range of services. 3) Intellectual property management.
2. Thinking back over the past 5 years, how has the landscape of API development and manufacturing changed since 2009?
GE: The industry had to withstand both the reorganization of the pharmaceutical industry due to the patent cliff, and deep cuts to financing for Biotech during the global recession. The net result was a winnowing of pipelines and development budgets. A resulting trend is the corresponding reduction in development scope at the preclinical to phase I stage. This trend has pushed development formerly done at Phase I into Phase II. Many phase I projects are now based on medicinal chemistry processes and require substantive development for phase II and beyond. In some cases, these situations are more akin to a “process rescue” wherein the development of a new process and analytics is essential for economic or regulatory reasons. Alphora has seen an increasing number of such projects, applying process chemistry and analytical tools to provide an improved process suitable for phase II and commercialization.
KH: We have seen an increase in APIs for highly targeted therapies as opposed to the "blockbuster" approach. This in turn has led to lower volume requirements and, in some cases, faster, more streamlined clinical development programs. This potential for faster times to regulatory approval has put pressure on API development and manufacturing entities to establish process robustness and reproducibility, while developing analytical methods earlier in development than historically has been the norm. To accomplish this, new tools must be applied, such as Design of Experiments (DoE), and greater access to state-of-the-art analytical capabilities must be obtained. These developments have triggered investments in parallel reactor systems for DoE studies and newer, specialized analytical equipment.
3. What were some of the major trends that have come and gone since then?
GE:The trend for sourcing development to Asia is definitely reversing. There are several factors driving this. First is the continued concern for IP, with a number of highly publicized events giving innovators pause. Second, quality remains a concern and greater attention is being paid by regulatory authorities. Third, the cost incentive is not as great as it once was, as inflation continues to drive up salaries and operating costs towards western levels. The desire to source locally is further benefitted by the strengthening financial footing in Biotech. As a result, Alphora is seeing more and more Biotechs with a stated preference to develop their compounds within western markets.
KH:The movement of virtually all API development and manufacturing to suppliers located outside of United States.
4. Who would you say is leading the way in API development and manufacturing? What country or region is setting the current standard with regard to API development and manufacturing that others are following and what sets that region apart?
KH:In general, we think the majority of APIs that will be outsourced for development and manufacturing are coming from North American biotechnology and specialty pharmaceutical companies. As a group, these companies historically outsource and do not build API manufacturing capabilities of their own. Further, as regulatory requirements have become more stringent, these companies have demanded more of their suppliers and prefer to work with partners in the same geographic region to maximize efficiencies that can be gained from a collaborative relationship structure.
5. Let’s shift to looking forward. What do you think we can expect to see in the next 5 years in API development and manufacturing?
GE:The trend of virtualization within Large Pharma and Biotech is expected to continue. As a result, we expect to see the CRO/ CMO industry continue to develop to provide an increasingly sophisticated suite of process chemistry and analytical services for API development. The second trend is the expectation of a continued increase in regulatory requirements. This includes the growing expectations for QbD elements, increased understanding of the fate and purge of impurities, pGTI’s, and the use of DOE approaches. As a result, the demands on analytical will only continue to grow in importance in developing new API’s.
KH: We expect to see an increasing number of targeted therapies from the biotechnology company and specialty pharma segment. We anticipate that API development and manufacturing requirements for most of these compounds will be outsourced. Additionally, we expect utilization of existing generic drugs with improved delivery systems and/or new indications (ie, “re-purposing”) to continue to grow, and production of these generic APIs will be outsourced.
6. What are some recently improved methods or other improvements you’ve noticed that have been implemented in API development and manufacturing?
DS:The ability to safely manufacture highly potent API’s has improved greatly. With guidance from firms such as SafeBridge, manufacturers have been increasingly implementing more rigorous engineering controls, containment systems, and industrial hygiene methodology.
GE:There are a number of technology advances within the industry that have positively impacted API development. In particular, the costs and ease of implementation have improved as the technology matures. Alphora has taken advantage of a number of these advancements, including additional walk up instrumentation within the R&D labs (HPLC, LC-MS); parallel processing technology to screen conditions for QbD and DOE purposes; and flow technology.
Of particular note, the addition of flow technology has been instrumental in dealing with difficult chemistry issues and allowing development to proceed more quickly. Shortly after introduction, several processes benefitted from the application. Further, a larger unit was acquired for cGMP operations, ensuring seamless process transfer. Finally, broader adoption has occurred within the industry and examples of large scale manufacturing with regulatory acceptance are noted.
KH:We have seen a consistent utilization of Quality by Design (QbD) for all API process validations, including Design of Experiments (DoE) methodology, to fully understand the process design space. For development of a commercial process today, Albemarle uses the QbD approach to ensure that quality requirements can be met during development, through regulatory approvals and into full commercial production. Also, we see the formation of the 'Integrity of Supply Chain' initiative (a multi-organization effort coordinated by Xavier Health to develop and harmonize Good Supply Practices within the pharmaceutical industry) as a positive step by API industry participants to improve API supply chain performance. Albemarle is an active participant in this initiative along with governmental representatives, customers and fellow API suppliers.