As the pharmaceutical industry shifts its focus from blockbusters to targeted therapies and advances rapidly expanding numbers of increasingly complex molecules into clinical trials, the demand for active pharmaceutical ingredient (API) manufacturing capabilities at the kilogram scale is increasing. CDMOs with broad chemistry capabilities, extensive experience, a track record of performance and the flexibility to offer both non-GMP and GMP services at the large-laboratory/small-volume production scale are ideally positioned to meet the needs of the marketplace.
Flexible GMP Small-Volume API Manufacturing
Innovation in the pharmaceutical industry has never been greater. The numbers of novel therapies entering all stages of clinical trials are increasing at a dramatic rate. On ClinicalTrials.gov, the number of studies listed based on the first submitted date has increased from 5,627 on January 1, 2001, to 263,689 on January 1, 2018. In just over one month, the latter number rose to 265,793 (February 11, 2018).1
Many of these candidates — approximately two-thirds — are based on small-molecule active pharmaceutical ingredients (APIs).2 In 2017, 33 of 46 novel drugs approved by the FDA’s Center for Drug Evaluation and Research (CDER) were formulated using small-molecule APIs.3 Efficient and economic synthetic routes must be developed for the production of APIs that will ultimately be formulated into clinical trial materials. Contract development and manufacturing organizations (CDMOs) that have extensive experience and capabilities in both API process development and optimization, and GMP manufacturing at the kilogram-scale can accelerate development timelines and help their customers more rapidly get into the clinic.
Integrated Offering: Avara Pharmaceutical Services
At Avara, our API services are provided by sites in Avlon, UK and Shannon, Ireland. Both sites have a proven track record and vast experience in developing optimized routes to complex molecules, including hazardous processes. We have strong technology transfer records and cGMP manufacturing environments supported by the latest processing and finishing technologies and excellent FDA and MHRA inspection records.
Shannon adds value with different milling and blending technologies, while Avlon is a top-tier Control of Major Accident Hazards (COMAH) site. For kilogram-scale manufacturing, the capabilities of the two sites are complementary and support pre-clinical through Phase III projects. Together these two sites leverage their capacities and experience to serve as key components of our strategic global manufacturing model.
Flexible Small-Scale Manufacturing Capabilities
The Shannon multipurpose, flexible GMP-approved kilo plant has two reactors (65 and 70 L glass-lined and stainless-steel) and advanced isolation/purification equipment (Hastelloy centrifuge and inline Cunoi filter). A Jet Pharma MC-150 is available for pilot-scale milling. The kilo plant is supported by fully equipped cGMP analytical laboratories, a material staging area and waste-management capabilities. Hydrogenations can be performed in the facility, as can reactions at -30°C to 160°C.
Avlon is in the process of reopening an existing GMP small-scale manufacturing facility suitable for the production of APIs and intermediates on the kilogram-scale. The systems and equipment are being modernized to facilitate many types of complex chemistries and include six reactors (20-100 L) and various equipment for the isolation (vacuum Nutsche filters, Buchi rotary evaporator, vacuum/pressure filter, centrifuge) and drying (oven tray dryers) of solid compounds under GMP conditions.
To increase capabilities, the GMP small-scale manufacturing facility was designed as a flexible asset with the ability to accommodate additional specialized equipment as needed by individual processes. The reactors are designed to handle flammable solvents and have varying temperature capabilities ranging from -80°C to 200°C. Automation software provides temperature and agitation control, process monitoring and data recording.
Experience with GMP Manufacturing
The Avara Process Development Groups have a proven track record of developing API processes from Phase I/II to Phase III/commercial scale, as well as in process scale-up and optimization, process validation and technical transfer, and analytical method development/validation. Experts at both Shannon and Avlon have developed processes and analytical methods for new chemical entities from lab to commercial scale and demonstrated their technology transfer capabilities. In one example, significant cost savings were achieved introducing novel hydrogenation enantiomeric resolution and salt exchange steps; and re-engineering the crystallization process using Optimax modeling software and FBRM particle size analysis technology. In another example, process step improvements were made, and overall yield was increased through numerous enhancements, including modification of the crystallization process, which allowed for elimination of a micronization step. Commercial processes were also developed involving a patented alternative o-methylation process that replaced a process requiring a phase-transfer catalyst and pyrophoric BuLi, which also suffered from high levels of impurities.
Avlon also implemented a program of improvements that drove down manufacturing costs by 38% and improved the yield from 70% to 95% through reduction of the use of expensive starting materials. Manufacturing productivity increased plant output 6-fold with the same assets and staffing through application of Lean Principles.
Operational efficiency projects, chemistry improvements and process safety improvements were achieved over several years. Processes have been simplified, variability significantly reduced, and many manual interventions removed. For instance, process concentrations were increased through the application of Factorial Experimental Design. In addition, many process steps were optimized in the plant through lab development work, including the improvement of temperature ranges, optimization of reaction times and drying and wash cycles, and enhancement of automated controls for reduction of wait times in the plant.
All Avara sites are committed to delivering reliably, to the highest-quality standards, while using our skills and experience to reduce costs and manage supply chain issues.
On-Time, In-Full Delivery
All Avara sites are committed to delivering reliably, to the highest-quality standards, while using our skills and experience to reduce costs and manage supply chain issues. Shannon and Avlon exemplify this approach as both sites have established impressive records. In 2017, each site had an OTIF KPI greater than 99%.
As a testament to this, Avara has won a 2018 CMO Leadership Award from Life Science Leader magazine, receiving recognition for our performance in all six Core Award Categories: Capabilities, Compatibility, Expertise, Quality, Reliability and Service. This award reflects the success we have achieved by making a total commitment to our customers and delivering on our promises for scope, schedule, quality/regulatory compliance and price.
Special Thanks to Gary Butler, Vice President & Avlon Site Director and Werner Kunz, Vice President & Shannon Site Director for their contribution to this article.
Vice President & Avlon Site Director
Gary Butler is presently VP and Site Director at the Avlon Avara API Site in Bristol, UK. Gary holds a Bachelor of Science Degree in Mechanical Engineering, is a Chartered Engineer and is a Fellow of the Institute of Mechanical Engineers. Gary spent the first part of his career with ICI on major UK chemical manufacturing sites. Gary joined AstraZeneca and has led Engineering in API and Sterile manufacturing, and led Asset Management across multiple sites in the UK and Sweden. Gary became Avlon Site Director at Avlon in mid 2012, led the divestment to Avara in 2016, and is now leading the new Avara Avlon CDMO business.
Vice President & Shannon Site Director
Mr. W. Kunz is the VP and Site Director of Avara Shannon Pharmaceutical Services Ltd, a centre of excellence for manufacturing API with a modern manufacturing facility in Ireland. The facility covers the entire range from process development, scale up, clinical trial and commercial manufacturing services. Werner has over 30 years of experience in the Pharmaceutical Industry covering API, Finished Dose and Packaging operations and has worked in Europe and Far East. Mr. Kunz is a qualified Chemical Engineer from NTA Isny/Allg. in Germany.
- Number of Registered Studies Over Time, ClinicalTrials.gov.
12 Feb. 2018. Web.
- Jim Miller. “Small-Molecule API CMOs are Thriving.”
BioPharm International. 1 Oct. 2015. Web.
- Novel Drugs 2017 Summary. Rep. U.S. Food and Drug Administration. Jan 2018. Web.