Keeping Pace with Increasing Biopharmaceutical Manufacturing Demand
By Michelle Calhoun, AbbVie Contract Manufacturing
By all accounts, the current biologics development pipeline is healthy and R&D investment continues to drive growth in novel antibody development. Near-term forecasts indicate a growth rate so robust that it may continue to outpace contract manufacturing capacity. Contributing further is pressure to supply chains to address the increasing requirements for complex molecules such as antibody drug conjugates (ADCs) and bispecific antibodies. This article will explore both market drivers.
Recent trends reported by Future Market Insights (FMI) support the notion that:
- Over the past few years, biotech patent applications have increased an average of 23 percent annually.
- More than 1,500 biomolecules are currently undergoing clinical trials, and because the biomolecule success rate is twice that of small molecule therapies, that momentum continues to build.
- From 2003 to 2017, FDA-approved recombinant therapeutics development increased about 400 percent resulting in record approvals in this area year over year.
Biopharmaceutical contract manufacturing organizations (CMO) now play an ever-more-pivotal role in the commercial manufacturing capacity required to meet this demand. Overall contract manufacturing is poised to grow at 10.6 percent through 2027, according to FMI. Further, Zion Market Research indicates fill/finish manufacturing will grow from $2.99 billion in 2017 to $5.15 billion in 2024 representing an 8.8 percent CAGR.
Some CMOs have expanded facilities and coordinated resources or aligned with other partners to support the growth and complexities; however, suite reservation lead times continue to be long and unmet needs continue to exist. To prepare for the growing demand, AbbVie is adding sterile parenteral manufacturing in Sligo, Ireland. This will complement AbbVie’s existing linker-payload production capabilities in the area. The $139 million investment includes a new 38,000-square-foot state of the art sterile parenteral manufacturing footprint along with nearly twice as much square feet of supporting office and warehouse space at the new site. The IDA Ireland-supported expansion will create approximately 100 new jobs over the course of three years in a variety of technical and manufacturing positions. The new facility will begin to support both AbbVie and third-party contract client pipeline products, following commission and qualification in mid-2020.
The new fill/finish facility will be capable of aseptic filling at a rate of 225 vials per minute with 23 m2 of lyophilization capacity that supports both clinical and commercial manufacturing with vial finishing inspection inclusive of automated bad-crimp detection, manual and semi-automatic visual inspection, and 100 percent oxygen headspace analysis technology.
AbbVie also expanded its Bioresearch Center in Worcester, MA in 2017 to include conjugation services, to further expand capabilities to its already existing comprehensive biologic drug substance production at this site.
The Benefits of an Integrated Supply Chain in Contract Manufacturing
The implementation of the fill/finish line is strategic as it allows for integrating production of antibody drug substance and final fill/finish drug product representing a clear strategic advantage in reducing the need for site to site technical transfers. Benefits of this may include de-risking uncertainties commonly found with manufacturing suite availability and potential quality systems misalignment when operating at different CMO locations. AbbVie’s end to end offering therefore offers the ability to leverage one external manufacturer ensuring ease in material transfers in a controlled chain of custody approach – a key benefit when the value of the drug substances is a premium.
For ADCs, the existing conjugation and large molecule suites located in Worcester, MA contribute the flexibility of a global manufacturing network by aligning with Sligo’s existing the linker-payload capability. Clients therefore have the option to utilize AbbVie expertise for one portion, or a combination of production components to develop their biologic.
This enhanced CMO manufacturing footprint leads to many key advantages to AbbVie clients including:
- Cash Flow Benefits — Clients can place a single PO for the finished product, inclusive of drug substance and fill/finish, eliminating the need for multiple transactions with multiple partners. This reduces costs by consolidating third parties and streamlining the number of quality audit/systems reviews.
- Speed to market — An integrated supplier can offer flexible scheduling to minimize buffer times between the various unit operations and adjust as necessary due to program delays. In addition, since all steps of the process are under one quality system, the ability to forward process based on a subset of analytical testing can shorten product lead times.
- Risk reduction — Minimizing material transport the elimination of handling and testing by multiple parties, and stringent, analytics-backed quality standards contribute to a robust risk mitigation plan. CMO clients benefit from AbbVie’s integrated supply chain as it leverages the same quality processes, supplier qualification and equipment deployed ensuring that high standards are utilized for external products.
Analytics Drive Ongoing Improvement, Efficiency
Capacity and quality aren’t the only advantages of expansion. With the new technology deployed in modern facilities comes an advanced level of machine-to-machine connectivity that enables access to unprecedented volumes of data. Data happens to be an increasingly common and growing demand of pharma clients large and small. Yet, analytics shortcomings were pharmaceutical executives’ most often-cited concern in a recent open-ended survey conducted by Life Science Connect on third-party (CMO/CDMO) fill/finish challenges. A sampling of their responses to the question, “What are the biggest challenges you face with fill/finish?” include:
- Go beyond material focus (e.g., value analytical development as much as process development), with on-site expertise to investigate not only unexpected analytical results effectively, but also the built-in knowledge, skills, and credibility to drive process troubleshooting/development (i.e., keep the “D” in “CDMO”).
- They don’t have the full range of analytical testing capabilities they say they do and, therefore, cannot release product. Having capability to do 90 percent of tests is great, but it leaves one to have to qualify an alternate site to perform the remaining one or two tests.
- The coordination between analytical and manufacturing is typically less than optimal. While we press for manufacturing as quickly as possible, the analytical services cannot execute the transfer in time to meet the manufacturing timeline.
- At present most of our data exchange, specifically production data, happens manually. How can we integrate our IT systems so we’re able to do the same kind of real-time process monitoring and analytics we do for internal sites? What are the challenges of such an IT integration?
- Analytical method tech transfer and execution — the ability to handle laboratory investigation reports in a timely manner to minimize product and business risk exposure.
The challenge is clearly real, and solutions are available. Drawing on the analysis of an ever-increasing amount of data creates confidence and advantages from the outset of development and manufacturing engagements. CMOs have an opportunity to demonstrate value out of that data along each step and to incorporate what has been learned to continually improve processes, quality, reporting, and efficiency on behalf of their clients. The technologies and processes deployed in new and expanded manufacturing are being purposefully designed to facilitate capture of data. Analytical offerings for both ADC and fill/finish being employed at AbbVie include:
- development and investigative testing
- HPLC (SEC, IEX, affinity, reverse phase)
- host cell protein
- electrophoresis (CE, IEF, SDS-PAGE)
- peptide structure determination (LC, MS)
- oligosaccharide analysis
- NA qualification (threshold)
- DNA identification (PCR)
- spectrophotometry (FT-IR, UV VIS)
- HIC for DAR
In addition, downstream fill/finish operations must address any issues that might compromise product safety. Those might include cracks in the vials, improperly seated stoppers, and other container closure defects that could impact sterility or stability of the product. Approaches being taken for vial analytical capabilities include:
o head space analyzation for H2O and O2
o container closure development and validation
o sub-visible particulate identification
One hundred percent headspace analysis is an effective method to eliminate the risk of faulty vials reaching the patient population. By using a laser to interrogate the space above the product (which has been backfilled with nitrogen following lyophilization) any vials which do not meet predefined quality criteria can be discarded.
Meeting Throughput, Quality Objectives
As worldwide demand for biological therapies continues its path of significant growth, CMOs will continue to become an ever-increasing critical element of the biopharmaceutical supply infrastructure. It is therefore important that CMOs continue to invest in the development of the right facilities and technologies capable of the throughput necessary to meet changing demand and equip those facilities with the latest and best technology, processes, and quality control measures to ensure compliance and the safety of patients we serve.
AbbVie Operations Contract Manufacturing offers solutions to a broad range of contract services. If you are looking for a partner that has a critical eye on biologics manufacturing, we invite you to come speak with us. We can be contacted at 1-847-938-8524 or visit our website for more information on biologics drug substance, conjugation, linker-toxin and fill/finish capabilities at www.abbviecontractmfg.com.
Michelle Calhoun is Director of Business Development and Sales at AbbVie Contract Manufacturing