May 24, 2019 PAP-Q2-2019-CL-034
Many small molecule APIs in the pharmaceutical pipeline today have increased potency. These compounds can affect workers and the environment at very low concentration levels and therefore require special equipment and handling capabilities to ensure proper containment and prevent their release into the air.
UPM Pharmaceuticals has capabilities for processing potent compounds from development to commercial quantities. Manufacturing takes place in glove boxes with table-top equipment at bench scale and moves up to compound-dedicated suites with appropriate air flow controls and outfitted with the necessary full-scale containment equipment.
Hormones are another class of compounds that can affect operators at low exposure levels, whether via inhalation, ingestion, or absorption through the skin. Strict requirements therefore exist regarding manufacturing and handling procedures (for raw materials, intermediates, and finished products, as well as quality control testing) and the use of environmental controls.
UPM has three compound-dedicated suites for solid dosage manufacture of hormone products. The main principles for dealing with hormones include isolation, containment, and employee protection. The manufacturing equipment is analogous to what would be used for standard solid dose granulating, milling, blending, compression and coating processes, but with containment provided by split butterfly valves and sealed transfer connectors. The equipment is dedicated to each suite, and each suite is isolated from the rest of the manufacturing facility by airlocks or is accessible only through external doors.
Currently, UPM manufactures hormone products for both development stages and commercial production, with suites dedicated to the manufacture of liothyronine, levothyroxine and estrogen products.
Requirements for the manufacture of controlled substances impact all aspects of drug development, manufacturing and distribution. Avoiding diversion through the use of appropriate controls and record-keeping is crucial. An in-depth understanding of the regulations, long-standing positive relationships with regulators, and a track record of successfully working with controlled substances can accelerate product development and commercialization.
UPM has a long history of manufacturing and distributing many different types of controlled substances and takes a proactive approach to managing these products. We are vested in providing more than just capacity for the production of controlled substances. We work closely with our customers to make sure they understand all aspects and implications of the Controlled Substances Act (CSA).
UPM’s in-house training program ensures that operators and other employees who handle controlled substances understand the importance of following company procedures to ensure compliance with the CSA and avoidance of any diversion of controlled substances. Our analytical laboratory is approved to handle Schedule I-V controlled substances and listed chemicals, and conducts formulation development and stability/degradation testing. Our R&D group also investigates abuse-deterrence solutions for controlled substances that both the Drug Enforcement Agency and the U.S. Food & Drug Administration have promoted.
The ability to support controlled substance projects in-house from the proof-of-concept stage through to commercialization/product launch, including formulation development, process and method development, validation and warehousing, does away with the requirement for complicated technology transfer of these challenging projects off-site to other vendors. Clients save both time and money while getting their products into the hands of patients more quickly.
Peptides are attractive as APIs because they are naturally ubiquitous in the body, play specific functional roles, are well-tolerated and exhibit reduced systemic toxicity. In addition, they often have greater potency and specificity with reduced side effects and greater efficacy compared with small molecule drug substances. It should be no surprise that there are over 100 peptide drugs on the market and many more in development.
The challenge with peptides, like other biologics, is that drug formulations typically must be administered via injection to achieve high bioavailability. Researchers are developing approaches to the formulation of oral peptide drugs using specialized excipients, such as enzyme inhibitors and permeation enhancers, mucoadhesive polymeric systems and carrier systems (such as emulsions, nanoparticles, microspheres, and liposomes), among other technologies.
Because the formulation development of oral peptide drugs is so challenging, many pharmaceutical companies rely on CDMOs with specialized expertise in this field. With our extensive experience in formulation development for oral drug delivery, including knowledge of specialized excipients, UPM is ideally suited to tackle the challenge presented by peptides. We also have the latest chromatography column technology available for peptide analysis and have developed proprietary methods to ensure that the techniques are appropriate, robust, and readily transferrable to commercial quality control.
In addition, UPM has low-humidity suites designed to provide the type of controlled environment required during the manufacture of water- and moisture-sensitive peptide products. We also have low-humidity solutions in our packaging area and use heavy (thick-wall) bottles, desiccants, oxygen absorber and nitrogen purging to stabilize final products during storage.
UPM has been involved in the formulation development of two of the few FDA-approved oral peptide products. We invested in large-scale manufacturing capacity specifically for the commercial production of one of these peptides. Three additional oral peptide drugs are at the IND stage at UPM.
UPM uses the Xcelodose® precision powder micro-dosing system from Capsugel to obtain accurate and reproducible dosing down to as little as 100 micrograms of powder and can be used for dosing APIs alone, APIs blended with bulking agents and APIs in formulations.
The Xcelodose® system is particularly useful for preparing capsules containing just microgram quantities of API for use in stability studies. It also requires minimal formulation development. Simplifying these activities and minimizing the amount of API required reduces both cost and the time it takes to get into the clinic.
It is therefore an appealing option for many start-up companies concerned about consumption of their expensive APIs during early phase testing, while allowing them to get their product into human subjects as quickly as possible.
In the United States, serialization requirements were established in the Drug Quality and Security Act (DQSA), which became law in November 2013. The law applies to manufacturers, repackagers, wholesale distributors, dispensers and third-party logistics providers.
Implementing an effective serialization solution is challenging. In addition to its cost, serialization impacts many different company operations and thus requires input from representatives of all affected groups. Labels must be redesigned, and large quantities of new data must be properly managed and shared with appropriate partners throughout the supply chain. Contract manufacturers have the added challenge of needing to serialize different drug substances and/or drug products for many different clients, each with its own understanding of serialization and related set of expectations.
When developing our serialization solution at UPM, we recognized the need to maintain a high level of security while implementing a flexible track-and-trace solution that allows for tailored customer service, combined with robust and reliable performance. We adopted an offline serialization strategy, with the equipment existing as its own workstation, to have the greatest flexibility in supporting our three packaging lines. Labels are preprinted in advance, electronically verified, and then applied to bottles or cartons. This approach allows us to troubleshoot problems without tying up a packaging line. As a result, we are able to maintain production efficiencies and maximize capacities. Importantly, we are capable of working with whichever serialization codes are used by our clients.
Currently UPM is preparing for the next level of serialization — aggregation — in which labeling, including printing, application and verification, will be required online.
UPM operates from our Bristol, Tennessee plant, previously owned by Pfizer. Here, we are well-positioned with a Solids Formulation R&D Facility, modern manufacturing suites, and a state-of-the-art, full-service analytical laboratory to support the production of solid and semi-solid products at batch sizes from 100 g to 1000 kg. Two high-speed packaging lines with serialization capabilities enable basic packaging for solid dose products. UPM also has a separate 250,000-ft2 warehouse and provides warehousing and distribution services.
We have had numerous projects advance from the proof-of-concept stage to commercial production, and the bulk of our clients are now involved in later-stage development projects. We are therefore focused on enhancing services for these clients, including supporting scale-up and the production of registration batches, and are serving as a second supplier for several marketed products. Early stage support will continue to be provided for legacy clients and promising new projects.
At present, we have the capability to produce 700 million capsule units and 3.5 billion tablet units per year, with 50% of this capacity spoken for by 2021. We therefore have the capacity to onboard new business without creating any conflicts with our existing client projects. UPM’s experienced group of technical services scientists have an extensive background in scale-up, technology transfer, process development and validation and can support client products into commercial manufacturing.
We regularly receive requests for work in all of our commercial capabilities: tablets, capsules, semisolids, immediate-release, sustained-release, controlled substances, potent compounds, and drug and device combinations. We can support orphan drugs that require only one or two small batches per year, as well as commercial transfer projects requiring hundreds of millions of doses annually. We have requests for products that are ANDAs, NDAs, INDs, 505(b)(2)s, new formulation development projects and clinical supplies. As a full-service CDMO, UPM has the capability to succeed in all of these categories of work.
Joseph Szczesiul serves as Director of Technical Services in UPM’s Manufacturing department. He has over 30 years experience as a manager and scientist in formulation, process development, technology transfer and manufacturing support, with expertise in a variety of tablet and capsule modified release technologies.