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Accelerating the development of antibody-drug conjugates (ADCs) is critical to addressing unmet medical needs. The modality is transforming the lives of cancer patients by providing powerful anti-tumor effects without intolerable side effects. However, the complex supply chain poses challenges that can delay the filing of investigational new drug (IND) applications and ultimately the approval of life-changing drugs.
Filing an IND is a major milestone in the development of a drug candidate. The submission shows that a company has demonstrated that an investigational product appears safe and effective, based on animal models, and that it has control of the manufacturing process.
To meet the chemistry, manufacturing and control requirements (CMC), drug developers must show they have: full chain of custody of all the raw materials a repeatable, reproducible manufacturing process that works at clinical scale and is backed by the required process controls and analytical methods and tests that show the process is repeatable and provides control over the purity and identify of the drug.
Reaching the IND filing stage increases the likelihood that the drug candidate will come to market and, as such, increases the value of the program and the company that is developing it. INDs can unlock funding rounds and attract partners.
The importance of the IND applies two potentially conflicting pressures to drug developers. Companies need to get the submission right the first time, but also want to progress to the IND stage as fast as possible. Every day of drug development is vital when working in competitive indications and striving to address the unmet medical needs of cancer patients.
Managing the balance between moving quickly and doing things properly is particularly challenging in emerging areas such as novel modalities. Few companies have experience of developing modalities such as ADCs. Lacking experience, companies can struggle to effectively streamline the process and identify the core components they need for the CMC package.
Piramal Pharma Solutions is a rare example of a service provider with extensive experience supporting the development of ADCs. Having worked on ADCs since the genesis of the modality, Piramal knows what it takes to put together an IND package. The company used that experience to create ADCelerate, a service that delivers Phase-I appropriate ADC drug substance and drug product in as little as 12 months.
The service draws on the experience of Piramal's facilities in Grangemouth, UK and Lexington, USA. Over the almost 20 years that Piramal has worked as a contract manufacturer for ADCs, the sites have helped the company to make more than 270 commercial batches, 650 GMP batches and 200 distinct conjugates from 120 antibodies.
Grangemouth handles work on the drug substance, which in the case of ADCs is the antibody conjugated to the therapeutic payload. At Lexington, Piramal formulates drug substances, both from Grangemouth and from third-party sites, into drug products by combining the ADC with excipients, additives and buffer components. The work creates a stable, soluble product ready for administration to patients.
Biopharma companies can choose to outsource just drug substance or just drug product manufacturing to Piramal but there are benefits to contracting both Grangemouth and Lexington. The two sites have a history of working together, meaning that their individual expertise and experience is enhanced by open, effective communication and simplified project management for clients.
Recognizing the value of offering an integrated service, Piramal is working to incorporate other parts of its operation into an expanded ADCelerate service. The plan is to leverage Piramal's existing expertise in other parts of the ADC supply chain to extend the offering beyond conjugation and fill-finish work.
Piramal expanded its ability to make highly potent active pharmaceutical ingredients (HPAPIs) to its offering in 2016 by buying a plant in Riverview, MI, USA. From the 10.3-acre site, more than 200 employees provide development and GMP manufacturing services for complex pharmaceutical New Chemical Entities (NCEs). The plant has produced more than 20 non-GMP batches and more than 20 clinical GMP batches of HPAPIs.
Because Riverview is equipped to handle payloads and linkers, Piramal is integrating the plant into its ADC service. Once the integration is complete, the team at Riverview will use the site's dedicated HPAPI suites and ability to produce payload linkers for non-GMP and GMP operations, which can operate at up to kilogram scales where crystallization or silica flash purification can be applied, for the ADC service.
Integrating Riverview into the existing service provided from Grangemouth and Lexington will enable Piramal to cover more of the complex ADC supply chain. The three sites will collectively be able to make the payloads and linkers that are key components of ADCs, use those materials to make a drug substance and formulate the drug substance into a drug product.
The only piece remaining in the three-site integrated offering is the ability to make the monoclonal antibodies (mAbs) that direct ADCs to their targets in the body. Piramal is working with its affiliated large molecule partner, Yapan Bio, to integrate the ability to produce mAbs into ADCelerate. Working out of a site in Hyderabad, India, Yapan Bio provides services spanning early-stage process development to GMP clinical production for a range of biologics.
Across Yapan Bio and Riverview, Piramal plans to produce targeting antibodies, cytotoxic payloads and the linkers that connect them together. The sites will provide the components to Grangemouth, which will conjugate them and send the resulting drug substance to Lexington for formulation into a product that is suitable for administration to patients.
Piramal will continue to provide its capabilities on a standalone basis, allowing, for example, companies that only need conjugation to benefit from Grangemouth's long history of commercial ADC production, but it sees benefits to offering a complete, integrated package.
Working with one service provider on multiple steps in the ADC production process simplifies project management at biopharma companies. Rather than liaising with different vendors for each part of the complex ADC supply chain, companies can work with a single project manager at Piramal that serves as their point of contact for every step from the antibody through to the drug product.
Simplifying project management can eliminate risks, minimize logistical and administrative burdens and accelerate timelines. Communication and transfers between sites, critical processes that are a potential cause of setbacks and delays, are improved when outsourcing to a single vendor because the facilities are used to working together and are part of the same organization and work culture.
Piramal is bringing those benefits to the ADC market without compromising any individual step in the process. The company entered the ADC space in 2005 and the Grangemouth site has been a major player in the sector since the early years of the modality. Similarly, Riverview, a site established in 1962, has a long history of working with complex APIs, supporting seven fast-track approvals in the past 10 years.
The Lexington facility is tightly integrated with the Grangemouth site and is equipped to provide liquid and lyophilized formulations including potent and cytotoxic molecules. Established in 2007, the facility has a track record of providing fill-finish services for ADCs and other modalities and its location in the US makes it ideally placed to get drug product to the study sites that are often central to clinical trials.
Founded in 2019, Yapan Bio is a younger organization that is highly innovative and entrepreneurial. The site operates at the cutting edge of challenging novel modalities, working on cell and gene therapies in addition to monoclonal antibodies, and will bring those strengths to the ADC service once integrated into the offering.
The need for services that accelerate the development of ADCs is greater than ever. Over the past 20 years, technological improvements have turned ADCs from a promising modality into a cornerstone of the care of certain cancers. The challenge now is to quickly bring the benefits of ADCs to more patients and establish the modality as a safer, more effective alternative to chemotherapy in a range of cancers.
To meet that challenge, ADC developers will need to quickly develop rigorous IND packages that enable them to study their candidates in humans. Piramal is using its deep experience in ADC conjugation and fill-finish to address that need, and incorporating payloads, linkers and antibodies into its integrated offer to further enhance the service.
Drug developers that partner with Piramal will access expertise and capabilities that have facilitated the emergence of ADCs as one of the most powerful novel modalities in biopharma. Together, Piramal and its partners are improving the lives of patients by expanding access to breakthrough ADC treatments.
Piramal Pharma Solutions (PPS) is a Contract Development and Manufacturing Organization (CDMO) offering end-to-end development and manufacturing solutions across the drug life cycle. We serve our customers through a globally integrated network of facilities in North America, Europe, and Asia. This enables us to offer a comprehensive range of services including drug discovery solutions, process and pharmaceutical development services, clinical trial supplies, commercial supply of APIs, and finished dosage forms. We also offer specialized services such as the development and manufacture of highly potent APIs, antibody-drug conjugations, sterile fill/finish, peptide products and services, and potent solid oral drug products. PPS also offers development and manufacturing services for biologics including vaccines and gene therapies, made possible through Piramal Pharma Limited's associate company, Yapan Bio Private Limited.
