White Paper –
Linking Biological Molecules to Highly Potent APIs

Melissa Jacobs, Director, Global Marketing Communications

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Medical researchers are arming themselves with a new series of weapons in the war against disease – conjugated drugs that link biological molecules to a highly potent active pharmaceutical ingredient (HPAPIs).

“These bio-conjugates combine highly specific delivery of an HPAPI to cells with significantly reduced side effects compared to traditional chemotherapies,” said Cynthia Wooge, SAFC process development manager, and a leading expert on conjugation technology.

“Particularly exciting, is antibody-drug conjugate technology, which uses monoclonal antibodies to deliver conjugated HPAPIs to specific cancer tumors. In the conjugated form, the HPAPI exhibits more selective cytotoxicity, thereby sparing non-target cells many of the toxic effects,” Wooge said. “One such drug has already been commercialized, Wyeth’s Mylotarg for the treatment of acute myeloid leukaemia, and dozens of others are in pre-clinical or clinical trials.”

Genetic engineers have long worked on developing antibodies for cancer cells, but while these are highly targeted, they often have low efficacy. Meanwhile, the latest generation of highly potent chemical chemotherapies are efficient in killing cancer cells, but these tend not to be very bioavailable and are often toxic to non-target cells. But, combining these technologies via conjugation takes the HPAPI directly to the cancer cell, minimizing any potential side effects. “The analogy is one of a smart bomb versus a blanket bomb campaign,” Wooge said.

“Conjugation of biological molecules to non highly potent APIs is already an established technology, with applications ranging from vaccine delivery to in-vivo diagnostics. SAFC has more than 30 years of experience in that technology. However, conjugation with highly potent molecules is much more complex, mainly because of the requirements of containment needed when dealing with cytotoxic molecules — an environment markedly different from that needed for biomolecules,” Wooge said. “SAFC is the leader among a tiny handful of companies that can carry out conjugation of biological molecules with HPAPIs.”

“SAFC is a complete pipeline partner for pharma and biopharma firms involved in the development and custom manufacturing of APIs, and this includes highly potent biologic-HPAPI conjugates,” Wooge said.

SAFC combines world-class project management and chemistry support for all stages of the drug discovery and development process. In the case of highly potent conjugates, that includes many years of experience in biologics, conjugation technology, HPAPI production, a position as a primary manufacturer of linkers, and state-of-the-art facilities that meet the stringent HPAPI containment requirements.

Loading Isolator in the SAFC High Potent Conjugation Suite, St. Louis, MO

“When handling biomolecules, the key is avoiding contamination from people involved in the production process,” Wooge said. Processes are carried out in a clean-room environment at a positive pressure, to prevent the entry of contaminants. In the case of cytotoxic HPAPIs, however, the key is protecting workers from the agent itself, which means complex handling requirements with a high level of specialized containment. These processes are carried out at negative pressure to ensure containment, and workers wear full protective gear.”

SAFC is currently commissioning a high-potency biologic conjugation suite in St. Louis that will combine SAFC’s isolation and safety technology with biologics and quality control capabilities already in place at the site, with the experience of its Madison, Wisconsin, HPAPI facility. That includes industryleading containment facilities, personal protection equipment for workers and advanced training.

The St. Louis facility will initially handle clinical supplies of conjugates in the 50 g–100 g range, with scale-up to commercial manufacturing planned as projects advance. Commercial-scale estimates are in the 2.5 kg/batch range.

“While most projects are in early clinical trials, some projects could reach commercial scale within the next 2-5 years,” Wooge said.

High Potent Compound Handling in SAFC High Potent Suite, St. Louis, MO

Currently, there is no official guidance about safely handling highly potent APIs. As a result, industry has begun regulating itself, chiefly via a set of standards developed by SafeBridge® Consultants of San Francisco. That involves ranking a compound for potential potency and toxicity on a scale of I to IV. Category I covers low-irritant drugs, such as aspirin, while Category II, currently the largest, includes drugs that can cause organ toxicity. Category III is the first tier of potent drugs that cause genetic effects, plus organ toxicity, and finally, a tier Category IV, of the most potent compounds. The majority of new drugs under development fall into the latter two categories, according to SafeBridge.

SafeBridge has categorized handling practices for each of the levels: With Category I, there is limited generation of airborne material, so traditional technology with open handling can be used, in combination with exhaust ventilation. With Category II, local ventilation is needed, in addition to glove bags and closed material transfers. Category III requires a high degree of containment and control, with closed material transfers, no direct contact with the API, glove boxes, isolators and a closed manufacturing system. Processing of Category IV is carried out in a completely closed system.

High Potent Conjugation Reaction at SAFC, St. Louis, MO

SAFC’s Madison facility has been certificated by SafeBridge for the handling of products up to Category IV, and St. Louis is currently in the process of completing the requirements for certification. SAFC uses engineering controls to protect employees, in addition to its advanced procedures, facility design and training.

“In addition to containment systems for solid, powder and liquid handling, secondary protection is provided by protection suits and supplied air systems, customized for each project,” Wooge said.

“The development and manufacture of HPAPIs requires significant planning, proper equipment and facility design, as well as implementation of the necessary procedures to safely handle the compounds,” Wooge said. “The capital costs are large, and the knowledge gained through experience is invaluable. Sound systems must be employed in all aspects of the HPAPI handling program, from initial project evaluation, through equipment cleaning, to disposal of process waste. Few have all the facilities, equipment, systems and procedures in place to properly handle them as SAFC does.”

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