Cedarburg Hauser Pharmaceuticals

Custom Conjugated APIs

Custom Conjugated APIs – A Targeted Drug Delivery Paradigm Shift

New research approaches in the pharma/biotech industry are yielding some amazing, innovative therapeutics focused on unmet medical needs. Gone is the “me-too” approach to drug development and the silo-mentality to chemistry and biology – both hallmarks of the industry. New trends in the way pharmaceutical companies approach research now focuses on highly cross-disciplinary types of development such as chemical biology.

These two shifts, in part, are yielding successful commercial results. By mid-2011 the New York Times had reported that twenty innovative medicines that either effectively differentiate themselves from existing drugs, or tackle ailments lacking viable treatments, had won marketing approval according to the Food and Drug Administration.

Conjugates are One of the Fastest Growing Classes of Therapeutic Molecules

One of the primary focuses of chemical biology is the targeted delivery of therapeutic agents. Targeted delivery involves the use of a biologic vector that is conjugated with a therapeutic agent such as a drug, biologic, toxin, radionuclide, etc. to form a bio-conjugate hybrid or simply a conjugate.

Delivery vectors include cell-penetrating peptides, proteins or enzymes and monoclonal antibodies or antibody fragments. The new conjugates possess a better method of delivering the therapeutic agent to the site of action. This inevitably is resulting in an improved local (tissue) and cellular concentration. In addition, there is an opportunity for the therapeutic index to be maximized by less non-specific tissue toxicity. As a consequence, conjugates including ADC’s (antibody-drug conjugates) constitute one of the fastest growing classes of therapeutic molecules.

A Growing Trend: Conjugate APIs are Being Developed to Target Cancer

Cancer is one of the disease areas witnessing the most intense investigation of conjugation development. Many pharmaceutical and biotech companies have invested heavily in this approach and have new conjugate molecules at varying stages of pre-clinical and clinical development.

Conjugation of a cytotoxic or anti-neoplastic drug is of particular interest for its ability to localize concentration and improve the therapeutic index. Numerous research and development collaborations have been forged in recent years due in part to the complexity of pursuing conjugates. These partnerships are striving to remain competitive by jump starting or accelerating access to know-how (IP), talent, and infrastructure.

Challenges Associated with the Scale-Up and GMP Manufacturing of Conjugates

Typical research labs may be able to make milligram quantities of these materials efficiently and safely but manufacturing larger quantities presents classic scale-up challenges in addition to some new challenges.

SCALE-UP CHALLENGES
The classic challenges associated with the scale-up of any new API are roughly doubled in magnitude due to the simple fact that there are two different molecular properties to conjugate. You have to consider…

  • How you will proceed with the process development and optimization of each molecule?
  • Do you have the scientific expertise required to do the work for each molecule?
  • What are the capital equipment requirements within the facility?
  • If you are conjugating a potent, cytotoxic or controlled molecule does your facility have all the proper controls, SOPs, and permits?

GMP MANUFACTURING CHALLENGES
The way a facility is designed to accommodate the cGMP manufacturing of these types of hybrid products needs to be considered as well. A facility that manufactures conjugates for anti-cancer APIs must have…

  • cGMP manufacturing space that facilitates the control of microorganisms to achieve very low bioburden material (API).
  • Engineering controls that limits occupational exposure to the biological effects of the conjugate and/or its building blocks and limit cross contamination.
 

Cedarburg Hauser Pharmaceuticals has the Expertise, Experience, and Facilities for the Development and Manufacture of Your API Conjugate

Cedarburg Hauser Pharmaceuticals has both expertise and experience with providing development, scaling and manufacturing services for API conjugates. Our process development and manufacturing facility has a team of scientific and manufacturing experts – along with the equipment and controls – that you need to develop and manufacture the pre-clinical and clinical grade conjugates for your project.

Expertise Related to Developing & Manufacturing API Conjugates

  • Development, scale-up and manufacturing of peptide conjugates, polymer conjugates and glyco conjugates
  • Extensive experience handling, manufacturing and conjugating potent, cytotoxic and controlled agents
  • Successful completion of several API conjugate projects that have provided high quality material for preclinical toxicity studies, clinical trials and reference standards

Services We Offer

  • Process development, optimization, scale-up and transfer
  • Analytical method development, optimization, scale-up and transfer
  • Processing — cleavage, purification and isolation
  • Quality control and assurance
  • Non-GMP and GMP manufacturing of pre-clinical, clinical and commercial API’s
  • Centralized Project management – delivers 90%+ on-time, on-budget project completion rate

Key Development & Manufacturing Facility Components

  • Ability to manufacture potent and cytotoxic peptides that require containment at levels between 1-10 ug/m3.
  • Gram to kilo-scale GMP isolation suites
  • Engineering controls and work practices (procedures, PPE, secondary containment) to provide detection, containment and prevention of cross-contamination occupational exposure
  • Permits to handle, manufacture, store and ship controlled substances
  • Security and controlled access
  • Excellent audit history
 

Experience & Expertise with Developing and Manufacturing API Conjugates

A lot of companies can claim to have the expertise of developing and manufacturing API conjugates, but the fact is Cedarburg Hauser can prove it. We have worked with several of our clients on API conjugate projects and the successful outcomes to those projects speak for themselves.

Because we place a very high value on the confidentiality agreements with have with our clients, we cannot disclose all of the details of the work we have performed on their behalf. We can, however, share the type of work we did and the overall achievements in non-specific terms to give you a sense of our track record of success.

Please take a moment to review these case histories and then contact us to discuss your project. We welcome the opportunity to help you with your API conjugate development and manufacturing project.

Case Studies

Development and GMP Manufacture of a Polymeric Conjugate Including a Potent, Controlled Substance
Cedarburg Hauser successfully developed, optimized, scaled and manufactured a potent, controlled substance polymeric conjugate API. Working closely with our client we were able to meet their aggressive timeline and generate 1.3 kg of the target API conjugate under GMP conditions for their clinical trials. The material was high purity and the final optimized process produced an overall yield of 52%.

Development and GMP Manufacture of a Peptide Conjugate Including a Potent Therapeutic Agent
Cedarburg Hauser successfully produced a peptide conjugate API under GMP conditions at 25 times the scale ever achieved prior to our involvement. We were able to provide enough high purity material for our client’s phase II clinical trial needs. We were also able to develop and generate high purity material of a second conjugate to satisfy their needs for their toxicology studies, phase I clinical trials and reference standards.

Development and GMP Manufacture of a Anti-Cancer Peptide Conjugate
Through careful study, Cedarburg Hauser scientists were able to identify and optimize key chromatographic parameters that resulted in an improved separation, a significantly increased resin life, and an overall process yield increase to 65-70%. The conjugate API was delivered on schedule and exceeded the customer requested amount by >10%.