» Home

  » About

  » Services

  » Speaking

  » Case Studies
       » Follow the Literature

       » Keep it Simple

       » Find the Right Talent
       » Efficient CRO Oversight

       » Realistic Timelines

       » A Detailed RFP

       » 2-Way Communication

  » Publications

  » Testimonials

  » Blog

  » Media

  » Affiliates and Partners

  » Contact

Case Study #1 - Follow the Literature

DEL BioPharma was engaged to evaluate why a literature compound failed to perform according to the reported biological assays.  The compound in question was prepared by an offshore CRO.  Analytical data included the following:

  • HPLC - high purity
  • MS - consistent with desired compound
  • NMR - consistent with desired compound

Because the compound in question was entirely aromatic, all signals in the NMR appeared in a region between 6-8 ppm.  Furthermore, while consistent with the structure, there were no signals that could be identified that conclusively confirmed the structure.  Following this evaluation, the client was asked if the CRO prepared the compound in question according to the literature protocol.  The CRO indicated that the literature synthesis was not used and a "shortened and more efficient" sequence was used instead.  Upon evaluation of the alternate synthesis, DEL BioPharma determined that a fully aromatic regioisomer was actually prepared.  When the compound was prepared according to the literature protocol, it performed exactly as expected.

Case Study #2 - Keep it Simple

DEL BioPharma and an offshore CRO were each engaged to propose an SAR study around a known kinase inhibitor.  The CRO proposed an SAR based upon modifications to the core structural motif and requiring multi-step syntheses for each compound.  DEL BioPharma proposed a systematic evaluation of the substituents around a single core permutation and requiring minimal synthetic modifications for each new compound evolving from a common core structure.  Because the DEL BioPharma proposal allowed a more rapid evaluation of novel structures, this proposal was selected.  Within 3 months, 2  diverse, novel and patentable structural classes were generated with lead molecules from each exhibiting single digit nM potency against the target kinase.

Case Study #3 - Find the Right Talent

DEL BioPharma was engaged to design and synthesize a novel heterobifunctional poly(ethylene)glycol reagent.  One month after project initiation, DEL BioPharma became aware that a competing CRO was working on this project for 2 months (engaged one month prior to DEL BioPharma).  Within the next few weeks, DEL BioPharma began supplying the competing CRO with advanced intermediates and teaching the CRO the required chemistry to successfully complete the project.

At a later stage in this synthesis, the CRO was unable to repeat a reaction developed by DEL BioPharma.  The reaction was extremely time-sensitive and required monitoring.  Discussions with the CRO revealed that the reaction was not being monitored and was simply being run according to the time specified in the DEL BioPharma protocol.  The CRO was instructed to monitor the reaction using thin layer chromatography (TLC).  When implemented by the CRO, no improvement was noted in the reaction.  When evaluating another aspect of the CRO chemistry, DEL BioPharma realized that the CRO was monitoring the reaction using 20cm x 20cm preparative TLC plates requiring approximately 60 minutes to develop.  This was in contrast to analytical TLC plates that require 5 minutes to develop.  Overall, this time-sensitive reaction was being run at least one hour longer than required and resulted in formation of significant impurities.  When the CRO switched to analytical TLC plates, the reaction performed exactly as described.

Case Study #4 - Efficient CRO/CMO Oversight Requires Chemistry Expertise

DEL BioPharma was retained to provide chemistry oversight of a complex multi-step synthesis consisting of:

  • 18 Linear synthetic steps
  • 22 Total synthetic steps
  • Multiple protecting group manipulations
  • Use of toxic heavy metal reagents in 3 steps
  • A scale-limited Birch reduction

Upon review of the protocols developed during the pilot synthesis, immediate recommendations were made regarding workup and isolation procedures that resulted in an overall doubling of the product yield.  Additional modifications and improvements to the chemistry resulted in the following:

  • Identification of a new target compound with stronger IP and comparable (if not better) biological properties
  • 16 linear synthetic steps
  • 18 total synthetic steps
  • Minimal use of protecting groups
  • No toxic heavy metal reagents
  • No Birch reduction
  • >90% Reduction in cost of goods
  • Incorporation of additional improvements is ongoing

The new target compound is currently entering phase I clinical trials. 

Case Study #5 - Keep Timelines Realistic

DEL BioPharma was retained to commission and oversee the preparation of a set of target compounds within a strict 6-week timeframe.  The 10 target compounds were selected by a patent attorney and DEL BioPharma was assured that each compound could be prepared in 3 synthetic steps beginning with off-the-shelf commercial starting materials.  On evaluation of the project, the following was noted:
  • Preparation of several of the target compounds would not be successful due to compound stability issues
  • According to synthetic protocols, each compound would be a mixture of diastereomers
  • The required stereochemistry for each compound was not known
  • None of the required starting materials were commercially available
  • While the target compounds could be assembled in 3 synthetic steps, due to the lack of available starting materials, 9-11 synthetic steps were required to prepare each target.
In approaching this project, DEL BioPharma drafted a detailed RFP with the goal of achieving synthesis of at least 6 target compounds in the required period of time.  This was consistent with the client needs as resources were available for biological testing of only 6 compounds.  Following RFP drafting, DEL BioPharma
  • Recruited qualified CROs
  • Identified a group capable of successfully executing this project
  • Negotiated contract terms
  • Provided chemistry support and oversight
Within the 6-week timeframe, the following was accomplished:
  • 7 Target compounds were completed as diastereomeric mixtures
  • All 7 target compounds were separated into their individual diastereomers
  • 14 total compounds were delivered to the client

While all goals of this project were exceeded, this project had an extremely high risk of failure as evidenced by the refusal of most CROs to submit a bid given the tight time constraints.

Case Study #6 - Begin with a Detailed RFP

DEL BioPharma was retained to commission the synthesis of a family of sugar-derived kinase inhibitors.  The client had already obtained a proposal from a CRO according to that CRO's independently derived chemistry plan.  On review of the chemistry plan, DEL BioPharma noted that the synthetic route was redacted in order to prevent sharing of the details with competing CROs.  In addition, many of the synthetic steps were problematic and the proposed sequence required use of extremely expensive starting materials.

In approaching this project, DEL BioPharma drafted an independent RFP (Request For Proposal) that contained
  • A detailed synthetic scheme beginning with common sugars
  • Supporting literature for all synthetic steps
  • Clearly defined program objectives
  • Expected target compound specifications
The results of this effort were reflected in the following:
  • The initial CRO provided a lower bid compared to their original bid
  • The client was able to generate competing bids from competing CROs all based upon the same RFP

A detailed RFP is the essential first tool supporting project design, tech transfer and generation of high quality bids from CROs and CMOs.

Case Study #7 - Success Depends on 2-Way Communication

DEL BioPharma was retained to commission the synthesis of a known literature compound.  The RFP was generated and bids were obtained from multiple CROs.  The selected CRO did not provide the lowest bid but did have specific experience with related compounds commissioned through DEL BioPharma.  On initiation of this project, the following was agreed upon:
  • Weekly teleconferences would address ongoing progress
  • Any challenges regarding the project would be communicated by email as needed.
Initially, the CRO apidly advanced the expensive raw materials to advanced intermediates.  However, during the later stages of the synthesis, the CRO
  • Failed to communicate the status of the chemistry in an efficient and timely manner
  • Advanced impure materials into final stage reactions resulting in failed reactions and unnecessary consumption of intermediates
  • Demonstrated a lack of ability to separate the final diastereomeric mixture
  • Failed to request appropriate amounts of replacement raw material resulting in higher costs to the client
Because the only communication for this project was either during the scheduled weekly teleconferences or when initiated by DEL BioPharma and because the CRO failed to follow suggestions and protocols regarding chemistry and purification, the CRO was terminated and the project was transferred to an alternate group.  Based on guidance from DEL BioPharma, the alternate CRO successfully completed the target compound.

Copyright Daniel E. Levy, All Rights Reserved