Perspectives from emerging pharma
Zhengming Chen, PhD and vice-president of chemistry and pharmaceutical process research and development with DOV Pharmaceutical
(Somerset, NJ), explains the various needs that an emerging pharmaceutical company may have throughout the drug-development
cycle. DOV Pharmaceutical is focused on the discovery, acquisition, and development of novel drug candidates for treating
disorders of the central nervous system. The company principally operates in the United States but also conducts preclinical
and clinical studies abroad. DOV has drug-development programs that are at the preclinical, Phase I and Phase II clinical
stages, including "DOV 21,947" (in a Phase II clinical trial for depression), "DOV 102,677" (which has completed a Phase I
clinical trial), and a preclinical discovery program in reuptake inhibitors and GABA modulators. The company has sublicensing
agreements for the development and commercialization of certain product candidates with XTL Biopharmaceuticals (Valley Cottage,
NY) for bicifadine, with Blue Note Pharmaceuticals (Troy, NY) for DOV diltiazem, and with Neurocrine Biosciences (San Diego,
CA) for indiplon.
In outsourcing a medicinal chemistry project, Chen points out the key considerations that the company makes internally and
in its requests for proposal (RFPs). "Internally, we decide what is our available budget for a project, and we evaluate how
we can maintain, control, or reduce costs," he says. "In RFPs, we clearly define our needs in terms of target compounds, amounts,
purity, and timelines. We also have to define our contribution in terms of resource and technology such as information on
starting materials, synthetic procedures, reference papers, and reference compounds."
Before sending a RFP to prospective CROs, Chen says the company first performs certain key steps, including:
- Having a confidentiality agreement in place
Evaluating each CRO's track record, references, website, and other publicly available information
- Identifying the location of the CRO and determining whether distance will have an impact on the project timelines and deliverables.
In terms of the contract, Chen points to other key issues to consider such as specifying clear definitions. "For example,
in defining guidelines for the use of 'expensive reagents,' it is important to define what is meant by expensive and then
provide the CRO with the guidelines for purchasing the reagent," he says. The contract should also provide mutual agreements
on numbers, quantities required or expected, analytical requirements, methods, purities, and electronic file submission. It
also is important for the sponsor or pharmaceutical company to own intellectual property from the project and to have a backup
plan in place if preliminary chemistry fails.
When evaluating CRO's quotes, Chen refers to value, quality, and speed as "the magic triangle" in the evaluation process.
Intellectual property security and innovation are also important criteria. As a sponsor company, Chen says that DOV is looking
for competitive prices, a good understanding of chemistry, a reasonable timeline, a track record of past performance, flexibility,
and confidence from a prospective CRO.
Once the contract is secured and the CRO is selected, Chen says it is important to put into place communication vehicles between
the sponsor and the CRO. This communication involves weekly updates, which include conference calls as needed, which provide
details of the project's status and timelines as to how the CRO is meeting the objectives set forth in the RFP.
A final report should be made in a format agreed upon by a joint operating committee of representatives from the sponsor company
and CRO. The report should include synthetic schemes, procedures, yields, and analytical results. "In evaluating the success
or quality of the project," says Chen, "numbers are important, but number-driven metrics alone will distort the objectives
from quality, which is more challenging to define and measure."
A small pharmaceutical company may also use several contract players in meeting the needs of a particular project, a point
illustrated by Chen in a recent example of a process development project that DOV Pharmaceutical had for an active pharmaceutical
ingredient. "In the route-scouting stage, we selected a US CRO, which has proven ability to quickly work through a variety
of different synthetic routes. One industrially viable route was developed," he said. For scale-up on a kilogram scale, the
company selected an European company with expertise in screening hydrogenation reactions, which was a key step in the process.
For further scale-up and potential manufacturing, the company consulted experts in chemistry, manufacturing and controls (CMC)
and collaborated with CMOs on a global basis.
Chen outlined the various players that were involved at each stage in the project. For raw materials, building blocks, scaffolds,
and libraries, the company works with CROs on a global basis with the selection process driven by price. At the next stage,
hit-to-lead and lead optimization, the company works with a preferred set of CROs. For process research, polymorph screening,
salt screening and selection, the company worked with specific CROs with expertise in those given areas. For non-CGMP intermediates
(i.e., intermediates early in the synthesis and not required to be manufactured under current good manufacturing practices
(CGMPs), the company used a pool of select CMOs. In the final stages, once the project advances to Phase I-III development
requiring CGMP material, the company works with a group of preferred CMOs.
These examples reflect the network of suppliers and skill sets needed to serve small and emerging drug companies and the opportunities
for CROs and CMOs to meet those needs.
Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org