UPCOMING EVENTS

	Informex 2009
	January 27-30
	San Francisco, CA

IN THIS ISSUE

CML Europe Completes Facility Expansion

An Introduction to Design of Experiments (DOE)

The Future of CML will be shaped by Expanding Capabilities and Partnerships

CONTACT US

info@c-mlabs.com

262-251-5044

Construction of New North American API Manufacturing Site Underway

On June 5, 2008, the company broke ground on the new 112,000 square foot, state-of-the-art API manufacturing site next to its headquarters in Germantown, Wisconsin, US. After only a few short months, the building exterior is nearly complete and most of the reactors have been installed. The facility will be the most modern and sophisticated facility in North America.

Following is a visual construction update on CML’s most anticipated new development.

The construction is on schedule to complete the main portion of the building. Roof installation is scheduled to be complete before the end of November 2008. The goal is to have the facility fully operational by mid 2009. Four manufacturing suites (up to 2000 gallons) and two specialty reactor suites (hydrogenation and cryogenics) are part of the initial project, with infrastructure for an additional two manufacturing
suites up to 4000 gallons.

The new facility is located directly adjacent to CML’s global headquarters and US development center. The close proximity is a benefit enabling smooth technical transfer between US sites.

In addition, all of CML’s development facilities globally will feed larger scale opportunities into the new facility. CML continues to develop plans and procedures
for equipping the new facility and the team is working on all the details to ensure a smooth start-up next year. Currently CML is seeking experienced process development chemists, chemical operators, and analytical chemists to staff
the new facility. All this construction is part of an exciting future for CML.

CML Europe Completes Facility Expansion

We are pleased to announce the completion of a major expansion at CML Europe. New state-of-the-art laboratories are now fully operational and the addition of these labs gives CML Europe the opportunity to further broaden our areas of expertise for customers who are interested in more specialized chemistry projects.

cGMPLab - CML Europe

The expanded capability essentially doubles CML Europe’s capacity for process R&D, GMP kilo lab manufacturing, and analytical development. In addition to the new laboratories, CML Europe is undergoing a pilot plant expansion targeting the end of this year for completion. The new reactors and equipment will add 40% more reactor capacity and enable larger production runs up to 100kg scale.

From left to right: Process Research & Development Lab, Analytical Lab - CML Europe

An Introduction to Design of Experiments (DOE)

By Scott Duncan, Ph.D., Senior Project Manager

CML is proud to announce that DOE, a powerful technique for rapid process development and validation, has become part of the extensive process development capabilities available at both our US and European sites.

So, what is DOE? “The statistical analysis of a randomized series of planned experiments in which multiple variables are varied by pre-determined amounts within a single experiment to determine the effect of all possible combinations of variables tested on the result.” In practical terms for API development, DOE translates to “How can a pharmaceutical company gain the most amount of knowledge with a high degree of confidence with the least amount of resource?” Although this is a diverse subject, the goal of this article is to provide a useful introduction into some of the basics of DOE and their benefit to pharmaceutical companies and practicing chemists.

Three major uses of DOE:

1. Identity of major factors that affect an outcome (i.e. range finding)
2. Optimization of conditions to obtain the desired outcome (i.e. process optimization)
3. Establishment of all combinations that will provide an acceptable result or conversely which ones provide a
   unacceptable result (i.e. determine acceptable design space for validation of a process)

Two significant benefits of DOE:

1. Preservation of time and materials by performing fewer experiments to reach the same outcome as a ‘one
   variable at a time (OFAT) approach”. For example, if one were to study 6 factors at 2 levels each, that would result in 64 experiments with the traditional method. By using fractional factorial DOE of level IV resolution (2 to the power of 6-2) only 16 consistently performed experiments can provide a result with 95% confidence the same information.
2. Significant increase in design space knowledge. If 3 factors at 2 levels are studied, each by the traditional
   method, knowledge is gained regarding the vertices of a cube. By using DOE knowledge is gained of every
   point within the cube.

The results of a DOE can be interpreted visually a variety of ways. One of the most common is the Half-Normal plot in which statistically significant points/variables can quickly be identified. An example of that presentation style is shown on the right. The predictive power of the DOE can be illustrated in simple 2D or 3D plots. A contour plot is shown below for the dependence of the outcome (E / Z ratio) for a Wittig reaction as a function of the temperature and solvent volume.

As powerful as this technique is, it is not applicable in all circumstances. A famous person once stated that “Absolute power corrupts absolutely”.

In this case a poor design or improper application will result in large amounts of minimally useful data, which could more likely lead to a weak / unfounded conclusion resulting in an inefficient use of resources and time. DOE, however, has been used successfully in many ways to improve both mechanical and scientific processes. DOE, used properly can result in substantial financial, efficiency and time savings along with greater confidence that a given process will provide acceptable results on a consistent basis. If you have questions regarding the applicability and / or benefit of this approach to your project please contact a member of the CML Business Development team.

The Future of CML will be shaped by Expanding Capabilities and Partnerships

By Roger Mcdonald, Business Development Director, CML Europe

With the current restrictions in the capital markets, it is more important than ever to make sure every cent is spent wisely. CML has long been expert in the concept of “appropriate development”. This is particularly important when tasked with the supply of an API for early clinical phase application.

How does a company get an API ready for firstin- man trials as fast as possible whilst meeting all required safety and GMP standards – and not be forced to reinvent a synthesis for phase 2 after making the wrong choice at the outset?

Such a task draws on a multitude of different skills – synthetic and physical chemists, regulatory experts and supply chain professionals. Above all is required the experience and a commitment to open and honest communication.

The business model of Cambridge Major Labs is one of partnership and openness: we firmly believe if we aim to optimize the use of available resources to achieve a shared objective we can succeed together. The fact that we have so many repeat clients is testament that this approach works.

Cambridge Major Laboratories Europe (formerly Chemshop) has built a ten-year reputation in supply of development services: hundreds of medicinal chemistry routes have been scaled up to support clinical trials. The focus has been on traditional synthetic chemistry, whilst other ancilliary services, such as preformulation studies, biocatalysis, and physical form work such as polymorph screening have usually been managed by the client separately.

In recognition that timelines are now under more pressure than ever, CML has decided to partner with class-leading companies who have expertise CML does not have available inhouse. We expect that by extending our service offering to include these capabilities, and on the basis that we already have good working relationships with these companies, timelines and tech-transfer risks can be further minimized. This is however not the “one-stopshop” model. We work with these companies because of their expertise, but there is no obligation.

The initial areas on which we will focus are biocatalysis – enzyme screening; microbial metabolite generation – this technique can be used to mimic mammalian metabolism for the characterisation of drug metabolites circumventing the need for very challenging and therefore time consuming chemistry – possibly speeding up the preparation of the regulatory package; physical property developability characterization – including polymorph screening; crystallization development including ultrasonic technologies.

Over the last five years, many service companies have invested in facilities to handle the synthesis of highly potent and cytotoxic materials. However, the complexity of the chemistry involved in making many of these compounds has resulted in a mismatch between facility and synthetic skills: there is a market need for a company with a highly developed technical background and appropriate containment systems to support the early clinical phase requirements for highly potent and cytotoxic compounds. CML is currently appraising the possibilities to enter this market.