The Aptuit acquisition of Evotec’s Chemical Development business in 2007 proved to be the catalyst for a collaborative relationship that now extends beyond its original scope. Today Evotec is partnering with Aptuit across multiple business lines.

At the time of the acquisition, Aptuit was engaged in the development of an Evotec API and the progressive optimization and scale up of the process chemistry over a number of key intermediate stages. The ability to manage this project at Aptuit’s Oxford (UK) site and Aptuit Laurus (India) facilities provided an immediate benefit through reduced timelines, increased scheduling flexibility and combined expertise. Dedicated Project and Technical Management within the global Aptuit team ensured a smooth transfer of both technology and materials from one location to another.

Since the success of various API projects, the range of services that Aptuit provides to Evotec has been expanded, including support from Aptuit’s Solid State Chemistry, API, Radiolabeling, Pharmacokinetic and Clinical Manufacturing and Packaging services. The developing Aptuit- Evotec association provides an example of a relationship whereby the client accesses the required services from the comprehensive range that Aptuit offers.

The ability to share and transfer knowledge across sites and service areas is a principal advantage of working with Aptuit as a single provider or across multiple business lines. Implicit is the assurance that the client benefits from a global network of expertise that is integrated through dedicated project management expertise.

The initial case studies and some overviews of ensuing projects follow to serve as examples of a partnership that continues to develop between Evotec and Aptuit.

API Development: the transfer from small to large scale API manufacture

The development of a drug substance and its transfer from small to large scale manufacture is a process that frequently requires pharmaceutical companies to work with more than one service provider. Integrating global logistics to move projects from development to manufacture may be thwarted by inflexible and cumbersome procedures that vary from one site to another. Aptuit was able to address these challenges because multiple activities could all be performed within the Aptuit Oxford and Aptuit Laurus organizations. The role of Aptuit’s Project and Technical Management expertise in coordinating these activities cannot be overstated since it has been this leadership that has created a seamless, flexible approach in achieving Evotec’s goals in a variety of projects.

Project 1:

Evotec provided 5 g scale patent-based details in a five-step synthesis for the initial API development. Polymorph screening as part of Aptuit’s solid state chemistry services added key knowledge to the process. Aptuit’s Phase I analytical services, including stability studies and a CMC report, were simultaneously generated as well as a Product and Research Development program that supported the effective scale up in manufacturing. The cGMP plant manufacture of 9 kg was delivered on schedule.

Project 2:

Evotec provided a 1 kg lab scale API sample in optimized physical form in an eight-step synthesis procedure. Aptuit used process and analytical methods development, including stability studies, to deliver 30 kg and 150 kg cGMP batches as required. The 30 kg batch was initially delivered from Aptuit’s Oxford facility and the process was transferred to Aptuit Laurus for manufacture of the larger 150 kg cGMP batches.

Project 3:

Evotec provided pilot plant scale API samples in a six-step synthesis for technical transfer to produce 70 kg cGMP batches. The scope of the work performed included analytical method development and validation, stability studies and radiolabeling (Figure 1).

After making the initial lot, Evotec needed more product at an increasing scale. The technology and methodology were transferred from Aptuit Oxford, to Aptuit Laurus in India. Preparation of the 14-C radiolabeled molecule was achieved on time at the Aptuit Kansas City facility.

Aptuit West Lafayette: using solid state chemistry to identify a stable, solid amorphous dispersion

While Aptuit Oxford and Aptuit Laurus were continuing work on the development of a process and manufacture of the API at 20 kg scale in single crystalline form, Aptuit’s solid state chemistry group in West Lafayette was contracted to investigate an alternative formulation that would improve bioavailability. Working in partnership with Evotec from Aptuit’s West Lafayette facilities in the United States, the challenge included identifying a compound with acceptable physical stability.

A study (Figure 2) evaluated the comparative physical stability of amorphous dispersions of the API with the following pharmaceutically acceptable polymers HPMC-AS; HPMC-P; Eudragit® L100; and PVP K-90. API loadings of 50 weight% and 90 weight% were chosen with X-ray Powder Diffractometry (XRPD), and modulated Differential Scanning Calorimetry (mDSC) and Polarized Light Microscopy (PLM) characterizations were set.

The 50/50 HPMC-P/API compound was selected as the lead dispersion. It was found to be x-ray amorphous and isotropic by PLM. A single glass transition temperature (Tg) at ~100°C by mDSC was identified.

Acceptable physical stability was achieved:

• 36°C in media for 24 hours, with no devitrification by PLM except in pH 6.8 phosphate buffer
• 60°C for 3 days, with no apparent change by XRPD
• 40°C/75% RH for 72 hours, with no devitrification by PLM and a single Tg by mDSC

Evotec offered the following comparison of the micronized form with the 50% Dispersion (HPMC-P) as corrected for differences in dosing solution concentrations (Figure 3). The new formulation was an improvement when compared to the initial compound.

Radiolabeling: a comprehensive 12-step synthesis that involved two labeling positions

Radiolabeling experts at Aptuit’s Kansas City site were challenged to investigate two labeling positions to establish a drug safety profile. Aptuit needed to conduct a long and involved process using a 14-C chiral material. Aptuit was called to work with other partners working with Evotec at the time when this project was initiated. Although the project had complexities, it was completed within an aggressive timeline and to the required specifications (Figure 4).

Aptuit's Clinical Manufacturing, Clinical Packaging and Logistics Services

Most recently, Aptuit was selected to carry out clinical drug product manufacture and packaging services in the US for a Phase II Evotec project on an API compound that was synthesized by Aptuit, Oxford. A partial regulatory package for an IND was created, with follow up activity due to commence later in 2010. Aptuit was able to complete this work successfully due to the company’s global information sharing processes.

An evolving partnership

What began as an API project for Evotec with Aptuit - producing Phase I clinical trial API at the gram to multi-gram scale at their Oxford facilities and then ensuring efficient transfer of processes to Aptuit Laurus in India - has evolved to a deep, developing relationship. Evotec generally uses the services of more than one drug development provider although it is increasingly turning to Aptuit’s expertise across multiple business lines. Whether clients partner with Aptuit for a specific service, for multiple services or for a comprehensive integrated suite of services that Aptuit offers, the sharing and transferring of knowledge under the leadership of a dedicated Project Manager ensures on-time and in full results that every client expects.

Dr. Mario Polywka, Chief Operating Officer, Evotec AG, summed up the advantages of Evotec’s developing partnership with Aptuit by stating, “…we have worked extensively with Aptuit and Aptuit Laurus on progressing a number of our small molecule drug candidates through the pre-clinic and into the clinic. In all aspects of CMC and drug product development, we have found Aptuit and Aptuit Laurus to be the ideal partner, combining industry leading pharmaceutical expertise with a strong emphasis on timely delivery and cost effectiveness. We are happy to recommend Aptuit as a partner for drug development outsourcing.”

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