Solvias Customer Magazine

Antibody drug conjugates – Challenges of combining small and large molecules

New method for heavy metals testing <231>: An interview with Anthony De Stefano, USP

Crystallization – Understanding and developing the process

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2 SolviAS ProSPeCtS — 1/2010

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Preface of the Head of Marketing and Sales 4

Crystallization – Understanding and developing the process 10

New USP method for heavy metals testing <231>: An interview with Anthony De Stefano, USP vice President for general chapters 13

Antibody drug conjugates – Challenges of combining small and large molecules 23

A new ligand class for asymmetric hydrogenation – Mixed secondary phosphine oxide-phosphines

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News 30

events

Content

3SolviAS ProSPeCtS — 1/2010

Dr. StePhAn hAitz — Head of Marketing and Sales

Dear reader and valued customer

Welcome to our latest edition of Prospects. the last issue was devoted to our 10th an-niversary, and now that we are into the next decade we wish to share with you some news that Solvias has been involved with in the past six months. We continue to dedicate our efforts to improve our service particularly by implementing valuable so-lutions to gain the most effective cost-to-benefit ratio through meaningful science. read on and find out what exactly is happening at Solvias in this direction.

Crystallization – Compared to other separation methods, crystallization processes have a number of benefits. our crystallization projects which take a team approach guarantee seamless process development for your drug candidate without time and money consuming technology transfers at this stage.

New USP method – the traditional sulfide precipitation test for elemental impurities <231> is expected to be replaced by a better but potentially expensive instrumental method. As you will learn from Anthony De Stefano, USP vice President, the old sulfide precipitation test is still valid. Solvias will continue to offer service to these standards even though we already have well-established accurate and validated instrumental- based methods. We strive to offer the best solution for our customers.

Mixed Secondary Phosphine oxide-Phosphines – read about our new class of hy-drogenation ligands which can be prepared on a large scale at reasonable costs and which have been shown to have good hydrogenation performance for the rh-cata-lyzed hydrogenation of functionalized alkenes. As you can clearly see from the examples above, our efforts in support of our cus-tomers continue unabated. We achieve this by putting our collective know-how and competence to work towards furthering the science for more innovative solutions that make economical sense.

in our rapidly evolving environment changes occur all the time and in all our interests we make every effort to stay in tune with the times. Please do not hesitate to let us know your thoughts, your needs or even just to stay in touch.

We hope you enjoy this edition of Prospects

Dr. Stephan Haitz


Crystallization – Understanding and developing the processin order to achieve controlled production of a desired polymorphic form it is essential to primarily understand the product and be intimately familiar with the process. Furthermore, scaling up the crystallization process requires an expert team of experienced scientists working closely together to ensure reliable and seamless development.Interview: Dr. Michael Becker

Crystallization processes are presently the most widely used techniques for purifying solid drug substances. independent of chemical or chiral purity enhancement, specially de-signed crystallization processes are the best choices for processing. Compared to sepa-ration by chromatography, crystallization processes, in most cases, also have economic benefits. But not only purity aspects favor the use of crystallization techniques, even the controlled production of a desired polymorphic form, typically via seeding processes, can be achieved.

in active pharmaceutical ingredients, several polymorphs and solvates may be present. A change of the crystalline form and/or the presence of an amorphous part may induce important changes concerning the physical properties such as dissolution rate, bioavail-ability, stability or processability of the corresponding drug product.

Needless to say, an ideal crystallization process must be robust, reproducible and scalable. therefore, for the development of robust processes it is mandatory to determine the influ-ence of significant parameters such as temperature and solvents of crystallization, drying, milling, and storage conditions on the crystalline form and on its crystallinity.

to guarantee reliable and seamless development and scale up of a crystallization process, a team of experienced scientists should closely collaborate. Starting from the initial crys-tallization screening process to kg-scale production and the final supply of material (GMP and non-GMP), a multidisciplinary team is required.

Dr. MiChAel BeCker — Product Manager Solid-State Development


inveStigAting PolyMorPhiSM – iDentifying AnD UnDerStAnDing the Profilethe key step towards a robust crystallization process is a detailed solid-state characteriza-tion and polymorphism investigation which provides an overview of the polymorphic transformations, including the identification of the most thermodynamically stable form at a given temperature, and an understanding of the temperature-dependent behavior of all forms. For example, an important part of a polymorphism profile is to determine whether the thermodynamic stability ranking of polymorphs changes with temperature (i.e., enantiotropy). to control reactions in an enantiotropic system, determining the tran-sition temperature at which the ranking of polymorphs changes is of great significance, especially if this temperature is within the range of operation (e.g., between the tempera-ture of cold filtration and the boiling point of the solvent).

For solvates and hydrates, both thermodynamic parameters and solvent activity must be examined. in particular, it is crucial to determine whether a given polymorph results directly from the chosen process conditions or whether it is obtained by the desolvation of an intermediate solvate or hydrate while drying. in the latter case, the choice of solvent for the final crystallization step will be restricted and the product may be difficult to dry, leading to elevated levels of residual solvent. Dehydrated hydrates often have the dis-advantage of being hygroscopic and can tend to rehydrate (dependent upon moisture levels or water activity).

Figure 1: A crystallization process for a nonspecified pharmaceutical drug substance

PolyMorPhiSMinveStigAtion

forM SeleCtion &ProCeSS DeSign

CryStAllizAtionProCeSS oPtiMizAtion

MUltigrAM to kilogrAM SUPPly(GMP/non-GMP)


DeSigning the ProCeSSBased on the polymorph landscape and the chemical compatibility of the drug substance with various solvents, a first set of solvents or solvent mixtures is selected to determine the temperature-dependent solubility of relevant polymorphs. this screening type of process provides the metastable zone width (MSZW) of the system and is the basis of a preferable seeding process for a robust crystallization. Seeding is the most favored technique for crys-tallization of pharmaceutical drug substances as it ensures a controlled and reproducible process.

essential for such a seeding process is the addition of the seeding crystals at a tempera-ture at which the system enters the metastable region. Figure 1. if seeding crystals are added at higher temperatures (= stable region), they will dissolve without nucleation. if seeding crystals are added in the labile region, nucleation will start spontaneously and the system will crystallize in an uncontrolled manner.

Figure 2 shows a typical cooling crystallization supplemented by the addition of seeding crystals. After complete dissolution of the starting material, the temperature (green line) is lowered till the system enters the metastable zone. Seeding crystals are added and the temperature is continuously reduced. the controlled crystallization is monitored by fo-cused beam reflectance measurement (FBrM) to determine the number and diameter of particles generated (purple, blue and orange lines).

Within cooling crystallization processes the addition of antisolvent, pH shifts or salt for-mation are also appropriate supporting tools. At this point, other crystallization processes such as azeotropic distillation may also be considered in order to broaden the knowledge of the crystallization process.

Figure 2: T/C graph of solubility and MSZW


even at this early stage of crystallization process design, later specifications for large-scale production will be taken into account. variation of solvent systems (e.g. technical solvent quality versus highly pure solvent), exchange of solvents (e.g. class-1 or class-2 to class-3 solvents), stirring time and speed or variation of substrate concentration will be tested on a ml scale to generate necessary information for further optimization and production to ensure rapid development and feed the production chemists with information necessary to guarantee reproducible results.

oPtiMizing the ProCeSSonce an initial crystallization process is established further work has to be carried out for process optimization. even small changes in a crystallization process may lead to undesir-able events such as agglomeration, polymorphic conversion, and nucleation. the system-atic variation of relevant process parameters such as cooling profile, stirring (type of stirrer, speed), seeding, purity (spiking with relevant side products) and water activity will identify the critical factors that influence the characteristics of the solid product and form the basis for a robust crystallization process design.

Beside these parameters, space volume yield, compression and filterability of the crystal-lization process or crystallization product will be varied and optimized.

A further important step is the harvesting and drying of the crystalline product which may include drying hydrates to the desired hydration level. Comprehensive analysis of the solid product – by HPlC, headspace GC, X-ray powder diffraction, particle size distribution, mi-croscopy, or other techniques – will provide all the information needed to optimize both the crystallization of the desired polymorphic form within the defined product specifica-

Figure 3: Seeding process monitored by FBRM


tions (crystal size, shape, and purity) and a high productivity of the overall crystallization process (e.g., good yield, short batch cycle time).

SCAling-UP froM MUltigrAM to kg SUPPlythe designed process is repeated on a larger scale (250 g to >1 kg) for proof of concept or direct delivery. As all relevant information was previously gained during the design and optimization stage, involving specialists from all disciplines, production of the desired quantity can start immediately. By implementing this integrated approach for crystalliza-tion development and scale-up, a fast and reliable process is guaranteed without time- consuming technical transfer efforts from one company to another.

As our target is always to ensure the best, cheapest and most effective production meth-od, we offer production under both GMP but also non-GMP quality standard. For non-GMP material (e.g. for formulation development or toxicology studies), substance-specific validations for test methods can be avoided by using general methods according to iCH, pharmacopeia test methods or through one of the ready-to-use Solvias standard meth-ods. if the material should be used for GMP processes, the production will be accordingly under full GMP quality standard. Figure 3. it is worthwhile to note that in most of the cases crystallization demands a substrate which is also produced under GMP. the use of a non-GMP starting material in such case will not result in a GMP-compliant product.

Implementing this integrated approach for crystallization development and scale-up, a fast and reliable process is

guaranteed without time-consuming technical transfer efforts from one company to another.


100L GMP reaction vessel

For every crystallization process under GMP an iCH-conform release testing will be per-formed either with customer-specific methods, analytical methods transferred to our lab-oratories, or by in-house validated methods. As Solvias is equipped with production facili-ties under certified GMP quality standard, we could either just crystallize your substrate or even further produce the starting material in our own facility ensuring complete GMP coverage. in addition, our scientific experts are always available for consultation at any stage of the process and can advise the client how best to utilize our extensive portfolio of products and services to complete the technology transfer.

Why Work With SolviAS?the unique combination of Solvias’ expertise in solid-state development, crystallization process development, pilot plant production scale under GMP and non-GMP and state-of- the-art instrumentation enables us to tackle the majority of drug development candidates. our approach to set up crystallization projects right from the start with a team approach comprising physicochemists, organic and analyticalchemists guarantees seamless process development for your drug candidate without time- and money-consuming technology transfers at this stage.


New USP method for heavy metals testing <231>An interview with Anthony De Stefano, USP vice President for general chapters.Interview: Silke Oeschger

the pharmaceutical industry generally agrees that the century- old USP standard for metal testing – based on a simple visual comparison after sulfide precipitation – is not “state of the art”. the United States Pharmacopeia (USP) is planning to replace the sulfide precipitation limit test as described in USP-NF gener-al chapter “Heavy Metals <231>”1 with more sensitive methods, based upon modern instrumentation. A first draft chapter was published in october 2009, for public comments, and the com-ment period ended on April 15. in a telephone interview with Solvias, Anthony De Stefano, USP vice President, describes what consequences this change will have on the industry and when the industry will have to implement the changes.

When do you expect the new guideline to be finalized? there is no real timeline at this point to finalize the chapter. A draft chapter was out for comment until April 15, 2010, and what happens next will depend on the extent of comments that we get from the industry. Nothing will be finalized for a while and once it is published in the USP-NF it will certainly have a delayed implementation date. We anticipate that it will

take a number of years. A determining factor is that our chapter borrows heavily from the european guidance on metal cata-lysts of the eMeA2 which only becomes official in September 2013. We are targeting a timeframe somewhere around there, but again the general chapters are currently open for discus-sion and it may actually go beyond that.

It is said that the timeframe which will be set for the industry to implement the new standard in their processes after the chapter is finalized will be about five years? Is this realistic? that’s what it is appears to look like. i can’t say for sure, but that is the right order of magnitude.

The deficiencies of the heavy metal limit test according to cur-rent USP <231> have been obvious for a long time. What trig-gered the revision of the heavy metal test at this present time? there are a number of factors. on the one hand it is the meth-odology. the sulfide precipitation methodology for metal determination has been in the US Pharmacopeia for over a hundred years. We know that it is not very specific and it is not very sensitive, it only sees a very limited number of metals and it is a visual acuity test, which is primarily limited to the level of lead precipitate you can see. So the test isn’t very good in terms of its ability to see the relevant metals. We’ve had that data for years and we have published stimuli articles in the Phar-macopeial Forum dating back to 1995, stating that we should replace the chemical test with instrument testing. there was another stimuli article in 2000, and some technical articles writ-ten by others regarding the inaccuracy of the test. But, what really drove the process was our desire to finally have a stan-dard which is toxicologically meaningful; we wanted to have a chapter that looked at metals that are important and at levels that are important. So we had a meeting convened by the U.S. institute of Medicine where it was decided that the key impuri-ties to look at were what we call the big 4: cadmium , arsenic,

Dr. Anthony De StefAno — USP vice President for general chapters


lead, and mercury and then we added to that list 12 of the 14 catalysts that were in the eMeA (european Medicines Agency) Guidance.

How did you then proceed?We had an advisory panel and they reviewed the limits that were in the various toxicological databases. For the 12 catalysts from the eMeA we used the eMeA limits and for the other 4 we used either ePA (environmental Protection Agency), FDA or Agency for toxic Substances and Disease registry (AtSDr) data- base limits. the intention was to identify the metals that are most likely to be present and try to set specification at levels that are toxicologically meaningful. in a next step we looked at the methodology, because we were not trying to set the limit based on how low an instrument can go. We want the limits to be toxicologically based and then have a methodology which could easily meet those limits.

regarding how they see the chapter, because there is a differ-ence between having advisory panel discussions and formal comment from the Agency on the draft chapters.

I guess you have received a lot of comments from the indus-try. What criteria are used for taking comments into consid-eration? Can you explain the decision-making process? We take all comments into consideration and try to address them to the extent that we can. the main criteria are primarily what the scientific merit of the comment is and how it does impact either public health or the ability to put the standard into practice. i think one primary issue with industry is one of implementation; how long it will take the industry to go back and check all the material that they need to check and their state of readiness to actually implement the standard. Many companies of course have a very large number of compounds and products that they deal with and to be able to say that they are in compliance, given that they have always used the old test method and not the new one, can take quite some time. So the major issue is to give them enough time so that they can evaluate their material and if necessary bring the products into compliance.

ABoUt USP

The United States Pharmacopeial Convention (USP) is an independent scientific nonprofit that sets standards for the quality, purity, identity, and strength of drugs, food ingredients, and dietary supplements. USP’s drug standards are enforceable in the United States by the US Food and Drug Administration, and all three types of standards are used in more than 130 countries. USP’s mission is to improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods.

The intention was to identify the metals that are most likely to be present and try to set specification at levels that are toxicologically meaningful.

Does the FDA (US Food and Drug Administration) actively support the change?the FDA has been involved on our advisory panels from both the toxicological and the instrument side. they have not yet commented on the chapter but they have helped us decide on the limits and have been involved in discussions about the methodology. We do not have their official comments yet


Could you suggest how to deal with the method in the meantime?in the meantime, what is official is our chapter <231>. We are proposing the new procedures and the new limits but they have no force of law at this point. So what is official is official. that means, what you submit today you would submit with the limits and the testing as for USP <231>.

Have you noticed a trend towards the industry already using a parallel method?in development, i think that almost every modern pharma-ceutical company has tested their products in one form or an-other using techniques other than our wet chemical methods. Most pharmaceutical companies have either their own testing methods for key metals using their own equipment or send them out to a contract laboratory. once they file with the regu-latory agency, they are confident that there are no major issues and they are confident in their supply chain, they may use the compendial method as a way to test on a routine basis because it is an inexpensive way to test without having to use the instru-ments. i think that’s what goes on with many of the companies.

What about the future of this inexpensive current sulfide limit test <231>? Will it be completely removed from USP-FN? At a minimum, General Chapter <231> will need substantial revi-sion, particularly issues with Method ii and the use of thioacet-amide for the generation of hydrogen sulfide. Whether it will con-tinue in the pharmacopeia long term is still under discussion.

There are a lot of articles or should we say rumors in the lit-erature that the chapter will change very soon and that com-panies have to be prepared for this. What is your opinion?We have no control over what, for example, the instrument companies do. it is possible there are cases where an instru-ment company has taken the draft chapter and run with it, say-ing ’you have to do this and you have to do that,’ but at this point that’s simply not true. right now, this is only a propos-al and no one has to do anything different to what they have been doing in the past.

Do you foresee a harmonization between the international guidelines (e.g. European Pharmacopoeia or Japanese Pharmacopoeia)?We are actively engaged in discussions with the eP and JP. right now there is an expert working group (eWG) that has been set up by iCH (international Committee on Harmoniza-tion) called Q3b3. it is a new eWG that has been formed which will be meeting in tallinn/estonia in June 2010, for the first time. We will be considering internationally the metals and the limits, and i expect that metals and limits will likely to be harmonized through that Q3b process. What we can say is that there is now an international forum to decide on which metals to include at which levels. toxicologists and people from the measurement side will both be at the table for the discussion.

When will the FDA or other health organizations start to conduct their audits in accordance with the new guidelines?it is too early to comment. the FDA will not enforce the chap-ters until the standard becomes official which will be years from now. i don’t anticipate any short-term changes. After it goes official, the FDA can decide how they choose to enforce it. it is really different than europe, as the USP is not ministerial and we have no enforcement authority. We are only a standard-setting body. the FDA will decide how they will enforce it.

Is there in the foreseeable future another general updated method with similar impact on your agenda?Not of this magnitude. We are updating our chapters on a rou-tine basis but in terms of industry impact this is our biggest one in a while. the previous big one was our chapter <467> for residual solvents. But for now there is nothing on the horizon that rises to this level.

Tony, thanks for the update and the insight into the current thinking of the USP.

USP DefineS, SolviAS ProviDeS

Change is coming to the USP for heavy metal analysis but when? our in-depth interview with the USP revealed that the current sulfide precipitation test will remain effective for a few more years. Solvias will therefore continue to provide tests under the current guidelines USP-NF <231> and Ph. eur. 2.4.8. Nevertheless manufacturers are being prompted to identify risks of metal impurities in existing products. in the

meantime, however, the latest multielement screening tech-nologies such as iCP-oeS and iCP-MS are in common use dur-ing development and may eventually become mandatory. Solvias already performs validated analyses based on these methods. our philosophy is about providing our clients with choice and in particular access to the most appropriate fit for purpose technologies.

References1. http://www.usp.org/hottopics/metals.html or www.usp.org2. http://www.ema.europa.eu/home.htm3. http://www.ich.org Impurities in New Drug Products


Antibody drug conjugates – Challenges of combining small and large moleculesit has emerged that the “quality” component of regulatory success with ADCs necessitates an integrated drug and biologic approach by both the industry and regulatory agencies. this presents the devel-opment community with the challenge of satisfying the regulators through the integration of pertinent analytical methods for both small and large molecules. Author: Dr. Frank Moffatt

A century ago, the chemist Paul ehrlich dreamt of curing diseases with chemical “magic bullets”1. only during the last decade and still today, despite there being just one antibody drug conjugate (ADC) on the US market, there are increasing activi-ties in patenting and late-phase clinical trials with the involvement of many major pharma companies.

ADCs, the latest generation of magic bullets very much resemble “Go onto loca-tion-in-Space”-guided missiles programmed to detonate at a fixed location. the des-tination is a tumor cell containing receptors that are recognized by the antibody component of the ADC. After internalization, a lethal cytotoxic small molecule drug is released within the cancer cell through a chemical or biochemical process. Figure 1. Drugs are seldom free from side effects but the linkage of a toxin to an antibody results in a prodrug situation. the risk of target-independent toxicity is assessed in nonclinical studies in one rodent and one nonrodent species, ideally in a species that contains the target 2.

this article explores the technoregulatory challenges faced by the analyst respon-sible for quality control and stability. Since most developments are in the USA, the focus will be upon the expectations of the Food and Drug Administration (FDA).

MylotArg™ – A CASe StUDy of the only CoMMerCiAl ADCAs of March 2010, the only ADC on the market is Pfizer’s Mylotarg™ (gemtuzum-ab ozogamicin)3 which received FDA authorization on May 17, 2000, for the treat-ment of CD33-positive acute myeloid leukemia. Mylotarg™ combines an antibody to CD33, a sialic acid-dependent adhesion glycoprotein, commonly found on the surface of leukemic cells with an antibiotic calicheamicin that is highly efficient at cleaving DNA, leading to cell death. once internalized into the cell, the ADC releases a toxin under the acidic conditions found in the lysosomes. the toxin NAc-gamma

Dr. frAnk MoffAtt— Product Manager Biopharmaceutical Analysis


calicheamicin DMH becomes conjugated to glutathione to produce the pharmaco-logically active substance 4. Calicheamicin is a fermentation product of the Actinomy-cete (filamentous bacterium) Micromonospora echinospora subspecies calichensis. each ADC molecule has 2–3 molecules of toxin, but the physical bulk is dominated by the monoclonal antibody (MAb).

ADC reSeArCh ACCelerAteSthe research pipeline took a dip in patent activity between 2006 and 2008, but now looks more productive than ever. Figure 2. At first sight the small number of toxins and linker chemistries appears limiting; however, when the full range of permutations are considered there is a huge area to be explored. on the antibody side alone we have whole MAbs including igG1, igG2 and igG4, and various fragments thereof such as FAb, F(Ab’)2, ScFv, and single vH domains. linkers include cleavable peptides, disul-phides and hydrazones. toxins range from tubulin inhibitors (maytansineoids, au-ristatins and taxol) to DNA disruptors (calicheamicin and duocamycins) and topoi-somerase inhibitors (doxorubicins and camptothecins). each part and any particular combination of antibody, linker and toxin may have an impact upon quality, safety or efficacy.

> Figure 1: Antibody drug conjugate activity leading to cell death


riSkS AnD reWArDS of DeveloPMentDrug development operates against a backdrop of continuous change in a highly competitive environment. Despite promising data from cancer trials, in 2005, the Seattle Genetics product employing the toxin doxorubicin (SGN-15, cBr96-Doxoru-bicin) was dropped in favor of even more promising ADC candidates. indeed, tak-ing the industry as a whole, the development pipeline shows an acceleration in iND filings for ADCs. Figure 3.

Figure 3: Development activity – Number of ADC IND submissions to FDA

Figure 2: Research activity – ADC patents. Source: http://www.faqs.org/patents/app/20090226465

2005 h2

2006 h1

2006 h2

2007 h1

2007 h2

2008 h1

2008 h2

2009 h1

0 10 20 30 40 50

1993–1997

1998–2002

2003–2007

2008–2009

0 10 20


CAliCheAMiCin (Pfizer)

MylotArg™ Acute myelogenous leukemia Anti-CD33 Pfizer

CMC-544 lymphomas Anti-CD22 Pfizer

MAytAnSinoiD (iMMUnogen)

Bt-062 Multiple myeloma Anti-CD138 Biotest

iMgn901 Multiple myelomarelapsed or refractory solid tumors

Anti-CD56 immunoGen

iMgn388 Solid tumor Anti-integrin immunoGen

t-DM1 (trAStUzUMAB-DM1)

Breast cancers Anti-Her2 roche (Genentech)

SAr3419 Non-Hodgkin’s lymphoma Anti-CD19 Sanofi-Aventis

BiiB015 Solid tumor Anti-Cripto Biogen idec

AUriStAtin (SeAttle genetiCS)

MeDi 547 Solid tumor Anti-ephA2 AstraZeneca (Medimmune)

Mn-iC Solid tumor Anti-MN Bayer

Cr-011 Breast cancerMelanoma

Anti-GPNMB Curagen

PSMA ADC Prostate cancer Anti-PSMA Progenics

Sgn-35 (BrentUxiMAB venDotin)

lymphoma, large-cell, anaplastic, and Non-Hodgkin

Anti-CD30 and Anti-GPNMB Seattle Genetics

Sgn-75 renal cell carcinoma Non-Hodgkin’s lymphoma

Anti-CD70 Seattle Genetics

UnDiSCloSeD toxin (BMS/MeDArex)

MDx1203 renal cell carcinoma Non-Hodgkin’s lymphoma

ANti-CD70 BMS/Medarex

Table 1: ADCs in United States’ Clinics – Grouped by Toxin Innovators


What is in the ADC development pipeline? Currently there are 14 drugs in the clinic, including pivotal trials, based on the toxins calicheamicin, maytansine and auristatin. Table 1. Many other companies license ADC technologies from the leaders immuno-Gen6 and Seattle Genetics with chemistries based on the toxins maytansine Figure 4 and auristatin Figure 5 respectively and associated linkers. the linker in Seattle Genetics’ brentuximab vendotin consists of the amino acids valine and citrulline that is cleaved inside tumor cells enzymatically by cathepsin.

Figure 4: Antibody-maytansineoid conjugate. Courtesy of Godfrey Amphlett, ImmunoGen, Inc.

Figure 5: The chemical structure of monomethyl auristatin E ADCSource: http://en.wikipedia.org/wiki/Monomethyl_auristatin_E


AnAlytiCAl CoMPlexity ASSoCiAteD With qUAlitythe analyst must resolve complexity, heterogeneity, and establish stability indicat-ing assays. Additional measurements beyond those for a MAb are needed owing to the presence of a cytotoxic agent and a linker and the possible presence of free and bound agents.

in the case of Mylotarg™, the chemistry of ADC formation leads to aggregation pos-ing a theoretical risk of immunogenicity, therefore the monomer is purified by size exclusion chromatography. other process-related impurities are reduced to low levels. the only evidence of immunogenic response in the clinic was associated with the linker and was transient in nature. Gemtuzumab ozogamicin has been characterized structurally by spectroscopic, electrophoretic and chromatographic assays, and func-tionally by eliSA and immunoassays.

Superimposed upon heterogeneous glycosylation, the toxin is linked to multiple sites. this further heterogeneity may be observed in the deconvoluted mass spectrum of an intact ADC. Figure 6. All sites are not fully occupied resulting in a distribution of drug anti-body ratios (DArs). Deglycosylation simplifies the picture revealing a distribution of DArs. Figure 7. Despite the heterogeneity, current manufacturing processes reliably deliver products of a highly reproducible quality. And then, beyond the desired chemi-cal reactions, there are well-known side reactions such as the reaction of succinimide groups with the oH of tyrosine residues that may be observed to some extent.

> Figure 6: Mass spectrum of a maytansineoid conjugate. Courtesy of Godfrey Amphlett, ImmunoGen, Inc.


> Figure 7: Mass spectrum of a deglycoslated maytansineoid conjugate.

Courtesy of Godfrey Amphlett, ImmunoGen, Inc.

Standard analytical techniques include SeC, MS, Ce-SDS, imaged cieF, peptide map-ping and rP-HPlC. For cysteine-linked ADCs, nondenaturing hydrophobic interac-tion chromatography (HiC) is especially useful in resolving the species by the number of conjugations. the average DAr is an essential parameter but must be linked to the loading distribution of the ADC population. For cysteine-linked ADCs, a DAr near 4 appears to be optimal.

Critical quality attributes (CQAs) of the MAb intermediate are variation in size (SeC or Ce), charge (ieF), sequence (peptide mapping) and potency (target binding eliSA). For the ADC itself the CQAs are size variants (SeC or Ce), DAr (Uv absorbance spec-troscopy or mass spectrometry), free drug and potency (cell killing and eliSA). if the small molecule has a chromophore that is distinct from the antibody, Uv absorbance spectroscopy is a convenient and cost-effective method for DAr. QC methods must be both specific for linker and toxin and sensitive enough to detect clinically signifi-cant levels of unbound molecules. Free antibodies need to be determined.

if we compare lysine versus cysteine-linked conjugates, the information provided by charge- versus size-based separations of intact ADCs also depends upon the linker chemistry. reactions with lysine change the charge distribution reflecting the charge heterogeneity of the conjugate rather than the underlying antibody. For cysteine-linked conjugates, on the other hand, the situation is more straightforward in that the conjugation does not change the charge heterogeneity of the antibody.


Peptide maps contain a large amount of information often encompassing the entire primary structural features of the ADC. A comparison with the free MAb can identify sites of conjugation. Peptide maps are consequently a powerful tool for providing evidence of batch-to-batch consistency.

Whilst the MoA is cytotoxicity, binding of the ADC to the target antigen is a neces-sary component. therefore, in addition to the drug concept of strength that depends upon purity, as a measure of activity to control the dose, we require the biologics concept of potency meaning a quantitative measure of the specific ability to effect a given biological result. For ADCs cytotoxicity is used to measure potency and an-tibody content is used to determine strength and to support the establishment of consistent composition. it was demonstrated that conjugation does not change the structure of the antibody part of Mylotarg™ and neither is the binding of the anti-body to CD33 cells affected by the presence of calicheamicin.

From a thermodynamic perspective ester or disulphide bonds are less stable than amide bonds, however, the release of cytotoxic agents is generally not observed upon long-term storage of maytansinoid ADCs 5.

All the usual stability concerns with a protein biologic apply, including aggrega-tion, oxidation, and deamidation. Glycosylation contributes to the heterogeneity, the pharmacokinetics and other biological properties, but in practice is not usually a con-cern from the point of view of product stability.

the antibody class igG4 used for Mylotarg™ has a specific tendency towards Fab-arm exchange or fragmentation whereas igG2 is prone to disulfide scrambling 5. Mylo-targ™ is administered by intravenous infusion of the drug (5 mg) over two hours. the product is a preservative-free, sterile, freeze-dried, white solid containing dextran 40, sucrose, sodium chloride, mono- and di-basic sodium phosphate with a shelf life of 36 months at 2–8°C 4.

Peptide maps are consequently a powerful tool for providing evidence of batch-to-batch consistency.


regUlAtory AgenCy ProCeSSeS At fDAPrimarily, the FDA regulates ADCs as drugs with the additional application to the an-tibody component of relevant guidance for biologics, meaning that a new drug ap-plication (NDA) applies rather than a biologics license application (BlA). the review process involves coordination between the office of New Drug Quality Assessment (oNDQA) and the office of Biologic Products/Division of Monoclonal Antibodies (oBP/DMA). oNDQA oversees the small molecule starting materials including both the toxin and the linker. oBP/DMA oversees the fermentation process including cell banking. Under the leadership of one reviewer, the two offices have responsibilities for aspects of drug substance and drug product according to their competencies. the office of Compliance (oC) conducts all aspects of facilities inspections 5.

During the course of development, comparability assessments may be required for each of the ADC components and intermediates, therefore a scientifically sound combination of characterization tools must be in place as well as QC methods. it is essential to demonstrate long-term stability of the linker MAb bond in the drug sub-stance (DS) and drug product (DP). Stability data must also support the storage of any process intermediates and the route of administration, for example infusion over several hours versus injection.

An oPPortUnity for generiCS?Mylotarg™ is no blockbuster and has the complication of small and large molecule dimensions, and for the time being it appears to be below the radar of the generics companies. intriguingly, the USA has no regulatory pathway for the approval of biosimilars7, including therapeutic MAbs that are regulated under the Public Health Service Act, but Mylotarg™ is approved as a drug even though the MAb component has many of the features of a biologic. Since ADCs are regulated as drugs under the Federal Food, Drug and Cosmetic Act there is a regulatory pathway for the approval of generics via the Abbreviated New Drug Applications (ANDA) provisions of the Hatch-Waxmann Act.


finAl reMArkSlinking a toxin to an antibody leads to quality issues straddling small and large mole-cule domains. this in turn leads to a hybrid approach for the assessment of iNDs and NDAs. Solvias, a specialist biopharma cGMP analytical service provider for both small molecule pharmaceutical drugs and biopharmaceuticals or biologics including MAbs, has the appropriate expertise and experience to support the analytical cGMP requirements of ADCs.

ADCs are shifting position from “one-hit wonder” to a core constituent of the port-folio of most if not all global (bio)pharma organizations testifying to a high level of commercial confidence that will inevitably accelerate investments in discovery.

in summary, the development pipeline testifies to a great deal of commercial interest and therefore confidence in the future of ADCs. the dream of taking mankind one step further in the treatment and alleviation of the suffering caused by a multitude of cancers by deploying guided missile technology at the molecular level may soon become a reality.

References

1. Dr. Ehrlich’s Magic Bullet, 1940, Warner Bros. Pictures

2. Addendum to ICH S6: Oct 29 2009, http://tiny.cc/PRECLINICALSAFETY

3. The story of Mylotarg, http://tiny.cc/Mylotarg

4. Refusal assessment report for Mylotarg, Procedure No. EMEA/H/C/000705, http://tiny.cc/EUMylotarg

5. Presentations by Godfrey Amphlett, ImmunoGen, Inc., Marjorie Shapiro and Michael Folkendt, FDA, Fred Jacobson,

Genentech, Inc., Elsie Webber, Pfizer, Inc., Naathan Ihel, Seattle Genetics, Inc., CMC Strategy Forum, Jan 24 2010,

Washington DC, http://tiny.cc/CMCADC

6. ImmunoGen Web site, http://tiny.cc/IMGN901 and http://tiny.cc/IMGN388

7. Frank Moffatt, Biosimilars, Prospects Magazine 02/2009, Solvias AG

Linking a toxin to an antibody leads to quality issues straddling small and large molecule domains.


in our view there are three major reasons to do this: First, it is still not possible to pre-dict the performance of a catalyst for a given substrate molecule, especially if this is multifunctional and sterically more demanding than the simple test substrates usu-ally applied. Secondly, the activity of most catalysts is not sufficient for technical ap-plications and thirdly, many of the most efficient diphosphine ligands are not easy to prepare on a larger scale and rather expensive. Since we thought that it is not easy to find yet another diphosphine which would meet these challenges, we decided to try a combination of a phosphine group with a secondary phosphine oxide (SPo), a group that has so far only been minimally explored in catalysis. our hopes that such a ligand might behave differently were based on the following considerations: SPos are stable molecules which exist in equilibrium between two tautomeric forms: the preferred pentavalent phosphine oxide and the trivalent phosphinous acid. Figure 1.

When two different substituents are attached to the P atom, a configurationally stable P-chiral group results which can coordinate to metals either via phosphorus or via oxygen, thereby strongly influencing the electronic and steric nature of the ligand. Also, we saw the possibility that in its trivalent form, the oH group of the SPo may undergo interesting interactions with substrates. last but not least we planned to link the SPo and the phosphine either with a cheap chiral backbone or to attach a cheap chiral group to the SPo, which should lead to competitive costs. Figure 2.

Figure 1: Tautomeric forms of SPOs and coordination modes.

A new ligand class for asymmetric hydrogenationChiral diphosphines are undoubtedly the most important class of ligands used in asymmetric hydrogenation. it is probably fair to say that there are now a few hundred ligands known which are able to hydrogenate unsaturated substrates with very high enantioselectivity. the question then is: Why design and synthesize yet another ligand?Author: Dr. Hans-Ulrich Blaser and Dr. Benoît Pugin

teChniCAl note

SPo-PhoSPhine


< Figure 2: Our new mixed SPO-phospine ligands

Here we describe the initial results of our proof-of-principle studies where we decided to use the well-established ferrocenyl backbone and a menthyl substituent. the first approach leads to ligands structurally similar to the well-known Josiphos ligands (therefore called JoSPophos) whereas the second approach gave menthyl-substituted SPo-P ligands (therefore called terSPophos). As can be seen, both ligand classes are of a modular nature because it is very easy to introduce different r and r’ groups, allowing tuning of the ligand properties with little synthetic effort. indeed, up to now we have prepared a total of about 30 JoSPophos and terSPophos ligands and tested a number of them using established hydrogenation test reactions. relevant results can be summarized as follows:

• the synthesis of most derivatives (i.e. with different r and r’ substituents) is readily scalable using established chemistry. the absolute configuration at the SPo center is controlled by the ferrocene or the menthyl group.

• Both ligand families give excellent enantioselectivities for the rh-catalyzed hydro-genation of a variety of functionalized alkenes such as α- and β-dehydro amino acid derivatives or methyl itaconate (see Scheme). As expected, the choice of the r and r’ group is an important design element and has a strong influence on the catalyst performance for a given substrate. Somewhat surprisingly, JoSPophos 1b gives ee values in the range of 90–>99 % with all substrates, a rather unusual, but very pleas-ing result.


Figure 3: Enantioselectivities obtained for the Rh-catalyzed hydrogenation of functionalized alkenes

• of special interest is the fact that e- and Z-eAAC generate products with the same absolute configuration allowing the use of e/Z mixtures.

• Concerning catalyst activity, we have already demonstrated that MAA and DMi are hydrogenated within <5 minutes, applying substrate/catalyst ratios of 200–1,000 at a hydrogen pressure of 1bar, giving turnover frequencies in the range 2,000–20,000 per hour!

• Ketone hydrogenation is also possible, but as yet less successful. the ru-catalyzed hydrogenation of ethyl 3-oxo butanoate gives 92 % ee rendering complete conver-sion within <17 h at s/c 5,000. Figure 3.


in conclusion, we have created a new class of hydrogenation ligands which can be prepared on a large scale at reasonable costs and which have been shown to have good hydrogenation performance for the rh-catalyzed hydrogenation of function-alized alkenes. We are optimistic that some of these ligands will perform well with the “real-world” molecules of our customers. indeed several of the ligands have been added to our research ligand library which is the basis for our high throughput screening offered as an valuable service by Solvias.

Dr. hAnS-UlriCh BlASer — Chief technology officer

After obtaining a PhD degree from the ETH Zurich and

several postdoctoral positions at the University of Chicago,

Harvard University and Monsanto (Zurich), Blaser joined

the Central Research Laboratories of Ciba-Geigy in 1976

and has been involved in building up the catalysis

department ever since, first as research chemist and later

in various executive functions. At Solvias he has been

Chief Technology Officer since its start.

Dr. Benoît PUgin — Solvias leading Scientist

B. Pugin made his PhD in the field of metal organic chem-

istry and catalysis at the ETH Zurich. In 1982 he moved

to Ciba Geigy for a postdoctoral period where he acquired

experience in molecular modelling and synthesis plan-

ning. Since 1983 he has been working in catalysis research.

He has always been attracted by interdisciplinary research

and has contributed in the fields of sonochemistry,

enantioselective hydrogenation, oxidation, catalyst

immobilization and ligand synthesis.

inforMAtion — New ligands

Out of our newly available SPO ligands, Solvias plans to launch the JoSPOphos ligands first. We will soon offer the following ligands to our customers: SL-681-1 and SL-688-1 and the corresponding enantiomers SL-681-2 and SL-688-2. While research quantities <5 g will be available through our distribution partners (Strem and Sigma Aldrich), larger quantities including commercial quantities will be available directly from Solvias.

Solvias AG, Dr. Michael Quirmbach: [email protected], + 41 61 686 61 61


october 2009

SolviAS Ag & SArCoDe CorPorAtionSolvias AG and SArcode Corporation enter an expanded chemical development and manufacturing agreement.

Solvias will provide ongoing process r&D support and deliver SArcode’s active pharmaceutical ingredient (APi) SAr 1118 for use in phase ii clinical studies produced in its GMP-approved APi manufacturing facility. Solvias first became involved with SAr 1118 in 2006, when conducting initial process r&D studies, working on analytical and solid-state chemistry development, and supplying APi for toxicology studies. Major process im-provements that were implemented successfully during the development program allow cost-effective and efficient access to this chiral complex APi today. SAr 1118 is a potent novel small molecule antagonist of lym-phocyte function-associated antigen-1 (lFA-1; CD11a/CD18; αlβ2) that can be targeted against a broad range of ocular inflammatory conditions in ophthalmology and dermatology. SAr 1118 topical ophthalmic Solution is currently under inves-tigation in a phase ii study in dry eye disease and future devel-opment plans include a topical dermatologic formulation for atopic dermatitis. “We have been working successfully with Solvias for the last three years and truly appreciate the professional performance, enthusiasm, and can-do attitude of Solvias’ staff,” said John Burnier, President of SArcode. “We look forward to this next phase of our collaboration.”

About SArcode SArcode is a privately held biopharmaceutical company focused on the development of best-in-class small molecule lFA-1 antagonists as novel nonsteroidal immunomodulators/anti-inflammatory agents for the treatment of t-cell mediated inflammatory diseases.

For additional information on SArcode Corporation, please visit www.sarcode.com.

News

october 2009

SolviAS Ag WinS eUroPeAn oUtSoUrCing AWArD 2009the award was received in the category “Best Analytical Contract Project.” Solvias performed the complete analysis within strict deadlines for the CMC documenta-tion for iDM Pharma’s orphan medicinal product MePACt®.

the combination of professional project management, skilled technical staff, state-of-the-art equipment and practices and an ingrained GMP culture were vital factors.

the task for Solvias was to develop, validate and perform tests for batch release including comparability and stability studies. the analysis of Mifamurtide was not only challenging due to the physical and chemical properties of the molecular entities them-selves, but these challenges were compounded by the need for a transition from older methods to ones that meet current stan-dards within a tight timescale. the project’s success was also thanks to teamwork, as close collaboration between the three key contract manufacturers on three continents, Switzerland (drug substance), Japan (lipids) and the US (drug product), was necessary. the strategy of separating analysis from manufactur-ing requires strong project management but has proven to be a cost-effective model that mets all the sponsor’s demands. iDM Pharma’s MePACt ® (Mifamurtide, l-MtP-Pe) received approval in europe in March 2009, for treatment of patients with high-grade resectable nonmetastatic osteosarcoma.

“We are very proud to have contributed to the success of our customer and to this project which provided us with the oppor-tunity to win the european outsourcing Award. the award is a great honor for Solvias and a testimonial to our competence in handling complex, analytical tasks within strict deadlines to sup-port our customers in a cost-effective way,” stated Dr. Hansjörg Walther, Ceo of Solvias AG.

More about the Award: www.europeanoutsourcingawards.com


october 2009

going greenGoing Green is the root of Solvias’ footprint.

Cutting Co2 emissions, reducing paper waste, and recycling stand materials were behind Solvias’ winning the CPhi’s inaugu-ral UBM Green Award. Solvias earned the award for its innova-tive efforts to prevent and reduce environmental impacts of its exhibition stand. Applicants had to meet the following criteria: minimizing environmental impacts, economic indicators, along with demonstrating commitment to change, community and conservation. Solvias ticked all the boxes.

the booth minimized the use of computers, reduced Co2 emis-sions by cutting long distance shipping, and is structured in such a way so as to be reused for other exhibitions in the future. together with an environmentally friendly local stand builder in Madrid, it was decided that 85% of the graphics used for the booth should be made from fabric as the printing process is less toxic than for plastic-based materials and takes up less room during transportation.

Solvias executive vice President Stephan Haitz said recyclable/reusable material and sustainable practices was part of the com-pany’s ethos. “We are very much embedded in our society and environmental issues are very important for management and employees. this is the general set-up of our company.”

october 2009

8th SolviAS SCienCe DAy – BeyonD CheMiCAl DeveloPMent AnD CAtAlySiSthe last Solvias Science Day combined, for the first time, the traditional Chemical Development and Catalysis program with parallel sessions on analytical aspects of research and development processes.

the 15 lectures were attended by 220 colleagues from research, development and production in the life science and fine chemi- cals industry. Whereas the majority of visitors came to follow the well-established presentations on Chemical Development and Catalysis, the newly launched Analytical Development pro-gram was a success attracting more than 50 participants.

the Science Day was also a suitable setting for honoring the winner of the Solvias ligand Contest 2009. the jury of the annual Contest awarded the 2009 first prize jointly to Prof. F. Dean toste (UC Berkeley, USA) and Dr. Nicolai Cramer (etH, Zürich) in recognition of their significant contributions in the area of asymmetric catalysis and the application of Solvias ligands.

Missed the event? We look forward to welcoming you at our 9th Solvias Science Day which is planned for october 25, 2010. For up-to-date information about the program and speakers, please sign up for our Science Day newsletter www.solvias.com/News&events/SolviasScienceDay

Dr. Justice Tettey from the Laboratory and Scientific Section of the United Nations Office on Drugs and Crime (UNODC) talked about Making Laboratories fit for purpose: The UNODC Forensic Work Program.


January 2010

neW SolviAS heADqUArterS: toPPing-off CereMony helDConstruction work on our new head-quarters in Kaiseraugst, Switzerland, is moving ahead at full speed. After just 10 months of construction, the frame-work of the building was already com-pleted in late November 2009, while the traditional topping-off ceremony was held on January 20, 2010.

the useable space of 14,000 m2 over six stories is the ideal area to consolidate most of the Solvias services at one central loca-tion. the model lab built by Waldner in November offers a first impression of how the space will be used in the future. this walk-in prototype will help with the planning and ordering pro-cess for the proper fittings for all laboratories. Solvias is working with Dr. Heinekamp labor- und institutsplanung Gbr to plan this state-of-the-art laboratory space in detail.

the planning for the relocation which is expected to occur at the end of 2010 is in full swing. “the move will have little im-pact on our clients; only the address will change,” says Hansjörg Walther, Ceo of Solvias. “our extensive array of machinery and equipment will allow us to move most labs gradually, posing minimal interruption to our operations.”

the construction costs of CHF 70 million, including the prop-erty purchase, are being financed by way of a real estate lease agreement with our partner Credit Suisse AG. this first step into the future also takes the next steps into account: a space of 6,800 m2 has been set aside for growth in the coming years.

February 2010

gMP MAnUfACtUring AgreeMent With vitAe PhArMACeUtiCAlSvitae Pharmaceuticals has entered into an agreement for the manufacturing of the active pharmaceutical ingredient (APi) for its lead product candidate, vtP-27999, an orally available renin inhibitor for the management of hypertension and end organ protection.

in 2008, Solvias conducted initial process r&D studies includ-ing analytical and solid-state chemistry development and sup-plying the APi for preclinical studies. Several process improve-ments were successfully achieved during the development program, which has significantly lowered the costs while purity and ease of synthesis of this APi were improved.

richard Gregg, Chief Scientific officer of vitae Pharmaceuti-cals, found good reasons to extend the collaboration saying: “the Solvias GMP facility enables us to significantly improve our timelines by eliminating the need for tech transfer between process optimization and GMP manufacturing. the quality, capability and our confidence in Solvias led us to choose them for this critically important work.”

About vitae Pharmaceuticalsvitae Pharmaceuticals is a clinical-stage biopharmaceutical company building a portfolio of novel, small-molecule, best-in-class compounds that address large markets, including hypertension, diabetes and Alzheimer’s disease. vitae’s pipeline of programs focuses on high-value, hard-to-drug targets, inte-grating a proprietary, structure-based drug design platform with the experience and insights of a world-class r&D team. vitae is located in Fort Washington, Pennsylvania.

For more information on vitae, please visit the company’s Web site at www.vitaepharma.com.


events

AAPS – NAtioNAl BioteCHNoloGy CoNFereNCe

May 16 –19, 2010San Francisco, CA, USA find out more about • Biopharmaceutical Analysis

BioteCH oUtSoUrCiNG StrAteGieS (BoS)

June 17, 2010Copenhagen, Denmark

SolviAS SoliD-StAte DAy

September 10, 2010Boston, US

for more informationMichael Becker, +41 61 686 61 41 [email protected]

BioteCH oUtSoUrCiNG StrAteGieS (BoS)

September 21, 2010London, UK

CHeMoUtSoUrCiNG CoNFereNCe

September 14 –16, 2010Ocean Place Resort – Long Branch, NJ, US find out more about • Chemical and Analytical Development• GMP Manufacturing• Catalysis

CPHi WorlDWiDe

October 5–7, 2010Paris, FranceBooth 6F38 find out more about • Polymorphism, Salt, and Crystallization• Chemical and Analytical Development• GMP Manufacturing• Catalysis

9tH SolviAS SCieNCe DAy

October 25, 2010Congress Center Basel, Switzerland

the program features contribution from world leading scientists of the life sci-ence industry and academia, presenting new trends, technologies and solutions for research and development of drug compounds. the Solvias Science Day offers parallel sessions with focus on chemical development, catalysis, analyti-cal and solid-state chemistry framed by special talks and case studies. the pro-gram will be completed by the well-known ligand contest. For up-to-date information about the program and speakers, please sign up for our Science Day newsletter www.solvias.com/News&events/SolviasScienceDay


SolviAS – yoUr reliABle PArtner in the PhArMACeUtiCAl inDUStryif you are looking for increased capacity or profound know-how for your development or manufacturing activities, our ex-perience and proven track record gives you confidence that your projects will be expertly performed and delivered on time. With our services, products and technologies in the field of analytical, chemical and biopharmaceutical development, we provide integrated solutions to enhance the value chain of our customers.

• Analytical Services • Biopharmaceutical Analysis• Polymorphism, Salts, and Crystallization• Chemical Development and GMP Manufacturing• Catalysis• Process Analytical technology (PAt)• Patent and Search Services

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Picture credits:Patrik Hänggi, Solvias AG Archive, USP

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