Prospects 02/2010 - The Solvias Magazin

High throughput – High science, a prosperous liaison?

Biosimilars – A selection of updates

Improved product quality via NIR – Real-time monitoring of tablet coating thickness

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2 SolviaS ProSPectS — 2/2010

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Preface of the Head of Marketing and Sales 4

News 6

improved product quality via Nir – real-time monitoring of tablet coating thickness 13

Biosimilars – a Selection of updates 19

High throughput – High science, a prosperous liaison? 21

asymmetric hydrogenation of unfunctionalized olefins

24

Fiber optic probes – Keeping an eye on processes 28

9th Solvias Science Day 2010 30

events

content

3SolvIaS PRoSPectS — 2/2010

DR. StephAn hAitz — Head of Marketing and Sales

Dear reader and valued customer

Summer is slowly coming to a close, and whilst most people were enjoying a cer-tainly well-earned holiday, we at Solvias have been plowing ahead, busy ensuring that the transition to our new headquarters will move along smoothly. and we are well on track to achieve this, as you will notice from some of the exciting news we have to share with you.

on time for tomorrow. Solvias recently received the certificate of GMP compliance for the new site in Kaiseraugst. We are ready to move in over the seasonal holidays and expect to be fully operational by early January 2010.

When tablet coating thickness matters – How near-infrared (NIR) spectroscopy as a process analytical technique for real-time determination of tablet coating thickness during the coating process can lead to improved product quality.

Keeping an eye on your process with fiber optic probes. Did you know that Solvias has more than 26 years of experience in probe construction and is recognized as one of the pioneers in this area? a smart team provides customized probes for process control – meet some of them on page 24.

Scientific expertise at Solvias – asymmetric Hydrogenation of Unfunctionalized olefins. thanks to their very special hydrogenation profile PN-Ir catalysts open the door to many attractive chiral molecules. as the first company to make such cata-lysts commercially available, Solvias has also given these catalysts a fixed place in our ligand/catalyst platform.

talking about science, on october 25, 2010, the 9th Solvias Science Day will be held at the congress center Basel. In three parallel lectures leading experts from science and industry will provide insights into trends in chemical and analytical development in-cluding catalysis and solid-state development. We look forward to seeing you in Basel!

We sincerely hope you will enjoy reading this magazine as much as we enjoyed putting it together for you.

Yours,

Dr. Stephan Haitz

4 SolvIaS PRoSPectS — 2/2010

august 2010

new heADquARteRS ReceiveS GMp AuthoRizAtionGetting a manufacturing license for Solvias’ future headquarters in Kaiseraugst is an important achievement in the company’s relocation strategy.

Both the future analytical facilities as well as the planning and concept of the move were successfully inspected by the RHI (Regional Medicines Inspectorate of North-Western Switzer-land) on June 25, 2010. the inspection was also an essential precondition to apply to Swissmedic (National competent authority) for the GMP Manufacturing license. the license con-firms that the new laboratories will be GMP-approved for all an-alytical services once the transfer is accomplished as planned.

as both the interior and exterior construction work is on sched-ule, Solvias aG will be able to move into the new building by mid to late December 2010. as of January 1, 2011, our address will be: Solvias aG, Römerpark 2, 4303 Kaiseraugst, Switzerland. With 14,000 m2 distributed over six stories, the new building is ideal for centralizing most of our services at one location. the certificate of GMP compliance for the new site is already available for download at: http://www.solvias.com/english/quality/gmp/index.html

News

august 2010

SAlt pRoGRAM foR ReSeARch oR eARly DRuG DevelopMentSolvias has set up a new salt screening program which requires only 200 mg of drug substance.

In order to speed up the drug development process and to reduce the attrition rate during this phase, it is important to acquire as much information as possible on drug substances as early as possible. Because of this, a growing number of phar-maceutical companies are shifting salt screening programs from early development to late research with the intention of selecting the “right” candidate (free drug or salt) at this stage and thereby avoid investments in “wrong” forms at a later stage.

to support our clients accordingly, Solvias has set up a salt screening program which uses only 200 mg of drug substance for a screening which comprises 12 counter ions, 96 crystalliza-tion experiments and scale-up of 2 leads up to 20 mg scale for further analytical investigation or other purposes.

By utilizing our long-term scientific experience, paired with lab automation technology on low mg scale and high throughput analytical investigation, we can support our customers with a fast salt program to gain scientifically sound information for candidate nomination.

FirstimpressionsofourfuturelaboratoriesinKaiseraugst,CantonAargau Afullyautomatedplatformforsolid-statedevelopmentexperiments


September 2010

SolviAS ADDS enzyMe AnD clASSicAl ReSolution ht-ScReen-inG cApAbilitieSSolvias has implemented enzyme screen-ing and classical resolution capabilities to its screening platform as part of its chem-ical development service.

With this further addition, Solvias now offers rapid evaluation of chemo-, biocatalysis and classical resolution steps to identi-fy economically feasible routes on behalf of its customers. this fast and cost-effective solution can enhance the route selec-tion process for any chiral intermediate or aPI.

the enzyme collection contains approx. 200 proprietary enzymes (mainly ketoreductases) from various established pro-viders. enzymes were selected on the basis of guaranteeing supplies of larger quantities within a short period of time to ensure a seamless scale-up to multi kg-scale.

classical resolution is generally performed using either 32 chiral acids or bases, respectively, depending on the substrate and pKa values. experiments are generally conducted on a 0.4 ml scale and analysis and determination of ee using SFc-chroma-tography.

Michael Quirmbach, Product Manager at Solvias, says: “By ex-panding the utilization of our screening platform we enhance our route-identifying process to provide the pharmaceutical industry with fast results.”

Recognized as an expert in asymmetric homogenous cataly-sis, Solvias started implementing Ht-Screening services in the area of asymmetric hydrogenation in 2003. Since then, the capabilities have been successively expanded in the fields of cX-coupling, heterogeneous hydrogenation as well as cus-tomized screening capabilities in the rapidly growing area of organocatalysis. customers today can benefit from standard-ized plates at a low price to highly sophisticated customized plates running even the most complex catalytic chemistry. complemented by scale-up and manufacturing capabilities for aPIs up to clinical phase II, Solvias supports its customers dur-ing the entire chemical and analytical development process.

august 2010

extenDeD licenSe foR the MAnufActuRinG AnD hAnDlinG of contRolleD SubStAnceSSolvias has recently been authorized by the Swiss authorities (Swissmedic) to manufacture and handle narcotic and psychotropic substances (aPIs) at its chemical development and manufacturing sites.

this represents an extension to the existing license to handle controlled substances in its analytical division.

Michael Quirmbach, Product Manager at Solvias, comments: “the license will strengthen our integrated service and will now give our clients the possibility to benefit from a complete package ranging from chemical and analytical development to supply of aPIs up to phase II for this class of compounds.”


Improved product quality via NIR–Real-time monitoring of tablet coating thicknessthe coating of medicinal tablets is a complex science as the thickness of the coating plays a critical role on the therapeutic effects of the compound being delivered. Precise knowledge of coating thickness can now be gained through process analytical methods with near-infrared (NIR) spectroscopy that deliver fast and cost effective results.Author: Dr.DominiqueKummli

intRoDuctiontoday most pharmaceutical tablets are coated after compression. coating tablets can have therapeutic, technologic or marketing aspects. therapeutic aspects include e.g. avoiding inactivation of the drug in the stomach (enteric coating), improving drug effectiveness or taste masking whereas technologic aspects include e.g. reduc-ing environmental influences or shelf life. In the case of improving drug effective-ness coatings are often chosen to control (i) the rate of dissolution (functional coat-ing) and (ii) the location of the release of the drug. Precise knowledge of the coating thickness is therefore crucial for therapeutic aspects and have to be monitored by analytical methods.

In 2002, the FDa initiated Pat (Process analytical technology) with the goal of ensuring final product quality.

In its guidance for the industry, the FDa considers Pat to be a system for designing, analyzing and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes. Near-infrared (NIR) spectroscopy can be employed as a process analytical technique for real-time determination of tablet coating thickness during the coating process.

expeRiMentAltaBlet coatINGFor this study, two batches of tablets produced in a thomas engineering accela-cota FleX 05 benchtop coater with a coating time of 300 minutes were investigated both off- and in-line. the tablet core consisted of magnesium stearate and lactose which

DR. DoMinique KuMMli — Project leader Process analytical technology

DominiqueKummlididhisPhDinthefieldofhighresolutiontimedomainlaserspectroscopyattheUniversityofBern.Afterashortpostdoctoralperiod,wherehefocusedmainlyoncomputationalchemistry,hemovedtoSolviasAGin2008.SincethenhehasbeenworkinginthefieldofProcessAnalyticalTechnology(PAT).Hismaininterestshavealwaysbeeninappliedspectroscopy,wherehecontributedinthefieldsofstructuredeterminationaswellasPATapplications.


was coated with opadry® orange and rhodamine as a tracer. the tablets were coated up to 10 % weight gain, which corresponds to a coating thickness of about 120 μm. For the off-line analysis, a total of 20 tablets per batch sampling time points were measured by means of NIR, weight and coating thickness. For the in-line measure-ments, a total of 30 tablets per sampling time were taken and the diameter was again determined. 32 NIR spectra were averaged resulting in data points every 30 seconds. In both cases, samples were taken every 30 minutes.

SPectRoMeteR aND PRoBe NIR measurements were conducted with a Bruker MatRIX-F spectrometer and a Solvias Reflector diffuse reflection probe. the tablets were measured off-line with an in-house developed tablet holder, where the tablet-probe distance was about 1 mm. For the in-line experiment, the probe was installed through an existing port of the coater.

ReFeReNce MetHoDSeveral different reference methods can be used for predicting film coating, e.g. the often used weight gain method, microscopic thickness measurements or thickness measurements with micrometer screws. Since the weight gain method is considered to be less than ideal we focused on the microscopic and micrometer screw methods and compared them. Both yield similar results concerning the accuracy and since the determination of the thickness by means of measuring the tablet diameter with a micrometer screw is much simpler it was taken as the reference method. the measur-ing error of the reference method was determined to be about 1σ = 3μm.

In the case of improving drug effectiveness coatings are often chosen to control the rate of dissolution.


ReSultS AnD DiScuSSionSPectRal cHaNGeSFigure1 shows the first derivative of the averaged spectra. arrows symbolize the direc-tion of the change in the spectra during the coating process in the selected wave-length regions. Both regions are spectral features, which can be related to signals from the tablet core and are therefore decreasing during the coating process.

5,0006,0007,0008,0009,000

Absorption/a.u.

Wavenumber/cm-1

Figure1:Firstderivativeofaveragedspectrafrom20tabletspersamplingtime.Arrowsindicatethechangeinthesignalsduringthecoatingprocess

QUaNtItatIve calIBRatIoNMultivariate models were developed by correlating NIR spectral data with the coat-ing thickness. the partial least squares (PlS) fit using the first derivate and multipli-cative scatter correction (MSc) as data pretreatment yielded a root mean square er-ror of cross validation (RMSecv) of 0.98 μm and a R2 of 99.92 for the off-line analysis. Figure2 shows a three-dimensional plot of the optimization of one of the wavelength regions compared with the RMSecv. It can be seen that the optimal region is be-tween 5,350 and 5,900 cm-1.


For the in-line model the same wavelength region was used together with MSc data pretreatment. the PlS fit yielded a RMSecv of 0.89 μm and a R2 of 99.95.

valIDatIoN oF tHe oFF-lINe MetHoDFor each sample time, two tablets were used for the validation of the off-line model. the tablets were measured on both sides and analyzed with the developed model. Table (seepage11) lists the results obtained. the root mean square error of prediction (RMSeP) is 2.86 μm. the NIR results (chemometric prediction) are the averaged results from both tablet sides with the corresponding standard deviation ±1σ. as mentioned above, the standard deviation of ± 3μm is the measuring error of the reference method. largest deviations are found to be about 5 μm absolute (first measurement at 270 min), which yields an absolute error of 5%. Figure3 shows the measured and pre-dicted coating thickness with the corresponding standard deviations.

Figure2:Three-dimensionalplotoftheoptimalwavelengthregioncomparedwithRMSECV


valIDatIoN oF tHe IN-lINe MetHoDthe results of the in-line coating thickness measurements are illustrated in Figure4. after a warm-up time of five minutes the measured tablet thickness increased linearly from 0 μm to about 125 μm. Deviation from the linear trend originates from the batch sampling of the tablets, which can be observed after 60 or 150 minutes. During the entire process, the difference between the actual coating thickness and the value estimated by the NIR remained within the measuring error of 3 μm. the obtained RMSeP is 3.83 μm for the in-line prediction of the coating thickness. Table.

0 50 100 150 200 250 300

120

100

80

60

40

20

–20

0

Coat

ing

thic

knes

s/μm

Coating time/min

Figure3:NIR-predicted(blackdots)anddetermined(orangedots)coatingthicknesswiththecorrespondingmeasuringerror


coAtinG tiMe/Min

RefeRence niR

00.0±3.0 0.2±0.3

0.0±3.0 0.5±0.3

153.5±3.0 4.8±0.3

2.8±3.0 4.9±0.2

304.9±3.0 9.4±0.5

7.7±3.0 10.9±1.0

4510.3±3.0 13.4±0.3

13.7±3.0 14.9±0.0

6016.5±3.0 19.2±0.4

18.5±3.0 17.2±0.1

9030.0±3.0 26.0±0.1

21.3±3.0 25.0±0.6

12041.2±3.0 40.7±1.1

39.3±3.0 36.0±2.1

18057.2±3.0 54.9±2.3

56.3±3.0 58.0±2.1

21059.0±3.0 60.4±1.9

65.0±3.0 68.3±0.7

24084.3±3.0 83.0±3.5

70.3±3.0 74.7±0.3

27095.3±3.0 90.4±0.3

86.0±3.0 87.7±1.2

30095.0±3.0 93.2±1.2

106.0±3.0 104.3±3.0

The determination of the coating endpoint and the monitoring of the process without manual sampling

can lead to significant reduction in coating times and costs.

>Table:Resultsofthevalidationmeasurementsofthecoatingthickness(μm)


concluSionSWith this dynamic approach to process control, one of the important tablet attri-butes is measured during the process to control it and to determine its endpoint, which is in line with the FDa’s definition of Pat. With small scale R&D equipment this technique can be used to develop a design space in line with the FDa/IcH Quality by Design (QbD) initiative for a specific coating process and subsequently to detect using NIR in-line monitoring in full scale production equipment any deviation from this space during operations. the determination of the coating endpoint and the monitoring of the process without manual sampling can lead to significant reduction in coating times and costs especially for enteric or functional coatings. •

140

0 50 100 150 200 250 300

120

100

80

60

40

20

0

Coating time/min

Coat

ing

thic

knes

s/μm

Figure4:In-lineNIRmeasurementsofthecoatingthickness.Thereferencevaluesaredenotedwithorangedotswiththecorrespondingmeasuringerror


Biosimilars – A selection of updatesafter years of debate in the USa, follow-on-biologics may now be licensed by the FDa as “biosimilar” or as “interchangeable.” Have the floodgates for biosimilars now been opened in the USa? Author:Dr.FrankMoffatt

Some biologic treatments cost well in excess of 100,000 USD per year so “generic” competition is expected to accelerate over the next three years although cost savings of only 10–30% are expected. all things considered, this is relatively modest in comparison with generic drugs but reflects the reality of manufacturing complex-ity and high regulatory hurdles.

there are now many well-established biologic targets Table including some blockbust-ers. Since the european Union has been approving biosimilars for several years it is natural to review these precedents. Whilst there is a biosimilar monoclonal antibody Reditux® (in India) it appears unlikely that this particular product would meet the comparability standards within North atlantic regulatory environments.1

bioloGicS potentiAl foR coMpetition

Human growth hormones (somatropin). Relatively simple structures. early pioneering products. Biosimilar approved in europe.

Recombinant insulins. 2013–2015 but switch to modified insulins may limit competition.

ePo (epoetin alfa). large target but technically challenging. Biosimilar approved in europe. Numerous versions in asia.

Granulocyte colony-stimulating factor (filgrastim). 2013 Biosimilar approved in europe.

Granulocyte-macrophage colony stimulating factor (sagramostim).

2014

Interferons . First generation products but these may be superseded by bio-betters such as PeGylated versions.

Monoclonal antibodies – various treatments for rheumatoid arthritis.

2014 european community in the process of producing guidelines for biosimilar Mabs. Precedent in India (copy of rituximab).

Table:Classesofbiologicmedicinesthatmaybetargetsfor“generic”competition


the fundamental basis for the future growth of sales of biologics is underpinned by the growing medical needs principally for diabetes and cancer. as a proportion, pharmaceutical costs represented by biologics continue to increase reaching 14.2% in 2009. Indeed the expectation of the congressional Budget office is that biosimilars will be responsible for savings of $25 billion by 2018.

Nevertheless the barrier to market entry for biosimilars remains high in comparison with traditional generic drugs.

In 2009, our previous article described some of the techno-regulatory differences between biosimilars and traditional small molecules. We also anticipated that the USa would establish a pathway for the authorization to market biosimilars.2 President Barack obama finally signed such legislation into law on March 23, 2010, within the monumental Patient Protection and affordable care act (PPaca). tucked away inside this bill is Section 7001 “Biologics Price competition and Innovation act of 2009.” the bill states: “It is the sense of the Senate that a biosimilars pathway balancing in-novation and consumer interests should be established.” In legal terms this amends Section 351 of the Public Health Service act (42 U.S.c. 262) under which biologics are regulated, now including a new provision for an abbreviated biological license application (aBla).

Nevertheless the barrier to market entry for biosimilars remains high in comparison with traditional generic drugs. Biosimilar producers will have the additional burden of mounting their own clinical trials; marketing in competition with an established product; facing regulatory uncertainty; and the real risk of obsolescence as second generation products, i.e. bio-betters emerge. It is claimed that development of a bio-similar can take eight years with an associated cost of $100–150 million.


who won the DebAte? innovAtoRS veRSuS GeneRicS the new bill is the product of intense lobbying. It may well take several years before the full impact of the legislation is realized. at face value the balance seems to be firmly tipped towards the innovators who had first of all urged caution on the basis of safety risks, and secondly emphasized the business need to recover costs and to generate some rewards for the risk capital staked by venture capitalists, private and institutional investors that fuels the growth of the biotechnology industry. Regarding data exclusivity, the innovators have definitely come out on top winning a 12-year shelter from generic competition although the possibility of interchangeability that would permit switching between innovator and biosimilar products without the intervention of the prescribing physician works in favor of the generics producers.

according to Kathleen Jaeger, President and ceo of the Generic Pharmaceutical association, “Simply put, the bill fails to infuse competition and choice into the healthcare system due to the excessive and unprecedented market exclusivity pro-tections for the brand industry.” 3

the fiRSt new option foR ReGiStRAtion: bioSiMilARitythe act defines biosimilarity in a flexible manner to accommodate advances in bio-technology and gives the FDa considerable discretion to waive some of the require-ments listed below. a biosimilar is “highly similar” to the reference product, possibly with minor differences in clinically inactive components but with no clinically mean-ingful differences in safety, purity and potency.

Requirements for registration:• analytical studies that demonstrate that the active biological in the follow-on

biologic (FoB) product is “highly similar” to the reference product• animal studies• clinical studies that are sufficient to demonstrate the safety, purity, and potency

of the FoB in use (including immunogenicity)• the manufacturing facility has standards to ensure the product is safe,

pure and potent• one reference substance is allowed per application


the last point would be a major issue if a reference product changes or becomes unavailable during the course of a biosimilar development program. this might undermine the whole project.

A fuRtheR new option: inteRchAnGeAbilityto be interchangeable a product will be “biosimilar” to the reference product mean-ing “expected to produce the same clinical result as the reference product.” there must be “no increased safety or efficacy risk by switching between use of the biosimilar and the reference product.” It must be demonstrated that “the biological product and reference product utilize the same mechanism or mechanisms of action.” the route of administration and dosage shall be the same as the reference product. Finally, the manufacturing process and facility of the biosimilar must be approved.

The key performance factors required to underpin successful launches of biosimilars will be operational excellence

and competence in performing a comprehensive assessment of the risks for each particular product.

the costs and complications of having to purchase and work with an innovator drug product are a significant, and for some, a determining factor in selecting the strategy for the development of a biosimilar versus a new version of an existing biologic.

Unlike biosimilarity, interchangeability offers the attraction of six months of market exclusivity for the first approved product. the task of demonstrating interchange-ability may even be insurmountable if current FDa thinking still reflects a 2007 state-ment: “there is a significant potential for repeated switches between products to have a negative impact on the safety and/or effectiveness. therefore the ability to make determinations of substitutability for follow-on protein products may be limited.” 4


optionS AnD SMARt choiceS foR AppRovAl – bioSiMilAR oR inteRchAnGeAble oR full ReGiStRAtion pAcKAGe?the whole point of the new legislation is to provide a pathway for abbreviated bio-logics application (aBla) facilitated by giving the FDa the power to define require-ments for registration on a case-by-case basis. this flexibility is simultaneously offset by uncertainty and the possibility that requirements will be onerous.

on the other hand a biologics license application (Bla) can be filed at any time, in secret with no requirement for disclosure by the innovator and will accrue 12 years of exclusivity that would make this particular biologic an unlikely choice as a reference substance. Patent issues would be resolved via the well-established court processes rather than by new and untested processes. It is difficult to draw any other conclu-sion than that the extent to which the new pathways will be used remains to be seen.

intellectuAl pRopeRty DiSputeSthe bill also creates a new process for the resolution of patent disputes that has been described as much more complicated than the by now well-established law govern-ing generic small molecule drugs, the Hatch Waxman act – that itself took many years to reach maturity. again years of uncertainty lie ahead.

bioSiMilARS – KeyS to coMpetitiveneSS the development of biosimilars is complicated. In comparison with innovation the potential returns on investment are limited. consequently, the key performance factors required to underpin successful launches of biosimilars will be operational excel-lence and competence in performing a comprehensive assessment of the risks for each particular product.

although excellence in cMc analysis is only one of several key factors it is the one that Solvias specializes in. the added value of our services includes:• laboratory data produced to an industrial standard by highly qualified staff• established cGMP system (audited by over 30 clients per year)• troubleshooting and development through our expert scientists• Risk of failure – mitigated by a professional project management team

A biosimilar is “highly similar” to the reference product.


the expertise and resources required for comprehensive cMc analysis are most likely to be found within a specialist service provider.

GlobAl peRSpectivelike it or not, numerous biologics products are being developed in semi-regulated, even unregulated jurisdictions around the world where some seriously differing views of the balance between risks and rewards are the order of the day. Inevitably data will be generated that will add to the safety and efficacy debate surrounding specific products whilst possibly influencing the seemingly opposing market de-mands for high quality but affordable medicines in highly regulated markets.

at last for biosimilars in the USa, the legislation is in place but the consequences are barely apparent! •

References1. ReedHarris,ComparabilityAssessmentStrategiesandTechniquesforPost-ApprovalCMCChanges,FABIAN2008

“Biopharma,Biosimilar,Biogenerics?Bioanalysis!”Groningen,theNetherlands,6November2008http://www.bioanalyse.org/slides/08S02.pdf

2. FrankMoffatt,BarrierstowinningtheapprovalofbiosimilarsintheUSA,ProspectsMagazine02/2009,SolviasAG3. RonLeuty,Biotechs,VCsshoot,scorewithreform,SanFranciscoBusinessTimes,March22,20104. JanetWoodcocketal.,TheFDA’sAssessmentOfFollow-OnProteinProducts:AHistoricalPerspective,

NatureReviewsDrugDiscovery,2007,6,437-442

DR. fRAnK MoffAtt — Business Development Manager

SinceJuly2010BusinessDevelopmentManageratSolviasAG.FromJuly2007–July2010ProductManagerforBiopharmaceuticalsatSolvias.


High throughput – High science,a prosperous liaison?to answer the question right away: Yes, it can be a prosperous liaison if done right.Author:Dr.MichaelBecker

the implementation of experimental methods to increase ef-ficiency within the drug development process is an important area in the pharmaceutical industry. constraints such as time, material or personnel resources are key drivers to establishing new ways of gaining useful information for the development process of a drug.

Particularly for solid-state development processes, automation has found its way into the drug development process.

on the one hand pharmaceutical companies want to know more about their drug compounds in early phases (i.e. late research). on the other hand originators try to secure their IP situation with a broad search for new forms that can be mar-keted, either as new chemical entities or as second-generation drugs. the driving force for this is the fairly low number of new chemical compounds that are registered every year.

DR. MichAel becKeR — Product Manager Solid-State Development

additionally, companies developing generic drugs are utilizing efficient experimental methods in order to find new marketable forms of existing drugs to gain market share. or simply to gain competitive advantage over other generic drug companies.

the following parameters can be critical:• Set of experiments with limited amount of material• very large number of experiments• time pressure to gain results

Particularly for solid-state development processes, automation has found its way

into the drug development process.

the optimal resolution of this dilemma is through the use of multi-parallel experiments for solid-state development pro-cesses followed by careful and scientific sound evaluation.

But is the sorcerer’s stone to be found in the purchase of high throughput equipment? or does the sole execution of hun-dreds or thousands of solid-state development experiments contribute to success?

we SuGGeSt not!If the setup for high throughput experiments is not correct, one might generate massive numbers of results that could turn out to be useless. For example, if all the experiments are conducted at 40°c for 24 h but initial stability data illustrate that the drug compound shows degradation at 30°c already within 4 h, the results of the high-throughput setup are gained rapidly but the results are worthless. the same is true if, for example, solvent


systems for the solid-state development experiments are not selected carefully. the risk of missing relevant forms is high and this can be a serious hazard.

therefore the design of the experiments is the crucial step for a successful high-throughput approach. this is where high throughput meets high science to form a prosperous liaison.

the design of experiments is key to the success of a broad solid-state development project utilizing high-throughput technologies. the following elements are part of Solvias’ design of the experiments:• Full characterization of the starting material to gain as much

information of the drug compound as possible• Based on the molecular structure and the outcome of

the characterization, the most promising crystallization techniques will be selected

• Selection of experimental conditions that will be varied within the project (e.g. temperature, concentration, time per run, etc.)

• Selection of solvents/solvent systems

the challenge of the design is to maximize the information re-turned from a minimum of experiments within the previously mentioned material, manpower and time constraints.

after the design, the process is transferred to an automated solid-state development platform Picture where experiments are conducted.

Therefore the design of the experiments is the crucial step for a successful high-

throughput approach. This is where high throughput meets high science to

form a prosperous liaison.

the solid forms will be analyzed by two independent technolo-gies (Raman Spectroscopy, X-ray Powder Diffraction) also utiliz-ing automated systems to speed up processes. all analytical details will be evaluated by special software. But as software- controlled handling of analytical data is not sufficient, to en-sure highest reliability our scientists review all results to avoid any unpleasant surprises – living up to the principle of: “trust is good, control is better.”

We at Solvias understand high-throughput systems as powerful tools that can profitably increase the coverage of experimental space for solid-state development projects. But to transform it into a success story, high science in terms of highly-qualified scientists with experience in the field of solid-state develop-ment are necessary to design the experiments properly, review the data and define meaningful recommendations to contribute to further drug development. •

Afullyautomatedplatformforsolid-statedevelopmentexperiments


asymmetric hydrogenation of unfunctionalized olefinsPN-Ir catalysts open the door to many attractive chiral molecules with very interesting potential in fields such as natural product synthesis, fragrances and electronic materials.Author:Dr.BenoîtPugin

technicAl note

In the last four decades, many chiral rhodium, ruthenium and iridium catalysts have been developed that are very efficient and selective for the asymmetric hydrogena-tion of olefins, ketones and imines. today, asymmetric hydrogenation is one of the most important catalytic methods for the preparation of optically active compounds, and several production processes are run in the industry. the ‘standard’ catalysts for asymmetric olefin hydrogenation are based on rhodium and ruthenium complexes with chiral diphosphine ligands. However, the range of olefins that can be hydroge-nated with high enantiomeric excess with these catalysts is still limited, since both systems require the presence of a coordinating group next to the c=c bond. With unfunctionalized olefins, these catalysts generally show low reactivity and unsatis-factory enantioselectivity.

Prof. andreas Pfaltz from the University of Basel was one of the first to recognize that iridium complexes with chiral P-N ligands can overcome these limitations. For a wide range of unfunctionalized olefins, excellent enantioselectivities could be achieved with these catalysts. Moreover, they showed exceptionally high activity in the hydro-genation of unfunctionalized trisubstituted and even tetrasubstituted olefins. In ad-dition, promising results were also obtained with certain functionalized alkenes for which no suitable catalysts are available yet.

one of the important clues for success was the right selection of the counter-anion of these Ir complexes. With classical anions such as PF6

- or BF4-, good enantioselec-

tivities but only poor turnover numbers were obtained. NMR-investigations indicated that this observed catalyst deactivation was caused by the fast formation of inactive hydride-bridged Ir oligomers. Many optimization and screening efforts later, Pfaltz and his coworkers found that this deactivation could be prevented by the use of the bulky and extremely weak coordinating BarF anion (BarF: tetrakis(bis-3,5-trifluor-methylphenyl)borate). this discovery opened the door to more productive catalysts (often 1,000 turnovers and more) providing the right leverage for this promising field.

DR. benoît puGin — Solvias leading Scientist

BenoîtPugindidhisPhDinthefieldofmetalorganic

chemistryandcatalysisattheETHZurich.In1982

hemovedtoCiba-Geigyforapostdoctoralperiodwhere

heacquiredexperienceinmolecularmodellingand

synthesisplanning.Since1983hehasbeenworkingin

catalysisresearch.Hehasalwaysbeenattractedby

interdisciplinaryresearchandhascontributedinthefields

ofsonochemistry,enantioselectivehydrogenation,

oxidation,catalystimmobilizationandligandsynthesis.

ubaphox

Ir


In the meantime, Professor Pfaltz’s team and others have developed a variety of efficient PN-Ir catalysts and the number of applications using these catalysts in the synthesis of biologically relevant chiral organic compounds is growing rapidly. a few examples are summarized in Figure1:

the unique scope of these PN-Ir catalysts and their very interesting potential in fields such as natural product synthesis, fragrances and electronic materials amongst oth-ers prompted Solvias to enter a collaboration with Professor Pfaltz to scale and com-mercialize selected PN-Ir systems. the first commercial catalyst family was named ‘UbaPHoX’ and consists of two derivatives both of which are available from Sigma-aldrich or Strem. a second catalyst family, ‘NeoPHoX’, is currently being developed. typical hydrogenation results for both PN-Ir families are shown in Figure2:

UbaPHoX catalysts were also successful in the hydrogenation of heteroaromatic alkenes and both UbaPHoX and NeoPHoX give promising results with imines.

Figure1:SomeapplicationsofPN-Ircatalystsinasymmetricsynthesis

catalyst Reaction

N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2

93% eedemethyl methoxycalamenene

NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2

90% yield(single diastereomer)

pseudopteroxazole(antitubercular agent)

–

N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2


NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2



–

N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2


NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2



–

N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2


NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2



–

N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2


NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2



–

N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2


NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2



–

N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2


NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2



–N

O

(o-T ol)2PIr

C OD

+

BArF

MeO MeO MeO

PN-Ir

H2


NO

O

P h2P

P h

P h P h

Ir

C OD

+

BArF –

OB nO

O B n

OB nO

O B n

O

OH

OHPN-Ir

H 2

equol93% ee

Ir

C OD

N(o-T ol)2P

O

P h

+

BArF –

O

AcO

O

AcO

tocopherol acetate

PN-Ir

H 2

>98 % RRR

N

OO

(o-T ol)2PIr

C OD

+

BArF–

MeO

H

MeO

H H

NO

PN-Ir

H2



–


>Figure2:Enantioselectivitiesobtainedforthehydrogenationofolefins

withUbaPHOXandNeoPHOXcatalysts

MeO

MeO

MeOMeO

C O O E t

O Ph, Me, C y

OH

S Ph

NO

P h

O

R2P

P h P h

Ir

C OD

+

BArF –

R= Ph SK-X001-2aR= Cy SK-X002-2a

95–99

99

92 99

99

89

9471

94

MeO

MeO

MeOMeO

C O O E t

O Ph, Me, C y

OH

S Ph

N

O

R '

R2PIr

C OD

+

BArF –

n.d.

n.d.

94 98

89

96

n.d.94

95

UbaPHoX

MeO

MeO

MeOMeO

C O O E t

O Ph, Me, C y

OH

S Ph

NO

P h

O

R2P

P h P h

Ir

C OD

+

BArF –

R= Ph SK-X001-2aR= Cy SK-X002-2a

95–99

99

92 99

99

89

9471

94

MeO

MeO

MeOMeO

C O O E t

O Ph, Me, C y

OH

S Ph

N

O

R '

R2PIr

C OD

+

BArF –

n.d.

n.d.

94 98

89

96

n.d.94

95

NeoPHoX

thanks to their very special hydrogenation profile PN-Ir catalysts open the door to many attractive chiral molecules. as the first company to make such catalysts com-mercially available (UbaPHoX family), Solvias has also given these catalysts a fixed place in our ligand/catalyst platform which is the basis for our high throughput screening service. •


Fiber optic probes – Keeping an eye on processesFiber optic probes provide an insight into manufacturing processes, and for this they must function under even the toughest conditions. a clear case for Swiss quality – and teamwork.Text:SilkeOeschger

Producing fiber optic probes is a complex process. Not only are there technical issues that need resolving, there is also the fact that market needs are not unified. Solvias has developed a broad selection of probes together with a complete range of accessories. However, given the way in which customers’ production processes vary with regard to temperature, pressure and dimensions, 90 percent of the probes are custom-made to meet the customer’s specifications.

the process of developing a fiber optic probe starts not at the workbench, but be-forehand in consultation with the customer. “Before a probe is produced, all parameters are tailored to meet the customer’s requirements,” says Daniela Kern from customer Service. these include construction form, the material to be used, the

Daniela Kern customer Service, at Solvias since 2002

What does your working environment look like? I often work on several orders simultaneously, so orderliness is extremely important to me. all documents relating to open assignments are close at hand in a tray, while the others are filed away. My most important tool is my Pc, because I can be in constant contact with my customers even with time differ-ences. Undoubtedly, my coffee cup is also invaluable.

What is the best thing about your job?No contest: customer contact. every day sees a new challenge that involves balancing customer requirements with feasibility. and accompanying a project from the very first enquiry through to invoicing, and always being there as a point of con-tact for my customers.


physical properties of the place of use, the range of measurement (Uv/vIS/NIR), the type of measurement (transmission, reflection, transflection, atR) and naturally consideration of regulatory requirements. Where necessary, for example if pressure testing of the product is required, a caD design drawing is produced. this then forms an essential part of the pressure test document.

Solvias also develop specialized immersion probes or flow cells, such as those designed for use in high-pressure and high-temperature applications or in highly corrosive environments. For the probe’s exterior, a wide choice of materials is avail-able. For the optical component, sapphire is often the best choice, when the solution needs to satisfy a wide range of applications. the key principle underlying this entire

>AZAFIROBIOFITprobewithsapphireoptic

forinlineanalyticalapplicationsinfoodand

biopharmaceuticalproduction

Nicola Schmieder Fiber optic Probe engineer, at Solvias since 2007

What does your working environment look like?My colleagues would describe it as over tidy. But it is true, I like it organized and tidy. My most important tools for the finishing of customized probes are the lathe and the drill.

What is the best thing about your job?the wide variety on a daily basis, as most of the probes are custom made. I also enjoy the close collaboration with my team colleagues. every member of the team has different skills, which makes for an inspiring knowledge pool.

Which process steps do you least like to delegate? I prefer to process and adjust various mechanically produced parts myself, as well as inspecting newly received mechanical parts.


Harald Danigel Scientific expert in fiber optic probes, responsible for their production since 1984 and with Solvias since its spin-off in 1999

What does your working environment look like? Mine is a typical office, with important tools including the tele-phone and manuals and reference books. this is where I keep in touch with subcontractors.

What is the best thing about your job?the close work with our customers to find the best solution for their processes. Sometimes it is even necessary to inspect the point of use of the fiber optic probe – seeing the chemical plants is always impressive. and, of course, my colleagues.

Which process steps do you least like to delegate? communication with the precision mechanics workshops.

process is that nothing is impossible. “In practice this means that almost 100 percent of all enquiries, with all their associated problems, ultimately result in the delivery of the correct product,” says lars leuenberger, Fiber optic Probe engineer at Solvias. once all parameters are clearly defined production can begin.

inDiviDuAl builDinG-blocK MoDelStandardized small parts such as sapphire windows, optical fiber, lenses and seals such as o-rings are kept in stock at Solvias, while precision semi-finished products and optical components are manufactured externally to our specifications. Probe parts adapted to suit individual customer requirements are produced in our own pre-cision mechanics workshops, and all the stages needed to assemble and finish the probes – grinding, polishing, gluing, screwing, pressing, bending, and engraving – are also carried out here. this process also includes creating operating instructions and possibly certificates, and naturally quality control, enabling a perfect combina-tion of cost efficiency via standardization and high quality.

For the optical component, sapphire is often the best choice, when the solution needs to satisfy a wide range of applications.


SwitzeRlAnD AnD GlobAlizAtionHow, in a globalized age, can the cost factor be reconciled effectively with the bene-fits of premium Swiss standards of production? the answer is by choosing from the standardized range of Solvias probes and implementing the necessary specifications based on the customer’s requirements, enabling products to be offered at competi-tive prices and with the benefits of Swiss craftsmanship, robustness and the use of premium materials. this approach is particularly valuable in connection with custom-ers with framework agreements who need a special type of probe on an on-demand basis. a further advantage that Solvias, as one of the pioneers in this area, has to offer is its more than 26 years of experience in probe construction.

woRlDwiDe uSeSolvias develops and markets high-quality process sampling equipment for online analysis of liquids, gases and solids. the highly robust fiber optic sapphire probes set high standards of performance in spectroscopy, with the result that Solvias probes are in use throughout the world, from canada to Brazil, china to australia and natu-rally all over europe. •

lars leuenberger Fiber optic Probe engineer, at Solvias since 2001

What does your working environment look like? My eyes and hands are important in my work, as are of course the coordination and perfect interplay of these two tools. other important equipment includes for example scalpels and a wide range of mechanical tools, and caD software is vital in the planning process.

What is the best thing about your job?the ever-evolving customer requirements. and developing new probes. I enjoy coming up with new solutions for even the most challenging problems, and here I have a good deal of room to maneuver. the best part, however, is ultimately having produced a high-quality and useful product by hand.

Which process steps do you least like to delegate? caD drawings and the creation of prototypes. In general, whenever I produce a probe, I do not like to delegate any of the steps, right up to completion and the drafting of the oper-ating instructions.

28 SolviaS ProSPectS — 2/2010

9th SolviaS Science Day 2010 – with three parallel SeSSionS

on october 25, 2010, the 9th Solvias

Science Day will be taking place in the

congress center Basel.

a conference which has now established itself in Basel as a fixed annual date for experts in chemical development and catalysis. in three parallel lectures leading experts from science and industry will provide insight into trends in the develop-ment of pharmaceutical drugs and share with the audience how these can be used successfully in practice and to achieve a competitive advantage.

the focus will be on chemical development and catalysis, analytical aspects and solid-state development.

location: congress center Basel (Switzerland)Date: october 25, 2010

Speakers

General lecture

Dr. rene imwinkelrieD — roche

What Really Matters in Drug Substance Process Development

Session: chemical Development and catalysis Dr. ioanniS houpiS — Janssen Pharmaceutica

Selective, Tunable Cross-Coupling Reactions Directed by

the Carboxylate Ion

Session: chemical Development and catalysis

prof. Steven v. ley — Department of chemistry, University of cambridge

New Tools for Molecule Makers: Enabling Technologies

Session: chemical Development and catalysis prof. Gary molanDer — University of

Pennsylvania

Organotrifluoroborates: Organoboron Reagents

for the 21st Century

Session: chemical Development and catalysis chriStian möSSner — Solvias aG

Process Development for TV-7130 –

A Candidate for Treatment of Sepsis and Disseminated

Intravascular Coagulation (DIC)

Session: Solid-State Development

prof. marc DeScampS — University of lille

Perspective on the Crystal/Amorphous Duality

of Pharmaceuticals


Dr. chriStoph Saal — Merck Kgaa

Successfully Screening and Selecting Salts – Salt Selection

and Bioavailability



pRof. ulRich GRieSSeR — University

of Innsbruck

NatureandPracticalAspectsofDrugHydrates


DR. wolfGAnG becKMAnn — Bayer technology Services

ControlStrategiesforCrystallizationProcesses–

FromProcessResearchtoProduction

Session: pharmaceutical and biopharmaceutical Analysis

pRof. bRuce Jon coMpton — Northeastern University. Barnett Institute,

center for advanced Regulatory analysis

TheHistoryandDevelopmentofHybridSilica-BasedHPLC

Columns(Xterra)andInstrumentsOperatingatElevated

Pressure(UPLC)


DR. GuiDo SonSMAnn — Solvias aG

PeptideMap–aVersatileToolfromProteomics

toQualityControl


DR. DAviD MccAlley — School of life Science, University of the West of england

AConsiderationofthePotentialImpactofTwoEmerging

TechniquesinHPLC:a)FusedCoreParticlesand

b)HydrophilicInteractionChromatography


DR. iMRe MolnAR — Molnar Institute

AspectsofQualitybyDesigninHPLCMethodDevelopment


pRof. MARco MAzzotti — Swiss Federal

Institute of technology (etHZ), Zurich

ThePotentialofModelingofCrystallizationProcesses


pRof. GeRhARDuS J. De JonG — Utrecht University

CE-MS:NewPossibilitiesfortheCharacterization

ofBiopharmaceuticals

exhibitors

For detailed information and to register, please visit: www.solvias.com/scienceday


events

cPHI WoRlDWIDe

October5–7,2010ParisNordVillepinte,FranceBooth6F38 find out more about • Polymorphism, Salt, and crystallization• chemical and analytical Development• GMP Manufacturing• catalysis

9tH SolvIaS ScIeNce DaY

October25,2010CongressCenterBaselBasel,Switzerland

INFoRMeX

February7–10,2011Charlotte,NorthCarolina,USABooth1034 find out more about • Polymorphism, Salt, and crystallization• chemical and analytical Development• GMP Manufacturing• catalysis


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

tel. +41 61 686 61 61Fax +41 61 686 65 [email protected]

publisher’s detailsSolvias aGKlybeckstrasse 191P.o. Box4002 BaselSwitzerland

editor-in-chiefSilke oeschgertel. +41 61 686 61 41, [email protected]

DesignFurore, Basel

picture creditsPatrik Hänggi, Solvias aG archive, eva Schaub, Foto Basilisk

how to unsubscribeto unsubscribe from this magazine, please send an e-mail with your contact details to [email protected]

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