european industrial pharmacy issue 20 (march 2014)

europeanINDUSTRIALPHARMACY

ISSUE 20 • MARCH 2014www.industrialpharmacy.eu

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features4 UNSTANDARD STANDARDS

The need for a single worldwide acceptedpharmacopoeia has been recognised for about 150years. It seems intuitively obvious that wherever youare born, you deserve drugs meeting the same highquality standards and this was the goal behind theestablishment of the International Pharmacopoeia.by Michael Anisfeld

6 IN A NUTSHELL – IMPROVINGBIOPHARMACEUTICAL PERFORMANCE OFORAL DRUG PRODUCTS An active pharmaceutical ingredient needs to fulfilseveral criteria in order to be successfully brought toa patient in medical need, such as clinical efficacy,an acceptable safety profile and desiredpharmacokinetics, and certain physicochemicalproperties and biopharmaceutical performance.by Uwe Muenster

9 THE YOUNG BIOPHARMACEUTICALCOMPANIES USE AND DEPENDENCE ONCMO/CRO The young biotech companies have a limited know-how concerning development of pharmaceuticals.This article describes how the CMO can supportbiotech companies and what they should do to besuccessful and build a mutually beneficialrelationship.by Jan Gunnar Gustafsson

13 DIVISION OF LIABILITY BETWEENPHARMACEUTICAL COMPANIES ANDSUPPLIERS USING THE EXAMPLE OF THE LAWIN THE FEDERAL REPUBLIC OF GERMANYDivision of liability within the pharmaceutical supplychain saves money and efforts of testing. It requiresa shift of duties to take care of that part of thechain where the risks arise through themanufacturing process. Sufficient insurancecoverage should be in place.by Martin Wesch

regulars3 EDITORIAL COMMENT17 REGULATORY REVIEW19 NEWS FROM THE EIPG20 EVENTS

2 european INDUSTRIAL PHARMACY March 2014 • Issue 20

europeanINDUSTRIALPHARMACYIssue 20 March 2014

ISSN 1759-202X

MANAGING EDITORSue Briggs

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldClaude FarrugiaMichael Gamlen

Linda HakesJohn Jolley

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european INDUSTRIAL PHARMACYis the official publication of the European IndustrialPharmacists Group (Groupement des Pharmaciens del’Industrie en Europe) www.eipg.eu

Cover photo: Oral drugs (see In a nutshell- improving biopharmaceuticalperformance of oral drug products onpage 6).

associate editors

Belgium: Philippe Bollen

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Denmark: Marie Fog

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Shilpa Gohil, Janet Halliday

Greece: Ioannis Nikolakakis

Hungary: Sylvia Marton

Ireland: Anna O’Mahony

Italy: Piero Iamartino

Latvia: Inta Saprovska, Anita Senberga

Malta: Claude Farrugia

Netherlands: Amon Wafelman

Norway: Wenche Gordon

Portugal: Nuno Moreira

Spain: Beatriz Artalejo

Sweden: Marianne Andersson

Switzerland: Valter Gianesello

european INDUSTRIAL PHARMACY March 2014 • Issue 20 3

In a departure from the norm, the PresidentJean-Pierre Paccioni has allowed me the honourto present this edition’s editorial. As immediatePast-President, I would like to acknowledge thehard work, commitment and resources thatJean-Pierre has injected into the EIPG. As I writethis document, I can tell you that the GeneralAssembly in Bulgaria is shaping up to be a greatevent with some first class speakers and,importantly, we are growing in number and ininfluence. One of the reasons for writing thiseditorial is to highlight one of the areas ofinterest for EIPG, and that is drug shortages,their causal factors and, more importantly, howwe provide solutions to this problem. Recently, I was asked to participate in a panel

debate on the threat of anti-microbial resistanceand what could be done to avert what seems tobe an impending disaster to clinical health. Notwanting to dwell on the past and to proposesolutions, I was, however, quite surprised tolisten to how the global widespread use ofantibiotics in veterinary and farming has beenone of the major causes of resistancedeveloping – in fact, the Lancet has quoted thatantibiotic resistance has now been observed inthe polar bear in Svalbard!The debate focused on how the industry can

generate new antibiotics when the climate ofantibiotic stewardship and the restriction ofusage mean that a viable reimbursement modeldoes not exist, and are not conducive tostimulate research in this area. So what ishappening in this area to help the discovery anddevelopment of new antibiotics?Well, in the USA, the Food and Drug

Administration (FDA), as part of the FDA Safetyand Innovation Act, has introduced theGenerating Antibiotics Incentives Now (GAIN)Act. Under GAIN, the Agency can designate anantibiotic as a qualified infectious disease

product (QIDP). QIDP status provides priorityreview and a 5-year extension of marketexclusivity if approved. To date, 30 QIDPdesignations have been granted. In addition,last year, the US Federal Government granted a$200 million fund to GlaxoSmithKline to developnew antibiotics.In Europe, moves to deal with antibiotic

resistance are afoot and are very visible with theInnovative Medicines Initiative (IMI) funded bythe European Federation of PharmaceuticalIndustries and Associations. IMI is the biggestpublic–private initiative in Europe. It is distinctfrom the EU framework programmes and aims toaccelerate development and improvecollaboration between industry and academia. Itis estimated that circa 40 projects are in motion.What was refreshing about the meeting and

the intelligent discussions that resulted was thatthere were no recriminations but rather acollegiate spirit to do the right thing and solvethis impending health crisis. As I keep telling mystudents, in order to predict the future look atthe past. At King’s College London, we haveaccess to the Gordon museum, and we certainlydo not want to be treating infections like weused to in the pre-antibiotic era.The EIPG will continue to play an active role in

proposing solutions to drug shortages and tosupport the many initiatives to help with thediscovery and development of new antibiotics,particularly the IMI programme.If members would like to know more about this

topic area, they are more than welcome to emailme on [email protected] us hope that a viable solution to this global

health issue is resolved sooner rather than later.

Best wishesProfessor Luigi MartiniImmediate Past President, EIPG

editorial

european INDUSTRIAL PHARMACY March 2014 • Issue 204

Deciding that they could not wait forthe IP, which was first published in1951, in the 1800s and early-mid1900s, many countries developedtheir own pharmacopoeias with theirown specifications, standards andtest methods (see list of nationalpharmacopoeias in the appendix).This has resulted in a plethora ofdifferent drug standards. In theUnited Kingdom, walk into anypharmacy and the standard dosageof Acetaminophen Tablets (officiallycalled Paracetamol in the UK) is atablet containing 500mg of drug;while in the United States thestandard dosage of AcetaminophenTablets – the exact same chemicalentity – is a tablet with 325mg ofdrug. Surely British headaches arenot more severe than Americanheadaches requiring higher dosagesof the same drug to cure the sameheadache?In 1989, the pharmacopoeias of

Europe (the EuropeanPharmacopoeia – Ph.Eur.), Japan (theJapanese Pharmacopoeia – JP) andthe United States (the United StatesPharmacopoeia – USP) concludedthat by harmonising monographsand general test methods,tremendous savings could be

achieved globally; a re-statement ofwhat they had concluded 125 yearspreviously. They determined that inthe global marketplace of the 21stcentury, regulators could savedossier approval time, industry couldsave time and effort by the need torepeat the same test to meetdifferent worldwide pharmacopoeialcriteria, and patients couldpotentially receive cheaper drugswith faster regulatory approval – andperhaps the many different world’spharmacopoeias would merge into asingle Global UniversalPharmacopoeia (GUP*). Twenty-fouryears on after the current round ofPharmacopoeial harmonisationstarted, what has been the progresstowards this admirable goal ofharmonisation between the Ph. Eur.,the JP and the USP?The current harmonisation process

was performed under the collectiveleadership of the PharmaceuticalDiscussion Group (PDG), which laterassociated with the InternationalConference on Harmonization (ICH)and published its deliberationsunder the ICH-Q4 Guidelines. As ofSeptember 2013, it was reported atthe 3rd Global Summit onPharmacopoeias1 that, of 35 general

chapter test methods identified ascandidates for harmonisation, 28have been harmonised (80%). Of 62excipient monographs identified forharmonisation, 43 have beenharmonised (69%).The USP lists 194 general chapter

test methods while the USP NationalFormulary section lists about 250excipient monographs, meaningthat only about 14% of these USPgeneral methods and 17% of theexcipient monographs have beenthe subject of global harmonisationbetween pharmacopoeias. And,most strangely, the world’s mostcommonly used excipient – purifiedwater – is not on the list ofexcipients whose monographs areto be harmonised. Clearly progressis painfully slow, but the question iswhy? Why have the world’s scientistsand regulators not been able tospeed the process ofpharmacopoeial harmonisation?How could it be that collectivelyhundreds or thousands of hours, oreven more, of work by scientistsglobally has yielded such a paucityof results?When discussing progress towards

a single GUP, globally recognised byall the world’s regulators, it isgenerally conceded that two of the46 pharmacopoeias currentlypublished have the greatest impacton international commerce. Theseare the Ph.Eur. and the USP. Withoutin any way disparaging the value ofthe pharmacopoeias of Iran, Mexicoand Ukraine (to name but 3 of the 44other national pharmacopoeias withnational legal standing but havinglittle use outside their borders), threeother pharmacopoeias also need tobe taken into account in anyglobalisation effort – the BritishPharmacopoeia widely used in over100 countries, primarily in the BritishCommonwealth but an almost totalclone of the Ph.Eur., the IP widelyused in the developing countries ofAfrica, Asia and South America dueto its less sophisticated cheaper testmethodologies, and the ChinesePharmacopoeia, a nationalpharmacopoeia but with impact onthe quality of drugs used by aquarter of the world’s population.

UNSTANDARD STANDARDSby Michael Anisfeld

The need for a single worldwide acceptedpharmacopoeia (compendium of drug quality

standards) has been recognised for about 150 yearswhen work first started in 1874 on developing theInternational Pharmacopoeia (IP). This harmonisationwork, started over a century ago, ultimately resulted inthe World Health Organization’s (WHO’s) publication“The International Pharmacopoeia”. It seems intuitivelyobvious that whether you are born in Albania, Canada,China, Mexico or Zimbabwe, you deserve drugs meetingthe same high quality standards and this was the goalbehind the establishment of the IP.

Michael Anisfeld, Globepharm Consulting, Inc., is an industrial pharmacist with over 35years’ experience working as a consultant with companies and governments in thefield of “Good Manufacturing Practices”. He has assisted in drafting GMP codes, andworks with clients to ensure they pass EMA, FDA, HPFBI and TGA GMP inspectionsfirst time through.

* Author’s own terminology.


UNSTANDARD STANDARDS continued

Scientifically, lack of progresstowards a GUP can be attributed tothree possible reasons.a.Pharmacopoeial scientistsand/or regulators cannot agreeon which tests need to beperformed for a specificpharmaceutical ingredient(active or excipient).

b.Pharmaceutical scientists and/orregulators cannot agree on thetest parameter specificationsthat should be applied.

c. Pharmaceutical scientists and/orregulators cannot agree on thetest methods to be used.

Any or all of these reasons mightbe true; and perhaps others.The concept of a pharmacopoeia

is to be a list of quality standards fordrugs that were known to be safe,however, this has not always provento be true, and it is very difficult toremove a drug listed in apharmacopoeia once its safety isdoubted. Consider Aspirin(acetylsalicylic acid), known forhundreds of years as a folk medicineused by people with assorted painswho would either suck on the barkof the willow or boil the bark anddrink the infusion to achieve relief. Itwas first chemically synthesized byFelix Hoffman in 1897, and today islisted as an active pharmaceuticalingredient in most of the world’spharmacopoeias. Aspirin is a drugthat, if it had been discovered by Dr.Hoffman in 2013, would never havebeen approved by any of today’sregulatory agencies due to itsplethora of life-threatening sideeffects (the risk of Reye's syndromein children, gastrointestinal ulcers,stomach bleeding and tinnitus), norbe listed in any of the world’spharmacopoeias. Cynics might cite the lack of

progress in pharmacopoeialharmonisation as due topharmacopoeias being bigbusiness; that there are vestedinterests in not harmonisingpharmacopoeias. Consider theultimate conclusion of internationalharmonisation. If pharmacopoeiaswere harmonised, then, instead ofeach pharmacopoeia needing theirown dedicated staff, the GUP,

wherever it might be located, wouldhave a single staff and a singlebudget meeting the entire world’spharmacopoeia and referencestandard’s needs. As with anycorporate merger, the synergieswould bring tremendous costsavings – not having a need for the717 staff at USP (in Rockville andUSP’s other worldwide offices andlaboratories) currently incurring USPa US$216 million annual budget; ornot having a need for the 260 staffat the Ph.Eur.’s Strasbourg officesand their current €46 million(approximately US$60 million)annual budget. Or, ifpharmacopoeias were harmonised,then there would not be a need fordifferent references standards (RSs)for the same drug. Legally, to claimthat a drug meets the specificationsof the USP, it must be tested againsta USP RS, purchased from the USP.For Acetaminophen RS purchasedfrom the USP, this costs US$210 for500mg2. Legally, to claim that adrug meets the specifications of thePh. Eur., it must be tested againstthe Ph. Eur. Chemical ReferenceStandard (CRS) purchased from theEuropean Directorate for theQuality of Medicines andHealthcare, the publisher of the Ph.Eur., or its agents, at a cost of €79for 50mg3 (equivalent at US pricesas US$1068 for 500mg). Howdifferent can these RSs be for thesame molecule? Both RSsunderwent the samecharacterisation studies to becomeRSs, so how different can they be?Why does pharmacopoeialharmonisation not start with havingthe pharmacopoeial RSs beinginterchangeable – scientifically andlegally? Surely the reason for thenon-interchangeability cannot be assimple a reason as these RSs beingbig money-making business forpharmacopoeial authorities?The deeper one delves into the

potential for a single GUP, the moreone has to question whethernational pharmacopoeias really wantto harmonise into a single GUP.We’ve been harmonising for 139years – surely it is time to rapidlyfinish the task for the benefit of all.

References1 www.usp.org/meetings-courses/symposia/3rd-global-summit-pharmacopoeias

2 www.usp.org/sites/default/files/usp_pdf/EN/referenceStandards/dailycatalog.pdf

3 http://crs.edqm.eu/db/4DCGI/search?vSelectName=1&vContains=1&vtUserName=Paracetamol&OK=Search&vTypeCRS=

Appendix 1. National andinternational (shown in bold)Pharmacopoeias.African PharmacopoeiaArgentine PharmacopoeiaAustrian Pharmacopoeia Belarus Pharmacopoeia Belgian Pharmacopoeia Brazilian PharmacopoeiaBritish PharmacopoeiaChinese Pharmacopoeia Croatian Pharmacopoeia Czech Pharmacopoeia Danish Pharmacopoeia Egyptian Pharmacopoeia European Pharmacopoeia Finnish PharmacopoeiaFrench Pharmacopoeia German PharmacopoeiaGreek PharmacopoeiaHungarian Pharmacopoeia Icelandic Pharmacopoeia Indonesian Pharmacopoeia International PharmacopoeiaIranian Pharmacopoeia Irish PharmacopoeiaItalian Pharmacopoeia Japanese Pharmacopoeia Kazakhstan Pharmacopoeia Korean Pharmacopoeia Lithuanian PharmacopoeiaMexican Pharmacopoeia Montenegro PharmacopoeiaNorwegian Pharmacopoeia Philippines PharmacopoeiaPolish Pharmacopoeia Portuguese Pharmacopoeia Romanian Pharmacopoeia Russian Pharmacopoeia Serbian Pharmacopoeia Slovakian Pharmacopoeia Slovenian PharmacopoeiaSpanish PharmacopoeiaSwedish Pharmacopoeia Swiss Pharmacopoeia Thai Pharmacopoeia Turkish Pharmacopoeia Ukrainian PharmacopoeiaUnited States Pharmacopeia Vietnamese Pharmacopoeia


Certainly, the most frequentphysicochemical challenge for thepharmaceutical scientist is pooraqueous solubility and/ordissolution of new chemical entities,and as a consequence solubility-and/or dissolution-limitedabsorption. Unfortunately, it lies inthe nature of the interplay betweenphysicochemical properties of anAPI and the human body’s (cell’s)biology that usually the morelipophilic a drug candidate is, thehigher its affinity to thepharmacological target (e.g. ahuman cell receptor or an enzyme). Thus, during recent decades,

pharmaceutical companies’ researchand development pipelines havebecome more and more populatedwith poorly water-solublecompounds. This was especiallytriggered by the beginning of theera of high-throughput screening inthe early 1990s. Since then, ligand-binding assays are usuallyperformed on an API by putting theAPI into screening wells as adimethyl sulfoxide stock solution,not considering at all the dissolutionprocess of a drug from crystalline

API, and all-in-all promoting theselection of compounds with pooraqueous solubility. However, it is thisvery dissolution process startingfrom crystalline API that is relevantfor a market product consisting of astandard immediate-release tabletcontaining the crystalline form of theAPI. Associated risks of poor drugdissolution in the humangastrointestinal (GI) tract includelack of efficacy and an increasedabsorption variability, the latterrepresenting an increased risk ofside effects for drugs with a smallsafety window. As a consequence,enabling formulation technologiesare needed that correct for poorsolubility properties of respectiveAPIs. What does poorly soluble mean?

The term poor water solubility withrespect to biopharmaceuticalperformance has evolved over thelast 20 years. Within thebiopharmaceutics classificationsystem (BCS), originally designed asa regulatory tool to decide onbiowaiver approval, and whichevolved in 19951, �low solubility� iswhen the highest daily drug dose

does not dissolve in 250mL ofaqueous media of pH 1–7. However,applying this criterion as abiopharmaceutical performancepredictor of drug developmentcandidates, the majority ofpharmaceutical pipeline compoundsare BCS class 2 or 4, implyingbiopharmaceutical performanceissues. However, in practice for manyBCS 2 and 4 drugs, no enablingtechnologies are needed. Thisindicates that the BCS, for the sakeof patient�s safety, is veryconservative on the one hand, andon the other hand may not be veryuseful to make biopharmaceuticalperformance predictions of newchemical entities.Therefore, in 2010, a refinement of

the BCS, namely the developabilityclassification system (DCS)2 wasproposed, in which the low solubilitycriterion has been lifted from 250mLto 500mL for poorly permeablecompounds, and up to several litresfor highly permeable compounds. Afurther in vitro-in vivo correlationmodel established in 20113 (volumeto dissolve applied dose (VDAD))reveals pH-dependent criticaldose/solubility ratios, which, whenexceeded, increase the probabilityof the need for enablingtechnologies (e.g. pH 4.5, >7L andpH 7, >35L). The main strategies to overcome

solubility- and/or dissolution-limitedabsorption include: i) prodrugs, ii)salts or co-crystals, iii) particle sizereduction, iv) solid dispersions, v)lipid systems, vi) cyclodextrins, andvii) carrier-mediated dissolutionenhancement (e.g. mesoporoussilica).

ProdrugsProdrugs with increased solubilitycompared to their respective poorlysoluble parent drugs are chemicalderivatives of the API containinghydrophilic groups, such as aminoacids or phosphate esters4. Usually,prodrugs do not possess anypharmacological activity, ratherduring and/or after absorption, theyare converted quickly into thepharmacologically activecompound. The conversion mayhappen enzymatically, e.g. byesterases/amidases, or by non-

IN A NUTSHELL – IMPROVINGBIOPHARMACEUTICALPERFORMANCE OF ORALDRUG PRODUCTS by Uwe Muenster

An active pharmaceutical ingredient (API) needs tofulfil several criteria in order to be successfully

brought to a patient in medical need. Besides clinicalefficacy, an acceptable safety profile and desiredpharmacokinetics, certain physicochemical properties aswell as biopharmaceutical performance of the API and itsformulation are required.

Uwe Muenster, PhD, runs a Material Science and Early Characterisation laboratory atthe Bayer Research Site in Wuppertal, Germany. His focus is formulation feasibilityrisk assessments, including physicochemical/biopharmaceutical characterisation ofdevelopment candidates (drug substance and preformulations) as well as generatingand applying biopharmaceutical prediction models, the latter being one of his maininterests. [email protected]


IN A NUTSHELL – IMPROVING BIOPHARMACEUTICAL PERFORMANCE OF ORAL DRUG PRODUCTS continued

enzymatic hydrolysis. Severalprodrugs have been launched tothe market, however, they possesscertain drawbacks requiringincreased development efforts,including a more complex synthesisand bioanalytical profiling, as wellas greater efforts to secure chemicalstability throughout storage andhandling (e.g. certain humiditycontrol measures needed in case ofnon-enzymatic hydrolytic activation).

Salts/co-crystalsSalts usually consist of two partnerswhich are held together by ionbonds. In the pharmaceutical field,one binding partner is the activedrug molecule, the other may be aninorganic ion (e.g. Na+, K+, Cl-, Br-,PO4

3-, etc.) or an ion of an organicacid (e.g. maleate, citrate).Generally, salts tend to form fromsaturated solutions if the differencein pKa of the two partneringcomponents is >35. It is hoped thatdue to the ionic character, a salt caninteract with water molecules betterand faster and thus form a solutionfaster than a salt’s correspondingfree base or acid. However, it needsto be considered that salts mayinitially dissolve very fast, but oncein solution may, depending on pH(which would be salt-specific), re-precipitate to form the respectivepoorly soluble free base or acid.Even then, a salt usually stillimproves bioavailability, sincepermeability of dissolved API maybe faster than the speed of re-precipitation. Co-crystals are being engineered

aiming, like salts, at a betterinteraction with water molecules,thus at faster dissolution in the GItract when compared to the freeform of the API. Co-crystals usuallyconsist of partners with pKadifferences of <3, otherwise a saltwould form. The field of co-crystalsis not as well-established in thepharmaceutical arena as salts. Amajor challenge is the limitedphysical stability during handlingand storage of co-crystals. At thetime of writing, no co-crystal-containing pharmaceutical drugproduct has been launched to the

market (excluding hydrates,solvates, and racemates, which, inthe literature, are sometimes alsoassigned to being co-crystals), butthe ever increasing research beingperformed in this field may soonlead to respective drug approvals.

Particle size reductionReduction of particle size isassociated with an increasedcontact surface area to surroundingGI fluids. This allows fasterdissolution of the API and leads toan increased oral bioavailability ifabsorption is dissolution-limited.On the other hand, particle sizereduction will not increase oralbioavailability if absorption issolubility or permeability-limited.Generally, particle size reductionmight be a good strategy for so-called brick dust molecules. Theseare molecules that dissolve neitherin aqueous media nor very well inorganic solvents, making them veryhard to formulate with otherenabling formulation strategiesdiscussed below (e.g. soliddispersions, lipid systems).Technical options to achieve small

particle sizes (submicron) can beeither top-down or bottom-up. Forboth approaches numerous patentsexist (e.g. >1000 patents/patentapplications on top-down wet-milling procedures), and severalmarketed products containingnanoparticles manufactured byeither wet-milling or high-pressurehomogenisation have beenlaunched since the late 1990s. In top-down processes,

mechanical forces are applied inorder to break down larger particlesinto much smaller particles, e.g. bywet-milling or high-pressurehomogenisation6. In bottom-up approaches, the

starting point is usually an APIsolution, in which, at some point, acontrolled precipitation event isinduced. The type of precipitationtrigger may differ, and numerousprecipitation techniques to achievenanoparticles have been described.One of the broader investigatedbottom-up approaches issupercritical fluid (SCF)

technology7. SCF itself can besubdivided into several subtypes ofprecipitation principles, one ofwhich is the “RESS” (rapidexpansion of supercritical solutions)in which the API dissolved in, forexample, supercritical carbondioxide is released through anozzle by which carbon dioxideinstantly evaporates and APInanoparticles start to form fromresulting precipitation. Anadvantage of the SCF technology isthat a fairly narrow particle sizerange can be achieved.Furthermore, it might be a goodmethod for thermolabile APIs, andno organic solvents will reside inresulting nanoparticles. However,SCF is fairly high-maintenance and,to date, no drug product is on themarket based on SCF or otherbottom-up precipitation methods.

Solid dispersionsIn solid dispersions, the metastableamorphous form of the API isembedded in a polymer8, whichtogether with other excipients canbe pressed to a tablet. Ideally, theamorphous API is physicallystabilised by the polymer in a waythat prevents recrystallisation for atleast the intended storage time atthe established storage conditionsof the drug product. Since theamorphous form is always moresoluble than the respectivecrystalline phase of an API, anincrease of dissolution and henceoral bioavailability can be observedwith solid dispersions, compared tostandard immediate-releaseformulations containing thecrystalline API. Two main manufacturing

strategies are usually applied withinthe industrial setting, namely meltextrusion and solvent evaporationprocesses, both extensivelydescribed in the literature, andseveral solid dispersion drugproducts having been launched tomarket within recent years. Eventhough the basic principle hasclearly proven that it does its job,certain physicochemical APIproperties are required to enablemanufacturing of solid dispersion


IN A NUTSHELL – IMPROVING BIOPHARMACEUTICAL PERFORMANCE OF ORAL DRUG PRODUCTS continued

drug products. For example, forsolvent evaporation-basedprocesses, sufficient solubility of theAPI in organic solvents used for themanufacturing process is required.For hot melt extrusion, the APIneeds to be thermally stable, andfor both processes a certainmiscibility of the API with respectivepolymers is a prerequisite. If there isnot a certain miscibility,recrystallisation of the API mightoccur at some point, leading tounreliable drug productperformance.

Lipid systemsLipid systems are usually capsuledrug products which contain theAPI dissolved within liquid orsemisolid excipients. Depending onthe lipophilicity of the drug, theexcipients used may be lipids only(e.g. triglycerides) or mixtures oflipids, co-solvents and surfactants,where the composition is optimiseddepending on the physicochemicalnature of the API9. After swallowing,the capsule opens within the GItract, API plus excipients arereleased, and interaction with GIfluids takes place. With onlytriglycerides used as a carrier, adegradation of the lipid phase bylipase enzymes is required in orderto release the API and make itavailable for absorption. If co-solvents and surfactants arepresent, a micro or nano-emulsionforms upon contact with GI fluids,ideally keeping the API dissolvedfor a long enough period of time inorder to allow its absorption. Someof the excipients used for lipidsystems may also influence drugpermeability, thereby potentiallypromoting drug absorption not onlyof compounds with low solubility,but also of compounds with lowpermeability. However, it needs tobe considered that a certainlipophilicity of the API is required toallow for sufficient drug loading. Sofar, only a few oral lipid system drugproducts are on the market, butwith increasing knowledge on lipidsystem excipients, further launchescan be expected in the future.

CyclodextrinsCyclodextrins can form inclusioncomplexes with the API at variousratios, with an inner hydrophobiccavity in which the lipophilic API isbound on the inside, and an outerhydrophilic surface allowinginteraction with surrounding GIfluids10. Various cyclodextrins areavailable for formulation design. Ofthese, mostly beta or gammacyclodextrins, or derivatives thereof(e.g. hydroxypropyl- or sulfobutyl-beta cyclodextrin), are being usedsince they exhibit a highsolubilisation potential of lipophilicAPI in aqueous media. Various drugproducts have been launchedutilising the solubilising power ofcyclodextrins (e.g. Pansporin T, OnoSporanox, and other).

Mesoporous silicaMesoporous silica (MS) consists ofSiO2 polymers manufactured onstructure-directing templates, wherepore size can be controlled in thenanometre range11. The API is thenlayered into these pores, e.g. bystirring of MS polymer in aconcentrated API solution. The highpore volume and surface area (e.g.700m²/g) allow rapid dissolution ofthe API. Advantages are high drugloading potential (up to 50% drugload without API crystallisation hasbeen shown), little API–carrierinteraction (thus might work forbrick dust), as well as promisingthermal and mechanical stability.However, MS is hygroscopic whichmight interfere with downstreamprocessing. Thus far, there is no MS-containing pharmaceutical producton the market.

SummaryAltogether, in parallel to thesteadily growing number of poorlysoluble drug candidates, numerousstrategies have evolved fromchemical and pharmaceuticallaboratories in order to overcomepoor biopharmaceuticalperformance. As a consequence,attrition arising from lack ofabsorption caused by low-solubility/dissolution only accounts

for a small proportion of all attritionreasons (only 5–10% of attrition isrelated to poor biopharmaceuticalperformance). However, with furtherexploration and expansion ofchemical space during leadoptimisation programs, innovationfrom formulation scientists iscontinuously required to supportdevelopment and guarantee areliable biopharmaceuticalperformance of complex newchemical entities.

References1 Amidon GL et al. A theoretical basis for abiopharmaceutic drug classification: thecorrelation of in vitro drug productdissolution and in vivo bioavailability.Pharm Res 1995;12(3):413–420.

2 Butler JM, Dressman JB. Thedevelopability classification system:application of biopharmaceutics conceptsto formulation development. J Pharm Sci2010;99(12):4940–4954.

3 Muenster U et al. Volume to dissolveapplied dose (VDAD) and apparentdissolution rate (ADR): tools to predict invivo bioavailability from orally applieddrug suspensions. Eur J Pharm Biopharm2011;78(3):522–530.

4 Jana S et al. Prodrug design to improvepharmacokinetic and drug deliveryproperties: challenges to the discoveryscientists. Curr Med Chem 2010;17(32):3874–3908.

5 Stahl PH et al. Polymorphism. Weinheim,Germany: Wiley-VCH; 2007, Chapter 12.

6 Gao L et al. Application of drugnanocrystal technologies on oral drugdelivery of poorly soluble drugs. PharmRes 2013;30(2):307–324.

7 Girotra P et al. Supercritical fluidtechnology: a promising approach inpharmaceutical research. Pharm DevTechnol 2013;18(1):22–38.

8 Warren DB et al. Using polymericprecipitation inhibitors to improve theabsorption of poorly water-soluble drugs:a mechanistic basis for utility. J DrugTarget 2010;18(10):704–731.

9 Pouton CW. Lipid formulations for oraladministration of drugs: non-emulsifying,self-emulsifying and 'self-microemulsifying' drug delivery systems.Eur J Pharm Sci 2000;11(Suppl 2):S93–S98.

10Alam MA et al. Commercially bioavailableproprietary technologies and theirmarketed products. Drug Discov Today2013;18(19–20):936–949.

11 Vallet-Regi M et al. Mesoporous materialsfor drug delivery. Angew Chem Int EdEngl 2007;46(40):7548–7558.


Present situationIt has become difficult to obtainfunding as venture capital is moreinterested in projects with shortdevelopment time. In particular, it isespecially difficult to obtain fundingfor the costly step of going fromdiscovery phase totoxicology/phases I, when goodmanufacturing practice (GMP) isrequired. For phase III, big pharmacan purchase or fund the project.The project has to fulfil theregulatory, clinical, market andchemistry, manufacturing andcontrols (CMC) requirements tohave the possibility to be sold,meaning that the manufacturingprocess has to fulfil therequirements for scaleup/commercial manufacturing(industrial), specification, GMP andregulatory requirements. The costof goods sold (COGs) requirementscan be a deal breaker; it is a criticalissue for the profitability of thedrug. That these criteria are fulfilledis crucial for the project to be

interesting for sale. However, many new products are

originating from small young, start-up companies that are creative andfast moving. Being strong in medicalresearch, they can generate ideasfor new treatment and products.These small companies do not havethese resources and know-how; theyare dependent on support fromCMC, a Contract ResearchOrganisation (CRO) and consultants.

Requirement to be successfulPharmaceutical developmentrequires know-how in the scientific,regulatory, industrial andclinical/medical fields, as well asknowledge of the diseases andpatient group the product will beregistered for, total number ofpatients and the number that can betreated with the drug, meaningmarket size and potential income.There are not many industrialsectors where the requirements onthe small/young companies are ashigh as on the pharmaceuticals

companies, especially for abiopharmaceutical company. Thecompanies are often started byphysicians and/or scientists who,even if they have the medical know-how, do not necessarily know how todefine a drug for the market anddefine the patient population thedrug will be used to treat. Thecompanies are developing acommercial drug; therefore, theyalso have to understand thebusiness developmentrequirements. Moreover, mostcompanies have limited or noprevious experience in thedevelopment of biopharmaceuticalsconcerning process development,manufacturing, and regulatory andcompetent authority requirements.

Business model, VirtualcompanyThose companies are operated asvirtual companies, meaning that alloperative activities are purchased,avoiding the cost for laboratoriesand manufacturing facilities whichhave to fulfil the GMP requirements.The company needs to have theknow-how to define that topurchase, which they normally donot have, making them vulnerableto making the wrong decision andalso increase the problems forgetting funding for their projects. Iftheir project fails, so does thecompany. This is also a risk for theCMO, for not getting paid for theirservice. The project has to becarefully evaluated before thedecision to start the project. It is anall or nothing situation, either it is aviable project so perform it, or if thethere are too many question marks,do not start. Medium-sizecompanies, having their own R&D,have to have a number of projects indevelopment. They cannot dependon one project. All these companies need a

management with experience and astrong drive for productdevelopment. For a companystarted by scientists, it is importantto have a management that can takethe company from science driven toproduct driven.

Medical need, marketThe product under development

THE YOUNGBIOPHARMACEUTICALCOMPANIES USE ANDDEPENDENCE ONCMO/CROby Jan Gunnar Gustafsson

The big pharmaceutical companies were previouslyperforming all steps from discovery research to

commercialisation. Today the big pharmaceuticalcompanies are organised to perform mainly phase IIIstudies and commercialisation. Big pharma companieshave a strong organisation for marketing and selling theproducts. They also have the recourses and capital toperform manufacturing of the drugs, either in their ownfacilities or at a Contract Manufacturing Organisation(CMO).

Jan Gunnar Gustafsson, MSc, MBA, has more than 25 years’ experience ofdevelopment, manufacturing and regulatory aspects of development ofbiopharmaceuticals, from the discovery phase to commercial manufacturing. He hasbeen responsible for selling and purchasing CMO service and is also working withbusiness development for start-up and small bio companies.


THE YOUNG BIOPHARMACEUTICAL COMPANIES USE AND DEPENDENCE ON CMO/CRO continued

has to fill a medical need. There hasto be a market for the product and amarket that can and will pay for theproduct when on the market. Forthe project to be interesting forpurchase, it has to have good profitmargin, no competition fromsimilar/better products or productsunder development.

Process development, QbDThe traditional way to handle theprocess development for a drugproject is to use the process thathas been developed for creatingthe substance for Proof Of Concept(POC) in animals. The methodsused during early development arenot suited for market, so there arealways huge demands formodifications. The processdevelopment is often driven by theaccelerated quality demands andthe development is performedstepwise without a proper plan andwith no control of either the cost orthe goals. It is an expensive way ofconducting process development asit is reactive not proactive. It will notgive an optimal process and will nottake into account a low COGs andan industrial process.The same tradition is also true for

the analytical methodsdevelopment. If the analyticalmethods have been of low quality,the new developments for phase IIIwill probably show new/higheramount of impurities, meaningprocess development has be doneagain. After POC in man (phase II),the focus should be on final tuningand validation of the process. If theanalytical method development isdone by the quality by design(QbD) concept, the knowledge ofboth accuracy and precision aremuch more secure than if one justuses an old method. By focusing onboth methods and specificationsearly on in a development project,the knowledge about both methodsas well as the substance are muchmore reliable than when trying tosolve the problems/questions asthey come by.More reliable knowledge about

both substance and impurities is anessential tool for process

development. The processdevelopment could never be betterthan the analytical knowledge.By knowing the substance early

on, the chances for nasty surprisesare reduced. Focusing on a well-designed process as early aspossible during the projectdevelopment is naturally a risk,investing both time and money in aproject that may then fail at a laterstage. However, the benefits for theproject, should it be successful,motivates the risk. Therefore, oneneeds to be careful and critical inthe choice of projects to developfurther. After deciding to develop aproject, plan for success and startall (assignment, investments,collaboration and so on) that isrequired for successfuldevelopment of the project.However, if the required know-howis not available, seek professionalhelp with the decisions on what tostart. Characterise the Master/Working

Cell Bank, active pharmaceuticalingredients (API) and drug product(DP – final product) from eachclinical phase to ensure thatcomparability is maintained duringthe clinical phases and differentmanufacturing sites if/whenmanufacturing has to be movedafter POC. The characterisationshould include potencymeasurements, preferably by abioassay/cell line. Development,manufacturing and characterisationhave to be well documented.The process used to produce the

drug for clinical phases I and II hasto be designed in such a way that,after modification, a COGs levelwithin the range that the productgives a good profit margin isobtained, by planning from projectstart. The virtual company has to

develop a manufacturing processfulfilling these requirements. Thishas to be done by the CMO, andunderstood by the purchasingcompany. They, therefore, have tochoose a CMO that can deliver thatservice, understood from the start,without having the required know-how – a catch 22.

QbDThe developed process has to fulfilrequirements for commercialmanufacturing, in the scale required.Thus the quality of the product hasto be planned and designed,namely QbD.QbD is often seen as an expensive

way to develop an early project.However, in the long run, it is quitethe opposite. The smart design ofthe process for the API and DPsecures the quality of the product.The quality is not created byanalysing the final product. Thus,QbD is a structured way of doingprocess development, gives arequired understanding of theprocess chemistry, and creates thecontrol strategy. It can also reducethe timeline for authorities’ handlingof your applications, and help topossibly achieve a low COGs.

CMO deliverablesIf the assignment is based onactivities, it is probable that newactivities will have to be added toachieve the goal. This will add costsand burn rate during performanceof the added activities. It willrequire that the purchasingcompany have the capital for theadded costs. Increased costs canalso create problems with fundingof the project. Deliverables, and notactivities, should be defined. If theassignment is goal driven, there willbe no added costs and no addedactivities as long as the scope of theproject is not changed. This makesit easier to get funding, as investorsknow what they will get for theirinvestment.

COGsThe COGs for commercialmanufacturing is one of the criticalsuccess factors. They should becalculated in such a manner that,once the product is on the market,it will generate a reasonable profit.One should also bear in mind therisk of potential competition. Thus,COGs should be set at the start ofthe project or, even better, as partof the evaluation of the projectbefore the decision to start. TheCOGs figure should be a



requirement for the processdevelopment goals. The COGsfigures should be verified for thecurrent and upcoming phases,including commercialisation, once ayear or if new competition arises.For commercial manufacturing, it isof utmost importance and can be adeal breaker.

RegulatoryThe regulatory requirements mustbe part of the project from the start.It should be ensured that theproject under development will fulfilall authority requirements, makingthe process for approval for clinicaltrials and registration as fast aspossible. The company should havea regulatory person/departmentwith up-to-date know-how,including process know-how.Alternatively, the company shoulduse a consultant. It is also a requirement to

understand the process chemistryand describe this in the applications.If QbD has not been used, the datathat would have been generated bythe QbD approach must be in theapplication, as specified in FDArequirements. The companies donot have to understand the processchemistry described in theapplications, but they areresponsible for the content as theproject/product owner.

ManufacturingThe chosen CMO for thecommercial manufacturing shouldbe inspected by the authority andapproved by the countries in whichthe product will be marketed. TheCMO should also have anorganisation, experience andinterest in commercialmanufacturing, and have therequired capacity and scale forlong-term manufacturing accordingto the product requirements. Allhandling, from purchase of rawmaterial to API/DP should beperformed according tospecifications and GMP. The CMOshould also be able to perform theanalytical methods andcharacterisations as required, andhave the scientific and industrial

know-how needed to manufacturethe product.

IPRFor the project to be of interest andbe purchased at a reasonable price,there must be some form of patentprotection. A strong patent portfoliowill increase the value of the projectand generate commercial interest.Therefore, it is important to protectthe patent right, not giving royaltyrights as part of payment fordevelopment cost. When workingwith a CMO, Intellectual PropertyRights (IPR) must be regulated in theassignment. Generally, no IPRshould pass over to the othercompany as a result of theassignment.

Patent issues The API process can be difficult toprotect by a patent. It is better toavoid publication of the process inthe form of a patent application,since it can be difficult to protect aprocess patent from infringement. Itwould probably require prosecutionof the company accused of theinfringement to be able to provethat this is the case, which is riskyand expensive if you are unable toprove it or are wrong. The formulation can, in many

cases, be protected by a patent.The product has to be described inthe drug description, therefore, it isno difference to have theformulation described in the patentapplication. Furthermore, it is easierto prove that patent infringementhas occurred.

AssignmentThe contract should be evaluatedfrom a scientific point of view toensure that it covers your needs,and should be based ondeliverables, not activities. Takeprofessional help with the draftingof the assignment and theassignment negotiation. If theCMO’s assignment draft is used,ensure that it clearly states theCMO responsibilities. In case offailure, how will it be handled? Cost,payment schedule, deliverables,project plan, IPR, specification,

audit rights, termination rights andquality agreement should beincluded in the assignment.The quality agreement should be

added to the contract, as anattachment, approved by theinvolved legal persons who havethe legal responsibility for the mainagreement, therefore, ensuring thetwo documents are in agreement.Termination rights are difficult;spend time on getting it right forboth parties. The legal, scientificand specification parts are ofutmost importance for success.They require knowledge from thecustomer, something that thesmaller/younger company seldomhas, and, therefore, the assignmentis then based on deliverables.Clearly define the responsibilities

and the next step if one part fails.Refund? New batch? When? Can abooked time slot for manufacturingor a study be moved? Make a planfor handling these situations. Theassignment should reflect and takeinto account the situation where theparties disagree. It is the only timethe contract is needed. Takeprofessional help with evaluationand negotiation.

Collaboration, win–win For a successful collaboration, theinvolved companies mustunderstand each other and what isof importance to each company.The CMO should understand whatthe customer needs, and thecustomer should understand whatthey need and what they will get. Ifthere is any doubt, get help fromexternal consultants. Both partiesmust receive what they need fromthe assignment to regard it as asuccess.

ConclusionsYoung small biopharmaceuticalcompanies are required forgenerating new pharmaceuticalprojects for big pharma to licensefor commercialisation. It requires aCMO/CRO that can develop,manufacture, regulate and conductclinical trials for these companies.Since the CMO/CROs have therequired know-how and the



purchasing companies do not havesuch know-how, the CMO/CROmust deliver defined goals, notactivities. The CMO/CRO has totake on the risk of delivering adefined process and manufacturingof API/DP, not activities, at a fixedprice and to a predetermined timeline. The pharmaceutical industry

and investors rely on suchcollaboration. If such collaborationsdo not exist, there is a risk of areduction in the development ofnew drugs, leading to increasedcosts for healthcare. However, thereseems to be moves by CMO/CROsin the right direction. To supportsmall biotechs is important for the

CMO, big pharma, the wholepharmaceutical industry and society.With this, there is the opportunityto reduce medical costs and satisfypatients’ needs. The pharmaceuticalindustry must take care of theirbabies, the small biopharmaceuticalcompanies, and ensure that theycan grow up.

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Warranty laws exist in cases ofdefective products which aredelivered in violation of theobligations under the contract. Aproduct is defective if it does notcontain the characteristics asagreed upon in the contract, or if itdoes not comply with thecontractual purpose. Warranty lawsprovide the right of conversion,abatement or compensation fordamages as a result of non-performance.Statutory liability has two pillars:

tortious liability and strict liability.Tortious liability is based on theviolation of an obligation incumbentupon every person to ensure safety.This is the case, for example, if oneslips on a banana skin or on afreshly cleaned and subsequentlyslippery floor. In such cases, thedefective cleaning could – in thecase of the banana skin or thelacking notice of danger –

constitute a violation of anobligation to ensure safety.The violation of law would have to

have taken place illegally. Theviolation of law is given in the lackof grounds of justification. Let usassume that someone had thrownanother person into the riverThames. This would, in fact,constitute bodily injury andconsequently a violation of law. If,however, the affected person hadpreviously taken away the wallet ofthe other with the support of Smith& Wesson, the violation of lawcould be justified.Moreover, the behaviour has to

be at least negligent. An individualparameter always applies in suchcases. Organisations as well ascompanies can be executed bydisclosing the careful selection,instruction and monitoring of theirpersonnel. It is often the case thatnegligence – from the injured

party’s point of view – cannot beproven in a court room. Not least asa consequence of this, the memberstates of the European Union (EU)agreed upon the Directive forproduct liability1. Consequently, it isenvisaged that consumers who havesuffered damage be grantedentitlements irrespective ofnegligence in cases of defectiveproducts.On the basis of the above, the EU

Product Liability Directive wasadopted in the Federal Republic ofGermany in 1989. This grants legalclaims which provide a link toendangering elements of anoffence. The endangering elementas such is accepted by the companyin the case of so-called typicalsocial behaviour. Such cases are, forexample, the operation of a rail orairline company, the participation inroad traffic, the operation of anatomic power plant, the putting intocirculation of products and, inparticular, drugs. The latter isprovided for in the Federal Republicof Germany by the MedicinalProducts Act.Consequently, the strict liability

system in accordance with theProduct Liability Act or inaccordance with the MedicinalProducts Act merely provides a linkto the putting into circulation of adefective product. This results inliability claims, which have an upperlimit in individual cases up to€600,000 or an annual pension inthe sum of €36,0002. In the case ofdamage suffered by several parties,the upper liability limit is set at €120million or pension payments of €7.2million annually. The companiessubject to strict liability must takeout insurance coverage againstthese risks3. In contrast to tortiousliability, the liability is not subject tocontrary agreement4.

Allocation of risksThis raises the question of how theliability between the pharmaceuticalcompany and the supplier can, if atall, be divided. Is thepharmaceutical company liable inany case irrespective of whether thenegligence applies to the companyor not? It is also the case that thisliability cannot be limited or

DIVISION OF LIABILITYBETWEEN PHARMACEUTICALCOMPANIES AND SUPPLIERSUSING THE EXAMPLE OF THELAW IN THE FEDERALREPUBLIC OF GERMANYby Martin Wesch

Liability systems

German law distinguishes between liability andwarranty. Liability deals with statutory entitlements

that may exist between any parties. Warranty laws areonly possible between parties to a contract.Pharmaceutical companies and suppliers are, on a regularbasis, parties to a contract. Accordingly, questions as toboth liability and warranty may arise between them.

Dr. Martin Wesch is a lawyer specialised in medical and industrial law and works forWesch & Buchenroth, Stuttgart, which he founded in 2001. Since April 2002, he hastaught industrial law at the University of Stuttgart. He has authored several publications, both in journals and books, on legal demands of pharmaceutical qualityassurance. In 2007, he received the Wallhaeusser Prize for publications on ConceptHeidelberg, Europe’s leading advanced training and information services provider inpharmaceutical quality assurance and drug safety.


DIVISION OF LIABILITY BETWEEN PHARMACEUTICAL COMPANIES AND SUPPLIERS continued

excluded by way of contractualagreements. However, the statutoryregulations of strict liability merelyprovide for the claims of thirdparties, in particular consumers.This is the liability in an externalrelationship which cannot beamended5. In the case of an internalrelationship between apharmaceutical company and itssupplier, the liability can well bedivided6. Negligence aspects alsoplay a role here. With regard toliability of the participating partiesamong themselves, liability divisionapplies according to the lawwhether the damage was largelycaused by one or the other party7. However, the causal contributions

are usually disputed. In such cases,quality assurance agreements havethe effect of clearly distinguishingbetween the responsibilities of theparticipating manufacturers.Consequently, it serves as a divisionof liability. Pharmaceuticalcompanies may transfer the overallresponsibility for a product for thebought-in outside services, which isincumbent upon them in thecapacity of manufacturers offinished products, to the supplier. Insuch cases, regulations pertainingto the burden of proof frequentlyplay a role. Following the delivery ofa product, it is often unclearwhether a product defect hasoccurred on the premises of themanufacturer of the finishedproduct or on the supplier’spremises. In quality assuranceagreements, the burden of proofcan be turned around. The supplieris then required to furnish proof of aflawless production if he intends toward off product liability within aninternal relationship. The scope and limits of such

liability agreements arise on thebasis of the transferability of theobligations to ensure safety8. Theliability precedes the assumption ofobligations by the supplier. Strictand tortious liability are the same insuch cases. Insofar as it is possibleto transfer tortious obligations toensure safety to the supplier, thesame can also assume strict liabilitywithin an internal relationship. The

transferability of obligations toensure safety is limited in the lawpertaining to the regulation ofGeneral Conditions and Terms ofBusiness. According to the same,no agreements may be made whichconstitute an unreasonabledisadvantage to the contractingparty9. An unreasonabledisadvantage is given if anagreement with a considerablebasic idea of a statutory regulationcannot be reached. This would bethe case, for example, if a supplieris held responsible for the risks ofhis product even if he cannot exertan influence upon such products10.Mistaking a package for another ordamage caused to such a packagecan also occur at the drug company.A regulation that did not take thisinto account would, insofar, beinvalid.It is also the case that the transfer

of obligations to ensure safety maynot itself take place contrary to theduty under the contract.Obligations to ensure safety mayimpede this. These call for the drugcompanies to select their suppliersinitially according to their ability toperform a quality service.Otherwise, the manufacturer of thefinished product must completelymonitor the supplier or the suppliedproducts. Only in dealings with acompany known to be reliable andprofessional, can a specialsupervision by the manufacturer ofthe finished product be dispensedwith11. The release from one’s ownresponsibility is conditional on thefact that the supplier offers aguarantee for the adherence to therequired safety precautions.Consequently, it is not sufficient toselect a supplier on the basis ofprice and schedule criteria. Asupplier’s capability to provide aquality performance is crucial12. Themanufacturer of the finishedproduct must verify this capabilityand should not be satisfied with thesupplier merely giving theassurance that he shall perform thework professionally13.In addition, obligations to ensure

safety must be described in detail.The pharmaceutical company is,

insofar, under the obligation toprovide the packaging manufacturerwith precise details of the type ofquality assurance measures14. Theobligations to ensure safety must,therefore, be agreed upon in detail.Of course, it is possible in the fieldof drug production that theprocedural provisions of goodmanufacturing practice (GMP) whichapplies to drug manufacturers alsobe stipulated for suppliers. Ultimately, the supplier must be

willing and in a position to performthe tasks assigned to him. Thisrequires that insurance coverage betaken out regarding the productliability risks15. An internalexemption from liability only appliesto the extent to which the assumingparty can actually cover risksresulting from the same.

Economic purposeThe transfer of obligations to takecare to the supplier producespecuniary advantages. On the onehand, recourse is made available tothe supplier. These rights ofrecourse can also be asserted.Furthermore, the tortious liabilityextends beyond that of strict liabilityin accordance with the MedicinalProducts Act. The liability is notsubject to an upper limit. Claims fordamages for non-material damage,in particular compensation for painand suffering, are also included.Insofar as the tortious liabilityextends beyond the strict liability,the supplier is solely liable; in otherrespects secondary, but he isultimately liable. The drug companycan find relief in this respect fromthe risks of the bought-in partialproducts. The transfer of obligations to

ensure safety also simplifies themovement of goods. The drugcompany can restrict its inspectionof incoming goods to a minimum.This merely requires that incominggoods deliveries be inspectedregarding easily detectablevariations from the contractualagreements16. This includes obviousdefects, shortages and wrongshipments. The superficialinspection of a sample of a batch


can, therefore, be sufficient.However, less should not be carriedout. Otherwise, the drug companycould be charged with the violationof an obligation to which it issubject in accordance with the lawat least as regards the incominggoods. Consequently, the flat-rateelimination by way of an agreementof any kind of incoming goodsinspection is not permissible17. Insuch a case, the drug companywould jeopardise the entire purposeof a quality assurance agreement ofkeeping its warranty laws andtransferring liability risks to thesupplier. In this respect, not toomuch is expected of the drugcompany – as is the case with anyother manufacturer of finishedproducts. It is not required to carryout a 100% check. Furthermore, itneed not perform representativerandom checks. Merely that what iseasy to detect is to be verified. Inthe case of the inspection, forexample, of a collapsible cardboardbox, it will establish whether it is awrong shipment, whether theprinting ink is dry and not smearedand whether easily detectablewrong prints can be recognised. The reduction of the inspection of

incoming goods is, on the otherhand, conditional on the transfer ofobligations to ensure safety. Themanufacturer of the finished productcarries the overall responsibility forthe product, including the bought-inparts. In the case of key supplierparts whose faultiness mayjeopardise life and limb, this calls forincoming goods to be subject to a100% check18. The reduction of theinspection of incoming goods in themanner described is onlypermissible if the obligations toensure safety regarding the suppliesare transferred to the suppliers in alegally valid manner. Fewer checksregarding incoming goods requiregreater checks on the part of thesupplier19. Both are linked like waterlevels in communicating pipes. If thewater level on the one side isreduced by ram force, it will beincreased on the other side by thesame amount. The link between theinspection of incoming goods and

the verification of suppliers is nodifferent. However, the drug company is not

under an obligation to carry out theverification of suppliers itself (byAudits). It may transfer this to thirdparties20. There are institutionswhich perform such tests. However,the pharmaceutical company has tocheck the compliance of the qualitymanagement system of the supplierwith the needs of its own qualitymanagement system21.

Quality assuranceagreementsThe economic success of thetransfer of obligations can besecured by way of quality assuranceagreements. Primarily, the qualityrequirements placed on theproduct, and the product andmaterial specifications are to bestipulated therein. Furthermore, thequality assurance measures whichthe supplier is to carry out need tobe determined. These are theobligations to ensure safety whichare transferred from themanufacturer of a finished productto the supplier. The consequence ofthe agreement results in theexemption of liability which thesupplier declares as regardsdealings with the drug company.The supplier assumes the productliability for the supplies up to anupper liability limit. The suppliertakes out insurance coverageagainst the liability risk. In addition,the supplier enables the drugcompany to reduce the inspectionof incoming goods and undertakesto have his capability of performinga quality service verified by aprofessional and independent thirdparty.To cut a long story short, this type

of quality assurance agreementresults in a series of advantages fordrug manufacturers22. First of all, thequality assurance measures adoptedby suppliers reduce the risk ofproduct defects. Drug companiesfind themselves in a situation similarto that of airline companies.Damage which becomes publicresults in a considerable loss oftrust. This frequently by far exceeds

the material damage that issuffered. Consequently, situationslike these should, ideally, not occur.Quality assurance agreements are,therefore, primarily geared towardsthe prevention of damage. In addition, the capability of a

supplier to provide a qualityperformance, which is subject toreviews, creates the preconditionfor a permanently reliable supplierrelationship. As a result of thecoordination of quality assurancemeasures via the preventiveavoidance of errors during theverification of production processes– and even during productdevelopment – both companiesmove closer towards each other.This promotes trust. Bothcompanies can build on this.The third advantage is that the

division of liability enables the drugcompany to largely unburden itselfof the dangers of the bought-inproducts. This creates real costadvantages. A further advantage is the fact

that drug companies can reducetheir scope of verification. Thisapplies not only to the inspection ofincoming goods but also to theverification of suppliers, which canbe outsourced.Everything is consequently in

favour of transferring theimplemented procedures of GMP,to which drug companies aresubject by law, to suppliers, andsecuring this by way of qualityassurance agreements. In thisrespect, it is envisaged thatsuppliers do not wait until they areapproached by the drugcompanies. Rather, they should takethe initiative to approach the drugcompanies and offer suchagreements. Consequently, they cansecure market advantages over rivalcompanies. They should make useof this opportunity.

References1 Council of the European Union. Directive85/374/EEC. Brussels: Council of theEuropean Union; 25 July 1985.

2 § 88 AMG, the German MedicinalProducts Act. www.gesetze-im-internet.de/englisch_amg/index.html





5 Taschner HC, Frietsch E.Produkthaftungsgesetz und EG-Produkthaftungsrichtlinie, 2nd Edition.München: CH Beck; § 14 sec. 10. Rolland.Produkthaftungsrecht. München: CH Beck§ 14 sec. 6.

6 Kullmann HJ. In: Produzentenhaftung.Kullmann HJ, Pfister B, Stöhr K, SpindlerG, Eds. Berlin: Erich Schmidt; Vol. 1, no.3250, p 11.



9 § 307, Section 1 of BürgerlichesGesetzbuch [German Civil Code]. Berlin:Federal Ministry of Justice. www.gesetze-im-internet.de/englisch_bgb/index.html

10 Schmidt, Neue Juristische Wochenschrift (NJW,http://rsw.beck.de/cms/main?site=NJW), 1991:p 150; Link, Betriebsberater (BB, www.betriebs-berater.de/), 1985: p 1424 (1428); Graf vonWestphalen, Der Betrieb (DB, www.der-betrieb.de/content/), 1982: p 1655.

11 Bundesgerichtshof [BGH (Federal Court ofJustice in Civil Law),www.bundesgerichtshof.de/EN/Home/home_node.html], 22 October 1974;Versicherungsrecht (VersR,www.versicherungsrecht.de), 1975: p 87 (88).

12 Kullmann HJ. In: Produzentenhaftung.Kullmann HJ, Pfister B, Stöhr K, SpindlerG, Eds. Berlin: Erich Schmidt(http://www.esv.info/978-3-503-01849-9);Vol. 1, no. 3250, p 12.

13 BGH (Federal Court of Justice in Civil Law),www.bundesgerichtshof.de/EN/Home/home_node.html, 26 May 1954; VersR,www.versicherungsrecht.de, 1954: p 364(365).

14 Lemppenau, DB (www.der-betrieb.de/content/); 1980, p 1679 (1680).


16 RG [Supreme Court of the German Reich] of12 January 1923, JW (http://www.jura.uni-muenchen.de/fakultaet/institute/leo-weng/lwi_abteilung_b/bibliothek/interne_links/zeitschriften/zst_12a.html), 1924, p 814;Steinmann, BB (www.betriebs-berater.de/),1993, p 873 (874, 877); OLG [High Court]Frankfurt, NJW-RR, 1986, p 838; Graf vonWestphalen, l.c. § 17 sec. 35.

17 BGH (Federal Court of Justice in Civil Law),www.bundesgerichtshof.de/EN/Home/home_node.html, 19 June 1991; NJW(http://rsw.beck.de/cms/main?site=NJW),1991, p 2633 (2634).

18 BGH (Federal Court of Justice in Civil Law),www.bundesgerichtshof.de/EN/Home/home_node.html, 7 June 1988; BGHZ 104, p323 (335).

19 BGH (Federal Court of Justice in Civil Law),www.bundesgerichtshof.de/EN/Home/home_node.html; VersR(www.versicherungsrecht.de), 1975, p 922(923). Kullmann HJ. In:Produzentenhaftung. Kullmann HJ, PfisterB, Stöhr K, Spindler G, Eds. Berlin: ErichSchmidt; Vol. 1, no. 3250, p 10.

20 EU-GMP-Guidelines, Annex 8 no. 3.http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

21European Commission. CommissionDirective 2003/94/EC of 8 October 2003.Art. 12, no. 2 and 4. Official Journal of theEuropean Union 14 October 2003.http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

22Ensthaler, NJW(http://rsw.beck.de/cms/main?site=NJW);1994, p 817.


Clean Air and Containment ReviewThe journal to enhance your knowledge of cleanroom, clean air and containment technology

• Learn about different aspects of these technologies from clearly written articles by experts• Keep up to date on standards with regular updates by standards committee members• Read about innovations• Understand the jargon• Become an expert yourself

To subscribe, or for more information including contents lists for all previous issues, visit www.cleanairandcontainment.com

Visit the website: www.industrialpharmacy.eu for PharmaTV andQuality by Design videos, Regulatory Review, Financial Pharma News

and other current items concerning Industrial Pharmacy

www.industrialpharmacy.eu


regulatory reviewThe current review periodhas seen a number ofchanges in the regulation ofmedicines and regulatoryguidance in the EuropeanUnion (EU), Internationalmarkets and the USA.

USAPermanent discontinuance orinterruption in manufacturingof certain drug or biologicalproductsThis proposed rule requires allapplicants of covered approveddrugs or biological products,including certain applicants of bloodor blood components and allmanufacturers of covered drugsmarketed without an approvedapplication, to notify the Food andDrug Administration (FDA)electronically of a permanentdiscontinuance or an interruption inmanufacturing of the product that islikely to lead to a meaningfuldisruption in supply of the productin the USA.

FDA and EMA launch genericdrug application inspectionsinitiativeThis is a joint FDA and EuropeanMedicines Agency (EMA) initiativeto share information on inspectionsof bioequivalence studies submittedin support of generic drugapprovals. It provides a mechanismto conduct joint facility inspectionsfor applications submitted to bothagencies.

Draft guidance for industry onsize, shape, and other physicalattributes of generic tabletsand capsulesFDA is concerned that thesecharacteristics of generic drugs aretoo varied compared to theoriginator drug and could affectpatient outcomes.

EuropeQ&A on Design SpaceVerificationFollowing the EMA and FDA jointevaluation pilot, there are

agreements on a wide range ofquality by design (QbD) elements.The joint Q&A document reflectsharmonisation on some QbDaspects. Of the 9 Q&As, the first 6cover common expectations. Twoseparate EU expectations arecovered by questions 7 and 8 andthose for the FDA by question 9.

Report on personalisedmedicine This addresses the progress made inpersonalised medicine and theopportunities and challenges itpresents for healthcare systems. It recognises the potential for

personalised medicine to offer newtreatment opportunities, bettertargeted treatment, avoidingmedical errors and reducing adversereactions. It recognises thechallenges to its successfulincorporation into healthcaresystems.

AEDs: changing productsConcerns about switching betweendifferent manufacturers’ products ofantiepileptic drugs (AEDs) havebeen raised by patients andprescribers. These include switchingbetween branded original andgeneric products, and betweendifferent generic products of aparticular drug.The UK Commission on Human

Medicines advised that AEDs couldbe classified into three categories,based on therapeutic index,solubility and absorption, to helpprescribers and patients decidewhether it is necessary to keep usinga supply of a specific manufacturer’sproduct.

Statements of non-compliancewith GMP now publiclyavailable in EudraGMDPThese statements of non-compliance with goodmanufacturing practice (GMP)contain information on the nature ofthe non-compliance and the actionstaken or proposed by the issuingauthority in order to protect publichealth.

EU GMP GuideResponses to proposedchanges in the EU GMPThe European Commission (EC) haspublished comments from interestedparties regarding the followingproposed changes to the EU GMP.• EC Medicinal Products GMPGuidelines Part I, Chapters 3, 5, 6and 8.

• The formalised risk assessment forascertaining the appropriate GMPfor excipients of medicinalproducts for human use.

• The draft guidelines on theprinciples of good distributionpractice (GDP) for activesubstances for medicinal productsfor human use.

• The revision of Annex 16:Certification by a Qualified Personand Batch Release.

Revised Guidelines on GDP forMedicinal ProductsThis 5 November 2013 versionreplaces that of March 2013 andcorrects factual mistakes identified insubchapters 5.5 and 6.3. It also givesmore explanations on the rationalefor the revision. Both take intoaccount recent advances in practicesfor appropriate storage anddistribution of medicinal products inthe EU, as well as new requirementsintroduced by Directive 2011/62/EU.

MHRASelf-inspection and dataintegrityThe Medicines and Healthcareproducts Regulatory Agency (MHRA)requires pharmaceuticalmanufacturers, importers andcontract laboratories to review theeffectiveness of their governancesystems to ensure data integrity andtraceability and will check thisduring 2014 inspections.

Voluntary parallel scientificadvice with NICE and theMHRALicence applicants may request ajoint scientific advice meeting withNational Institute for Health and CareExcellence (NICE) to discuss their

Continued on page 18


REGULATORY REVIEW continued

development plans for medicinalproducts. This process offers:• a guaranteed face-to-facemeeting with both organisationstogether,

• discussion of clinical study(s)design that will be used to satisfyregulatory and NICErequirements,

• optional advisory input fromClinical Practice Research Datalink.

InternationalRevised PIC/S GMP Guides Revisions of these twoPharmaceutical InspectionCooperation Scheme (PIC/S) Guidesto Good Practices for the IndustrialManufacture of DistributedMedicinal Products and Preparationof Medicinal Products in HealthcareEstablishments will enter into forceon 1 March 2014.

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For further information on these andother topics we suggest you refer tothe websites of relevant regulatorybodies and to current and pasteditions of “GMP Review News”published by EuromedCommunications. To subscribe to thismonthly news service [email protected]


Bureau meeting During their January meeting, theBureau discussed education andfinancial matters, and the final draftof the Domestic Rules, which will bevoted on by delegates in April. Aswell as the Bureau members, themeeting was attended by theBulgarian Industrial PharmacyAssociation (BIPA) representativeEvgeni Grigorov. The format andagenda for the 2014 GeneralAssembly to be held on 12–13 Aprilin Sofia were agreed. BIPAannounced the arrangements for aScientific Symposium on ClinicalTrials Research to be held on Friday11 April.

European Commission The European Commission haslaunched the public consultation onthe revision of European CommissionGuidelines on GMP, Annex 15:Qualification and Validation. Theconsultation document is availableon the Commission’s website.Industrial pharmacists belonging toMember Associations should providefeedback to their representative by 1April in order for EIPG to consolidateits response to the Commission.

EMA’s meeting withinterested partiesAs mentioned in the last issue,Claude Farrugia represented EIPGat the meeting of the EuropeanMedicines Agency (EMA)Inspectorate with “interestedparties” on 28 November and thefollowing is a summary of his report.

David Cockburn, Chairman of theInspectors Working Group openedthe meeting. The main topics ofdiscussion were the burdens on theindustry in terms of auditing and theapplications of the latest gooddistribution principles for active

pharmaceutical ingredients (APIs)and finished products alike.The EMA update on their work plan

provided a summary of the presentposition on GMP and GDP guidance.

Final and upcoming final guidelinesGMP Guide Chapter 2GDP Guide for Finished ProductsGMP Guide Chapters 3, 5, 6 and 8GMP Guide Annex 16GDP Guide for Active Substances

Upcoming public consultationsGMP Guide Chapters 3, 5, 6 and 8GMP Guide Annexes 15 and 17GMP for excipients

EXCiPACT delivered apresentation on a proposedCertification Scheme to help reducethe audit burden for pharmaceuticalexcipient users and suppliers. Thiswas followed by a presentation byRx-360, who outlined their proposalsfor a role in supply chain securityand audit burden sharing. Twopresentations on GDP were thendelivered; the Active PharmaceuticalIngredients Committee firstpresented an update on their draftguideline on GDP for APIs, followedby a presentation by the EuropeanFederation of PharmaceuticalIndustries and Associations (EFPIA)on implementation questions on thelatest GDP guidelines for medicinalproducts.In the course of the latter

presentation, Claude Farrugiasupported the EFPIA call for clarityand common understanding. Inparticular, he referred to the EFPIAcall for science and risk-basedapproaches in the determination oftemperature control and theestablishment of qualification oftransport routes, and stressed that,whilst such approaches wereacceptable in terms of the supplier’s

obligation with regards to storageconditions during transportation, onealso had to be cognisant of the needfor Responsible Persons to be able toverify such storage conditions priorto release to saleable stock. In thisregard, common interpretations byplayers in the pharmaceutical supplychain and by inspectors, especiallywhere cross-border movement ofmedicinal products was concerned,were crucial. He also called on EMAto clarify the GDP guidelines withregards to the conditions underwhich returns of medicinal productsto wholesale dealers could bereleased to saleable stock, and wasinformed that such a clarification hadindeed been addressed in an updateto the GDP guidelines that waspublished in the same period.

Education PHAR-INThe kick-off meeting of PHAR-IN, theproject looking at competencies andcoursework in the field ofbiotechnology, was held on 20December 2013. Vitor Sousa (AretaInternational, representing an SME)Gunther Pauwels (Genzyme,representing a large company) andJane Nicholson (EIPG) attended themeeting with a number of academics,including Professor Bart Rombaut(Belgium) and Professor JeffreyAtkinson (France). Competencies inbiotechnology which are needed byboth undergraduate pharmacystudents and postgraduate scientistsare being prepared.

Anyone working in a biotechcompany who is interested inproviding their opinions on stafftraining in biotechnology iswelcome to contact Jane Nicholsonat [email protected]

Jane Nicholson, Executive DirectorEIPG, [email protected]

news from the EIPG

Death of Professor Bart Rombaut, Head of School of Pharmacy at the Vrije University in BrusselsIn January, Bart Rombaut, President of the European Association of Faculties of Pharmacy (EAFP) died suddenly. He had a vision for thedevelopment of pharmacy education to prepare students both for professional and scientific activities for the future new demands andtechnologies. He was a driver for EAFP to take a leadership role in the developments of pharmacy education and the profession at aninternational level. He was successful in leading applications for EU-funded projects, namely PHARMINE, PHAR-QA and PHAR-IN, andattended several EIPG General Assemblies to champion these projects. Our condolences go to his family and many friends in EAFP.

eventsMARCH24–26 March 2014 – Heidelberg,GermanyICH Q7 Compliance for APIsManu-factured by ChemicalSynthesiswww.gmp-compliance.org

25–26 March 2014 – London, UKPAT & Quality by Designwww.patandqbd.com

25–26 March 2014 – Lyon, FranceModern BiopharmaceuticalManufacturingwww.pda.org

26–28 March 2014 – Barcelona,Spain19th Congress of the EAHP: TheInnovative Hospital Pharmacist –Imagination, Skills andOrganisation www.eahp.eu

31 March–3 April 2014 – Lisbon,Portugal9th Pharmaceuticals,Biopharmaceutics andPharmaceutical TechnologyWorld Meeting www.apv-mainz.de

APRIL1–4 April 2014 – Barcelona, SpainWorld Generic MedicinesCongress Europe 2014www.healthnetworkcommunications.com

1–4 April 2014 – Barcelona, SpainBiosimilar Drug DevelopmentWorld Europewww.healthnetworkcommunications.com

2–3 April 2014 – Berlin, GermanyCompliant Handling and RecallManagementwww.gmp-compliance.org

2–3 April 2014 – Barcelona, SpainWorld Generic MedicinesCongress Europe 2014 www.terrapinn.com

2–4 April 2014 – Vienna, Austria4th Annual Pharmaceutical

Logistics & Cold Chain Forum www.flemingeurope.com

8–9 April 2014 – Berlin, GermanyCross-contamination: The NewEU Requirements for the Use ofMultipurpose Equipmentwww.gmp-compliance.org

9 April 2014 – London, UKThe Quality of Medicines –Future Evolutionwww.mhra.gov.uk

10–11 April 2014 – Copenhagan,DenmarkThe New FDA/EU Approach toProcess Validationwww.gmp-compliance.org

13–16 April 2014 – Melbourne,Australia5th FIP Pharmaceutical SciencesWorld Congresswww.fip.org

16–18 April 2014 – Egmond aanZee, The Netherlands13th European Symposium onControlled Drug Deliverywww.escdd.eu

25–26 April 2014 – London, UKThe Clinical Pharmacy Congress2014www.pharmacycongress.co.uk

28–30 April 2014 – Frankfurt,GermanyEurope Annual Conferencewww.ispe.org

MAY4–8 May 2014 – Fajardo, Puerto RicoRespiratory Drug Delivery 2014www.rddonline.com

13–14 May 2014 – Copenhagan,DenmarkRisk Management in SterileManufacturingwww.gmp-compliance.org

17–18 May 2014 – Geneva,Switzerland3rd World Health ProfessionsRegulation Conferencewww.fip.org

19–20 May 2014 – London, UKADC Summit 2014www.smi-online.co.uk/pharmaceuticals/uk/conference/adc-summit

19–21 May 2014 – Budapest,Hungary4th International RegulatoryWorkshop, on A to Z onBioequivalence, Bioanalysis,Dissolution and Biosimilarityww.fip.org

21–23 May 2014 – Budapest,HungaryGMP Meets Developmentwww.gmp-compliance.org

22–24 May 2014 – Ljubljana,Slovenia2014 European Association ofFaculties of Pharmacy AnnualConference www.fip.org

27–28 May 2014 – Barcelona,SpainImprove your Quality Reviews –PQR, APR, Managementwww.gmp-compliance.org

JUNE2–5 June 2014 – Baltimore, MD,USAPharmaceutical Quality Weekwww.ispe.org

4–5 June 2014 – Berlin, GermanyDocument Management – GMPRequirements and Best Practicewww.gmp-compliance.org

17–18 June 2014 – London, UKGlobal Pharmaceutical ContractManufacturingwww.gpcmevent.com

18–19 June 2014 – Basel,SwitzerlandPharmaceutical Packaging andLabellingwww.pharma-iq.com

24–26 June 2013 – Uppsala,Sweden5th World Conference on DrugAbsorption Transport and Deliverywww.eufeps.org

20 european INDUSTRIAL PHARMACY March 2014 • Issue 20

european industrial pharmacy issue 20 (march 2014)

Documents

young biotech companies

european industrialpharmacy

oral drugs

supportbiotech companies

pharmaceutical supplychain

medical need

inta saprovska

piero iamartinolatvia