1
`
`Introduction and Perspective
`
`Mark Gibson
`AstraZeneca R&D Chan1wood
`Loughborough, United Kingdom
`
`Th.is book is intended to be a practical guide to pharmaceutical preforinulati,111-iin<l r,mnulll(cid:173)
`tion. It can be u:.ecl l'l!I A reference source .and " guicli,ncc tool for thos(' working in the
`pbannaceutical industry or related industries> for example, medical devices and bioph.1:.r(cid:173)
`m;1ccu1ical~, or anyone w.111ti1,g .111 tnSiRht inro 1his subject area. The informal ion presented is
`es.4ientia1Jy based oa the: cxtco.sive C.Xp<'Iicnc,::s of the editor and various other contributors
`who an: c1II activel)• working i 1l the indusny and ha\l'e l~arned .. hest practke" from 11,~ir t!xpc(cid:173)
`riences.
`Tbcrc arc \•arious ~xcellent books aJready available wh-ich cover d1e tlteoretical aspe<.::1, or
`different types of pharmaceutical dosage- form~ and pnK-C?'Sscs.. A variety ot books are also
`available thal focus 011 the drug deve]opment process, bu~iness, regulatory and ptojl'!CC m:-ln(cid:173)
`.i~entent aspects. In m>• opinion. lh<.>rc has been a long-standing need for~, pragmatic guide to
`_pharmaceutical preformula.do11 and formul.aLion wi1h an entphasi,s on what pt;.1c.Licol sn1die.s
`need to be unde-rtaken, for what rl-asons and during what key stages of lhe drug development
`process. The important ~ltgf.!S where prefor-nmlano11) blopharmaceutit.:$ and for1nulaclon vh1y
`a kc)' role an: candidate drug selection through ihc v,uious stages of product development.
`This book has been written to l ry ;met addre:,~ 1lii~ neeti.
`A logical .tpproad , 1.0 product de\·elopment is described in the book. with the key stages
`identified and Lhe preformulal.ion. biophanna,cculics :md formula, ior1 a,.1 i\lil it~ ~ud I ypic ,I ii,(cid:173)
`!.Ues at each stage di!>-eu~ed. Wherever possible, the book is illuslrated with real or work..~
`CELGENE 2042
`APOTEX v. CELGENE
`IPR2023-00512
`
`1
`
`

`

`2
`
`PharmaceutJcal Prcformulat,•on and r ormuk1tinn
`
`cxamplcs from contributor:. whll h:.wl." l.'.◊Til>ii.li,:rahle rdevam expe;ience of prefom,ulaLion.
`hiopl1r1r1n;)c.:eu1ics -and formulation development.
`Jim -\VcUs' book on prcformulaLlon ( \Veit~ I 9R8} ornde a strong impact on trainc.:s and
`pharm.i.ceULicaJ scientif.t.., (induding 1ll}'SelO working jn this Oddo( 1he phnrm,1teutic.1I in
`dustry when ii was introduced over IO f<.!••r'i ago. II dcsc.rlhes the important con..:eptS and
`methods useJ in preformulation with the underlting theory. To hi:. c-r<.-dit. \Velis' book is still
`us<.·ful to<.ht)', but :.a<lly, lh1: bouk is now o u1 of print, ,ind existing .:opies arc hard to obtain. fl
`aJso requires updating to indude modern prcformu.Jation in1>tnimcntal tc<...hniques which have
`cmcrf.cd ov<.·r the la~1 Jec~•dc. such (1~ thc::ru10 ;p.r'1vi1uel.J k analysis (TGA), hot Sl'ttgC' mi(cid:173)
`croscopy (HSM), X ray powder dfffr.Ktion (XRPD), raman and infra•r1,:d :,,pt:ct.ro1,cop>7 and
`M>1kl•t-t.Jtt· mu;lt•:u m:1gm:1 ic rc~onan<.<.~ {J\'.M R). 10 oarne a few. These tedmiques can be used
`to provide vaJuable jnformation to characterise the drug substance· ;uul ,lid fott11ulatio11 de
`velopn1ent usini; dw minnnal an,ounl;(l of C()1t1pt)UJ\cl
`Pliam1t1re1m;;n/ Prefommlnticm mul Formrtlr,Jtion: A Pmcttf(i! Gu.itle fr1Jm f.a,1dfriJ11e Drug
`Sclet·1io11 ro Cou-w,erdnl f'orrnu!ariou covers a 'A'lder subject area Lb.an just prcformu!Jlion.
`Topic:, include bivphann;-1cculic~ ... lru~ ddi, cry. formllblinn dnd proces..1, developmem aspt:'Ct.S
`of product dewlopme-nl. The book also describes a Jogical and structured ttpproat-h tL1 llu;:
`proJu,J clcvdc1pn-u:n1 pn>tes:-.. rt:eo111n1erlJing at wl1,ll ~Lag~$-apJ>topriate preformuJatioa1 bio(cid:173)
`pharm~Kemics and formulation work is best m1dcrt.tkco.
`
`DRUG DEVELOPMENT DRIVERS,
`CHALLENGES, RISKS AND REWARDS
`
`Jt is important that the reader is aware of the nature of pharmaceutical research and de\'?lop
`mcnt (R&O) in order 10 ;,pprtdale the ir11p<1rl,mLC of l'lrcfi:lrmul.-1ti<1n ;lnd forrrtulatic)n ir1 the
`O\'er-J.U ptoce::.s .•
`In simple terms, the ohjeCLive of pharmaceutical J<&I.) can be defined as "conver,i11g ideas
`into c.indidalc drugs for development'', .u:id tbc objc..:tj\'c or produ,·1 rleveloprncut <lcfinc<l a.5
`"'converting candidate drugs into products for re-gistration and sale': In realit}\ these goals are
`c<tlrcmcl)' c;h:tlle;:noing and dif€iwlt 10 ad1iC\1e bru,u.;;t! of 1he rmmy :-.iW1ificanl hunllcis :i ph~1r(cid:173)
`maceutical ..:ompany has.. to ovcrc-0mc duri11g the- course of drug development. Some of the
`mJ.jOr hurdle.,; are listed in Ta.hie 1.1.
`The high risk ol failure in drug discovery and dcvelopJnent througboat the pharmaceu
`tic.tl indu.m'Y st.uisrkall}' shows that, on average, only J Ill 5,000 to 1 io 10.000 compo,mds
`scn .. -cn<..J ia r<?'st".arch will rcac;h lhc rm1rkct (Tutk(:r L98◄), Q( those Lhat are nominated for de(cid:173)
`\.,.elopment, the failure rilte will vary from I in 5 to 1 in 1U compounds th.al will achii::v~ resi~·
`tr al ion ,md re.1ch the rnarkct-pla,c. On top o( I h~1, I here i:) a significant commcrcfal risk from
`those that arc mark--cted; onJr 3 out of LO are likely to achie·ve a fair return on in.veslr"n~nl. The.
`proJm.t.., which giw poor return ,,11 inve~tmenl MC c1ftcn I be rt-suJ1 of poor candidate drug se(cid:173)
`lection {the compound doc!> not have Lhe desired properties of safety, sclectiv11y, cffic:,11.;y, po(cid:173)
`tency urdutation) and/M poor prt1duc1 devc1,,1nnen1 {the clt.:vi.'lopmcnt programme doe5 not
`estabLish the ,,;iJuc o( the product), The latter scenario should, and can be, d\roided br (ttreful
`JSSCS$1He11t at the "producl design" \tage of development.. Product dc:.ign is discusst-d further
`in Chapter S.
`
`

`

`/11/r<Xluc/Jon and Perspect,ve
`
`3
`
`Tablel.1
`Major hurdles to successful product registration and sale.
`
`Ac:tlvity
`
`Research
`
`Safely
`
`Drug pfocc.ss
`Pharmaceutical
`
`Rerp1tiuory
`Manu'a~unng
`
`Ma1Xet!llgiCOffllOO(Ci;)I
`
`R<.--quircments
`
`Nuvcl cnmpoond (pa1enu1ble'?)
`Nove-i hil)I-Ogical mechan,sm (pa1e:ntabJo?}
`Unmet medical needs
`Polen1 and selectNC
`High margin ol safety
`Non · toxic tnot can:inOgcnic, 1atrato11enic. mutagenic. etcJ
`Tolero bit) Sid(H?II OC::LS: pmnte
`
`Efficacious
`
`A.occpt.able duration of action
`
`Bulk drug CAIi be synlhes1.5ed/scoled up
`
`Acceptable lorm11tati9fllpactt (meets customer needs)
`Orug dc1ivery/pmrluct pertormMce acceplOble
`Stab.Q/aooeptable shelf-lif~
`Clinical trial process robust anrt ctln he scaled up
`
`Quality ol data/dnc:um,mtAtion
`
`Manufacturable
`
`Able lo pas~ prewApprnval mRpect,Oll
`
`Compel.dive
`
`Meets cu!'ilomer nM rls
`
`Valur. tor monf!Y
`
`Cnmm~tT.U!il ff,!fllrn
`
`To be :>Ucccssful and competitive. rcs-'l!,m.:h-bas.:d pharmaCl'UticaJ companies mu,)t ensure
`tfo:it ne"1 discoveries are frequently brought 10 the market to generate cash flow. This is re(cid:173)
`quired to fund the next gcnl'nttion o f comp(1t1nd-. to med lhc lhcrap('Ulic nee.xis of patients.,
`and of t.'Oorse. 10 henef1l the share.holders-. '11,is 0•de of events is sornetimes reforred to as I he
`"produce life C)'de') and is furthc.·r iJlu.sl r.Jh.:d in Figure I.I,
`Th(":. costs of drug <li'-covery and development to bring a New C.hemicaJ l:.ntity {NCh) lo
`the m::.rker .ire ever increasing. IL ~ currently estim.i.tcd that in execs:> of U.S. $500 million is
`required to recoup th~ cc.1s1::. of reseatch, <levelop01enL nunufacturing. <lisrrihutio11> rnarket(cid:173)
`ing and s..1les. A i;ignificant proportion of this totaJ i~ for the cost of failun.·s. or in other words.
`the elimination of un~uccc:,.sfol ..:(Impounds. R&U expenditure for :m NCE fl'nd~ to increase
`StJbstanliaUy .-~ Lhe compound progresses from drug discoYCT)' research through the various
`clinical u•ial phases of d(•vdoprm.·nl. The pivolHI Pl1r,,;e Il l 1,a1ie111 lriah are u.,;ual)y tJ,e fargest,
`involving th<.lU.SJ.nds vr pal ieni-s, and hence the most expensive, To reduce devt.'lopruent costs,
`
`

`

`Pharmacet/lJcal Pref-Om1111auon and Formulat//ln
`
`Figure 1.1 Product life cycle.
`
`EXPLORATORY
`tU)Sl'.AKCI I
`
`CA~DJOATE.
`%LCCTlON
`
`c.m"icl:lte dmK
`~l.xli..">d
`
`S I RA rF.(11(
`l{F.SEARCH
`
`lbscd oo oomp:m)'
`Strut~
`
`Funber ma~ei1med-r:il 1'\C-.-4-,
`-
`nc:•.i.• 10J1.:11tiou.."-
`
`h 111he:r inatl:cL
`U)Cdji!ll] t1ttds
`-
`producl ltDC
`extmslQJl$
`
`MARKETING &
`co,tMI .RCIAI
`
`Regufa:ory
`~•l>mi~:o.ina
`
`FULL.
`l>EVI LOPMJ; N·t
`
`S...ftN 1&.11<1 dfo.:a<;v
`d .. ; .,,,n;;lnl11:J •
`
`L:XPLORATOR Y
`IJl \' l'(.(WM I IVI
`
`Proof of c.oocept
`1k,-1l)l>f'l',.lr,il,:,I
`
`l,()IJ'IC cQ1r1ra1\ies ,;electively screen and eliminate compounds earlier in the drug development
`process based on results. from ::im,1ll-~;1lc, less expensive !,tudies in man and prl'lg.res~ fewer,
`more certain compounds to later clinical phases.
`[n \pit~ of 1he high ri~ki, tUld high rn<a$ irwol\red, there is still a huge incentive for phar(cid:173)
`maceuticaJ companies to seek the- fiaancial rewards from successful marketed products, and
`t;SJh~ci;1lly frttm the pherwrnenal succe.~s of the rare "blockbuster" {J'e.:.chi1,g ~Jes of> 1 hill ion
`U.S.$ per year). This can cam the- company significanl profits to reinvest in research and fond
`the product development pipeline.
`Anolhcr factor, the risk of delay l◊ reglt;tr31ion and launch, can .a1so hci,·e a significant im·
`pi:lct on the financial success of a marketed product. McKinsey & Company, a m-an.tgement
`con~ultao~y~ c1sscssed that a 1>roduc1 th;~I is 6 monll\..s la1e to m.trket will mi~ om on one-third
`of the potential profit over the product's lifotimc. ln comparison, the}' found that a develop
`rnc.:111 c.os1 over.;µeud of $0 pt:rct:rll would reJu,c prol"ilS br just 3.5 percent, and ~1 9 pc.·rc.;.-m
`overspend in production costs reduced profits by 22 peromt (McKin""Y & Co. 1991 ). 'llte lo;s
`of produc.1 revt:nue is often <lu..: lo \.On'lp<::tilor t:On\f';mie.-; hcin~•. fir~t tf) m~rkct, c..1ptt1.ring lhe
`market share and dictating the market price, in addition to the loss of effective pah!ot life.
`licnce, thi; 1mporl,lflLt' of acceJera11ng onrl opti1t1isi11g d ru>;t disc◊"WY .urd clevclopmcnt, and
`getting to the market firsl with a new thc.·rapeutic class of medicinal product, can nor h~ un(cid:173)
`dcrc:,limAl{-<l. The seco11d product co tnarke.1 in lht' sai:ne c-lol>S will u:,uall)' be compared with
`the market leader, often unfavourably.
`
`

`

`ln11oductio11 and Perspective
`
`5
`
`The avemge time froin drug discovery lo product Jaunth j,, curn,:nlly c~timal<xl lo t,tkc
`10 to 11 years. Sever.ti facrnrs may h,1vc comribuu:d to lengthening developmenL Jjme~ over
`l.be years,. indudjr\{t an increase in the preclinical pha.~ 10 se1e1.1 lhc c,rn<lid,Hl' drug. ,mll also
`an iucrcasc in Lhe duratio,, of I he dink.il .md n_--gu.1:Hory period required for 1l1a.rketing ap.
`proval. Hent.h111.-1rking studies show wide gaps herwecn incluslry (l\'Crotgl' or worst pcrfonnancc
`compared to what is achicv.1bk as be.st practice performance (Spence 1997). On aVet'age, che
`preclioicll phase currently take.lo 4 co 6 ~1et1N; 10 complete, wh1.:rcas the tll:nc from candid,nc
`drug oonunat ion 10 regllbtory submission takes on a\'erage 6 to 8 years.. longer for 1rea1ment1,
`of chronic conditions. Most forwar'd-lot1king phannaCC\lticalcompanics arl' aiming to cc-duce
`these omes by rc-evah.mLion and s:ubsequenlJ)' streamlining the developmem prnces.~. ror ex(cid:173)
`,uhplc, by inlroducmg mol'e effective dinic,;11 progrc.t1nmcs ,.md more cfllcit·nt data reporting
`systems.. for'w:\rd pl;,mning and conducting multiple activities in parnfleL Howe,•er, this, in
`I urn. may put fo.mllllntion dcvefopnaml am.I dillic(II supplies on the crilical path. wlLh pres(cid:173)
`sures to C(nnplct.,. these activities in condensed time scales. Suggestions are offer'ed th.tough
`om th.is book on how prefor01ulaho11, hioph:u,mu;culks and formufotioo can be conducted
`in tht.' mO!<>I dlkicn1 W(I)' lo avoid deleys in development ti.mes.
`An)' reduction ia the 10Lal Li1ne-fra1ne of drug__ di~c(wer)' to m,1rkt1 ~h,mld improve. 1hc
`company\ profitabiLil)'· ln ., hi~hly cornp<-titivc mark<'l, product liJetimes are being eroded
`due to the pa.cce of introduction of compefitor products, the r.apid immduc1i,,n of gl!neric
`1)rodu'-L~ ,vhcri pJlt1lli> t:xpirc :md movt.'8 w "o,,.:r-thc-,ounlcr" t'OTC) statu,s. Succc:,sful phar(cid:173)
`maceutical companies are focusing on stralegies for optimum .. produce life cycle manage
`mc:nl" Lo max.imi..,e Ilic early gn)\¥111 of lhc prod uc:I on the: IT)arklil, S-U!'>tain peak ~Jes for a.\
`long as the product is in patent and delay the post-patent expiry decline for as long as possi
`bJe. l'hi~ ~hould 1mlxlmisl~ the r<~Lum oo im•'t:Mment <luriog a product life cydc to eoablc I he
`company to re.cover development costs and make further investments in R&D. Figure 1.2
`shows a das.sic cash now profile for a oew drug product developed and matket.ed. During de(cid:173)
`velopment there is a negative cash flow, and il may be sumc time aft~r l;,,un<.:h before s.:1les rev(cid:173)
`enue crOl>seS from loss m profit because of manufacturing, distribution and advertising cosrs.
`Profits continue to incrca.se as the market i.s i.:stablishe<I to rcc1c.h peak :w1e,, .ar1er which S;1lc:~
`c.leLrt:~..-e~ eSpedallf aftet tJ1e prllna11· patent expires and generic c.ompetitiou is i.J.1uoduced.
`Throughout the- life span llf" prmluc.t, it i:. in " co.mp,1oy'~ inkrt:sl Hl c.1,sure Lhe llesl
`pa1t•111 protection in order to achieve the longest possible market cxdusivit)', Prior lo the pri(cid:173)
`mary patent expiring ( norm..iUy for I he chemical drug_ :.uhst.tnce), il is imperative to introduce
`nt"\>1 indic,Jtions, fomlUlations, manufactming prnccssc-s, dcviC(:l> ;md gtneral l<-chnology,
`which are patCI1L prot<.·ued. I<> e.x1e,,d the life of the product and maintaln revenue. A patenr
`generally ha$ .a rerm of about 20 years, bul as dcvclc)pmc.:111 timc."S :-ire ge11ing ltw1ser. there will
`be a limited duratioo or pn:'llcx:tio11 rl!maining once the product is marketc-d (the ctfocth·e
`p~lcnl lifr). /\ comparison of effective patent ~fl· for pb,irrnC1tcu1ical uew ,hemical eulilil::l iri
`various counuics around lhe world .s-1,ow$ the same downward u·end benveen the 1960s and
`the J980s (Karia et .I. 1992; Lis and Walkor 1988).
`Getung to Lhe market quickl)• is ;.1 ru:1jor husine~:-drh•ing force, bm this has to be balanced
`with the clevdopmcl)l of a product ot Lbe appropriotc quality. Theel' is a nc:t:d 10 geuer:lle suf(cid:173)
`ficienl information to enable t-ound decisiOl)S on the selection of a candid ate drug for devel(cid:173)
`op men 1. as wcU a& co develop do~age forms whkh arc "fit for purpo!i-t'' <11 1 I ,e ,•arious Sli)ges of
`dcvdop111e1'lt. Anything more is w:,i-;ling precious resoul'ces (people J.nd drug substance).
`addfrig WU1eccssary co:,.i to I he programrne and, more importantly, cxlcndin);; the dt:vdopmelll
`time. Pcrfccl CJu,,lity should not b<.> tbc t.argci if ~o,()d c1u.allr>• Is. ~uftkie.nt for the intended pur(cid:173)
`pose.. 11,is can onJy b<' achic\'1;,."t) i( 1.hete L~ a clear understanding of the customi:r reqoirc111c.,, 1~.
`
`

`

`6
`
`Pharmaceut,ca/ Prcformula1ion and rorm,la/Ton
`
`Figure 1.2 Product hre cycle mana9e111ent
`CA~II
`n O\\
`
`+
`
`--~-...~ Ma.tl.o.'t ~l1at'~ ~Id wi.th liM
`ex!cn~1un.~
`
`I!
`Mau11faciun.ng
`lnett-~"\•Clil
`dcw:lopiucn1 ~oos<----_,,... .. llt•I bulll. h ,;(le.L'i
`
`,.
`
`Loo cx1cnsioo
`do.'\· :klp111C!ll CO!!b
`
`For exam pit:, if ,1 .~imple, non-op1imi~d fr,rnml:ltion with a rdacivdy ~horl iohdf life 1~ aCLepl(cid:173)
`able for Phase I clinical studies, any further opomisation or stability testing might be consid(cid:173)
`ered wastt~ful, unles:.~ rhe data generated car, b? ust:d I.tier in the dt:vclo1,me111 ptogr,unme.
`There can be a si~nificanl rhl< a)sociat~d whh doing a minimum dc\'elopmc:nt pro(cid:173)
`gramme and cutting comers to fast track to markeL Post launch, the cost of a retrospectivt fix
`clue 19 p(H)r produc-l/pruu!s..:. tl~ig11 and/-Or dt\'(,'loprm:nl can be extremely high. The -addi(cid:173)
`tional financial cost from work in product/process redevelopment, manufacrunng a11d \•aJj.
`d.t1ion, t1.:c.hni1...-il su1"Jport, r~gulalory an<l :,ales and rn;frkeling (clue lO a product rcc.i:U) can
`easily wipe out the profit from an earl)' launch. This can have several u.npJei\Sant knock-on ef(cid:173)
`fects; 11 11).ay aJfect 1hc market share aod the annpan)"s rela1ionship with the rcgu..latory .i.u(cid:173)
`tborilh.~ and its crttdibility w·itb customers (both externally and imema.lly within the
`company; may be threatened.. These factor'; nt>ed t(l be cak<"n in 10 .,u..0un1 when planniag prc(cid:173)
`formulatitm/lormuJation s1udkt:S which c,m di.:c.'Cll:y inilueucc tbc progress of o product to
`market and final product qu.:ihty.
`
`CURRENT TRENDS IN THE PHARMACEUTICAL INDUSTRY
`
`Locrea.sing competition and Lhre,us Lo lhe pharm:,<;e,11iclll industry with rcsped to ma.intaw
`iog co11Linued )aJes growth ~nd income mean :.haL s-ucce.~s:fu.J wmpan,es goin~ forward will
`be 1·hose which have a portfolio of prnduc1 s 1,:ap.1ble of ~bowing volume growlh. 1-fm.,,·ever, to
`sbow volume t,.rrowt.h ionov:n.ivc new produchare required. 'llte cost of dn1~ dii,.eo\·cry and
`developmen1 i~ escalaung because I here arc nn ca!>y l.irgcts left and tbe cost of devclopmenl
`
`

`

`lntroduC!IOn and Perspective
`
`7
`
`and the CO!il of goods sold is i1·11,:re:1sing. ThHc ha"'"' been sevcraJ mergers and ac.:quish·ions of
`rcscarch~based ptrnrn1;;1ccuticaJ compaoies, .i.nd mcreas .... .J c;oJIRboraUons ~ad inward lic:cosing
`of products and technologies, in nttcmpts to acquire new leads, 10 -share coses, co reduce th~
`time to licence and lo maintain growth. U1·fortunJh~I>•, rm:rg .... rs and acquisitions also result
`in .streamlining and job l(1s.s(·s whiC"h imprtwr effiriPn<y -:inti ciPo-.PMt" 1Wt>l'hr"l1d co,;r<. ,11 1hc
`same 1iroe.
`There is a chau~ing tread in the naturr of tJ1e candidate dr'Ug erner"8,i11g from plaamit1-
`cet11ical R&D. from a low 111oleu1lar wcir,h1 ('.hcmicid 10 a more complex macromolecule (bi(cid:173)
`ologicals), ,vhich c-..o be- a peptide~ protein, enzrme, ancibody, nucleic. add, gen~tic l'IH:ileri~1l or
`:i multicomponent \'3ct:11H!. Some u( the:;(' compounds hav(' been derived from blotechnolog(cid:173)
`ic:11 proc..,-sses to produce biotechnologicaJ medicinal pmducti. tha.c fight i11fectio11 .lfld disease.
`The U.S. Pood nnd IJrug Adminis1ni1ion (FDAi '1nd European t\gency for the Evaluation of
`J\,tedicinal Pn.1duccs (EM.EA) have aJread}' approved bio£echr1ologkal u1edku~al products fol'
`anaemia, cystic fibl'O,sis, 1:,rt>wlh ddldcm:y, h(_•p.ititis and transpJant rcj<:ction.1'.fany more arC'
`hdog d1.:vdl1pcd to treat cancer, human iffrum1odetlcie1lcy vfrus (J-IIV) inrectio11s .and ac(cid:173)
`quired immuoodeflcieoq symh-ome {A[OS:~ multiple sclerosis. and stroke. A major chalkngc
`10 1hc fonnulator is to dl:'\ldop self-admiuistered forrn.ulations Lo deliver mac,·0111olecules
`such as proteins and polypeptidt>.,; i,uo rhe hody> for txa1n11lc. by the or:11 or inhalation roule,
`:Vlone sophi.sLic.i.tt--d <lrug dclivnt S)'Slcns :,re being dt·veloped to O\'t>rcome the limit.a•
`tfoos of conventional forms <>f drug delivtq· systems {e.g.1 tabltt..~ and int r<h'l!rlou~ I IV} solu(cid:173)
`tion.;}. h) ovcri.:(1mc problems of poor drug absorption, the non-compliance of patients and
`inaccurate targeting of therapeutic agents. One exarnple of .an emel'ging drug delive.J·y tech(cid:173)
`nc,1ogy i~ I he u:,c o( low-k:vd dccl ric::il (~n(·r~y lo assist the lrao~-port of drugs ;1cros:; the skin
`in a process known as electrophoresis. This method could be particularly useful for the deliv·
`erv of peptides ,mc:I protcio.s which ::ire no1 adeq\l::itdy tran:,portt."(I by p:\SS-h·e I l'tms<lem:iul
`therapy. The drug absorption rate is very ripid and more controlled compared with passive
`diffusion ~cros:; the :,kin. Another exo111,,Je ls lhe Improvement io mllalel' cedrnology to ffl·
`sure a more efficient delivery to the Juugs, with minimaJ drug deposition in the mouth and
`lr~H.:hca. The 11:,.t: o( a lm:;11 h-ae:1u~Ht:d aeroso: is desigoed to co-ord.inate dmg delivery witll che
`patient's inhalation to achieve this. A third example is the use o( biocrodabtc polymers I hac
`Cito be irnplHntc<l or iojec1t:d WJlhlu the ()Qd'.7 ~o adrninisterdmgs from a marrix which ..:an be
`formu.Jate-d to degrade over a long dm-ation from one t.fa}' 10 ~ix mvntl,~. an,I do mJI require
`n:tric\';d. Some of the.,;~ .~pt!cific delivery systems are explained in more detaiJ in later chapters
`of Lhis book on the various do:,;.,ge form>.
`Ful urif;I it: drug deli\•ery systems are being devclopc.>d which hope to facilitate the trans(cid:173)
`port of a drug with a carrier to iLs i11k.rJc.le4 desri1h1tlo1) in the body and thell release it there.
`Liposom~, monodo11al a,,cibodjes and modified viruses arc bring con,.idcrcd to ddh·c.·r "re·
`pair genes" by IV injection to l:~rgt'i d1c re.-.--,iratory epithelium in the treatment of cystic fi.
`bros.is. These novel drug delivery systems not only offer dear m<.·dkJI benefits to the patient
`b111 cau afso be opportuniti<.·s for cc.muni:rcial C)q)loit:niou, e!;pedally 1.1.lle-ful if a drug is ap(cid:173)
`proaching the end of it~ pate1'lt life.
`There ::ire pre~sures on the ph11rmac<"u.i~I in<.h1.~ilr}' whkh affect the way products are
`being developed. For cx:unplc> I here 1.s a trend for more comprehensive docwncntJtion lo
`dcmonstr,11c ,o.,npliance witb current Good Maou(,1c.l urirJ.S Prac1 ke (c(l.\rl P) and Good Lab(cid:173)
`oratory Practice (GLP} and lo demonstrnte :hat systems and procedures have b<.-cn validated.
`The Lr<:nd is lor more information required for t1 rcgulat1.1ry ,;uhmi!).Sion. with littlt: fltxihility
`for du111ges once submitted. Thcrdcm\ 1 he pte!;.,;1.u·e is for a compan)' to submit early and d<."(cid:173)
`velop the product 1origh1 tlr.1;1 ti.me•:
`
`

`

`8
`
`Pharmaceutical Prefom1u/vtion and rorrm1/,1lmn
`
`•
`ln s.-pitc ol cl lorl~ to harmonise l~t:., )lamhmls nnd pl1an11acopoeias, there is stiU diver-
`sity between the maior global maJ'kets
`J:.mope, the United States aad Japan-which h,we h'I
`be la.ken in to account in lb<:dcsign ol prc:formulation ,md lc1m1u1Jtio11 programmes IAnony(cid:173)
`runu.~ 1993). This Lldi~cu.ssed further ia C:hapter 5 on proJuct des.ign.
`Ot.hcr pn.'$s.urcs facing the ph::irmao..'utical iudusbr>· .ire ur 11 poli1 ii.-:al/etr,nomicaJ or envj
`ronmentaJ nature. Some gO\'crnmcm~ .1.re u·ying_ to com.1.in heaJLhcare tost'i by inLroducing
`hcal1h~Jrc reform~. wh.kh may lead 1<) rcdu1.:cJ price:., and pr<>fil m3rgin1. for companies, or re•
`stricted markets where onfy certain drugs can be prcsuibed. All.bough the bcocficial cffcd -of
`drug..-; i~ 11(Jt qu1..·Stioncd in general, Lhc prC'i!.ure lo conl11in 1h~ heahhcart ,o~ts is acute.
`Healthcare costs are increasing partJr because people- a.re Irving lougcr and more LCcatmcnl~
`are c1.v.til:ib1c. Thi:,. may iuOul·ncc dw o>mmer.:.:i.11 price ~h;\I ca.u he obi.dined for a ne'\<1 prod
`uct entering the- market and, in turn, the "cost of goods (CoG> target'~ The- industry 3Vl'r.tg-<.·
`for t.he CciC 1ruHe1 is 5 rn 10 percent of I he commetdaf p,ice with pre:.~s:ure to keep lt as low as
`possible. This ma)' 1111pact on the dtoice and cost of raw malcrials, components and packag(cid:173)
`ing for the product and the design and cost of manufacturing the drug and producL
`[ nvironmemal prci:.,,sun:s arc to use environment.a.II)' l:ritndly mah.:riaJs in produt:ls and
`processes and to accomplish the reduction of waste emissions from manufacturing proc-:.sses.
`A go,,d e.x';uuptc:- i~ 1 he: replacement of 1,.i,[(.lrofluun1c11rbl1n, tGFCs} pTOrdL-mLS ir1 prc:s~urG,ed
`metered dose inhokrs lpMDls) with hydrofluorocorbons (HFAs). The production of CFCs in
`de .. ·efoped cou.01des W<L~ ha11r1ed hy d ie Mon1re;il J>rott'l<!OI (an 1n1cr-n,uion.tl Ire.ti)') apart
`from "'cs~ntfa.l uses'~ such .is propellant~ in pl\,U)J..s,. to reduce- the damage l'o the: carth~s ozone
`layer. However. there ls increasing pre.~ure to pha.~e out CFC.~ altogether. The transition from
`CH; LO I IFA produ<...l$ involves- :1 m,1'isivc rcformula1iun c.xerdi,c wilh :J~nificaat lcclutical
`challenges and costs for pharmaceutic.al companies invoJ,;ed in developing pMDis, as de
`scribed in Chapter 10 "lnhal,11io11 Dos.age t•ormf~ How~\'er, Lhis- t:an he 11,micd into ._. com(cid:173)
`mcrcfal -opportunit)' for some comp~mic-s whk.h have developed patent·protec.ted delivery·
`systems to extend the prod uct life cycle of their CPC pM DI product<..
`
`LESSONS LEARNT AND THE WAY FORWARD
`
`To ac:bicw 1hc OOst cbann· of a fust -and efficient dcwlopment programme to bring d candi(cid:173)
`date drug to market, several important me~sages uu he gle:.-intd from projects which ha\'C
`~one \oJ~U and from oompanic) with ,.omistcolly good track records
`There are benefits. for pharmaceutical devdopment m gel involved early with pr-edin.ical
`rt-search during the ctindidale dnig ~k'<ti◊n pb,m:. This is to move away from ao "overrthe
`waW' hand-over approach of tbe candidate drug to bi! developed from "rese-,in:h" to "d~wlop(cid:173)
`ment': The drug s.eleetio11 criteria 'I-Viii be 1,rirnarily ha~cd on ph,1rmacologica.J propertiec; such
`as pott'ncy, selectivity. du.ration of action and safety/toxicology as.~essrne11t,. I luwe\'c:r, ii' RII
`these factors are s.at.isfactorr ai1<l similar, 1l1crc nH1y be ,m importJ.nt difference be1, ... ·een the
`ph,1rm,1ceutic..-1l prop,:rtics ot candidate drugs. A candid,ue drug \.\'ith prefr:trecl r h.umnccuti(cid:173)
`cal properties, for example, good .aqu~nu."- ~o.lubilil)1, cryt,l'nllinc, nonhygroscopic and good
`:;tal>ilil)', should b~ .1,dCctl·d lO minimise Lhe d mlknges involved in developing~ suilablc for(cid:173)
`m.ulation. Thls is discussed further in Chap1er 2.
`t\nuLher importanl foclor i:; g.ood long 4 term planning. ideally from <:..indidltlc drug nom(cid:173)
`ination to launch, i,,dtb conside-rnuon for the ~fol r, clinical. ph:mnaceutica1 develo1>me1u,
`manufacturing opcn1tions and rl-g_ulatory strategies involved 10 devr:101) lhl~ product. Tbere is
`a ne~ for ooe central• integrated, co,npany project plaa that bas been agreed 011 by all IMTli<.~
`
`

`

`tmroduttior: and Persper:;1ive
`
`9
`
`with a vested interes1 in lh<.· projecL Needle.,;,-, 10 s.ay, tht: pl:rn '>hould comain d(.'tails of activi•
`1 ies, timings, respon/)ihilu ie~, mU~tom::., rt\·icws. :.md decision poinK Reviews ;1nd decision
`point,; are r~quirc(I nl Lhe end of n di51 inct ncrivicy 10 t!nh,1rc th:u 1J,c- project is still ml!eting its
`ohjt·ctives and ,;houh.l rrugrc-ss to the next stage of developmem. However, 1hese review~
`should nol c.lusc any delays t(I I ht rr<>grnm 111c, ml her. Lhc}' should rat.ify wbat is al read}· pro·
`gressing. Th~ 1radilion;:1l sequential phases of ptoduct deve1o1>meut (:see Chil1>kr 2) mu:,1 1'11.:
`uwrl;.ppc:d to accelern.te I he produc-1 10 markl't. ln rcalit}'. pJans will i.m;vitn.bly change with
`ume; they sho\ild hi:: "living" docurnent.ii which are reviewed ,111c.l up<lakd ,,c n:g~1f,1r inh'n·;,a1\
`and then communicah:d lo all p~lrtics. There m,1y be several more detailed, lower-level plans
`focusin~ on <lc-partmental act.ivitk·i.. ~-fh for pharrn:1ccu1ic:d de,,elopmen1, brn 1h,~s(' r,lans
`must be linked 10 1he 1op h;v(.~I Ct"ntraJ project plan.
`forward planning should provide rhe op 1>(lrl lu'lily for :1 wdJ lhOlq;,ht Ou{ and tffkienc 3J)(cid:173)
`proach to product t.l<!vdoprncm, id.;,•tllifying requirements up front so as to avoid too much dc(cid:173)
`lilJ<.·ration and backtracking along the \v;)y. 11 ulso $hf1uld provide ,l visible ..:onuuunic:Jti<►u l,(ti)I.
`Good phumin~ b supported h)' adopting a systematic. and structured approach to prod(cid:173)
`uct developmenL The development process can be: bmkeu dm.,11 inlo scvt:nll key defined
`s:tag~-1,rodut,:C ,le8ign, prO\"'.('::,S dcsi~n. product optimisation, proce~s op.tim.isation, scale-up
`and so on. Each stage will have inputs and outpuu. as shown in figure 1.3, a simphfied frame(cid:173)
`, .. ·nrk for product tievelopment. The 11ppi:oprit1tc dcfinilion .ind rcquirc.mtnb 31 c~•ch st.;1ttc t1rc
`dcstrilxd in Chapters 5 and 8 of the, text.
`As product dt'.'vdopn1t'.'11I CAn lake sev~ra I ytarS to comp1¢ce, ii is irnp(1rt.anl 1(1 have ;'In ef(cid:173)
`tCctiw document management system in place to record the work. The.- primary rdCTcncc.(cid:173)
`:-.ource fl-,r recnr<lins e,11pt:rin1en1aJ work wi•II u:;ually he a laho(ator y nMehook. l'he wnrk
`should be checked, dated and counter-signed to saris!), GLP and intcUcctual property n·(cid:173)
`quire.men1,. F.xp,eriruc:,,tal protncoJ..:: are 'lometimes useful for defining progrnmmes of work,
`
`Figure 1.3 Framework for product development
`-----'-' LccANc..c•cc".co'-no'-'-'c'-'""'--"-"'-''-.'-"'"''-' ____________ _.,I>
`
`[
`
`lwm.l!
`
`l'lln<t I\"
`
`

`

`10
`
`Pnurm:u;eu!,c;JJ Prefar111uM1m11 and FormulaUon
`
`e-xplainiug: 1J1c 1111io11aJe for the studies and defining the acceptance criteria. \\/hen Che studies
`arc completed, the n:sults c.an be reported with n:fcn·ncc 10 lhc protocol and acceptance cri(cid:173)
`l~ria. l . ..th<intlOr}' 11()tebnoh :u·e r~fere11ced in the protocols and reports so that lhe n1w J.at.t
`can be retrieved in the event of an ,mdil.
`Al I he co1ltpld ior, of ke>• im1ge,; of the work. surnmary reports can be written. rcfcrt<nc.;mg
`alJ other protocols and reports rele\'ant to that st~,gc and highHf~hling 1t,e major rec:omme.n(cid:173)
`d.Ut()rh ,rnd cooclusio,,s. In I hi,S way, a produce development docwnent tile c.an be buiJl up for
`transfer of information and lechnology, including the clcvclop1ne111 hisrory and rnuonaJe for
`progression. The tile will also bt vital for data retrieval in the e\'cnt of a rcgulalory in~rcctiuu.
`Finally, successful product dcvclopme111 i5 often ::1-::,odated with good teamwork. The
`proctss is muJLidis'-1plinary, re1yi.11g on people with different spocfalisl I-kills workin~ logerhc:r
`w m.ak1.· il happru. This is panin1t::1rlr irnpurLrnt al the kcf interfaces such as precli11kal re(cid:173)
`search with pb.i.rma,eutical de\·elopmem and pharmaccutlcaJ dcvclopm1.·n1 with manur:tdur(cid:173)
`ing ◊pl:rntions JI 1lu~ fi,rnl pt'c.,>dudioi·, site. It is Lherefore useful to have representation on the
`project teams from all thl! key specinlist functions lo ensure buy-in lt> 1hc pJarts, Mr;Heg,ie..; and
`decisions and rn have a good projecl management system in place.
`
`SCOPE OF THE BOOK
`
`Thi~ book b ~trndurt:d in a logic:11 order to cover thi.: \1ariou:, ~t1:1ge-. of drug dt!vdoµmt:Jll from
`candidate drng selection to development of the intended oommc,rcial dosage form.
`In C:hapler 2> Lhc key s1.agc:s of the K&D proce!\..'l are exp)aiued in some detail, with Lhe out
`puts t".x-pcctcd from C'ach stage. to -affor(I ao appreciation of the c-atirc proocss. The rcmainclc:r
`or the-book concentrates on candidate drug selection for development and development of Lhe
`commcrci,11 dosage fon:n ,,,here preforrnul..aion, biophi1rm,'ILC~li<:s and fornrnl.icion plat· n
`vital role. Initial emphasis is on candidate drug selection and the importance of prefom1ula(cid:173)
`tion1 formulatio,, and biopharmaceuti.:s inpul at this stage. 'lraillLioHally, no1 all pht1rnhlc:eu(cid:173)
`tical companies optrnlc in this w,1y, and the res uh from cxpcricnc:c is ohcn Lhat pharmacc.•utical
`developmem has to accept whatever candidate drug comes out of research and address-an}r un
`forc~l;t'n difficult it'.~ during devdop1m:nL The Jismlvano1geo,: of I his ,tpproach, and the oppor(cid:173)
`tunities and benefits of pharmaceutical input to the c.and.idat~ selectioa process, are dearly
`exvlaioed in the early chapters.
`Available drug substance for prdom1uJation a.nd bioph:mnaccutics studies at the cand.i~
`date drug selectio11 stage can be a major challenge. Ch,1pte:r 3 describes che prcformul.ufon
`'.>tu<lic'.-1 lh•it can be umJcrtaken lU 111..tximiSe the inlOrm"tion gained lrom small amounts of
`drug substauce iu order to select the preferred candidate drug for developmem. Various rnod(cid:173)
`cm pl'eforutulaliun teclmit}U~ which u~ 111inim,1I .trnc,1mt:.or On,g arc described to evaluate
`the physicocb,micol properties of compounds, salts .tnd polrmorphs.
`C:hapter 4 descril,~.; the 1mpMl.it1ct: of drug deliver)' .1nd bioph:.trmaccutieal fuc.tocs in the
`candidate drug selection phase. Consideralion b given to the intended route of adn)ini!.tra(cid:173)
`tion and what predictfons ct1n be made and useflll ioiorrH:ttion gJi..ned from biophtumaceuti(cid:173)
`cal assc.·ssmc.-nt of th~ c.1mlidatc drng.
`l·olJowmg candidate selection. usually one C.llld