Handbook of Pharmaceutical Manufacturing Formulations, Vol 6 Sterile Products

458 Pages·2009·4.216 MB·English

by  Niazi, Sarfaraz K

VOLUME
V O L U M E S I X
Pharmaceutical Science
SiX
Second Second Edition
Edition

about the book…
Handbook of
No other area of regulatory compliance receives more attention and scrutiny by regulatory authorities H
a
than the regulation of sterile products, for obvious reasons. With the increasing number of potent
n
products, particularly the new line of small protein products, joining the long list of proven sterile d Pharmaceutical
products, the technology of manufacturing sterile products has evolved into a very sophisticated b
o
industry.
o
k

Highlights from Sterile Products, Volume Six include: o
f Manufacturing
• formulations of sterile dosage forms, regulatory filing requirements of sterile preparations,
P
and cGMP compliance, all of which are tied together in the final preparation of the CMC h
a
sections of regulatory applications
r
• specifications of a manufacturing facility to manufacture compliant sterile products m
• NDA or aNDA filing requirements of sterile products a Formulations
c
• an alphabetical presentation of formulations of pharmaceutical products based on their e
S
generic names t u
e t
about the author... rile ica
SARFARAZ K. NIAZI is Consultant, Pharmaceutical Scientist, Inc., Deerfield, Illinois, USA. Dr. Niazi has Pro l M Sterile Products
d
over 35 years of worldwide experience in managing multidisciplinary research; he has been teaching u a
n
and conducting research in the field of pharmaceutical and biotechnology sciences and has published c
t u
s
over 100 research articles, dozens of books, both technical and literary including several textbooks. f
a
He is a recipient of several research recognition awards. He is a licensed practitioner of patent law c
t
before the US Patent and Trademark Office and serves the global pharmaceutical and biotechnology u
industry in the transition of research ideas into useful technology. Dr. Niazi holds several major US and r
i
n
worldwide patents for his inventions and writes in the fields of philosophy, sociology, rhetoric, and
g
poetry; he is the author of the first book on clinical pharmacokinetics and the largest work on
F
pharmaceutical manufacturing formulations and also on the manufacturing of therapeutic proteins. o
r
He has extensive experience in global management of research in healthcare systems. m
u
Printed in the United States of America
l
a
t
i
o
n
s
H8130
Niazi S a r f a r a z K . N i a z i
PMS 202C
Niazi_978-1420081305.indd 1 5/27/09 4:51:16 PM
V O L U M E S I X
Second Edition

Handbook of
Pharmaceutical
Manufacturing
Formulations
Sterile Products
S a r f a r a z K. N i a z i
Pharmaceutical Scientist, Inc.
Deerfield, Illinois, USA
Niazi_978-1420081305_TP.indd 2 5/27/09 4:50:32 PM
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
Handbook of
Pharmaceutical Manufacturing Formulations
Second Edition
Volume Series
Sarfaraz K. Niazi
Volume 1
Handbook of Pharmaceutical Manufacturing Formulations:
Compressed Solid Products
Volume 2
Handbook of Pharmaceutical Manufacturing Formulations:
Uncompressed Solid Products
Volume 3
Handbook of Pharmaceutical Manufacturing Formulations:
Liquid Products
Volume 4
Handbook of Pharmaceutical Manufacturing Formulations:
Semisolid Products
Volume 5
Handbook of Pharmaceutical Manufacturing Formulations:
Over-the-Counter Products
Volume 6
Handbook of Pharmaceutical Manufacturing Formulations:
Sterile Products
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
InformaHealthcareUSA,Inc.
52VanderbiltAvenue
NewYork,NY10017
(cid:1)C 2009byInformaHealthcareUSA,Inc.
InformaHealthcareisanInformabusiness
NoclaimtooriginalU.S.Governmentworks
PrintedintheUnitedStatesofAmericaonacid-freepaper
10987654321
InternationalStandardBookNumber-10:1-4200-8116-0 (Volume1;Hardcover)
InternationalStandardBookNumber-13:978-1-4200-8116-9 (Volume1:Hardcover)
InternationalStandardBookNumber-10:1-4200-8118-7 (Volume2;Hardcover)
InternationalStandardBookNumber-13:978-1-4200-8118-3 (Volume2;Hardcover)
InternationalStandardBookNumber-10:1-4200-8123-3 (Volume3;Hardcover)
InternationalStandardBookNumber-13:978-1-4200-8123-7(Volume3;Hardcover)
InternationalStandardBookNumber-10:1-4200-8126-8 (Volume4;Hardcover)
InternationalStandardBookNumber-13:978-1-4200-8126-8(Volume4;Hardcover)
InternationalStandardBookNumber-10:1-4200-8128-4(Volume5;Hardcover)
InternationalStandardBookNumber-13:978-1-4200-8128-2(Volume5;Hardcover)
InternationalStandardBookNumber-10:1-4200-8130-6(Volume6;Hardcover)
InternationalStandardBookNumber-13:978-1-4200-8130-5(Volume6;Hardcover)
Thisbookcontainsinformationobtainedfromauthenticandhighlyregardedsources.Reprintedma-
terialisquotedwithpermission,andsourcesareindicated.Awidevarietyofreferencesarelisted.
Reasonableeffortshavebeenmadetopublishreliabledataandinformation,buttheauthorandthe
publisher cannot assume responsibility for the validity of all materials or for the consequence of
theiruse.
Nopartofthisbookmaybereprinted,reproduced,transmitted,orutilizedinanyformbyanyelectronic,
mechanical,orothermeans,nowknownorhereafterinvented,includingphotocopying,microfilming,
andrecording,orinanyinformationstorageorretrievalsystem,withoutwrittenpermissionfromthe
publishers.
For permission to photocopy or use material electronically from this work, please access
www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc.
(CCC)222RosewoodDrive,Danvers,MA01923,978-750-8400.CCCisanot-for-profitorganization
thatprovideslicensesandregistrationforavarietyofusers.Fororganizationsthathavebeengranted
aphotocopylicensebytheCCC,aseparatesystemofpaymenthasbeenarranged.
TrademarkNotice:Productorcorporatenamesmaybetrademarksorregisteredtrademarks,andare
usedonlyforidentificationandexplanationwithoutintenttoinfringe.
LibraryofCongressCataloging-in-PublicationData
Niazi,Sarfaraz,1949-
Handbookofpharmaceuticalmanufacturingformulations/SarfarazK.
Niazi.–2nded.
p. ; cm.
Includesbibliographicalreferencesandindex.
ISBN-13:978-1-4200-8106-0(set)(hardcover:alk.paper)
ISBN-10:1-4200-8106-3(set)(hardcover:alk.paper)
ISBN-13:978-1-4200-8116-9(v.1)(hardcover:alk.paper)
ISBN-10:1-4200-8116-0(v.1)(hardcover:alk.paper)
[etc.]
1. Drugs–Dosageforms–Handbooks,manuals,etc. I.Title.
[DNLM: 1. DrugCompounding–Handbooks. 2.DosageForms–Handbooks.
3. FormulariesasTopic–Handbooks. 4. Technology,Pharmaceutical–Handbooks.
QV735N577h2009]
RS200.N532009
(cid:2)
615.19–dc22
2009009979
For Corporate Sales and Reprint Permission call 212-520-2700 or write to: Sales Department,
52VanderbiltAvenue,16thfloor,NewYork,NY10017.
VisittheInformaWebsiteat
www.informa.com
andtheInformaHealthcareWebsiteat
www.informahealthcare.com
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
ToProfessorShamsuzZoha
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
Preface to the Series—Second Edition
Thescienceandtheartofpharmaceuticalformulationkeeps urgedtomakeuseofthisinformation.Whereasthisin-
evolvingasnewmaterials,methods,andmachinesbecome formationisprovidedfreeofcharge,theprocessofob-
readilyavailabletoproducemorereliable,stable,andrelease- taining the information may be cumbersome, in which
controlled formulations. At the same time, globalization of case, commercial sources of these databases can prove
sourcing of raw and finished pharmaceuticals brings chal- useful,particularlyforthenon-U.S.companies.
lengestoregulatoryauthoritiesandresultsinmorefrequent 6. AlsoincludedarethenewGoodManufacturingGuide-
revisionstothecurrentgoodmanufacturingpractices,regu- lines(2007)withamendments(2008)fortheUnitedStates
latoryapprovaldossierrequirements,andthegrowingneed andsimilarupdatesforEuropeanUnionandWHO;itis
forcostoptimization.Sincethepublicationofthefirstedition stronglyurgedthatthecompaniesdiscontinueusingall
ofthisbook,alothaschangedinalloftheseareasofimpor- olddocumentsastherearesignificantchangesinthere-
tance to pharmaceutical manufacturers. The second edition visedform,manyofthemarelikelytoreducethecostof
builds on the dynamic nature of the science and art of for- GMPcompliance.
mulations and provides an evermore useful handbook that 7. Detailsondesignofcleanroomsisanewentrythatwill
should be highly welcomed by the industry, the regulatory beofgreatusetosterileproductmanufacturers;whereas
authorities,aswellastheteachinginstitutions. thedesignandflowofpersonnelandmaterialflowisof
The first edition of this book was a great success as it criticalnature,regulatoryagenciesviewthesedifferently
broughtunderoneumbrellathemyriadofchoicesavailable andthemanufacturerisadvisedalwaystocomplywith
toformulators.Thereaderswereveryresponsiveandcom- moststringentrequirements.
municatedwithmefrequentlypointingouttotheweaknesses 8. Addition of a self-auditing template in each volume of
aswellasthestrengthsofthebook.Thesecondeditiontotally theseries.WhilethecGMPcomplianceisacomplexis-
revisedattemptstoachievethesebymakingmajorchanges sueandtherequirementsdiversifiedacrosstheglobe,the
tothetext,someofwhichinclude: basic compliance remains universal. I have chosen the
European Union guidelines (as these are more in tune
1. Complete, revised errors corrected and subject matter withtheICH)toprepareaself-auditmodulethatIrec-
reorganized for easy reference. Whereas this series has ommendthateverymanufactureradoptasaroutineto
six volumes differentiated on the basis of the type of assure GMP compliance. In most instances reading the
dosage form and a separate inclusion of the U.S. OTC templatebythoseresponsibleforcompliancewithkeep
products, ideally the entire collection is needed to ben- themsensitivetotheneedsofGMP.
efit from the myriad of topics relating to formulations, 9. OTCproductscross-referencedinothervolumeswhere
regulatorycompliance,anddossierpreparation. appropriate.Thiswasnecessarysincetheregulatoryau-
2. Totalnumberofpagesisincreasedfrom1684to2726. thoritiesworldwidedefinethisclassofdrugdifferently.
3. Totalnumberofformulationsisexpandedbyabout30% Itisimportanttoiteratethatregardlessoftheprescrip-
withmanynewlyapprovedformulations. tionortheOTCstatusofaproduct,therequirementsfor
4. Novel formulations are now provided for a variety of compliancewiththecGMPapplyequally.
drugs;thesedataarecollectedfromthemassiveintellec- 10. OTCmonographstatusisanewsectionaddedtotheOTC
tualpropertydataandsuggesttowardthefuturetrend volumeandthisshouldallowmanufacturerstochoseap-
offormulations.Whilesomeoftheseformulationsmay propriateformulationsthatmaynotrequireafilingwith
nothavebeenapprovedintheUnitedStatesorEurope, theregulatoryagencies;itisimportanttoiteratethatan
thesedoprovideadditionalchoices,particularlyforthe approvedOTCmonographincludesdetailsofformula-
NDA preparation. As always, it is the responsibility of tionincludingthetypesandquantitiesofactivedrugand
themanufacturertoassurethattheintellectualproperty excipients,labeling,andpresentation.Toqualifytheex-
rightsarenotviolated. emption,themanufacturermustcomplywiththemono-
5. A significant change in this edition is the inclusion of graphinitsentirety.However,subtlemodificationsthat
commercial products; while most of this information aremerelycosmeticinnatureandwherethereisanevi-
is culled out from the open source such as the FOIA dencethatthemodificationwillnotaffectthesafetyand
(http://www.fda.gov/foi/default.htm),Ihavemadeat- efficacy of the products can be made but require prior
tempts to reconstruct the critical portions of it based approvaloftheregulatoryagenciesandgenerallythese
on what I call the generally acceptable standards. The approvalsaregranted.
drugcompaniesareadvisedtoassurethatanyintellec- 11. Expandeddiscussiononcriticalfactorsinthemanufac-
tualpropertyrightsarenotviolatedandthisappliesto turing of formulations provided; from basic shortcuts
all information contained in this book. The freedom of tosmartmodificationsnowextendtoalldosageforms.
information act (FOIA) is an extremely useful conduit Pharmaceutical compounding is one of the oldest pro-
forreliableinformationandmanufacturersarestrongly fessions and whereas the art of formulations has been
v
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
vi PrefacetotheSeries—SecondEdition
relegatedtomoreobjectiveparameters,theartneverthe- lentdrugproductsshownosignificantdifferenceinthe
less remains. An experienced formulator, like an artist, rate and extent of absorption of the therapeutic ingre-
would know what goes with what and why; he avoids dient[21USC355(j)(8);21CFR320.1(e)].BEstudiesare
the pitfalls and stays with conservative choices. These undertaken in support of ANDA submissions with the
sections of the book present advice that is time tested, goal of demonstrating BE between a proposed generic
althoughitmayappearrandomattimes;thisisintended drug product and its reference listed drug. The regu-
forexperiencedformulators. lations governing BE are provided at 21 CFR in part
12. Expandeddetailsoncriticalstepsinthemanufacturing 320. The U.S. FDA has recently begun to promulgate
processesprovidedbuttokeepthesizeofthebookman- individual bioequivalence requirements. To streamline
ageable, and these are included for prototype formula- the process for making guidance available to the pub-
tions. The reader is advised to browse through similar lic on how to design product-specific BE studies, the
formulations to gain more insight. Where multiple for- U.S.FDAwillbeissuingproduct-specificBErecommen-
mulationsareprovidedforthesamedrug,itintendedto dations (www.fda.gov/cder/ogd/index.htm). To make
show the variety of possibilities in formulating a drug this vital information available, an appendix to each
andwhereasitpertainstoasingledrug,thebasicformu- volume includes a summary of all currently approved
lationpracticescanbeextendedtomanydrugsofsame productsbytheU.S.FDAwherearecommendationon
class or even of diversified classes. Readers have often conductingbioequivalencestudiesismadeavailableby
requestedthatmoredetailsbeprovidedintheManufac- the U.S. FDA. When filing an NDA or an ANDA, the
turing Direction sections. Whereas sufficient details are filer is faced with the choice of defending the meth-
provided,thisisrestrictedtoprototypeformulationsto odsusedtojustifythebioavailabilityorbioequivalence
keepthesizeofthebookmanageableandtoreducere- data. The U.S. FDA now allows application for waiver
dundancy. of bioequivalence requirement; a new chapter on this
13. Additionofalistingofapprovedexcipientsandthelevel topic has been added along with details of the dissolu-
allowed by regulatory authorities. This new section al- tiontests,whereapplicable,approvedforvariousdosage
lows formulators a clear choice on which excipients to forms.
choose;theexcipientsarereportedineachvolumeper- 15. Dissolution testing requirements are included for all
taining to the formulation type covered. The listing is dosageformswherethistestingisrequiredbytheFDA.
drawnfromtheFDA-approvedentities.Forthedevelop- Surrogatetestingtoproveefficacyandcomplianceisget-
ersofanANDA,itiscriticalthatthelevelofexcipientsbe tingmoreacceptanceatregulatoryagencies;inmyexpe-
keptwithintherangegenerallyapprovedtoavoidlarge rience,awell-designeddissolutiontestisthebestmea-
expenseinjustifyinganyunapprovedlevel.Theonlycat- sure of continuous compliance. Coupled with chapters
egoryforwhichthelistingisnotprovidedseparatelyis onwaiversofbioequivalencetesting,thisinformationon
the OTC volume since it contains many dosage forms dissolution testing should be great value to all manu-
andthereaderisreferredtodosageform–specifictitleof facturers;itisrecommendedthatmanufacturersdevelop
theseries.Thechoiceofexcipientsformskeepsincreas- their own in-house specifications, more stringent than
ingwithmanynewchoicesthatcanprovidemanyspe- thoseallowedintheselistingsandtheUSP.
cialreleasecharacteristicstothedosageforms.Choosing 16. Best-sellingproducts(top200prescriptionproducts)are
correctexcipientsisthusatediousexerciseandrequires identifiedwithanasteriskandabrandnamewhereap-
sophisticated multivariate statistical analysis. Whereas plicable;inallinstances,compositionoftheseproductsis
theformulatormaychooseanynumberofnovelorclas- providedandformulationofgenericequivalents.Despite
sical components, it is important to know the levels of thevastexpansionofpharmaceuticalsalesandshifting
excipients that are generally allowed in various formu- ofcategoriesofblockbusterdrugs,basicdrugsaffecting
lationstoreducethecostofredundantexercises;Ihave gastrointestinaltract,vascularsystem,andbrainremain
thereforeincluded,asanappendixtoeachvolume,alist mostwidelyprescribed.
ofallexcipientsthatarecurrentlyapprovedbytheU.S. 17. UpdatedlistofapprovedcoloringagentsintheUnited
FDA along with their appropriate levels. I suggest that States,Canada,EuropeanUnion,andJapanisincluded
aformulatorconsultthistablebeforedecidingonwhich toallowmanufacturestodesignproductsforworldwide
levelofexcipienttouse;itdoesnotmeanthattheexcipi- distribution.
entcannotbeusedoutsidethisrangebutitobviatesthe 18. Tablet-coating formulations that meet worldwide re-
needforavalidationandlengthyjustificationstudiesin quirementsofcolorselectionareincludedintheVolume1
thesubmissionofNDAs. (compressedsolids)andVolume5(OTC)becausethese
14. Expanded section on bioequivalence submission was representtheproductsoftencoated.
required to highlight the recent changes in these re- 19. Guidelinesonpreparingregulatoryfilingsarenowdis-
quirements.Newentriesincludeacomprehensivelisting persedthroughouttheseriesdependingonwherethese
of bioequivalence protocols in abbreviated form as ap- guidelinesaremorecrucial.However,thereaderwould,
provedbytheU.S.FDA;thesedescriptionsareprovided asbefore,needaccesstoallvolumestobenefitfromthe
in each volume where pertinent. To receive approval adviceandguidelinesprovided.
foranANDA,anapplicantmustgenerallydemonstrate,
amongotherthings,equivalenceoftheactiveingredient, Asalways,commentsandcriticismfromthereadersare
dosageform,strength,routeofadministration,andcon- welcomed and these can be sent to me at Niazi@pharmsci
ditionsofuseasthelisteddrug,andthattheproposed [email protected]
drug product is bioequivalent to the reference listed quiriesrequiringclarificationoftheinformationenclosedin
drug[21USC355(j)(2)(A);21CFR314.94(a)].Bioequiva- thesevolumes.
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
PrefacetotheSeries—SecondEdition vii
“I would like to express deep gratitude to Sherri R. Inthefirstedition,Ihaddedicatedeachvolumetooneof
NiziolekandMichelleSchmitt-DeBonisatInforma,thepub- mymentors;thesecondeditioncontinuesthededicationto
lisherofthiswork,forseeinganimmediatevaluetotheread- thesegreatteachers.
ersinpublishingthesecondeditionofthisbookandallowing
meenoughtimetopreparethiswork.Thediligenteditingand
composingstaffatInforma,particularlyJosephStubenrauch,
BaljinderKaurandothersarehighlyappreciated.Regardless, SarfarazK.Niazi,Ph.D.
allerrorsandomissionsremainaltogethermine.” Deerfield,Illinois,U.S.A.
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
Preface to the Series—First Edition
Noindustryintheworldismorehighlyregulatedthanthe erationshaveledtotheclassificationofproductsintothese
pharmaceuticalindustrybecauseofpotentialthreattoapa- sixcategories.
tient’slifefromtheuseofpharmaceuticalproducts.Thecost Each volume includes a description of regulatory filing
oftakinganewchemicalentity(amortizedoverthecostofall techniquesfortheformulationsdescribed.Alsoincludedare
moleculesracing)tofinalregulatoryapprovalisastaggering thecurrentregulatoryguidelinesoncGMPcompliancespe-
$800million,makingthepharmaceuticalindustryoneofthe cifictothedosageform.Adviceisofferedonhowtoscaleup
mostresearch-intensiveindustriesintheworld.Intheyear theproductionbatches.
2004,itisanticipatedthattheindustrywillspendabout$20 Itisexpectedthatformulationscientistswillusethisin-
billiononresearchanddevelopment.Thegenericmarketof formationtobenchmarktheirinternaldevelopmentprotocols
drugsasthenewentitiescomeoffpatentisoneofthefastest andcuttheracetofileshortbyadoptingformulaethathave
growingsegmentsofthepharmaceuticalindustry,withevery survivedthetestoftime.Manyofuswhohaveworkedinthe
majormultinationalcompanyhavingasignificantpresence pharmaceuticalindustrysufferfromacloseparadigmwhen
inthisfield. itcomestoselectingformulations—“notinventedhere”per-
Whereas many stages of new drug development are in- hapsreignsinthemindofmanyseasonedformulationsscien-
herentlyconstrainedwithtime,theformulationofdrugsinto tistssubconsciouslywhentheyprefertochooseonlyacertain
desirable dosage forms remains an area where expediency platformfordevelopment.Itisexpectedthatwiththequick
canbepracticedwithappropriateknowledgebythosewho reviewofpossibilitiesavailabletoformulatemadeavailable
havemasteredtheskillsofpharmaceuticalformulations.The in this book, scientists will benefit from the experience of
HandbookofPharmaceuticalManufacturingFormulationsisthe others.
first major attempt to consolidate the available knowledge Fortheteachersofformulationsciences,thisseriesoffers
about formulations in a comprehensive, and by nature a awealthofinformation.Whetheritisaselectionofapreser-
rathervoluminous,presentation. vativesystemorthechoiceofadisintegrant,theseriesoffers
The book is divided into six volumes, based strictly on awidechoicetostudyandrationalize.
thetypeofformulationscienceinvolvedinthedevelopment Manyhaveassistedmeinthedevelopmentofthiswork
of these dosage forms: sterile products, compressed solids, that has taken years to compile, and I thank scores of my
uncompressed solids, liquid products, semisolid products, graduate students and colleagues for their help. A work of
and OTC products. The separation of OTC products even thissizecannotbeproducedwithouterrors,althoughIhope
though they may easily fall into one of the other five cate- that these errors do not distract the reader from the utility
gories is made to comply with the industry norms of sep- ofthebook.Iwouldsincerelyappreciateifreaderspointout
arate research divisions for OTC products. Sterile products thesemistakesforcorrectionsinfutureeditions.
require skills related to sterilization of product, and of less
importanceisthebioavailabilityissue,whichisaninherent SarfarazK.Niazi,Ph.D.
problemofcompresseddosageforms.Thesetypesofconsid- Deerfield,Illinois,U.S.A.
viii
SPH SPH
IHBK039-fm IHBK039-Niazi-FM May26,2009 19:58 CharCount=
Preface to the Volume—First Edition
The(HPMF/SP)iswrittenforthepharmaceuticalscientistand toryapprovals.Theseformulationsareincludedtoshowto
othersinvolvedintheregulatoryfilingandmanufacturingof theformulationscientistuniqueopportunitiesthatexistfor
newsterileproducts.Nootherareaofregulatorycompliance thechemicalentityinquestion.
receivesmoreattentionandscrutinybyregulatoryauthorities Formulations of biotechnology-derived drugs are pro-
thantheregulationofsterileproducts,forobviousreasons. videdwithsomeadditionaldetailsandremainrestrictedto
Withtheincreasingnumberofpotentproducts,particularly declarationofcomposition,yettheyprovideagoodoverview
thenewlineofsmallproteinproducts,joiningthelonglistof ofthecomplexitiesinvolvedinsuchformulations.
provensterileproducts—mainlyparenteralandophthalmic Inconsolidatingthedetailsofformulations,effortshave
products—thetechnologyofmanufacturingsterileproducts beenmadetopresenttheminasunifiedaformaspossible;
hasevolvedintoaverysophisticatedindustry.Theentrybar- nevertheless,somenonuniformitiesexistbecauseofthelarge
riertothistechnologyismuchhighercomparedwiththose variety of presentations possible for the wide diversity of
forotherdosageforms.Consequently,thecostofproduction formulations presented in the book. A limited number of
remains high as well. In recent years, regulatory agencies productsintendedforveterinaryusearealsoincluded.These
aroundtheworldhavetakenveryseriousnoticeofthedefi- productsaresubjecttocGMPcompliancesimilartothatfor
cienciesinthemanufacturingspecificationsoftheactiveraw humanproducts.
materialintendedforparenteraladministration.Newguide- Theformulationsprovidedheremeetthe4Srequirements:
lines for the API and aseptic processing of sterile products
1. Safety.Thisisanimportantissueforparenteralproducts;
arethemainissuesofconcerntodayformanufacturers.This
the choice of excipients is limited by this consideration.
volume of HPMF/SP does not delve into details related to
Inmostoftheformulations,theingredientsarefullyap-
startingmaterialissues.Ofinterestinthisissueareformula-
proved by the regulatory authorities; in some formula-
tionsofsteriledosageforms,regulatoryfilingrequirements
tions, the active drug moiety may have been banned in
of sterile preparations, and cGMP compliance, all of which
somecountries,forexample,dipyrone.
are tied together in the final preparation of the chemistry,
2. Sterility. The compositions presented are fully steriliz-
manufacturing,andcontrol(CMC)sectionsofregulatoryap-
able either by terminal treatment or by aseptic process-
plications.
ing;wherepreservativesareadded,theseareinsufficient
Chapter1describesthespecificationsofamanufacturing
quantitytofulfillthededicatedfunction.
facilitytomanufacturecompliantsterileproducts.Chapter2
3. Stability. Besides the rigor of treatment in rendering a
outlinesthenewdrugapplication(NDA)orabbreviatednew
productsterile,incompatibilityissuesmayrenderaster-
drugapplication(ANDA)filingrequirementsofsterileprod-
ileproductpronetoinstability.Theformulationsincluded
ucts.Chapter3describesindetailthelayoutofformulations
herehavebeenfullyvalidatedtoprovidesufficientshelf
providedinthebook.Thischaptermustbethoroughlyexam-
life,dependingontheproduct.
inedtomakethebestuseofthisbook.Becausetheintentof
4. Scalability.Whereasthebatchformulationispresentedfor
theinformationprovidedinthisbookistohelptheformula-
a1-lbatch,theseformulationsarelinearlyscalable.Man-
tordevelopaproductforregulatoryfiling,boilerplatedetails
ufacturing losses have been included and these formu-
areleftout.Chapter3providesthesedetailsandalsomakes
lations can be readily scaled up to any size; of course,
strongrecommendationsonhowtheformulatorcanbenefit
therequirementsofsizechangeinthevalidationprotocol
fromtheinformationavailablefromsuppliersofcomponents
shouldbeconsidered.
andchemicalsusedintheformulation.
These three chapters are followed by the body of the One of the best utilities of the database included in this
book, which provides an alphabetical presentation of for- bookistobenchmarktheproductsintendedfordevelopment.
mulationsofpharmaceuticalproductsbasedontheirgeneric Alargenumberofformulationpossibilitiesexistforanydrug;
names.Therearethreetypesofformulationentries.Inthefirst thoughwiththe4Slimitations,thechoiceofingredients(ex-
type,boththebillofmaterialsandmanufacturingdirections cipients)narrowsratherrapidly.Multivitaminformulations
are provided. This type is further composed of two types, are one such example wherein extreme instability and cost
wherein greater detail is provided for some products. This considerationshaveresultedinavarietyofformulations.A
differentiationisintentionalbecausethecommondetailsare study of many possibilities tells us about the problems we
oftenomittedinsubsequentpresentations.Thesecondtype cananticipatewhileformulatingtheseproducts.Insomein-
offormulationsisprovidedwithbillofmaterialsonly.This stances, only composition details are provided, along with
may include products for which the manufacturing direc- raw material manufacturing details, because they are often
tionsareobvioustoaprospectivemanufacturer,particularly an integral part of the formulation, such as in the case of
inlightofthedetailsalreadyprovidedforsimilarproducts biotechnology-derived products. Whereas this information
elsewhere in the book, and also those products for which maybeatbestcursory,itisusefultoprovideastudyofthese
suchinformationisnotreadilyavailable.Thethirdcategory productformulations.
of formulations includes experimental formulations, which Theinformationcontainedinthisbookhasbeenobtained
may not yet have been commercialized or received regula- mainly from sources open to the public. It has taken years
ix