How to Develop Robust Solid Oral Dosage Forms from Conception to Post-Approval

172 Pages·2017·7.4 MB·English

by  Bhavishya Mittal

How to Develop Robust
Solid Oral Dosage Forms
From Conception to Post-Approval
Bhavishya Mittal
Series Editor
Michael Levin
Milev, LLC
Pharmaceutical Technology Consulting
West Orange, NJ, United States
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Author Biography
Bhavishya Mittal is a Staff Fellow at the
Office of Pharmaceutical Quality in the US
Food and Drug Administration (FDA) at
Silver Spring, Maryland. Previously, Bhavi
was employed as a Senior Scientist in the
Formulation Sciences Department at Takeda
Pharmaceuticals International Company
based in Cambridge, Massachusetts. Bhavi
holdsaPhDdegreeinMaterialsEngineering
fromthePennsylvaniaStateUniversityanda
BS degree in Chemical Engineering from
Regional Engineering College, Jalandhar,
India. Bhavi has 13years of industrial expe-
rienceinformulationandprocessdevelopmentofvarioussolidoraldosagesof
small therapeutic molecules (oncology, inflammation, and CNS indications)
aimed for New Drug Application (NDA) and Abbreviated New Drug Appli-
cation (ANDA) filings. He is the co-chair of the Formulation and Drug De-
livery (FDD) working group at Massachusetts Biotechnology Council
(MassBio). He is the author/co-author of one patent, 10 peer-reviewed man-
uscripts, and numerous conference papers and posters published/presented in
various international journals and conferences. He is an active member of
various international professional societies such as American Association of
Pharmaceutical Scientists (AAPS) and International Society for Pharmaceu-
tical Engineering (ISPE). His research interests include formulation design,
process engineering, scale-up, tech transfer, and computational modeling of
pharmaceutical unit operations for solid oral dosage manufacturing.
ix
Foreword
The task of designing and making a suitable drug delivery system or dosage
formthatisfitforthemarketisenormous,andtheprocessisusuallynotvery
efficient. It is a well-known fact that pharmaceutical manufacturing is one of
the least efficient industries in the business world. It takes 10e15years to
develop a medicinal product, from discovery and patent application, through
toxicity studies, pharmacology, clinical trials, scale-up, product registration
and approval, and, finally, marketing and sales in conjunction with
pharmacovigilance.
Despite our best efforts, product quality oftentimes remains elusive and a
lot of time and money are wasted in every unit operation compared, for
example, to automotive or aircraft manufacturing. This book describes all
stagesoftheprocessofmakingmedicalremediesfromconceptanddiscovery
to the final consumer product. When we see this process in perspective, as a
totallyinterconnected andinterdependenteffortofhundredsandthousands of
highly qualified individuals, the intricacies and potential pitfalls of drug
development become evident. It becomes patently apparent that there is a lot
of room for improvement at every phase of the process.
To the best of my knowledge, up to now, no book describes, step-by-step,
the modern process of pharmaceutical product development. Dr. Mittal’s
excellent presentation of this subject fills the void. This book can be used by
both student and practitioner of the art and science of contemporary phar-
maceutical industrial applications.
Withdecadesofhands-oninvolvement,BhavishyaMittaldefinitelyknows
whatheiswritingabout.Inmymanyyearsofeditingexperience,Ihavenever
seen amanuscript sowell organized and meticulously developed. The overall
impression from reading this ambitious and encyclopedic opus is over-
whelming. I am sure this book will find numerous readers and will become a
bestseller in its own niche.
Michael Levin
Series Editor,
Expertise in Pharmaceutical Process Technology
xi
Preface
Alonewe candoso little;togetherwecandoso much
HelenKeller
The development of drug products for human consumption is complex and
challenging, but a worthy undertaking for the betterment and advancement of
civilization.Throughouttheexistenceofhumankind,effortshavebeentakento
understandhowmedicinescanhelpinextendingpatients’qualityoflife.Inthe
21stcentury,thescienceofdrugdevelopmentisanestablishedfieldwhichre-
quiresadedicatedunderstandingofnumerousdisciplesandfostersasymbiotic
partnershipbetweenvarioussubjectmatterexperts.Giventheexperiencethatwe
now have in drug development, the steps taken toward establishing a drug’s
safety and efficacy, and the process for its commercialization, have long been
standardized. However, many areas remain for which scientific advancements
are still being actively pursued and an integration of good science and best
practicesisconstantlytakingplace.Intheauthor’sopinion,thedevelopmentof
solidoraldosagesisonesuchdynamicarea.
Aspeopleworkinginthisareawouldtestify,theFormulationSciencesarean
amalgamationofnumerousconceptsdevelopedinphysicalpharmacy,chemis-
try, material sciences, biopharmaceutics,and engineering. Because the subject
matter is spread over these numerous disciplines, more often than not, it is
difficulttovisualizethevariouschallengesthataformulatorneedstoanticipate
and address when developing the product. Although the answer to most ques-
tionssurroundingsolidoraldosagedevelopmentrequiresadetailedreviewofthe
scientific literature, it is alsoimperative to have an understanding of the inter-
connection of the various concepts. For example, it is quite common for a
formulatortoshowthattheirformulationmayworkreallywellinthelaborata
smallmanufacturingscale.However,someoftheissuessuchaspowdersegre-
gation,tabletingproblems,unfavorablechangesindissolutionprofiles,etc.may
notberealizeduntil themanufacturingprocess is scaled-up. If a formulator is
awareofthesepotentialproblemsthatmaybelurkinginthebackground,he/she
canevaluatetheirformulationevenatthelabscaletomakesuretheselarge-scale
problemsareproactivelybeingmitigated.
Similarly, in today’s day and age of ultracompetitive economics and man-
agingbusinessesthatmaybeholdingontorazor-thinmarketshares,itisquite
commontolaunchaproductgloballytoincreaserevenues.However,mostofthe
decisionsmadeinearlyformulationdevelopment donottake intoaccountthe
commercializationaspectofthedrugproduct.Asaresult,typicallynotenough
xiii
xiv Preface
guidanceisprovidedbythemarketinggroupsonwhatkindofcommercialimage
mayberequiredwhendealingwithproductlaunch.Forexample,foraproduct
intendedforglobaldistribution,itisveryimportantforaformulatortorealize
thatheorshemayneedtostudymultiplecontainerclosuresystemstomakesure
thattheproductdoesnotcontainweaknessesintheformulationdesignthatmay
showuplaterduringproductdevelopmentandscale-up.Similarly,itisequally
vitaltorealizethatthechoicesmadeforprimarycontainerclosuresystemsinthe
earlystagesofdrugproductdevelopmentarenotthesameaswillbemadeatthe
laterstages.Furthermore,significantcostscanbeincurredbylaunchingwithan
expensive primary packaging option when a cheaper yet robust option would
haveworked just fine. It is prudent to understand thevarious choices of pack-
aging materials and the impact of changing container closure options with
respecttopotentialmarketingchoicesthatwillbemadeatproductlaunch,andto
proactively evaluate and mitigate these issues. Therefore, if the marketing in-
formationisprovidedearly,theformulationdesigncouldaccommodatefuture
businessneedsbybuildingappropriatesafetymarginsintheproduct.Theseare
justsomeofthemanyexamplesthatarediscussedinthisbook.
Thisbookisintendedtoserveasacompaniontoexistingscientificliterature
foranindustrialpharmaceuticalscientistworkinginthefieldofsolidoraldosage
development. This book assumes that the readers are familiar with the basic
conceptsofpharmaceutics,engineeringpractices,unitoperations,andstatistics.
Therefore,itisnotmeanttobecomprehensivetreatiseofthesubjectmatterand,
whenappropriate,references areprovided tomoreauthoritativetextbooksand
researcharticles.Itisdifficultforonereferencebooklikethisonetocoverallthe
depthandbreadthofthefield;however,theauthorhopesthathehasdonejustice
inexplainingsomekeyconceptsandhowtheyapplytosolidoraldosageform
design.Thisworkismeanttosummarizetheauthor’sexperiencethathefacedin
hiscareerintheFormulationSciencesandhopestoprovideguidancetopeople
facedwithsimilarchallengesintheircareers.Theauthorhasprovidednumerous
decision-making criteria based on some commonly used techniques that the
authorhasobservedinthisfieldsofar.Nothingismoreinvaluablethantoapply
thelearningsinreal-lifeexperiments.Theknowledgeandexperiencegainedby
actuallydevelopingaformulationandprocessisinvaluabletoaformulator.In
addition, numerous lessons can be learned by being a careful observer of the
process.Itisequallyimportanttoseekfeedbackfromthemanufacturingoper-
atorswhoareproducingtheproducttounderstandthekindsofdifficultiesthey
are facingwhenprocessing thematerial.In that regard, the authoris naturally
indebted to the lessons learned in collaboration with his colleagues in the
manufacturingdepartments.Itistheauthor’ssincerehopethatthereaderswould
findthisinformationvaluableandcanaugmenttheirlearningandexperienceasa
FormulationScientist.
In this book, only the scenario of solid oral drug product development is
discussed. Therefore, other aspects of drug development, such as candidate
Preface xv
selection,drugsubstancedevelopment,nonclinicalstudies,clinicalstudies,and
registration-relatedtopicsarenotdiscussed.However,itisveryimportantforthe
reader to realize that drug product development is just a small portion of the
entirepictureofthedrugdevelopmentprocess.Afterall,thedrugdevelopment
processisoneofthemostcomplexteamsports!
BhavishyaMittal
Acknowledgments
I would like to express my sincere gratitude to Dr. Michael Levin for giving
me the opportunity to write this book. I am thankful for his insightful and
criticalcommentsthatwereinstrumentalinimprovingthequalityofthisbook.
I am also thankful to my parents (Dr. J.P. Mittal and Madhu Mittal) who
have positively influenced my life and have always provided their perennial
support and encouragement. I am extremely thankful to my loving wife,
Shalini,forherunconditionallove,positiveattitude,andconstantreassurance,
which helped me to complete this project in a timely manner. Last but not
least, I would like to thank my children, Kern and Ariana, for their patience
and understanding while I was busy working on this book.
xvii
About the
Expertise in Pharmaceutical
Series
Process Technology
Numerous books and articles have been published on the subject of pharma-
ceutical process technology. While most of them cover the subject matter in
depth and include detailed descriptions of the processes and associated the-
ories and practices of operations, there seems to be a significant lack of
practical guides and “how to” publications.
TheExpertiseinPharmaceuticalProcessTechnologyseriesisdesignedto
fill this void. It comprises volumes on specific subjects with case studies and
practical advice on how to overcome challenges that the practitioners in
various fields of pharmaceutical technology are facing.
FORMAT
l The series volumeswill be published under the Elsevier Academic Press
imprint in both paperback and electronic versions. Electronic versions
willbefullcolor,whileprintbookswillbepublishedinblackandwhite.
SUBJECT MATTER
l The series will be a collection of hands-on practical guides for practi-
tioners with numerous case studies and step-by-step instructions for
properproceduresandproblemsolving.Eachtopicwillstartwithabrief
overviewofthesubjectmatterandincludeanexpose´,aswellaspractical
solutions of the most common problems along with a lot of common
sense (proven scientific rather than empirical practices).
l Theserieswilltrytoavoidtheoreticalaspectsofthesubjectmatterand
limit scientific/mathematical expose´ (e.g., modeling, finite elements
computations, academic studies, review of publications, theoretical
aspects of process physics or chemistry) unless absolutely vital for
understanding or justification of practical approach as advocated by the
volume author. At best, it will combine both the practical (“how to”)
and scientific (“why”) approach, based on practically proven solid
theoryemodelemeasurements.Themainfocuswillbetoensurethat
a practitioner can use the recommended step-by-step approach to
improve the results of his or her daily activities.
xix
xx AbouttheExpertiseinPharmaceuticalProcessTechnologySeries
TARGET AUDIENCE
l Theprimaryaudienceincludespharmaceuticalpersonnel,fromR&Dand
production technicians to team leaders and department heads. Some
topics will also be of interest to people working in nutraceutical and
genericmanufacturingcompanies.Theserieswillalsobeusefulforthose
inacademiaandregulatoryagencies.Eachbookintheserieswilltargeta
specific audience.
The Expertise in Pharmaceutical Process Technology series presents
concise, affordable, practical volumes that are valuable to patrons of phar-
maceutical libraries as well as practitioners.
Welcome to the brave new world of practical guides to pharmaceutical
technology!
Michael Levin
Series Editor,
Expertise in Pharmaceutical Process Technology