Center  for  Drugs and Biologic8 
Food and Drug Administration 
Department of  Health  andHuman Services 
February  1987  Ebr further  informatim  regarding  the guideline  please ccmtact: 
FoodandDrugAdministratian 
Center for  Drugs and Biologic8 
OfficeofDrugResear&mdRmiew  (HEN-100) 
56COFishersLane 
Ibckville,  Maryland  20857 
(301-443-4330)  lnBIEm  -s 
I.lxmOmcmoN...........................  1 
II.DPLEPPfmcr(Nm'sandANm's)..................  2 
A.  callpalents  ..........................  2 
B.  Canposition  .........................  3 
1.StatementofCanpc43ition.  .................  3 
2.BatchFormula  .......................  3 
C.  Specifications  and Aualytical  Wthals  for  Inactive 
canpalents  .........................  4 
D.  Manufacturer  .........................  4 
E.  MethaIsof  ManufacturingandPackaging  ............  5 
1,  ProductionOperations.  ..................  5 
2.ReprocessingOperations  ..................  6 
F.  Specifications  and Analytical  Methods for  the  Drug Product  .  .  6 
1.  Intraluctim  .......................  6 
2.SamplingWthods  .....................  7 
3.  In-ProcessControls.  ...................  7 
4.  Regulatory  Specifications  and Methods for  Drug Products  .  .  8 
a.  Tablets,  capsules,  andother  soliddosage  forms.  ...  10 
b.  Solutions  (including  sterile  solids  for  injection)  .  .  10 
c.Suspensions  ......................  11 
d.Creams,enulsicms,andointments  ...........  11 
e.Transdermaldelive.rysystems  .............  11 
f.  Diluent  solutions  ...................  12 
g.  Sterile  plastic  devices containing  active  drugs  .  .  .  .  12 
h.Placebm  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .  ..l2 
III.  IMIEsrIGATIcNALF oRtwImI am  (DID'S)  .  .  .  .  .  .  .  .  .  .  .  .  .  .  .12 
CaIlponentS.........................14 
D.  Mufacturer  ......................  ...14 
E.  Methods of  Manufacturing  and Pa&aging  ............  14 
F.  Specifications  and Analytical  Methods for 
Investigational  Drug Products  ...............  15 
1.  Introduction  .....................  ..15 
2.Phasesland2  ....................  ..16 
3.Phase3..........................17 
4.Placebos  ......................  17  I.  Il?l!RXlCl?IcN 
This  guideline  caxerns  the documntation  of  the  manufacturing 
process used toprcducedosage  forms and theaccvyingquality 
control.  system inter&d  for  raw materials,  in-process  materials,  and 
the  finished  dosage form suitable  for  administration.  It  is  one of 
a series  of  guidelines  covering  topics  relevmt  to  the mnufacturing 
and controls  portion  of  investigational  new drug applications 
(m's),  new drug applications  (NIX's),  and abbreviated new drug 
a@ications  (ANIN's).  The guideline  does not  impoeem  andatory 
requirements [21 CPR1 0.90(b)].  Itdoes,haJever,  offerguidancem 
acceptablea~caches  tomeetingregulatoryrequiremnts.  Different 
approachesn  aybe  fol.lowed,buttheapplicautis  encouragedt o 
discuss significant  variations  in  advancew  ith  m  reviewers to 
preclude  expmding time andeffortinpreparinga  submissim that 
FDAm  ay later  determine to be unacceptable. 
Theinfonmtion  anddatadiscussed  in  this  guideline  relate  to  the 
identity,  strength,  quality,  andpurityof  the  dosage forma&l  the 
procedures for  assuring  that  all  batches manufactured cmform to  tie 
appropriate  specifications.  Information  relating  to  the container, 
closure,  stability,  and labeling  are discussed in  separate 
guidelines. 
-l-  Informaticn  included  in  a Drug Master File  (l%W)t o  satisfy  the 
~ntationneededtoevdluate~y~ticularpartof  the 
mamfacture mdmtrols  for  adrugpraiuctisacceptableprovided 
the  reference  is  specific,  current ,andapplicable  tothedrug 
product  described in  thea~licatim.  Hammer, theagencywill 
wnsider  the  information  in  a DIWo  nly  if  written  authorizatian  is 
grant&  with  specific  reference to  pertinent  sections,  including 
datesof  submissions of  them.  For information  cm preparing 
EME"s, refer  to  the Guideline for  Drug Master Files. 
II.  IXUEPFOMKX(NlW'sa ndANLIA's) 
The following  information  shtidbeincluded  in  theal@ication: 
A.  C-mts 
Prwide  a  list  of  cmpments,  includingallsubstancesand 
in-process  materials  used inproducinga  defined  finisheddrug 
orplacebopraduct.  Listallmbstances  used in  themanufacture 
ofadrugpaoduct~~~oa~~~a~inthefiniahed 
product,  aud state  thegmlitydesignatianorgrads  foa: each 
material  (e.g.,  Americian Chemical Society  (ACS), United States 
Pharmccpeia (UQ?),National  -ry  (m)).  Identifyeach 
catpment  by  its  established  nam,  if  any, or by caqlete 
ch~calMme,usingstructurdlfarrmlasHhennecessaryfar 
specific  identification.  If  anyprcprietqpreparations  or 
other  mixtures are used as cuupments,  their  identity  shailld 
-2-  l 
include  a caqlete  statement of  caqositim  and other 
information  that  will  praperly  describe  and identify  these 
materials.  Justify  prcposed alternatives  fop: any listed 
substances by demnstrating  that  the use of  these alternatives 
does not  significantly  alter  the stability  and bioavailability 
of  the drug product and the mitdbility  of  manufacturing 
cmtrols. 
B.  Canposition 
1.  Statemmt of  Caqxxitian 
A statement of  the qumtitative  cmpceition  @hcx.lds pecify, 
by unit  dose, a definite  weight or  measure for  each active 
drug substance and a definite  weight,  measure, or 
apprcpriate  range for  all  other  ingredients  cmtained  in  the 
drug product. 
2.  Batch mrmula 
Provide a canplete  list  of  the  ingr&ients  and their  amunts 
to be used for  the manufacture of  a representative  batch  of 
the drug product.  !%bmit a separate batch  formula for  erach 
formulatim  of  the drug product.  All  ingredients  should be 
included  in  the batch  formla  whether or  not  they remain in 
the  finished  product. 
-3-  C.  Specifications  and Analytical  Methoda for  Inactive  Caqawmts 
provide  acceptance specifications  and the  correspmding 
analytical  methods for  all  inactivevents  of  the 
formlation,  regardless  of  whether they  remain in  the  finished 
pxduct.  Limits  and methcds (applicable  to  the  finished  dosage 
form)  for  vents  thatareremved  in  themanufacturing 
process shouldbe  included.  Limits  and methods must be  included 
for  patentially  toxic  vents. 
D.  Mamfacturer 
State  thename,  locationand,  whereaIpmp%te,buildingW 
of  e%h facility  having  a part  in  the  manufacture or  controls  of 
the  drug prcduct.  This  includes  the  following,  as a=ropriate: 
1.  Manufacturer(s)  of  the bulk  drug  substance(s). 
2.  Mmufacturer(s)  of  the drug product. 
3.  mtract  packager(s)  and/or  labeler(s). 
4.  Cmtract  laboratories  performing cpality  cmtrol  tests  an 
rawmaterials,  drug  substance, or  the  finisheddrugprcduct. 
5.  Sqpliers  of  vents  lrscd in  the  manufacture  of  the  drug 
product. 
E.  Methcds of  Mauufacturing  and Packaging 
1.  ProductionOperations 
To facilitate  the  evaluation  of  the prOauction  and ccxltrol 
of  thedrugpraluct,  submitacopyof  theprcposedor  actual 
master/batchprcduction  andcontrol  records  or  a canprably  detailed  description  of  the praductim  prccess for  a 
repesentative  batch.  Describe themmufacturingand 
packagingprocess  far  a representativebatch,  incluainga 
descriptionofea&productim  step,  actualcperating 
ccnditions,  eguipnent to be utilized  and points  of  sampling 
for  in-process  ccntrols. 
A schematic diagram of  the production  process is  often 
helpful.  Suchadiagramshouldinclude  a superimpmed 
materials  flcwplan,  indicating  the eguippentused  and the 
points  of  sampling. 
2.  ReprocessingO  peraticns 
Before re~ocessiugadrugproduct,  theamlicantshculd 
consider  theeffects  ofreprocessingm  stability& 
bioavailability.  Topermitarproval  of  therepr-  ing  of 
batchesofbulk,  in-prccess,  and finisheddmgproducts  that 
donotccnfoxmtoestablished  specifications,  theoriginal 
submissionof  anNlNmayincludeproposals  for  reprocessing 
procedures thatcoverpcssible  foreseeable deviatiam  from 
specifications  (e.g.,  weight variatim,  content  miformity, 
macceptable  tablet  coating,  etc.).  Such repr-  iv3  =Y 
reguire  additional  amcmts of  cne or  more of  the vents; 
however, the amunts  added shmldnotresultin  a axqaxut 
beingpresentbeyaxd  the reasmablevariatiumparovided  for 
in  the  formulation. 
-5-  Reprocessing due todeviations  not  anticipatea  in  the 
origiMl~Bha;lldbeccrverelbyasu~lemental 
a@ication.  -oval  of  reprocessingprocekres  mustbe 
cbtained before  release of  the reprocess~ drug=drug 
product.  Ihesesupplemmtsmaybedirectedtothe 
reIzmcessingofa  specific  lot/batchor  maybesubmitted  as 
a new procedure.  Su~lemzntal a@icatims  for  reprocessing 
shculdinclude  the  following: 
a.  A specific  and canplete description  of  the rejected 
material  including  a statement of  thedeviatiorr(s)  fran 
the  specificatim(s). 
b.  Adetailed  descriptionof  theproposed  reprocessing 
procedure,  includingantrolsbeyaxl  those established 
for  rartineproduction. 
Astatemsntof  themaximmtime  elapriedbetween the 
C. 
initial  manufacture and the  time of  reprocessing,  and 
the  storage cmditiam  during  this  interval. 
F.  Specifications  and Analytical  Methodsf or  the Drug Product 
1.  Introduction 
The goal of  drug prcduct manufacture is  reproducibility 
within  all  specified  limits.  The significantchfmkal  and 
physical  parameters impmtant to  clinical  respace  of  the  drugproduct  shtidbedefined  atan  early  stage in  the 
investigational  atuSes,  m  that  the transition  to  routine 
production  lot  manufacture maybe mnducted ratiaxally.  A 
well-organized  drug a~lication  shoulddemnstrate  that  the 
manufacturing,  sampling, and cmtrol  processes have beem 
design63 toprovide  accmsistentprcduct  that,  withinany 
lot  and ma  lot-blot basis,  does not va.&beycnd  the 
established  specifications. 
2.  SamDlinQM emxls 
Describethesamplingplan  thatwillbeused  toassurethat 
the  sampleo  f  the drug product obtained is  representative  of 
thebatch.  Theplan  Elhcmldincludeboththesamplingof 
productia3batches  and the  selectianof  s&-samples for 
analytical  testing.  l%is  plan will,  of  curse,  be 
amlicableonly  tobatches  of  thatparticular  size,  so 
procedures for  wale-upor  scale-dmn of  this  samplingplan 
tootherbatch  sizesmust  alsobeprovided.  If  saqlesare 
pooled,  a justificaticmnustbegiven  fcrpmlingthem. 
3.  In-Process CaMx0l.s 
Theanalytical  cmtrols  used during  thevarious  stages of 
marrufa~ingandprocessingofthed~gefarmshouldbe 
fullydescribfxl.  Wheref easible,  the  in-process 
specifications  shculdbe  wrtedbyapprcpriatedata  that 
-7-  I 
I 
may include,  but  should not be limited  to,  representative 
mster/batchproduction  andcmtrol  records.  Inparticular, 
&m  theserecxxdsare  submitted in  sqportofa 
su~lemental  aslication  thatpropmes  thedeletion  or 
broadening of  specificatiare,  the  records shaildmver  a 
mnsecutive  series  of  batches.  Informationcn  i~+process 
controls  inrmnufacturingis  essential  toathoraxghreview 
of  thexmnufacturingandprocessingof  thedrug. 
4.  Regulatory Specifications  andMethaIt3 for  DnqPraiuctS 
Fkgulatory  specifications  are  the defined  limits  (e.g., 
physical,  chemical, biological,  micrcbiolcgical)  within 
&ich  test  results  foradrugsubstanceordrugproduct 
~~dfallwhendeterminedbytheregulat~methodol~. 
Theregulatorynrethcdoloqyis  theprocedureor  set  of 
~oceduresusedbythe~toascertainwhetheroanatthe 
drugsubetirmceordrugproductisinccnformvlcewiththe 
approvedregulatoryspecifications  in  theNI&  (See 
"Guideline  for  Submissiono  f  Samplesa ud Analytical  Data for 
Methcds Validatim.") 
Theregulatorytestsand  specifications  shauldbedesigned 
toensurethatthedosagefarmwillmeetacceptdble 
therapeuticaudphysicochmical  standards throumtthe 
shelf  lifeof  themarketedproduct.  As such, regulatory 
-8-  specificaticns  normally  include  all  criteria  that  apply  to 
thebulk  dceage form,  those related  to  thepadraged product, 
andthc8ethatindicatethepresenceorabeenceof 
degradaticn. 
Regulatoryspecificatiam  maydiffer  frm  in-hamepraluct 
release specifications.  Alldrugprducts  require  assay and 
identity  tests  and specifications.  For ampmdialproducts, 
the  specifications  @tests  in  theUnitedState8 
Phanmccpia/National  Fbrnulary  (Use/rsz) mmgraphs nay 
satisfy  relevant  requirements.  Additimal  specifications  or 
alternate  analytical  ~thcds  (e.g.,  tests  for  inprities,  a 
stability-indicating  assay, a seccnd identity  test,  etc.) 
nayberequired  as necessary.  Broader limits  than those in 
theUW/NE'mamgram will  not ordinarilybea~oved  as 
regulatoryspecificatiau3  mlesa  the  labeling  indicates  that 
the product differs  fran  the official  nmograph.  When 
alternateanalyticdlmefhadsthatareequivalentto,c#that 
areanimprovementover,thecanpndialmetha%are 
submitted to  theagency,  theapplicantis  encmrag&  to 
simultaneamlyask  themited  States Pharmaccpeial 
Convention (Us?c) tochangeormdifythemethalology  in  the 
mxlosraph. 
-9-  Assay arxI identity  specifications  using a well- 
characterized  reference  standardanddescriptimof~sical 
characteristics  (e.g.,  appearance, odor,  etc.,  where 
amlicable)  are  required.  A descripticn  of  other  attributes 
should alsobe  considered for  inclusim,  depending m  the 
typeofdosageform.  The following  list  is  advisory,  and is 
not  e&austive,  amI the  anissimofaprameter  framthe 
listshculd  not  lead to  the cmclusion  that  it  cannot be the 
subjectofaregulatory  test  mder  apmpriate  circumstances. 
a.  Tablets,  capsules,  and other  solid  dosage forms 
(1)  Uniformity  of  dceage mits. 
(2)  Rate of  release of  the  active  Ggredient  fr<mrt he 
dosage form by methodology (e.g.,  dissolution 
rate),  asa~cpriateforthedosageform. 
(3)  Maisturemtent,  where a@icable.  Special 
consideratim  should be given to  dosage forms in 
tiichamajor  caqamnt  isknam  tobehygroscopic. 
(4)  Softening  or  melting  points  for  sqpcsitories. 
b.  Sdlutions  (including  sterile  solids  for  injection) 
(1)  Clarity,  limit  of  particulate  mtter,  assay 
Of 
preservative,  isotmicity  (for  injectable  and 
o@ehalmic pralucts)  ,  and@determination. 
(2)  Sterility  of  injectable  and o#khalmic  pr&cts. 
(3)  Apyrogenicity  of  injectable  products. 
-lo-  .   
(4)  Leakaget est  for  anpubs,  aerosols, pa&packets, 
strips,  tubes,  etc. 
(5)  Metering tests  and specifications  (if  metered 
dosage) andccntainerpressure  for  aeroeols. 
Carpleteness and clarity  of  camtituted  solutions. 
(6) 
c.  Suspensions 
(1)  Assayofpreservativeand~determination. 
(2)  Sterility  of  injectable  and ophthalmic products. 
(3)  I@yrogenicity of  Injectable  prcxhcts. 
(4)  Particle  size  specificatiaw,  resuqmdability, 
viscosity,  sedimentation rates,  caking, and 
syringabilityof  suspensions. 
(5)  Metering tests  and specificaticms  (if  metered 
dosage) and cmtainer  pressure far  aerosols. 
d.  Creams,e mlsions,  and ointments 
(1)  Assayofpreservativeand~determinatian. 
(2)  Sterilitybbrerequired. 
(3)  Hanogeneity. 
(4)  Uniformity  of  doeagemitsas  appropriate. 
e.  Transdermald elivery  systems 
(1)  In  vitro  release rates. 
(2)  Uniformity  of  dosageu nits. 
-ll-  f.  Diluent  solutions 
Fullaaceptzmce  specificatiaxs  andanalytical  ~thbis, 
including  assays for  preservatives,  shauldbe  included 
for  diluents  with  dry  solids  or  for  liquid  azncentrates. 
Q*  Sterile  plastic  devices containing  active  drugs 
(1)  In  vitro  release rates,  sterility,  and limits  for 
residual  ethylene oxide and its  decauposition 
products,  as al@.kable,  in  a&litim  to  the 
,  identity  of  all  plastic  canpamats. 
(2)  Additicmal  *ical  tests  such as frame merry, 
resiliency,  tensile  strength,  and sealintegrityof 
the  immediatepackage. 
h.  Placbbos 
Asuitable  testdemmstratingtheabsenceof  thedrug 
subsbmeint3eplac&m 
III.  ImmsrI~Irn  l?cmmmIcIcJs( m's) 
The following  infornmtion  shaild  be included  in  the applicatiar: 
A.  Canpamts 
Prwide  a list  of  canpments,  including  allsubetances  and 
in-process materials  used in  pro&zkq  a defined  investigatimal 
-l2-  drug product or  placebo product.  List  all  s&stances  used in 
themanufactureofadrugpraluct  whether or  nottheyapr  in 
the dosage form and state  thequalitydesignatimor  grade for 
ea&  material  (e.g.,  ACS, US,  S). 
Eachcaqpcnentshouldbe~~lyidentifiedbyits  established 
name, if  any, orbymznpletechmical  name, using  structural 
formulas whenn  ecessary for  specific  identificatim.  If  any 
praprietarypreparations  orothermixtures  arerrredas 
caxpaxnts,  their  identity  shculdincludea  ccmplete statement 
of  caupceition  andother  information  that  will  properlydescribe 
and identify  them.  Justifypropceed  alternatives  for  any listed 
substances.  An ammdmnt shmldbe  filed  for  any  significant 
changes in  formulation  not proposed in  the  initial  IND. 
B.  Caupmitim 
Wmitaquantitativestatemntofcanpclsitim.  Its?mu.ld 
specify  an apopriate  range 00 a definite  wei@t  or  measuref or 
eachingralientcmtained  intheinvestigatiotlaldrug  prduct, 
whether  active  or  rmt,  and cakain  a batch  formula 
repxsentative  of  that  tobeused  far  the nmufacture  of  the 
investigatiaml  drug product. 
-13-  Each formulatim  of  defined  dosage forms, potencies/strengths, 
or  significant  changeso  f  inactive  ingr&ient(s)  shmld  be 
identified  with  a formulatim  n&xx  or  other  appropriate 
designation. 
Include  all  ingredients  in  thebatch  formla  regardless  of 
whether theyremain  in  theinvestigationaldrugproduct,  The 
oDntentofnewdrugsubstanceindicated  in  the  statemntsof 
caqositim  and the representativebatch  formula shabe  an 
thebasis  of  100%p otency/strengths  as stated  a3 the  label.  Any 
calculated  excess of  aningredientover  the  label  declaration 
&arldbedesigmted  as such, andpercentexcess  shaildbe 
sham.  Explainanyoverage  inthebatdhformula,  other  than 
U&a&led  to  caupmsate for  losses inmanufacturing. 
C.  Specifications  andAnalytical.Meth~s  for  InactiveCcmponents 
See secticnII.C.above. 
D.  Mamfacturer 
See sectimII.D.above. 
E.  Methodso  f  mfacturing  and Packaging 
Adocummtdescribingpraposed  production  and packaging 
operations  shouldbe  submitted for  INDeses.  Although it 
muld  lack  certain  features  of  the  final  record,  it  shmldbeas 
cacplete  as possible  under the circumstances. 
-14-  ,  . 
. 
. 
F.  Specifications  and Analytical  Msthais for  Investigational  Drug 
PXK%XtS 
1.  Introduction 
Theproduct  testsand  specifications  aercpriate  to 
investigational  drug products are,  Merstandably,  not  as 
b~lldeveloped  as Aen  an NL%is  submittea.  Hcwever, the 
safety  of  investigaticnal  prahcts  can be assured only  if 
agpropriateanalytical  inforr&knisprovided.  It  is 
necessary torealize  thatthedevelopmental  studies  of  such 
msthabarenotsoclearlyseparated  intophases  1,  2,  and3 
as the  clinical  studies.  %e  following  is  presented  as a 
general  INDdevelopntsecpnceintended  toprovide 
guidance for  the  develcpmsntofproduct  informatianduring 
the  investigational  -es.  The ultimate  gaal  of  this 
sequence is  the  develcpnentof  thsproducttests  and 
specifications  in  the  form Chat will  eventually  be submitted 
with  an MIA.  The level  of  detail  for  specifications  and 
analytical  methods set  forth  in  section  II.Fof  this 
guideline  must, therefore,  bs considered aa an ultimate 
gaal-  The fact  that  an itemnaynotbeincluded  in  fhis 
sectian  of  this  guideline  should not bs viewed as 
justification  far  its  anissicn  at  a later  developznt  stage 
of  the  IND.  2.  Phasesland 
Anassay~thod  includingadequateaoceptance  specifications 
for  content  of  the new drug substance (including  antibiotic) 
in  the dosage form &culd  be submitted.  The initial  limits 
ne&  notbeoverlynarr<wbutshouldbs  appropriately 
tighten&  as ezperience with  the drug aacuzulates.  Because 
the assayalonemightnot  senreasa  satisfactory  identity 
test,  usingadifferentmethod  rmybenecessaryduring  these 
phases.  Chemical and physical  tests  characterizing  the 
dosagefarmfhat~aildbeincludedfaraolidordldoeage 
forms are  uniformity  of  dosageu  nit  an3 dissolution  profile 
inana~ropriatemsdium.  Sterility  tests,  a measureo f 
particulatecontent,  and apyrogenicitytesting  shouldbe 
included for  injectables. 
The assay or  other procedure shouldmake useof  a reference 
standard or  interim  standard, and wqlytical  data to  suvt 
/ 
its  integrity  shuild  be 
Submitting Dxumantati 
substances.") 
Information  shaild  alsobe  &mitt&l  to  suportthe 
specificity,  linearity,  precision,  an3 accuracy amlicable 
t6  specific  quantitative  meth&s used to  test  the dcsage 
form. 
-16-  3.  Phase3 
h-wide  a  full  description  of  the  identity  tests,  assay 
methods,  and acceptance  specifications  as  well  as  any  other 
appropriate  chemical  and  physical  characteristics  of  the 
dosage  form.  These  should  amoach  m  requirements  in  the 
level  of  detail  provided,  including  tie  suitability  of 
specifications,  and data  to  omfirm  the  adequacy  of  the 
analytical  methodology.  In  vitro  dissolution  rate  tests  and 
specifications  shaxld  be  &mitted  for  solid  dosage  forms. 
Information  in  su-t  of  any  reference  standard  shculd  be 
-able  to  that  expected  in  an MIA  s&mission. 
4.  Placebos 
For  matching  placebos  med  in  clinical  studies,  a  full 
description  should  be  prwided  of  the  precautions  that  will 
be  taken  to  ensure  the  absence  of  the  new drug  substance 
fran  the  placebo  preparation.  The placebo  ard  active  dosage 
form  shtid  be  as  similar  as  pcssible  in  @ysical 
characteristics  and  identical  in  packaging. 
-17-