Guidance for Industry

Process Validation: General

Principles and Practices
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for iologics Evaluation and Research (CER)
Center for !eterinar" #edicine (C!#)
$anuar" %&''
Current (ood #anufacturing )ractices (C(#))
Revision '
Guidance for Industry
Process Validation: General
Principles and Practices
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Division of Drug Information, WO51, Room 221
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U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for iologics Evaluation and Research (CER)
Center for !eterinar" #edicine (C!#)
$anuar" %&''
Current (ood #anufacturing )ractices (C(#))
Revision '
Contains Nonbinding Recommendations
*A+E ,F C,-*E-*S
.. .-*R,DUC*.,-............................................................................................................. '
... AC/(R,U-D ............................................................................................................... 0
A. )rocess !alidation and Drug 1ualit" ..........................................................................................0
. Approach to )rocess !alidation ...................................................................................................2
.... S*A*U*,R3 A-D RE(U+A*,R3 RE1U.RE#E-*S F,R )R,CESS
!A+.DA*.,-................................................................................................................... 4
.!. REC,##E-DA*.,-S.................................................................................................. 5
A. (eneral Considerations for )rocess !alidation ..........................................................................5
. Stage ' 6 )rocess Design..............................................................................................................7
1' 7uilding and Capturing *rocess >no$ledge and ?nderstanding'''''''''''''''''''''''''''''''''''''''''''''''''''2
2' 8stablis&ing a (trateg6 for *rocess Control''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''!
C. Stage % 6 )rocess 1ualification.................................................................................................'&
1' Design of a 0acilit6 and @ualification of ?tilities and 8Auipment '''''''''''''''''''''''''''''''''''''''''''''''1
2' *rocess *erformance @ualification'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''11
"' **@ *rotocol'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''12
.' **@ *rotocol 81ecution and Report'''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''''1"
D. Stage 0 6 Continued )rocess !erification................................................................................'2
!. C,-CURRE-* RE+EASE ,F ))1 A*CHES ...................................................... '8
!.. D,CU#E-*A*.,-...................................................................................................... '5
!... A-A+3*.CA+ #E*H,D,+,(3.............................................................................. '5
(+,SSAR3................................................................................................................................. '7
REFERE-CES............................................................................................................................ '9
i






(uidance for .ndustr"
'
)rocess !alidation: (eneral )rinciples and )ractices
This guidance represents the Food and Drug dministration!s "FD!s# current thin$ing on this topic% It
does not create or confer any rights for or on any person and does not operate to bind FD or the public%
&ou can use an alternati'e approach if the approach satisfies the re(uirements of the applicable statutes
and regulations% If you )ant to discuss an alternati'e approach* contact the FD staff responsible for
implementing this guidance% If you cannot identify the appropriate FD staff* call the appropriate
number listed on the title page of this guidance%
.. .-*R,DUC*.,-
This guidance outlines the general principles and approaches that FD considers appropriate
elements of process 'alidation for the manufacture of human and animal drug and biological
products* including acti'e pharmaceutical ingredients "PIs or drug substances#* collecti'ely
referred to in this guidance as drugs or products% This guidance incorporates principles and
approaches that all manufacturers can use to 'alidate manufacturing processes%
This guidance aligns process 'alidation acti'ities )ith a product lifecycle concept and )ith
e+isting FD guidance* including the FD,International Conference on -armonisation "IC-#
guidances for industry* @2:R2< *&armaceutical Development* @! @ualit6 Ris9 )anagement* and
@1 *&armaceutical @ualit6 (6stem%
.
lthough this guidance does not repeat the concepts and
principles e+plained in those guidances* FD encourages the use of modern pharmaceutical
de'elopment concepts* (uality ris$ management* and (uality systems at all stages of the
manufacturing process lifecycle%
/
This guidance has been prepared by the Di'ision of 0anufacturing and Product 1uality* Center for Drug
2'aluation and Research "CD2R#* in cooperation )ith CD2R!s 3ffice of Pharmaceutical 4ciences* the Center for
5iologics 2'aluation and Research "C52R#* the 3ffice of Regulatory ffairs "3R# and the Center for Veterinary
0edicine "CV0# at the Food and Drug dministration%
.
To ma$e sure you ha'e the most recent 'ersion of a guidance* chec$ the CD2R guidance page at
&ttp:44$$$'fda'gov4Drugs45uidanceComplianceRegulator6Information45uidances4default'&tm* the C52R guidance
page at
&ttp:44$$$'fda'gov47iologics7lood=accines45uidanceComplianceRegulator6Information45uidances4default'&tm* or
the CV0 guidance page at
&ttp:44$$$'fda'gov4Animal=eterinar645uidanceCompliance8nforcement45uidanceforIndustr64default'&tm
%
Contains Nonbinding Recommendations
The lifecycle concept lin$s product and process de'elopment* (ualification of the commercial
manufacturing process*
6
and maintenance of the process in a state of control during routine
commercial production% This guidance supports process impro'ement and inno'ation through
sound science%
This guidance co'ers the follo)ing categories of drugs:
-uman drugs
Veterinary drugs
5iological and biotechnology products
Finished products and acti'e pharmaceutical ingredients "PIs or drug substances#
7
The drug constituent of a combination "drug and medical de'ice# product
This guidance does not co'er the follo)ing types of products:
Type medicated articles and medicated feed
0edical de'ices
8
Dietary supplements
-uman tissues intended for transplantation regulated under section 69/ of the Public -ealth
4er'ice ct
9
This guidance does not specify )hat information should be included as part of a regulatory submission%
Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining
the type of information to include in a submission%
This guidance also does not specifically discuss the 'alidation of automated process control systems
"i%e%* computer hard)are and soft)are interfaces#* )hich are commonly integrated into modern drug
manufacturing e(uipment% This guidance is rele'ant* ho)e'er* to the 'alidation of processes that
include automated e(uipment in processing%
6
In this guidance* the term commercial manufacturing process refers to the manufacturing process resulting in
commercial product "i%e%* drug that is mar$eted* distributed* and sold or intended to be sold#% For the purposes of
this guidance* the term commercial manufacturing process does not include clinical trial or treatment IND material%
7
4eparate current good manufacturing practice "CG0P# regulations for drug components such as PIs "drug
substances# and intermediates ha'e not published as of the date of this guidance* but these components are sub:ect to
the statutory CG0P re(uirements of section 8;/"a#".#"5# of the Federal Food* Drug* and Cosmetic ct "the ct#
"./ <%4%C% 68/"a#".#"5##% Process 'alidation for PIs is discussed in the FD,IC- guidance for industry* @, 5ood
)anufacturing *ractice 5uidance for Active *&armaceutical Ingredients "IC- 1=#* a'ailable on the Internet at
&ttp:44$$$'fda'gov4Drugs45uidanceComplianceRegulator6Information45uidances4default'&tm% 4ection >II of IC-
1= describes in detail the principles for 'alidating PI processes%
8
Guidance on process 'alidation for medical de'ices is pro'ided in a separate document* 1uality 0anagement
4ystems ? Process Validation* edition .* (ee infra note 9%
9
4ee the FD guidance for industry* =alidation of *rocedures for *rocessing of %uman ;issues Intended for
;ransplantation* a'ailable on the Internet at
&ttp:44$$$'fda'gov47iologics7lood=accines45uidanceComplianceRegulator6Information45uidances4default'&tm%
.
Contains Nonbinding Recommendations
FD!s guidance documents* including this guidance* do not establish legally enforceable
responsibilities% Instead* guidances describe the gency!s current thin$ing on a topic and should
be 'ie)ed only as recommendations* unless specific regulatory or statutory re(uirements are
cited% The use of the )ord s&ould in gency guidances means that something is suggested or
recommended* but not re(uired%
... AC/(R,U-D
In the 0ederal Register of 0ay //* /@A= "8. FR /=96A#* FD issued a notice announcing the
a'ailability of a guidance entitled 5uideline on 5eneral *rinciples of *rocess =alidation "the
/@A= guidance#%
=
4ince then* )e ha'e obtained additional e+perience through our regulatory
o'ersight that allo)s us to update our recommendations to industry on this topic% This re'ised
guidance con'eys FD!s current thin$ing on process 'alidation and is consistent )ith basic
principles first introduced in the /@A= guidance% The re'ised guidance also pro'ides
recommendations that reflect some of the goals of FD!s initiati'e entitled BPharmaceutical
CG0Ps for the ./st Century C Ris$D5ased pproach*E particularly )ith regard to the use of
technological ad'ances in pharmaceutical manufacturing* as )ell as implementation of modern
ris$ management and (uality system tools and concepts%
A
This re'ised guidance replaces the
/@A= guidance%
FD has the authority and responsibility to inspect and e'aluate process 'alidation performed by
manufacturers% The CG0P regulations for 'alidating pharmaceutical "drug# manufacturing
re(uire that drug products be produced )ith a high degree of assurance of meeting all the
attributes they are intended to possess "./ CFR .//%/;;"a# and .//%//;"a##%
A. )rocess !alidation and Drug 1ualit"
2ffecti'e process 'alidation contributes significantly to assuring drug (uality% The basic
principle of (uality assurance is that a drug should be produced that is fit for its intended use%
This principle incorporates the understanding that the follo)ing conditions e+ist:
1uality* safety* and efficacy are designed or built into the product%
1uality cannot be ade(uately assured merely by inDprocess and finishedDproduct
inspection or testing%
=
The /@A= guidance )as prepared by a )or$ing group that included representation from the Center for De'ices and
Radiological -ealth "CDR-#% 4ince that time* CDR- elected to reference a process 'alidation guidance prepared in
cooperation )ith the Global -armoniFation Tas$ Force "G-TF#% The principles and recommendations in that
document* @ualit6 )anagement (6stems B *rocess =alidation, edition . "a'ailable on the Internet at
http:,,)))%ghtf%org,sg6,sg6Dfinal%html# are also useful to consider for drug manufacturing processes%
A
(ee BPharmaceutical cG0P4 for the ./st Century G Ris$D5ased pproach: 4econd Progress Report and
Implementation Plan*E a'ailable at
http:,,)))%fda%go',Drugs,De'elopmentppro'alProcess,0anufacturing,1uestionsandns)ersonCurrentGood0an
ufacturingPracticescG0PforDrugs,ucm;=/A69%htm%
6
Contains Nonbinding Recommendations
2ach step of a manufacturing process is controlled to assure that the finished product
meets all (uality attributes including specifications%
. Approach to )rocess !alidation
For purposes of this guidance* process validation is defined as the collection and e'aluation of
data* from the process design stage through commercial production* )hich establishes scientific
e'idence that a process is capable of consistently deli'ering (uality product% Process 'alidation
in'ol'es a series of acti'ities ta$ing place o'er the lifecycle of the product and process% This
guidance describes process 'alidation acti'ities in three stages%
4tage / B Process Design: The commercial manufacturing process is defined during this
stage based on $no)ledge gained through de'elopment and scaleDup acti'ities%
4tage . B Process 1ualification: During this stage* the process design is e'aluated to
determine if the process is capable of reproducible commercial manufacturing%
4tage 6 B Continued Process Verification: 3ngoing assurance is gained during routine
production that the process remains in a state of control%
This guidance describes acti'ities typical of each stage* but in practice* some acti'ities might
occur in multiple stages%
5efore any batch from the process is commercially distributed for use by consumers* a
manufacturer should ha'e gained a high degree of assurance in the performance of the
manufacturing process such that it )ill consistently produce PIs and drug products meeting
those attributes relating to identity* strength* (uality* purity* and potency% The assurance should
be obtained from ob:ecti'e information and data from laboratoryD* pilotD* and,or commercialD
scale studies% Information and data should demonstrate that the commercial manufacturing
process is capable of consistently producing acceptable (uality products )ithin commercial
manufacturing conditions%
successful 'alidation program depends upon information and $no)ledge from product and
process de'elopment% This $no)ledge and understanding is the basis for establishing an
approach to control of the manufacturing process that results in products )ith the desired (uality
attributes% 0anufacturers should:
<nderstand the sources of 'ariation
Detect the presence and degree of 'ariation
<nderstand the impact of 'ariation on the process and ultimately on product attributes
Control the 'ariation in a manner commensurate )ith the ris$ it represents to the process
and product
2ach manufacturer should :udge )hether it has gained sufficient understanding to pro'ide a high
degree of assurance in its manufacturing process to :ustify commercial distribution of the
7
Contains Nonbinding Recommendations
product% Focusing e+clusi'ely on (ualification efforts )ithout also understanding the
manufacturing process and associated 'ariations may not lead to ade(uate assurance of (uality%
fter establishing and confirming the process* manufacturers must maintain the process in a state
of control o'er the life of the process* e'en as materials* e(uipment* production en'ironment*
personnel* and manufacturing procedures change%
@
0anufacturers should use ongoing programs to collect and analyFe product and process data to
e'aluate the state of control of the process% These programs may identify process or product
problems or opportunities for process impro'ements that can be e'aluated and implemented
through some of the acti'ities described in 4tages / and .%
0anufacturers of legacy products can ta$e ad'antage of the $no)ledge gained from the original
process de'elopment and (ualification )or$ as )ell as manufacturing e+perience to continually
impro'e their processes% Implementation of the recommendations in this guidance for legacy
products and processes )ould li$ely begin )ith the acti'ities described in 4tage 6%
.... S*A*U*,R3 A-D RE(U+A*,R3 RE1U.RE#E-*S F,R )R,CESS
!A+.DA*.,-
Process 'alidation for drugs "finished pharmaceuticals and components# is a legally enforceable
re(uirement under section 8;/"a#".#"5# of the ct "./ <%4%C% 68/"a#".#"5##* )hich states the
follo)ing:
drug % % % shall be deemed to be adulterated % % % if % % % the methods used in* or the
facilities or controls used for* its manufacture* processing* pac$ing* or holding do not
conform to or are not operated or administered in conformity )ith current good
manufacturing practice to assure that such drug meets the re(uirements of this ct as to
safety and has the identity and strength* and meets the (uality and purity characteristics*
)hich it purports or is represented to possess%
FD regulations describing current good manufacturing practice "CG0P# for finished
pharmaceuticals are pro'ided in ./ CFR parts ./; and .//%
The CG0P regulations re(uire that manufacturing processes be designed and controlled to
assure that inDprocess materials and the finished product meet predetermined (uality
re(uirements and do so consistently and reliably% Process 'alidation is re(uired* in both general
and specific terms* by the CG0P regulations in parts ./; and .//% The foundation for process
'alidation is pro'ided in H .//%/;;"a#* )hich states that BItJhere shall be )ritten procedures for
production and process control designed to assure that the drug products ha'e the identity*
strength* (uality* and purity they purport or are represented to possess%%%E "emphasis added#% This
regulation re(uires manufacturers to design a process* including operations and controls* )hich
results in a product meeting these attributes%
@
The statute and regulations described in section III of this guidance e+plain the re(uirement that the methods and
facilities used for the manufacturing of drugs be operated and administered under control sufficient to assure that the
identity* strength* purity* and (uality of a drug are as they purport or are represented to possess%
8
Contains Nonbinding Recommendations
3ther CG0P regulations define the 'arious aspects of 'alidation% For e+ample* H .//%//;"a#*
(ampling and testing of in+process materials and drug products* re(uires that control procedures
B% % % be established to monitor the output and to validate the performance of those manufacturing
processes that may be responsible for causing 'ariability in the characteristics of inDprocess
material and the drug productE "emphasis added#% <nder this regulation* e'en )ellDdesigned
processes must include inDprocess control procedures to assure final product (uality% In addition*
the CG0P regulations regarding sampling set forth a number of re(uirements for 'alidation:
samples must represent the batch under analysis "H .//%/9;"b#"6##K the sampling plan must result
in statistical confidence "H .//%/98"c# and "d##K and the batch must meet its predetermined
specifications "H .//%/98"a##%
In addition to sampling re(uirements* the CG0P regulations also pro'ide norms for establishing
inDprocess specifications as an aspect of process 'alidation% 4ection .//%//;"b# establishes t)o
principles to follo) )hen establishing inDprocess specifications% The first principle is that B% % %
inDprocess specifications for such characteristics Iof inDprocess material and the drug productJ
shall be consistent )ith drug product final specifications % % % %E ccordingly* inDprocess material
should be controlled to assure that the final drug product )ill meet its (uality re(uirements% The
second principle in this regulation further re(uires that inDprocess specifications B% % % shall be
deri'ed from pre'ious acceptable process a'erage and process 'ariability estimates )here
possible and determined by the application of suitable statistical procedures )here appropriate%E
This re(uirement* in part* establishes the need for manufacturers to analyFe process performance
and control batchDtoDbatch 'ariability%
/;
The CG0P regulations also describe and define acti'ities connected )ith process design*
de'elopment* and maintenance% 4ection .//%/A;"e# re(uires that information and data about
product (uality and manufacturing e+perience be periodically re'ie)ed to determine )hether
any changes to the established process are )arranted% 3ngoing feedbac$ about product (uality
and process performance is an essential feature of process maintenance%
In addition* the CG0P regulations re(uire that facilities in )hich drugs are manufactured be of
suitable siFe* construction* and location to facilitate proper operations "H .//%7.#% 2(uipment
must be of appropriate design* ade(uate siFe* and suitably located to facilitate operations for its
intended use "H .//%96#% utomated* mechanical* and electronic e(uipment must be calibrated*
inspected* or chec$ed according to a )ritten program designed to assure proper performance
"H .//%9A#%
In summary* the CG0P regulations re(uire that manufacturing processes be designed and
controlled to assure that inDprocess materials and the finished product meet predetermined
(uality re(uirements and do so consistently and reliably%
/;
The gency further e+plains this principle in the preamble to the final rule on BCurrent Good 0anufacturing
Practice in 0anufacture* Processing* Pac$ing* or -oldingE "76 FR 78;/6 at 78;8.* 4eptember .@* /@=A# "a'ailable
on the Internet at http:,,)))%fda%go',cder,dmp(,preamble%t+t#%
9
Contains Nonbinding Recommendations
.!. REC,##E-DA*.,-S
In the follo)ing sections* )e describe general considerations for process 'alidation* the
recommended stages of process 'alidation* and specific acti'ities for each stage in the product
lifecycle%
A. (eneral Considerations for )rocess !alidation
In all stages of the product lifecycle* good pro:ect management and good archi'ing that capture
scientific $no)ledge )ill ma$e the process 'alidation program more effecti'e and efficient% The
follo)ing practices should ensure uniform collection and assessment of information about the
process and enhance the accessibility of such information later in the product lifecycle%
Le recommend an integrated team approach
//
to process 'alidation that includes
e+pertise from a 'ariety of disciplines "e%g%* process engineering* industrial pharmacy*
analytical chemistry* microbiology* statistics* manufacturing* and (uality assurance#%
Pro:ect plans* along )ith the full support of senior management* are essential elements
for success%
Throughout the product lifecycle* 'arious studies can be initiated to disco'er* obser'e*
correlate* or confirm information about the product and process% ll studies should be
planned and conducted according to sound scientific principles* appropriately
documented* and appro'ed in accordance )ith the established procedure appropriate for
the stage of the lifecycle%
The terms attribute:s< "e%g%* (uality* product* component# and parameter:s< "e%g%* process*
operating* and e(uipment# are not categoriFed )ith respect to criticalit6 in this guidance%
Lith a lifecycle approach to process 'alidation that employs ris$ based decision ma$ing
throughout that lifecycle* the perception of criticality as a continuum rather than a binary
state is more useful% ll attributes and parameters should be e'aluated in terms of their
roles in the process and impact on the product or inDprocess material* and ree'aluated as
ne) information becomes a'ailable% The degree of control o'er those attributes or
parameters should be commensurate )ith their ris$ to the process and process output% In
other )ords* a higher degree of control is appropriate for attributes or parameters that
pose a higher ris$% The gency recogniFes that terminology usage can 'ary and e+pects
that each manufacturer )ill communicate the meaning and intent of its terminology and
categoriFation to the gency%
0any products are singleDsource or in'ol'e complicated manufacturing processes%
-omogeneity )ithin a batch and consistency bet)een batches are goals of process
'alidation acti'ities% Validation offers assurance that a process is reasonably protected
against sources of 'ariability that could affect production output* cause supply problems*
and negati'ely affect public health%
//
This concept is discussed in more detail in FD!s guidance for industry* @ualit6 (6stems Approac& to
*&armaceutical Current 5ood )anufacturing *ractice Regulations* a'ailable at
&ttp:44$$$'fda'gov4Drugs45uidanceComplianceRegulator6Information45uidances4default'&tm%
=
Contains Nonbinding Recommendations
. Stage ' 6 )rocess Design
Process design is the acti'ity of defining the commercial manufacturing process that )ill be
reflected in planned master production and control records% The goal of this stage is to design a
process suitable for routine commercial manufacturing that can consistently deli'er a product
that meets its (uality attributes%
1' 7uilding and Capturing *rocess >no$ledge and ?nderstanding
Generally* early process design e+periments do not need to be performed under the CG0P
conditions re(uired for drugs intended for commercial distribution that are manufactured during
4tage . "process (ualification# and 4tage 6 "continued process 'erification#% They should*
ho)e'er* be conducted in accordance )ith sound scientific methods and principles* including
good documentation practices% This recommendation is consistent )ith IC- @1
*&armaceutical @ualit6 (6stem%
/.
Decisions and :ustification of the controls should be
sufficiently documented and internally re'ie)ed to 'erify and preser'e their 'alue for use or
adaptation later in the lifecycle of the process and product%
lthough often performed at smallDscale laboratories* most 'iral inacti'ation and impurity
clearance studies cannot be considered early process design e+periments% Viral and impurity
clearance studies intended to e'aluate and estimate product (uality at commercial scale should
ha'e a le'el of (uality unit o'ersight that )ill ensure that the studies follo) sound scientific
methods and principles and the conclusions are supported by the data%
Product de'elopment acti'ities pro'ide $ey inputs to the process design stage* such as the
intended dosage form* the (uality attributes* and a general manufacturing path)ay% Process
information a'ailable from product de'elopment acti'ities can be le'eraged in the process design
stage% The functionality and limitations of commercial manufacturing e(uipment should be
considered in the process design* as )ell as predicted contributions to 'ariability posed by
different component lots* production operators* en'ironmental conditions* and measurement
systems in the production setting% -o)e'er* the full spectrum of input 'ariability typical of
commercial production is not generally $no)n at this stage% Maboratory or pilotDscale models
designed to be representati'e of the commercial process can be used to estimate 'ariability%
Designing an efficient process )ith an effecti'e process control approach is dependent on the
process $no)ledge and understanding obtained% Design of 2+periment "D32# studies can help
de'elop process $no)ledge by re'ealing relationships* including multi'ariate interactions*
bet)een the 'ariable inputs "e%g%* component characteristics
/6
or process parameters# and the
resulting outputs "e%g%* inDprocess material* intermediates* or the final product#% Ris$ analysis
tools can be used to screen potential 'ariables for D32 studies to minimiFe the total number of
e+periments conducted )hile ma+imiFing $no)ledge gained% The results of D32 studies can
pro'ide :ustification for establishing ranges of incoming component (uality* e(uipment
/.
'ailable at &ttp:44$$$'fda'gov4Drugs45uidanceComplianceRegulator6Information45uidances4default'&tm%
/6
BComponent means any ingredient Ira) materialJ intended for use in the manufacture of a drug product* including
those that may not appear in such drug productE "H ./;%6"b#"6##%
A
Contains Nonbinding Recommendations
parameters* and inDprocess material (uality attributes% FD does not generally e+pect
manufacturers to de'elop and test the process until it fails%
3ther acti'ities* such as e+periments or demonstrations at laboratory or pilot scale* also assist in
e'aluation of certain conditions and prediction of performance of the commercial process% These
acti'ities also pro'ide information that can be used to model or simulate the commercial process%
ComputerDbased or 'irtual simulations of certain unit operations or dynamics can pro'ide
process understanding and help a'oid problems at commercial scale% It is important to
understand the degree to )hich models represent the commercial process* including any
differences that might e+ist* as this may ha'e an impact on the rele'ance of information deri'ed
from the models%
It is essential that acti'ities and studies resulting in process understanding be documented%
Documentation should reflect the basis for decisions made about the process% For e+ample*
manufacturers should document the 'ariables studied for a unit operation and the rationale for
those 'ariables identified as significant% This information is useful during the process
(ualification and continued process 'erification stages* including )hen the design is re'ised or
the strategy for control is refined or changed%
2' 8stablis&ing a (trateg6 for *rocess Control
Process $no)ledge and understanding is the basis for establishing an approach to process control
for each unit operation and the process o'erall% 4trategies for process control can be designed to
reduce input 'ariation* ad:ust for input 'ariation during manufacturing "and so reduce its impact
on the output#* or combine both approaches%
Process controls address 'ariability to assure (uality of the product% Controls can consist of
material analysis and e(uipment monitoring at significant processing points "H .//%//;"c##%
Decisions regarding the type and e+tent of process controls can be aided by earlier ris$
assessments* then enhanced and impro'ed as process e+perience is gained%
FD e+pects controls to include both e+amination of material (uality and e(uipment monitoring%
4pecial attention to control the process through operational limits and inDprocess monitoring is
essential in t)o possible scenarios:
/% Lhen the product attribute is not readily measurable due to limitations of sampling or
detectability "e%g%* 'iral clearance or microbial contamination# or
.% Lhen intermediates and products cannot be highly characteriFed and )ellDdefined (uality
attributes cannot be identified%
These controls are established in the master production and control records "see H .//%/A9"a# and
"b#"@##%
0ore ad'anced strategies* )hich may in'ol'e the use of process analytical technology "PT#*
can include timely analysis and control loops to ad:ust the processing conditions so that the
output remains constant% 0anufacturing systems of this type can pro'ide a higher degree of
@
Contains Nonbinding Recommendations
process control than nonDPT systems% In the case of a strategy using PT* the approach to
process (ualification )ill differ from that used in other process designs% Further information on
PT processes can be found in FD!s guidance for industry on *A; C A 0rame$or9 for
Innovative *&armaceutical Development, )anufacturing, and @ualit6 Assurance%
/7
The planned commercial production and control records* )hich contain the operational limits
and o'erall strategy for process control* should be carried for)ard to the ne+t stage for
confirmation%
C. Stage % 6 )rocess 1ualification
During the process (ualification "P1# stage of process 'alidation* the process design is e'aluated
to determine if it is capable of reproducible commercial manufacture% This stage has t)o
elements: "/# design of the facility and (ualification of the e(uipment and utilities and ".#
process performance (ualification "PP1#% During 4tage .* CG0PDcompliant procedures must be
follo)ed% 4uccessful completion of 4tage . is necessary before commercial distribution%
/8
Products manufactured during this stage* if acceptable* can be released for distribution%
1' Design of a 0acilit6 and @ualification of ?tilities and 8Auipment
Proper design of a manufacturing facility is re(uired under part .//* subpart C* of the CG0P
regulations on 7uildings and 0acilities% It is essential that acti'ities performed to assure proper
facility design and commissioning precede PP1% -ere* the term Aualification refers to acti'ities
underta$en to demonstrate that utilities and e(uipment are suitable for their intended use and
perform properly% These acti'ities necessarily precede manufacturing products at the
commercial scale%
1ualification of utilities and e(uipment generally includes the follo)ing acti'ities:
4electing utilities and e(uipment construction materials* operating principles* and
performance characteristics based on )hether they are appropriate for their specific uses%
Verifying that utility systems and e(uipment are built and installed in compliance )ith
the design specifications "e%g%* built as designed )ith proper materials* capacity* and
functions* and properly connected and calibrated#%
Verifying that utility systems and e(uipment operate in accordance )ith the process
re(uirements in all anticipated operating ranges% This should include challenging the
e(uipment or system functions )hile under load comparable to that e+pected during
/7
'ailable at http:,,)))%fda%go',Drugs,GuidanceComplianceRegulatoryInformation,Guidances,default%htm%
3ther references that may be useful include 4T0 2.7=7D;9 B4tandard Practice for Pharmaceutical Process Design
<tiliFing Process nalytical TechnologyE and 4T0 2.7=9D;@ B4tandard Guide for Ris$ ssessment and Ris$
Control as it Impacts the Design* De'elopment* and 3peration of PT Processes for Pharmaceutical 0anufacture%E
/8
s discussed in section III of this guidance* process 'alidation "including process (ualification# is legally
enforceable under section 8;/"a#".#"5# of the ct% FD regulations re(uire that process 'alidation procedures be
established and follo)ed "H .//%/;;# before a batch can be distributed "HH .//%.. and .//%/98#%
/;
Contains Nonbinding Recommendations
routine production% It should also include the performance of inter'entions* stoppage*
and startDup as is e+pected during routine production% 3perating ranges should be sho)n
capable of being held as long as )ould be necessary during routine production%
1ualification of utilities and e(uipment can be co'ered under indi'idual plans or as part of an
o'erall pro:ect plan% The plan should consider the re(uirements of use and can incorporate ris$
management to prioritiFe certain acti'ities and to identify a le'el of effort in both the
performance and documentation of (ualification acti'ities% The plan should identify the
follo)ing items:
/% the studies or tests to use*
.% the criteria appropriate to assess outcomes*
6% the timing of (ualification acti'ities*
7% the responsibilities of rele'ant departments and the (uality unit* and
8% the procedures for documenting and appro'ing the (ualification%
The pro:ect plan should also include the firm!s re(uirements for the e'aluation of changes%
1ualification acti'ities should be documented and summariFed in a report )ith conclusions that
address criteria in the plan% The (uality control unit must re'ie) and appro'e the (ualification
plan and report "H .//%..#%
2' *rocess *erformance @ualification
The process performance (ualification "PP1# is the second element of 4tage .* process
(ualification% The PP1 combines the actual facility* utilities* e(uipment "each no) (ualified#*
and the trained personnel )ith the commercial manufacturing process* control procedures* and
components to produce commercial batches% successful PP1 )ill confirm the process design
and demonstrate that the commercial manufacturing process performs as e+pected%
4uccess at this stage signals an important milestone in the product lifecycle% manufacturer
must successfully complete PP1 before commencing commercial distribution of the drug
product%
/9
The decision to begin commercial distribution should be supported by data from
commercialDscale batches% Data from laboratory and pilot studies can pro'ide additional
assurance that the commercial manufacturing process performs as e+pected%
The approach to PP1 should be based on sound science and the manufacturer!s o'erall le'el of
product and process understanding and demonstrable control% The cumulati'e data from all
rele'ant studies "e%g%* designed e+perimentsK laboratory* pilot* and commercial batches# should
be used to establish the manufacturing conditions in the PP1% To understand the commercial
process sufficiently* the manufacturer )ill need to consider the effects of scale% -o)e'er* it is
not typically necessary to e+plore the entire operating range at commercial scale if assurance can
be pro'ided by process design data% Pre'ious credible e+perience )ith sufficiently similar
products and processes can also be helpful% In addition* )e strongly recommend firms employ
/9
4ee section III of this guidance* 4tatutory and Regulatory Re(uirements for Process Validation%
//
Contains Nonbinding Recommendations
ob:ecti'e measures "e%g%* statistical metrics# )here'er feasible and meaningful to achie'e
ade(uate assurance%
In most cases* PP1 )ill ha'e a higher le'el of sampling* additional testing* and greater scrutiny
of process performance than )ould be typical of routine commercial production% The le'el of
monitoring and testing should be sufficient to confirm uniform product (uality throughout the
batch% The increased le'el of scrutiny* testing* and sampling should continue through the process
'erification stage as appropriate* to establish le'els and fre(uency of routine sampling and
monitoring for the particular product and process% Considerations for the duration of the
heightened sampling and monitoring period could include* but are not limited to* 'olume of
production* process comple+ity* le'el of process understanding* and e+perience )ith similar
products and processes%
The e+tent to )hich some materials* such as column resins or molecular filtration media* can be
reDused )ithout ad'ersely affecting product (uality can be assessed in rele'ant laboratory
studies% The usable lifetimes of such materials should be confirmed by an ongoing PP1 protocol
during commercial manufacture%
manufacturing process that uses PT may )arrant a different PP1 approach% PT processes
are designed to measure in real time the attributes of an inDprocess material and then ad:ust the
process in a timely control loop so the process maintains the desired (uality of the output
material% The process design stage and the process (ualification stage should focus on the
measurement system and control loop for the measured attribute% Regardless* the goal of
'alidating any manufacturing process is the same: to establish scientific e'idence that the
process is reproducible and )ill consistently deli'er (uality products%
"' **@ *rotocol
)ritten protocol that specifies the manufacturing conditions* controls* testing* and e+pected
outcomes is essential for this stage of process 'alidation% Le recommend that the protocol
discuss the follo)ing elements:
The manufacturing conditions* including operating parameters* processing limits* and
component "ra) material# inputs%
The data to be collected and )hen and ho) it )ill be e'aluated%
Tests to be performed "inDprocess* release* characteriFation# and acceptance criteria
for each significant processing step%
The sampling plan* including sampling points* number of samples* and the fre(uency
of sampling for each unit operation and attribute% The number of samples should be
ade(uate to pro'ide sufficient statistical confidence of (uality both )ithin a batch and
bet)een batches% The confidence le'el selected can be based on ris$ analysis as it
relates to the particular attribute under e+amination% 4ampling during this stage
should be more e+tensi'e than is typical during routine production%
/.
Contains Nonbinding Recommendations
Criteria and process performance indicators that allo) for a scienceD and ris$Dbased
decision about the ability of the process to consistently produce (uality products% The
criteria should include:
G description of the statistical methods to be used in analyFing all collected data
"e%g%* statistical metrics defining both intraDbatch and interDbatch 'ariability#%
G Pro'ision for addressing de'iations from e+pected conditions and handling of
nonconforming data% Data should not be e+cluded from further consideration in
terms of PP1 )ithout a documented* scienceDbased :ustification%
/=
Design of facilities and the (ualification of utilities and e(uipment* personnel training
and (ualification* and 'erification of material sources "components and
container,closures#* if not pre'iously accomplished%
4tatus of the 'alidation of analytical methods used in measuring the process* inD
process materials* and the product%
Re'ie) and appro'al of the protocol by appropriate departments and the (uality unit%
.' **@ *rotocol 81ecution and Report
2+ecution of the PP1 protocol should not begin until the protocol has been re'ie)ed and
appro'ed by all appropriate departments* including the (uality unit% ny departures from the
protocol must be made according to established procedure or pro'isions in the protocol% 4uch
departures must be :ustified and appro'ed by all appropriate departments and the (uality unit
before implementation "H .//%/;;#%
The commercial manufacturing process and routine procedures must be follo)ed during PP1
protocol e+ecution "HH .//%/;;"b# and .//%//;"a##% The PP1 lots should be manufactured under
normal conditions by the personnel routinely e+pected to perform each step of each unit
operation in the process% Normal operating conditions should include the utility systems "e%g%* air
handling and )ater purification#* material* personnel* en'ironment* and manufacturing
procedures%
report documenting and assessing adherence to the )ritten PP1 protocol should be prepared in
a timely manner after the completion of the protocol% This report should:
Discuss and crossDreference all aspects of the protocol%
4ummariFe data collected and analyFe the data* as specified by the protocol%
/=
For additional guidance regarding outDofDspecification results* see FD!s Guidance for Industry* Investigating
Out+of+(pecification :OO(<;est Results for *&armaceutical *roduction* a'ailable at
http:,,)))%fda%go',do)nloads,Drugs,GuidanceComplianceRegulatoryInformation,Guidances,ucm;=;.A=%pdf%
/6
Contains Nonbinding Recommendations
2'aluate any une+pected obser'ations and additional data not specified in the
protocol%
4ummariFe and discuss all manufacturing nonconformances such as de'iations*
aberrant test results* or other information that has bearing on the 'alidity of the
process%
Describe in sufficient detail any correcti'e actions or changes that should be made to
e+isting procedures and controls%
4tate a clear conclusion as to )hether the data indicates the process met the
conditions established in the protocol and )hether the process is considered to be in a
state of control% If not* the report should state )hat should be accomplished before
such a conclusion can be reached% This conclusion should be based on a documented
:ustification for the appro'al of the process* and release of lots produced by it to the
mar$et in consideration of the entire compilation of $no)ledge and information
gained from the design stage through the process (ualification stage%
Include all appropriate department and (uality unit re'ie) and appro'als%
D. Stage 0 6 Continued )rocess !erification
The goal of the third 'alidation stage is continual assurance that the process remains in a state of
control "the 'alidated state# during commercial manufacture% system or systems for detecting
unplanned departures from the process as designed is essential to accomplish this goal%
dherence to the CG0P re(uirements* specifically* the collection and e'aluation of information
and data about the performance of the process* )ill allo) detection of undesired process
'ariability% 2'aluating the performance of the process identifies problems and determines
)hether action must be ta$en to correct* anticipate* and pre'ent problems so that the process
remains in control "H .//%/A;"e##%
n ongoing program to collect and analyFe product and process data that relate to product
(uality must be established "H .//%/A;"e##% The data collected should include rele'ant process
trends and (uality of incoming materials or components* inDprocess material* and finished
products% The data should be statistically trended and re'ie)ed by trained personnel% The
information collected should 'erify that the (uality attributes are being appropriately controlled
throughout the process%
Le recommend that a statistician or person )ith ade(uate training in statistical process control
techni(ues de'elop the data collection plan and statistical methods and procedures used in
measuring and e'aluating process stability and process capability%
/A
Procedures should describe
/A
4ome references that may be useful include the follo)ing: 4T0 2..A/D;6 B4tandard Practice for Process and
0easurement Capability Indices*E 4T0 2.8;;D;= B4tandard Guide for 4pecification* Design* and Verification of
Pharmaceutical and 5iopharmaceutical 0anufacturing 4ystems and 2(uipment*E and 4T0 2.=;@D;@ B4tandard
Practice for Demonstrating Capability to Comply )ith a Mot cceptance Procedure%E This is not a complete list of
all useful references on this topic% 0any industry standards* boo$s* and guides on these topics are a'ailable%
/7
Contains Nonbinding Recommendations
ho) trending and calculations are to be performed and should guard against o'erreaction to
indi'idual e'ents as )ell as against failure to detect unintended process 'ariability% Production
data should be collected to e'aluate process stability and capability% The (uality unit should
re'ie) this information% If properly carried out* these efforts can identify 'ariability in the
process and,or signal potential process impro'ements%
Good process design and de'elopment should anticipate significant sources of 'ariability and
establish appropriate detection* control* and,or mitigation strategies* as )ell as appropriate alert
and action limits% -o)e'er* a process is li$ely to encounter sources of 'ariation that )ere not
pre'iously detected or to )hich the process )as not pre'iously e+posed% 0any tools and
techni(ues* some statistical and others more (ualitati'e* can be used to detect 'ariation*
characteriFe it* and determine the root cause% Le recommend that the manufacturer use
(uantitati'e* statistical methods )hene'er appropriate and feasible% 4crutiny of intraDbatch as
)ell as interDbatch 'ariation is part of a comprehensi'e continued process 'erification program
under H .//%/A;"e#%
Le recommend continued monitoring and sampling of process parameters and (uality attributes
at the le'el established during the process (ualification stage until sufficient data are a'ailable to
generate significant 'ariability estimates% These estimates can pro'ide the basis for establishing
le'els and fre(uency of routine sampling and monitoring for the particular product and process%
0onitoring can then be ad:usted to a statistically appropriate and representati'e le'el% Process
'ariability should be periodically assessed and monitoring ad:usted accordingly%
Variation can also be detected by the timely assessment of defect complaints* outDofD
specification findings* process de'iation reports* process yield 'ariations* batch records*
incoming ra) material records* and ad'erse e'ent reports% Production line operators and (uality
unit staff should be encouraged to pro'ide feedbac$ on process performance% Le recommend
that the (uality unit meet periodically )ith production staff to e'aluate data* discuss possible
trends or undesirable process 'ariation* and coordinate any correction or follo)Dup actions by
production%
Data gathered during this stage might suggest )ays to impro'e and,or optimiFe the process by
altering some aspect of the process or product* such as the operating conditions "ranges and setD
points#* process controls* component* or inDprocess material characteristics% description of the
planned change* a )ellD:ustified rationale for the change* an implementation plan* and (uality
unit appro'al before implementation must be documented "H .//%/;;#% Depending on ho) the
proposed change might affect product (uality* additional process design and process
(ualification acti'ities could be )arranted%
/@
0aintenance of the facility* utilities* and e(uipment is another important aspect of ensuring that a
process remains in control% 3nce established* (ualification status must be maintained through
routine monitoring* maintenance* and calibration procedures and schedules "./ CFR part .//*
/@
Certain manufacturing changes may call for formal notification to the gency before implementation* as directed
by e+isting regulations "see* e%g%* ./ CFR 6/7%=; and 9;/%/.#%
/8
Contains Nonbinding Recommendations
subparts C and D#% The e(uipment and facility (ualification data should be assessed periodically
to determine )hether reD(ualification should be performed and the e+tent of that reD(ualification%
0aintenance and calibration fre(uency should be ad:usted based on feedbac$ from these
acti'ities%
!. C,-CURRE-* RE+EASE ,F ))1 A*CHES
In most cases* the PP1 study needs to be completed successfully and a high degree of assurance
in the process achie'ed before commercial distribution of a product% In special situations* the
PP1 protocol can be designed to release a PP1 batch for distribution before complete e+ecution
of the protocol steps and acti'ities* i%e%* concurrent release% FD e+pects that concurrent release
)ill be used rarely%
Concurrent release might be appropriate for processes used infre(uently for 'arious reasons*
such as to manufacture drugs for )hich there is limited demand "e%g%* orphan drugs* minor use
and minor species 'eterinary drugs# or )hich ha'e short half li'es "e%g%* radiopharmaceuticals*
including positron emission tomography drugs#% Concurrent release might also be appropriate
for drugs that are medically necessary and are being manufactured in coordination )ith the
gency to alle'iate a short supply%
Conclusions about a commercial manufacturing process can only be made after the PP1 protocol
is fully e+ecuted and the data are fully e'aluated% If 4tage . (ualification is not successful "i%e%*
does not demonstrate that the process as designed is capable of reproducible performance at
commercial scale#* then additional design studies and (ualification may be necessary
.
The ne)
product and process understanding obtained from the unsuccessful (ualification study"ies# can
ha'e negati'e implications if any lot )as already distributed% Full e+ecution of 4tages / and . of
process 'alidation is intended to preclude or minimiFe that outcome%
Circumstances and rationale for concurrent release should be fully described in the PP1
protocol% 2'en )hen process performance assessment based on the PP1 protocol is still
outstanding* any lot released concurrently must comply )ith all CG0Ps* regulatory appro'al
re(uirements* and PP1 protocol lot release criteria% Mot release under a PP1 protocol is based
upon meeting confidence le'els appropriate for each (uality attribute of the drug%
Lhen )arranted and used* concurrent release should be accompanied by a system for careful
o'ersight of the distributed batch to facilitate rapid customer feedbac$% For e+ample* customer
complaints and defect reports should be rapidly assessed to determine root cause and )hether the
process should be impro'ed or changed% Concurrently released lots must also be assessed in
light of any negati'e PP1 study finding or conclusions and appropriate correcti'e action must be
ta$en "HH .//%/;;"a#* .//%/A;"e#* and .//%/@.#% Le recommend that each batch in a concurrent
release program be e'aluated for inclusion in the stability program% It is important that stability
test data be promptly e'aluated to ensure rapid detection and correction of any problems%
/9
Contains Nonbinding Recommendations
!.. D,CU#E-*A*.,-
Documentation at each stage of the process 'alidation lifecycle is essential for effecti'e
communication in comple+* lengthy* and multidisciplinary pro:ects% Documentation is important
so that $no)ledge gained about a product and process is accessible and comprehensible to others
in'ol'ed in each stage of the lifecycle% Information transparency and accessibility are
fundamental tenets of the scientific method% They are also essential to enabling organiFational
units responsible and accountable for the process to ma$e informed* scienceDbased decisions that
ultimately support the release of a product to commerce%
The degree and type of documentation re(uired by CG0P 'ary during the 'alidation lifecycle%
Documentation re(uirements are greatest during 4tage .* process (ualification* and 4tage 6*
continued process 'erification% 4tudies during these stages must conform to CG0Ps and must
be appro'ed by the (uality unit in accordance )ith the regulations "see HH .//%.. and .//%/;;#%
Viral and impurity clearance studies* e'en )hen performed at small scale* also re(uire (uality
unit o'ersight%
CG0P documents for commercial manufacturing "i%e%* the initial commercial master batch
production and control record "H .//%/A9# and supporting procedures# are $ey outputs of 4tage /*
process design% Le recommend that firms diagram the process flo) for the fullDscale process%
Process flo) diagrams should describe each unit operation* its placement in the o'erall process*
monitoring and control points* and the component* as )ell as other processing material inputs
"e%g%* processing aids# and e+pected outputs "i%e%* inDprocess materials and finished product#% It is
also useful to generate and preser'e process flo) diagrams of the 'arious scales as the process
design progresses to facilitate comparison and decision ma$ing about their comparability%
!... A-A+3*.CA+ #E*H,D,+,(3
Process $no)ledge depends on accurate and precise measuring techni(ues used to test and
e+amine the (uality of drug components* inDprocess materials* and finished products% Validated
analytical methods are not necessarily re(uired during productD and processDde'elopment
acti'ities or )hen used in characteriFation studies% Ne'ertheless* analytical methods should be
scientifically sound "e%g%* specific* sensiti'e* and accurate# and pro'ide results that are reliable%
There should be assurance of proper e(uipment function for laboratory e+periments% Procedures
for analytical method and e(uipment maintenance* documentation practices* and calibration
practices supporting processDde'elopment efforts should be documented or described% Ne)
analytical technology and modifications to e+isting technology are continually being de'eloped
and can be used to characteriFe the process or the product% <se of these methods is particularly
appropriate )hen they reduce ris$ by pro'iding greater understanding or control of product
(uality% -o)e'er* analytical methods supporting commercial batch release must follo) CG0Ps
in parts ./; and .//% Clinical supply production should follo) the CG0Ps appropriate for the
particular phase of clinical studies%
/=
Contains Nonbinding Recommendations
(+,SSAR3
Capa;ilit" of a process: bility of a process to produce a product that )ill fulfill the
re(uirements of that product% The concept of process capability can also be defined in statistical
terms% "I43 @;;;:.;;8#
Commercial manufacturing process: The manufacturing process resulting in commercial
product "i%e%* drug that is mar$eted* distributed* and sold or intended to be sold#% For the
purposes of this guidance* the term commercial manufacturing process does not include clinical
trial or treatment IND material%
Concurrent release: Releasing for distribution a lot of finished product* manufactured
follo)ing a (ualification protocol* that meets the lot release criteria established in the protocol*
but before the entire study protocol has been e+ecuted%
Continued process verification: ssuring that during routine production the process remains in
a state of control%
)erformance indicators: 0easurable 'alues used to (uantify (uality ob:ecti'es to reflect the
performance of an organiFation* process or system* also $no)n as performance metrics in some
regions% "IC- 1/;#
)rocess design: Defining the commercial manufacturing process based on $no)ledge gained
through de'elopment and scaleDup acti'ities%
)rocess <ualification: Confirming that the manufacturing process as designed is capable of
reproducible commercial manufacturing%
)rocess validation: The collection and e'aluation of data* from the process design stage
through commercial production* )hich establishes scientific e'idence that a process is capable of
consistently deli'ering (uality products%
1ualit": The degree to )hich a set of inherent properties of a product* system* or process fulfils
re(uirements% "IC- 1@#
State of control: condition in )hich the set of controls consistently pro'ides assurance of
continued process performance and product (uality% "IC- 1/;#
/A
Contains Nonbinding Recommendations
/@
REFERE-CES
FD* "C52R#* =alidation of *rocedures for *rocessing of %uman ;issues Intended for
;ransplantation* guidance for industry* 0ay .;;.%
FD* "CD2R#* Investigating Out+of+(pecification :OO(< ;est Results for *&armaceutical
*roduction, guidance for industry* 3ctober .;;9%
FD* "CD2R* CV0* and 3R#* *A; D A 0rame$or9 for Innovative *&armaceutical
Development, )anufacturing, and @ualit6 Assurance* guidance for industry* 4eptember
.;;7%
FD* "CD2R* C52R* CV0* and 3R#* @ualit6 (6stems Approac& to *&armaceutical Current
5ood )anufacturing *ractice Regulations* guidance for industry* 4eptember .;;9%
FD,Global -armoniFation Tas$ Force "G-TFK medical de'ices#* @ualit6 )anagement (6stems
B *rocess =alidation* edition .* guidance* Nanuary .;;7%
FD,IC-* "CD2R and C52R#* @, 5ood )anufacturing *ractice for Active *&armaceutical
Ingredients* guidance for industry* ugust .;;/%
FD,IC-* "CD2R and C52R#* @2:R2< *&armaceutical Development* guidance for industry*
No'ember .;;@%
FD,IC-* "CD2R and C52R#* @! @ualit6 Ris9 )anagement* guidance for industry* Nune .;;9%
FD,IC- "CD2R and C52R# @1 *&armaceutical @ualit6 (6stem* guidance for industry* pril
.;;@%
4T0 2.7=7D;9 4tandard Practice for Pharmaceutical Process Design <tiliFing Process
nalytical Technology%
4T0 2.7=9D;@ 4tandard Guide for Ris$ ssessment and Ris$ Control as it Impacts the
Design* De'elopment* and 3peration of PT Processes for Pharmaceutical 0anufacture%
4T0 2..A/D;6 4tandard Practice for Process and 0easurement Capability Indices%
4T0 2.8;;D;= 4tandard Guide for 4pecification* Design* and Verification of Pharmaceutical
and 5iopharmaceutical 0anufacturing 4ystems and 2(uipment%
4T0 2.=;@D/; 4tandard Practice for Demonstrating Capability to Comply )ith a Mot
cceptance Procedure%