!"#" $%"

  $ &$ '( )!"$ !$
" &$ '"

      !"#$% &"'     

 '
 **
 * +


 ( ( ) ) 
,- . /00
11 3


 1 5

  1 1 7

1 2  3 1 1 H

1 * 
1 G

1  -2
* 
; G

/11 
2    42  ; G

/11/

2
 - +2  ; 3K

1/  
; ; 37

/1/1   3 ; 37

15 - 2 

  
; 3H

16 -

2 
  3 ; ; 3H

1 2   7

; 3H

18  3 

2 *   - - ; ; 3C

/181 - 2 

  3 

2 *   -
- ; 3C

/181/ - 7
   -  

2 *  
- - ; ; 3G

/1815 2 
  -2 3 

2 ; 4K

1 - 2 9- 2 1 1 43

1 2 
; 43

1/ - 2 

  3 ; 44

51/11 -$""""  &      :$"$  )!"$

 !"1 ; ; 44

51/1/ -$""""  &  "!$"    :$"$ 

)!"$  !"1 ; 44

51/15 -$""""  &   !;"    :$"$  )!"$

 !"1 ; ; 44

1 


1 4G
  

1 1 53

  
1 55

77* + 1 57
DEDICATORIA A Patricia Ponce, amiga, compañera y esposa; por el amor que día a día
cultivamos A mi abuelita Asunción, a Berita García; por que siempre alumbraron mi camino.
A San Marcos; mi alma mater, a la Facultad de Farmacia y Bioquímica y a la Residencia
Universitaria, siempre los llevaré en mis recuerdos

*+, -.""#$# / 0
""12# #% &"  * 3
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

4 *+, -.""#$# / 0
""12# #% &"  *
 




El presente trabajo muestra la forma de desarrollar la validación de uno de los pilares dentro del
sistema de apoyo crítico en la industria farmacéutica: la Validación Prospectiva del Sistema
Generador de Vapor Limpio, de tal manera que se establezca una evidencia documentada de que
el proceso es capaz de cumplir en forma consistente y repetitiva las especificaciones
establecidas.
Se procedió a elaborar los protocolos en donde se definen los objetivos específicos de las
evaluaciones a efectuar, las responsabilidades de cada una de las áreas involucradas; se
establecieron variables de interés a monitorear, incluyendo el plan de monitoreo respectivo,
además de incluir los criterios de aceptación que luego se compararon con los resultados
esperados.
Posteriormente se desarrollo el proceso de validación propiamente dicho, en el cuál se
realizó una evaluación del proceso y se hicieron pruebas de que todos los componentes del
sistema funcionan según lo especificado. Se sometió a prueba todos los controles de operación
normal, verificación: del sistema generador, del sistema de control, de alarmas, de bomba, y de
niveles de agua.
Se hizo la calificación de desempeño, para la cuál se analizaron el perfil de pureza: control
físico-químico (pH, conductividad, sustancias oxidables y sólidos totales) y control
microbiológico (prueba de endotoxinas y carga microbiana) del condensado de vapor en el punto
de uso por 30 días. Con los resultados obtenidos se concluye que el vapor producido por el
generador de vapor limpio en una industria farmacéutica local es apto para su uso.
Palabras Claves: Validación, Sistema, Generador, Vapor, Pureza.

*+, -.""#$# / 0
""12# #% &"  * 5
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

6 *+, -.""#$# / 0
""12# #% &"  *

 

 
The present work shows the form to develop the validation of one of the pillars within the system
of critical support in the pharmaceutical industry: the Prospective Validation of the Generating
Clean Steam System, in order to establish documentary evidence that the process is able to fulfill
in consistent and repetitive form the established specifications.
The protocols were elaborated in which the specific objectives of the evaluations, the
responsibilities of each of the involved areas are defined to carry out; interest variables to
monitor were established including the respective plan of monitoring; besides to sit includes the
acceptance criterias which will be compared with the expected results afterwards.
Then, the validation process itself was developed, in which an evaluation of the process was
made and all the components of the system were tested to check whether they work according to
the specifications or not. All the controls of normal operation were checked, verification: of the
generating system, of the control system, alarms, pump, and water levels.
The qualification of performance was made, for which analyzed the purity profile was
analyzed: physical-chemistry control (pH, conductivity, rusty substances and total solid) and
microbiological control (test of endotoxins and microbial load) of the condensed steam in the
point of use by 30 days. With the obtained results we conclude that the steam produced by the
clean steam generator in a local pharmaceutical industry is suitable for its use.
Key Words: Validation, System, Generator, Steam, Purity.

*+, -.""#$# / 0
""12# #% &"  * 7
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

8 *+, -.""#$# / 0
""12# #% &"  *
 1 2  3

1 2  3

 $%& #$ !,19 $1 &$#!  &" % $,+"% &" 1$&& ":1""%";  ". # #
& 1# &"#$%&#  ,$"% &"  "%!","&&< #= =$&#  ,">  1$&&
&" =$&<   1  %  "&" 2." " ,%$, ,+"%  " "; $% ",.+< 
"# &" # "#! "?# &" 1% - !.$11$@%< #" ":$+" % ,"> 1%$%  - ,A:$,#
+%# &"  1$&&;  "# "% " =%1"  1%#"+ $ %  &,$%$ &"  1$&&<
1 %& # +" " 1%1" &" =$&1$@%; B3CD
& &", "# E " 2- "% & ":$#" % $%"9# 1"1$"%"   )

&".$&  ,- 9%!#$# E " 2  "#  $%& #$ "% F# "1$"%"# 1% "#"1  #
",# &" #"+ ,$"% &"  $&& - ">,$"% 1%$% ;
" 2"12< " 1%1"
&" )$&1$@%  = % 9:$ "%  "& 11$@% &" # .",# &" ,% !1  E " "%
3GC5  
 $%& >  $," %, #." )$&1$@% &" 1"## E " #"$,"%"
! " "=$#& "% 3GCH< 1%=$$9%&#" "% % &" # $"&# %+ "# &" 1 ,$,$"%
&" #  "%# A1$1# &" % !1 ; BHDB4GD
# #$#",# &" - 1$1 B#$#",# &" + < #$#",# &" +#"#< #$#",#
"1$@% - =D< !,% " "# 1  &"% &"  $%& #$ !,19 $1I #
&$!""%"# 1"## 21"% # &" "## - # 1$&& #" 21" ":"%#$=  # %$&&"#
& 1$=# B3DB56D; % &" # $,"# #$#",# E " #" "# &$%  " "," "%
# %# ,% !1 "# !,19 $1# ! " " &" # #$#",# +"%"&"# &" =<
$$?&  +"%" = E " #"=$ 1, ! "%" &" %#!""%1$ &" 1 B=
%D -  "#"$$?  1 2J,"& B= $,$D BGD;
 #$#", = $,$<  % "# "# &$< $$? % 1&" "91$1 &" 1"

*+, -.""#$# / 0
""12# #% &"  * H
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

$%:$&." &" 7KK &" 11$&&< E " $$? +  &" #,#$# "="# - "# &$#$. $& 
 % &" #  % "& &" 1" $%:$&." 1$&& 538;  #$#", &" = 1, %
! "%" &" 1  1, % ,"&$   "#"$$?1$@% "# #&  # .> 1# - 
#" " ,9& ,A# "!$1? - %$="#,"%" ","& "%  "#"$$?1$@% #." & "% 
!.$11$@% &" & 1# "#9$"#; B35DB53DB58D;
.>"$='
",#  =$&"? &" #$#", +"%"& &" = $,$ "% % %
!,19 $1 1;

C *+, -.""#$# / 0
""12# #% &"  *
 1 * 

1 * 

1  -2
* 

/11 
2    42 
 %& #$ !,19 $1 "# % $,%" "","% &" # #$#",# &" #$#"%1$
#%$$ &" & " , %&I 1%#$ $&  % ,"## +%$?1$%"# J.$1# - $=&#
&"&$1&#   $%="#$+1$@%< &"#< !.$11$@% - 1,"1$$?1$@% &" ,"&$1,"%#
  # & 2 ,% - %$,; B8D
 ! %&,"% "#  $%="#$+1$@% - &"# &" !A,1#  "="%$   #
&$="## "%!","&&"# - "1$%"#; % "#" #"%$& # .$@+# ,"1 "#<
E ,$1# - !,19 $1# ,">% # ."%"!$1$# &" # !A,1#  ,"%%&  1$=$&&
-  "#"1$!$1$&&; ## =%1"# # #1$%<  # ="?< % % "= "1 1$@%  
"11$@% &"  # & -  #"+ $&& &" # .>&"# "%  $%& #$ !,19 $1 BCD;
+ %# 1,F# .>% % "% # ,"1&# %1$%"# 1, "% #
, $%1$%"#; % & 1#< # # 1$=$&&"# "#A% #,"$&#  "-"#< "+,"%# -
$1# $1."#  &"# - .1$@% &" !A,1#<  !.$11$@% - 1% &"
1$&&<  1,"1$$?1$@% - # ="%#; B3KD

*+, -.""#$# / 0
""12# #% &"  * G
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

 ,"## #"# 2% && "+,"%# $1."#  &"# - 

 $?1$@% &" 1,"1$$?1$@% &" # !A,1#; % "# #" "#."1"% "E $#$#
"#$1# &" . "%# A1$1# &" !.$11$@% E " +%$?%  $%"+$&& &" #
"1$%"# $%& #$"# -  1$&&< #"+ $&& - "!$11$ &" # & 1# !,19 $1#;
B33DB8D

/11/

2
 - +2 
# #$#",# &" - 1$1 !,% " "# 1  &"% &"  $%& #$ !,19 $1I
# &$!""%"# 1"## 21"% # &" "## - # 1$&& #" 21" ":"%#$=  # %$&&"#
& 1$=#; B38D
/11/1

2
 *
$%1$ #$#", &" - E " 1$% # &$!""%"# $# &" + ' + 
."< +   $!$1& - +   %-"11$@%;  +  E " "#  # #%1$< ,"$
$,  $%+"&$"%" &" ,- # "%  & 11$@%< 1"#,$"% - !, 1$@% &"
& 1#; B3HD
/11/1/

2
 *


"% &" "## #$#",# "# " $#", &" $" ,$,$&< $#",# &"
$@+"%< &" :$+"% - 4; B38DB3GD
/11/15

2    3
%"+  ="%$&"# &" # ,$%$# - "%< #""%$%"# &" "%!$,$"% -
1"%,$"%< &"#2 ,$!$1&"# - "#1$%"# &" !$1$@% B3GD;
/11/16

2  -
 #$#", &" = $"%"  !$%$&& +"%"< &$#$. $ - $$? " = 1% " !$%
&" ="12 # ","  - # &" 1!$1; #" #$#", &" - 1$1 "#
$$?& 1, ="21  &" "%"+ - #" 2 1%="$& "% % !":$." - ="#A$
2",$"%   $%& #$ 1 %& #" %"1"#$ +J% $ &" 1"!11$@% - ,.$9% "#
"1,"%&&  # 1"## &" "#"$$?1$@%;  = #" & 1" "=%& + 
E " "# "$=,"%" . - 11"#$." "% +% " &" , %&;  ","  #"
 "&" > # 1% , 12 "1$#$@% 1%%&  "#$@% ,"&$%" # &" =A= # , -
#$,"#I %# 1%$&&"# &" "%"+ "$=,"%" $,%"# 1% 1 ,# -
1 %& = "="  1%="$#" "% +  1"&" 1%$&&"# %."# &" "%"+; B38DB4KDB43D
<= -
, # # #%1$#< " +   "&" "# "% &$!""%"# "#&#< 1, +# "#
,& =; $ #" F&" 1  + < # ","   ,"% 2# E " 1%? %
=  $ &" 1  - %  "&" # .#$#$ 1, E $&;  "#" =  ,,# L %
&" # 1$@%M;  E $" % "= &$1$@% &" "%"+ =1 E " " &" +  2$"= -
#" 1%=$" "% =; # "=1$@% "E $"" 1%$&&"# &" "%"+ "$=,"%"
$,%" - ,$"%# 9# #" "#A F&$"%&< " +  - " = !,& ",%"1"% 
 ,$#, "," ; B4KDB55D
</= -    -

3K *+, -.""#$# / 0
""12# #% &"  *
 1 * 

 = "# % "#& !#$1 &&  " !"%@,"% &" =$?1$@%I 1 E $" &$1$@%
&" 1  +  2A  ,"% # "," < 2# E " #" 1%1"% # 3KKN  "% E "
#" $%$1$  ". $1$@%< $1." J%$1,"%"   "#$@% ,#!9$1;  E $"  ,"%
&$1$% &"  "% 21" E " " +  %  "& #"+ $ ,%"%$9%&#" "% !#" E $&
- % " 2$"= 1%=$$9%&#" "% =;
 "%  ""%$&  1& O+; &" +  E $&   ","  &" ". $1$@%
#" , L% "#"1!$1 &" +  # &M - #" &"#$+% 1% " #,. B2!D;
 "% &$1$% %"1"#$  1%="$ 3 O+; &" +  "% = #" ,
L% "#"1!$1 &" "=1$@%M - #" &"#$+% 1% " #,. B2!+D;
 "%  &" 1& O+; &" = "#  # , &" # &# %"$"#; " ,
L% "#"1!$1 &" )M - #" &"#$+% 1% " #,. B2+D; #A 1 E " B43D'
2! P 2!+ Q 2+
<5=   -
1 !"$ "
,& ,.$9% ) # & #"1< "# % = E " 2 #$& "=&
1,","%"< "# &"1$< % 1%$"%" +# &" +  E $&; %  A1$1< " = 
,"% & %1 "E "F# +# &" + < 1%  E " - %  "&" #" &"#1$ 1,
= # & #"1; $% ",.+ "# $,%" E " " = $$?&  1"## 
1"!11$@% #"  ,A# #"1 #$."  "# #" $$? #"&"# - ,# &" =;
 1$&& &" = #" &"#1$." ,"&$%" # !11$@% #"1< E " "#  1$@% &"
= 1,","%" #"1 "#"%" "% " = 1%#$&"&;
#" = "# " $&"  # $11$%"# &" 1"# - 1"!11$@%;
>1 !"$ ?@ "
,& ,.$9% ) #."# &< "# % = E " 1%$"%" +  1%&"%#&<
1#$ #$"," "% !, &" "E "F# +# B%$".D; ## +# &" +  % %#%
"% "#"1!$1 &" "=1$@%< 2- % "& 11$@% "% "1$@% 1%  "%
"#"1!$1 &" =  % "#$@% &"",$%&;  = ,"% &" = 2J,"& "#< 
%< ,"% E " " &" = # & #"1; % # +# &" +  "% # #"%#$@% #
E " 21"% =$#$."  =;  = 1,  "# % +# %#"%" " # +# &"
+  " &% % #"1 .%E "1$%  "!">   ?;
1 !"$ ">$"
# E " E " #" .$"%" 1 %&  ","  &" = "# # "$   E " "
1"#%&"   "#$@% E " #; $  %#!""%1$ &" 1 1%$%J &"# 9# E "
#" 2 "=& & " + <  ","  &" = #"+ $A  ,"%%&;  =
# & 1%&"%# A$&,"%" #." 1 E $" # "!$1$" E " "#9  ,"%
"," <  "# E " " 1, %$1 "% &" "=1$@% E " "#  "%"+ E "
# "% ,- 1$@%; %$,"%"< 1 %& " = #."1"%& 1"&"
% " &" # "%<  21" ,"&$%" % &$#,$% 1$@% &" "," ;  % %
2.A 1%&"%#1$@% 2# E " #" 1%1"  ","  &" # 1$@% - " ! > &"
"%"+ &"#&" " = #."1"%& "# ,"% E " " E " #"  "&" 1%? 1% =
# & #"1<  %E " " = #."1"%& "#A  ,- ","  B43D

*+, -.""#$# / 0
""12# #% &"  * 33
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

1 !"$ !
,.$9% ,& %" &" =< #" "!$"" E " +"%"&  % 2"=$& 
1&" E " $$? +  &" $,"%1$@% E ,$1,"%" &;  #" "1,$"%& # #
"% "#"$$?1$@%   "#"%1$ &" 1%,$%%"#;
1 !"$ &$"
# " = &" % E " 2 #&  =9# &" % !$ &" 1" $%:$&." &" 3K 
4K ,$1#  ",=" # 1 #I +"%","%" "#"% # ,$#,# .",#
=$## "% " = &" % "  ,"% "#1;
&1 !"$  !"
# E " E " =$"%" &" % +"%"& &" =< &" "!""%1$ &" 1" $%:$&."<
" +  &" $,"%1$@% "# +   $!$1&; #" = # ,"%" 1 ," 1% #
"E "$,$"%# &"   RR E " &"!$%" + %# $"&&"# E " &"."% "%" " =
- &" +  &" $+"% &" %  1=" "% " #"1 # &<   1$&& &" 1%&"%#&
&"." 1 ,$ # "E "$,$"%# &" +   $%-"11$@%; B4CDB57D
# $"&&"# !#$1# &" = $,$ "# 1, #"E "&&< #."1"%,$"% -
2,+"%"$&& =S$"< $%! -"% "% # $"&&"# &" "& 11$@% ,$1.$%;  =
 @#$# &" "#"$$?1$@% &"." #" #"1 - # &;  "#"%1$ &" # %$=""#
&" 2 ,"&& $+$%A 1%$&&"# ":1"#$=# &" 1%&"%#&; #<  # ="?<  "&"
=1 % "# &" ","  "% # A"# &%&" #" "#"%% # ":1"##I
&",A#< #" &$!1$ #"1  1+ &"# 9# &"  "#"$$?1$@%;  = #."1"%&
"$  2 ,"&& &" # .1"$# "#"%"#; $ # ,$1+%$#,# % #% 2$&&#
$&,"%" #" =="A% ,A# "#$#"%"#  1 - "E "$A% $",# &"
"#"$$?1$@% ,A# +#; B45DB57D
<6= *  3  -
 = "# +"%"& "% &$##$$=# ,& 1&"#  +"%"&"# &" =< E "
#% &$#"F&#  %#,$$ "%"+  +  &" $,"%1$@%<  ","  &" + 
 ,"% - 1 %& 1%? "  % &" # 1$@%I 2$"="<  +"%"#" " = E "&
1,$,$& - ">"1" % "#$@% "% &  E " " &"< $%1 $&  # "!$1$" &" +  <
  ,"%  "#$@% #."  # "!$1$" &" + <  ,"%  ","  &" + 
# &  "# E " # ,91 # %"1"#$% ,A# "%"+  .%&% 
# "!$1$";B43D
<= 
 3  -
% % 1, " = &">  1&"< ",$"?  1"&" " &" # "% 
1 E $" # "!$1$" 1% ,"% "," ;  21" "#< % " &" = 1%&"%#<
1%=$$9%&#" "% +    ,$#, "," ;  1"# "# ":1,"%" " $%="# &"
E " $"%"  + "%  1&" 1 %& " +  #" 1%=$"" "% =  F&$" 1;
 %& " = 1%&"%#< 1"&"  "% &" "=1$@% - " +  ,&
1%&"%#& &"." #" &"%&; B4KDB43DB57D
<8=   2  -
 = E " #" +"%" "%  1&" #" &"." %# ,"&$%"  ."#  #
 +"# &%&" #" "E $"" # #; T.A %  ,A#  ."# $%1$"#   ."# &"

34 *+, -.""#$# / 0
""12# #% &"  *
 1 * 

&$#$. 1$@%< &"#&"  1&" 2#  ?% 1%# ,$& &" =;  %&  =A=  &"
#$& &"  1&" #" ." B #  "#< "%,"%"D " = #" $%,"&$,"%"
21$   ." &" &$#$. 1$@%;  "# E " 9#< $%$1$,"%"< "#A !< " = "
%#,$$A 1;  %& % =A=  &" %  1%# ,$& &" = ."< "#"
= E " 1"&" &" #$#", &" &$#$. 1$@% "% "% " "E $ - = "="  %"#" "%
1%1 1% # "!$1$"# ,A# !#; "&" # "% &" "=1$@% - 1%&"%#; 
&" # ,$%$# #" &"." +"%" = 1%$% ,"%"; B44D
<A=  3  

 ,,"% "% E " " = "% "% " #$#", &"#&"  1&" - "%1 "% !#
# # "!$1$"# &" #  ."# &" &$#$. 1$@% - &" # "E $# #" "%! - 1%&"%#; 
&$!""%1$ &" ","  "%" " = - # "&"# ,"A$1# #"A% ,- "% "#"
"$& $%$1$ &" 1"%,$"% &"  E " #"A #"$,"%";  ,- ="1$&& &"
%#!""%1$ &" 1 $"%"  + 1 %&  &$!""%1$ &" "," # "# ,- - 
"# ?@% #" & 1" " ,A:$, &" 1%# , &" = & %" #  "## "% ,12; 
,"&$& E " " #$#", #" 1$"%  +&  &$#,$% 1$@% &" &$!""%1$# &" "," 
"= 1%#$+ % &$#,$% 1$@% "%  ="1$&& &" 1%&"%#1$@% &" =< 2# E " #"
1%? % = A1$1,"%" "#."; # &# ="# ":",# &" 1%$&& &"
1%&"%#& !,& #" 1%1"% +"%","%" 1, L1+ &" %E "M - L1+ &"
9+$,"%M; $ "%  " .> &" + % %" #" 1$1 % + >" &" &$A,"
&"1 &< & " 1%&"%#& E " #" !, #&A $.","%"  " ,$#,;  .",
"# E " " = ,.$9% "#1A 1%  1%#$+ $"%" "&$& &" "%"+ E "< "%
1 E $" 1#< "# $%"."; " =" 1,"%" E " "# %"1"#$ 1% 1% + E "
&"#1+ " 1%&"%#& #$% &"> "#1 =;
  "$,$%1$@% &" 1%&"%#& #" $$?% =A= # "&# ,% ,"%" -
=A= #  ,A$1#I  $," "# ,"%# "!$1?   "$,$%1$@% &" 1%&"%#& -
=1 9&$&# &" "%"+ $,%"#< #  ,A$1# #% 1? &" &""1 
&$!""%1$ "%" = - 1%&"%#& - "11$% "% 1%#"1 "%1$; % =A= 
 ,A$1 #" 1%1" 1% " %,." &" L ,  =M - # ! %1$@% "# &"#1+
1%&"%#& #$% ",$$ E " "#1" " = =$=; B44DB57D
/11/1 *  
 -
% &$##$$=# E " +"%"%  & 1"% = &" + ; # 1&"# 
+"%"&"# &" = #% &$#"F&#  %#,$$ " 1  =9# &" %#!,&
&" 1   # #%1$ &" .> B+ D; B44D
<= $$% :$   $(

U J," &" "$"

U 1
U F &" .$11$@%
U "#$@% &" .>
U "#$@% &"  ".
U 1$&& &" & 11$@% &" =

*+, -.""#$# / 0
""12# #% &"  * 35
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

U %# , &" + 
U "%1$
U  "!$1$" &" "!11$@%
U %# , &" %"+;

</= - 2
-  -
   
1 $!"(
, "# &" % 1$$%& &" 1" 2",9$1,"%" 1"& - 1 -# "","%#
$%1$"# #% '  "%= "< 1#<  .#< ! "< %$< .#"< #"< # "!$1$" &"
1"!11$@%< # "!$1$" &" =$?1$@%< 1%& 1# &" 2 ,< $< 12$,"%"#< ,"$
$#%"< !< #  1, "# - "!1$
>1 B $  : (
#1$ 1 &  " +  2# # %$=" &" .>< "%$"%& " = ,"% &"
$,"%1$@% &&<  # %$=""# ,%$, - ,A:$, &" "1$@%;
1 B $  )!"$(
#1$ 1 &  " =< E " +"%" "#$@% "% & " #$#",;
<5= 
  3  
 

1 -"$  "(
0 #1$%$#
0 @=$"#
>1 -"$  !$  $>C"(
0
"  "#$@% B,A# &" 47K #$D
0
" .> "#$@% B2# &" 47K #$D
1 -"$  $  &>$(
0
" 1" %:$&."
0
" T$" &
1 -"$  &"$ (
0 T$?%"#
0 )"$1"#
1 -"$  $&$  $:%(
0 91$1 B%1# &" "#$#"%1$D
0  +#
0  "@"  +#$%
0  1.@% ,$%"

36 *+, -.""#$# / 0
""12# #% &"  *
 1 * 

1/  

 )$&1$@% #" &"!$%" 1, " "#."1$,$"% &"  ".# &1 ,"%"# E " %
%  +& &" #"+ $&& &" E " % 1"# %$!$1& #" "!"1 A %$!,","%" "%
1%!,$&& 1% #  ".# "=$## "#"1$!$1&#; B4< 5< 6<7D
# "# &$# &" =$&1$%"# #% $1."#  #  ".# %$1#< # "E $#< #
#$#",# - #"=$1$# &" "#."1$,$"% B$"< + < =D - 1"## B, " &"
!.$11$@%< $,$"?< "#"$$?1$@%< "%& "#9$< $!$$?1$@%< "1;D;
 =$&"? &" # #$#",#< "E $#<  ".#  1"# #"  "&"% "#."1"
,"&$%" "# &$# #"1$=#< %1 "%"#  "#"1$=#; B36D
1  !$"!)(
" .# "% &# "1$&# &" 1%!,$&& 1% % 1 "=$,"%"
"#."1$&#; # , "#% "=$&"%1$# &1 ,"%&#  &",# E " % 1"#
1 ,$A 1% # @#$< .#&# "% $%!,1$@% ."%$& %"# &"  $,","%1$@%
&" ,$#,;
>1  "$$(
# " "#."1$,$"% &" "=$&"%1$ &1 ,"%&  &",# E " % 1"#
1 ," 1% # @#$< .#&# "% $%!,1$@% ."%$& & %"  $,","%1$@% &"
,$#,;
1  $$"!)(
#  "=$&"%1$ &1 ,"%&  &",# E " % 1"# 1 ," 1% #
@#$ .#& "%  "=$#$@% - %A$#$# &"  $%!,1$@% 2$#@$1 &" ,$#,I #"
","'  & 1# E " - #" "%1 "%% "% " ,"1& - 1 - 1"# &"
,% !1  #" 1%#$&" "#.";

"% &" "# &$ &"  =$&1$@%  1$!$11$@% "# % 2",$"% 1=" E " %#
="" $%!,1$@% %"1"#$  " "# &$;

/1/1   3

#  ">"1 1$@% &"  ".#< E " &"",$%% #$ " 1,%"%"< &" % 1"#I #"" #
$. # "E "$&#  ."%" % & 1 1% % 1$&& &"",$%&;
" 1$!$1 1% "#"1$!$11$%"# -S %,# %1$%"#  $%"%1$%"#; 
$!$11$@% %# #$="  ="" $%!,1$@% .A#$1 1"1 &" &$#"F< $%#1$@%<
"1$@%< ! %1$%,$"% - ,%"%$,$"% &" 1 E $" #$#",; &"% &" #  "%#
A1$1# &" % !1  "#" +, #"+  E " # 1"## ",%"1"% "% #
"#& &" =$&1$@%; B37D


   3(

*+, -.""#$# / 0
""12# #% &"  * 37
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

<= &  ;" <1 D1=

#  ="$!$11$@% &1 ,"%& &%&" #" &"!$%"% # "E "$,$"%#< #
"#"1$!$11$%"# - &"#1$1$%"# &" # "E $#; # % !#" ",$%"%","%" +%$?$=
B#." E 9 #" %"1"#$< E 9 #$.$$&&"# "#"% " ,"1&< E 9 "#1$%"# - 1@,
#$#!1"%  % # %"1"#$&&"# -< "% ! %1$@% &" ":,"% "=&  1.< E 9 &"."A
&#"D; %#$ $A % "=$&"%1$ &1 ,"%& &" E "  1$&& "# "%$& "% 1 "%
- 1%# $& &"#&" # &$#"F;
"." #" % !#" "=$   !#" &" 1, " $%#1$@%
&" "E $;
</= &   <1 D1( " D&"=
#  ="$!$11$@% &1 ,"%& &" E " &# # #"1# 1="# &"  $%#1$@%
"#A% &" 1 "& 1% # "1,"%&1$%"# &" !.$1%" - 1"#%&"%  #
"#"1$!$11$%"# .&# "% " &$#"F;
% 1$!$11$@% &" %#1$@% $%1 -" "%" #'

U ="$!$11$@% &" 1 ,$,$"% &" "#"1$!$11$%"# ;

U ="$!$11$@% &" # 1%&$1$%"# &" $%#1$@%;
U ="$!$11$@% &"  1"1 $%#1$@%;
U "#"1$!$11$%"# &" &$#"F &" "E $;
U "#"1$!$11$%"# &" "E $ "% %;
U 1"#$1# &"  #$#",# &" 1% - ,%$";
U
"# &"  &1 ,"%1$@% $%= 1&;
U
"#1$1$@% &" "E $ - # 11$&& &" .>;

<5= & "!$" <1D1( !$" D&"=

#  ="$!$11$@% &" E " # "E $# &" 1"# ! %1$%% "%  !, "#"& -
#% 11"# &" " #$#!1$,"%"%" #." & " %+ &" # A,"#
"1$%"#  # E " 2% #$& &$#"F&#; &# # 11"#$1# $,%"# &"
1% &" "E $ #" &"."% $%1 $ "% "# 1,.1$@%' ##< "#$%"#<
"," #< 1$1# &" $", - "+$#&"# &" &#;
&",A# &# # #"1# &" #"+ $&& ":$#"%"# &"."% 1%#"< $%1 -"%&
&$##$$=# &" "11$@% B " "#% - " "E $D #$#",# &" 1$""< $%&$1&"# -
,#;
("%","%" #" 21" "% 1%&$1$%"# #$, &#< $%1 -"%& # ,$"# ":",# 
%@,# E " #"  "&% "%1% "% % "1$@% %,; % "# 1$!$11$@%
$%"=$"%"% " "#% # $ B,"1A%$1#< "&"#< 91%$1#D;
<6= &   !;" <-1D( -$&"$  D&"=
E  #" &", "#  "!"1$=$&& - "& 1$.$$&& &" 1"#< .> &# $# &"
1%&$1$%"#'  $," #% # "1$%"# %,"# -  #"+ %&< .> ,$"# &"
"1$@%;
% ="? %#1 $& 1$" $", &" ! %1$%,$"%< "# %"1"#$ &",# E " "

38 *+, -.""#$# / 0
""12# #% &"  *
 1 * 

#$#", #" 2 ,%"%$& - 1$.& &" !, &"1 & 1% " !$% &" % "&" #
"#"1$!$11$%"# ! %1$%"#;

15 - 2 

  

% 1 "# % 1%> % &" $%# 11$%"#  "#1$ 1 - 1%1" "# ,- E " " &"
% 1"&$,$"% &" "1$@% "#%&$?& BD; # # #% # $%# 11$%"#
&"&#  "#1$  ">"1  1"&$,$"%# E " #" "!"1J% %,,"%" "% "
1 # &" 1 E $" &" # 1$=$&&"# "1$%&# 1%  !.$11$@% &" & 1#
!,19 $1#;  " 1%$< % 1 &"#1$." # &""# &" % "# &$ $%"+
%$!$1&  $%="#$+ " ! %1$%,$"% %$!," &" % % "= #$#",S"E $< %
% "= 1"&$,$"%   1".$$&& &" % % "= 1"# %"# &" ">"1 ; #
1# $%1 -"% %"1"&"%"# $,%"#< ":$1% " ! %&,"% @+$1 - " .>"$=
&" "# &$< !"1"% % &"#1$1$@% 1," &" # 1"&$,$"%# E " 2.A% &"
#"+ $#"< !$>% # A,"#  ,"&$#"< &"#1$."% 1@, #" %$?A% # "# &# -
!1$$% 1$"$# &" 1"1$@% &"",$%&# 1%  %"$$&&  ":" #
1%1 #$%"#;B36D

16 -

2 
  3
# % &1 ,"% E " F"  "#."1$,$"% "% # $&& - "% " E " #" &"#1$."
E 9 "E $#< #$#",#< ,9&# - 1"&$,$"%# 2.A% &" =$&#" - 1 A%&  #"A%;
% " &1 ,"% &"."A "#"1$!$1#"  !, &" "#"%1$@% %"1"#$  1&
&1 ,"% &" =$&1$@% B$!$11$@% &" %#1$@%< $!$11$@% &" "1$@%< -
$!$11$@%  %1$% "% " 1# &" "E $# - #$#",#D " $%&$1 E 9 $ &" $%!,1$@%
&"."A "!">#" "% 1& &1 ,"%;
 % ,"# &" =$&1$@% $%&$1A ,.$9%  E 9 - 1 A%& #" "!"1 A #
"=$&1$%"#< - #" &"# 9# &" 21" ,&$!$11$%"#  1,.$# "%  .$11$@% &"
"E $#  #$#",#< 1,.$# &" # 1"##  "E $# #&# "%  !.$11$@%< 
1,.$# "% # ,9&# &" =1$@%  "E $# $$?&# "% #  ".#; B36DB46D

1 2   7

% "# &$ &" =$&1$@% "# &$#"F&  A,"# &"!$%$&# - ,$&" "# &#
"#"1!$1#;  E $" ,&$!$11$@% 2"12  "E $#< #$#",#< 1"## 
1"&$,$"%#  "&"% 1,.$ # A,"#  !"1 # "# &# "=$##; 
1%#$+ $"%" & 1,.$ E " #" 2+ &"# 9# &" 2." "!"1 &  =$&1$@% $%$1$
&"." 1%#";
*+, -.""#$# / 0
""12# #% &"  * 3H
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

 1% &" # 1,.$# &"." #" % 1"# !, E " #" 1$F  % 1"&$,$"%
&"",$%& 1% %"$$&& "% % &1 ,"% &" +% &"  1$&&;
 1"&$,$"% &" 1% &" # 1,.$# $%1 $A  %$!$11$@% -  "#"%1$@%
&" %  "# &" 1,.$ "%  E " #" $%&$E "  > #$!$11$@% &" 9#" - #" 11 "% # #
""1 #$%"# #."  ! %1$@%<  "1$@% - " ! %1$%,$"%;   "# #"A
"&  " &","% E " #$1$" " 1,.$ - ":,$%& - .&  #
&","%# &" +% &" 1$&&< +""%1$ - # &","%# #"+J%
1"#%&; " $%&$1% # "!"1# &" 1,.$ #." " #$#",S1"# "#"1!$1
1"#%&$"%"< # 1, # 1%#"1 "%1$# ,A# ,$#  # #$#",# -
1"## &" "#."1$,$"%;

""%&$"%& &"  $,%1$ &" 1,.$  "&" #" %"1"#$  "=$&1$@% &"
#$#",S1"#  &" # #$#",#< % #" 2A% 1,.$# "% %$%+J% "E $< #$#",<
 ".  1"# .& - =$&& #$% %"# ."%" " ":,"% -  .1$@%
!$1$"# ,"&$%" " 1"&$"%& &" 1% &" # 1,.$#; B36DB47D

18  3 

2 *  
- -
#  &",#1$@% ":"$,"% &" E " #"  &" ."%" % = &" +& $,$
&"1 &  # 1"# &" "#"$$?1$@%  1 2J,"&< +%$?%& 
+"%"1$@% &" % = # & #"1 1 -# A,"# - #$#",# &" "1$@% #%
"#$ &# - "#"1$!$1&# 1 $&&#,"%" &"  ,%" E " &$12 1"# #"  "&"
1% ""$$=,"%"; B48DB38D
 =$&1$@% &" #$#", &" = $,$ "# % "E $#$ $%1$ "% % ,"##
":# !$1$"# 2- "% &' L &# # #$#",# &" - 1$1 "%  $%& #$
!,19 $1 &"."% #" =$&&#M #"+J%  ,1" $A%$1; B4HD

/181 - 2 

  3 

2 *  
- -
 1 &" =$&1$@% &" #$#", +"%"& &" = $,$ "# % &$#"F
":"$,"% &"& &" +, &" =$&1$@%; #" &1 ,"% "# # ,9&#
"1$##   ."%1$@% &" # &# %"1"#$#  " %A$#$# &" 1"#; 
1 &" =$&1$@% &" #$#", "%!1 $%1$,"%" ,%$" &" # A,"#
1$1# &" 1"# #1$&# 1% " 1"# &" +"%"1$@% &" =; % 1 &"
=$&1$@% &" #$#", +"%"& &" = $,$ &"." $%1 $' B48D B38D
3D% $%& 11$@%< &"!$%$"%& # .>"$=# &" "# &$ &" )$&1$%"#;
4D"#%#.$$&&"# &" "#% &" =$&1$@%;
5D&"%$!$11$@% -
"#1$1$@% &" # "E $# &" #$#", - # # &$##$$=# &"

3C *+, -.""#$# / 0
""12# #% &"  *
 1 * 

1%;
6D&"%$!$11$@% &"  &" # "E $# &" #$#",
7D
"#1$1$@% -S V#   1$.1$@% &" $%# ,"%#
8D$"$ &" 1"1$@% &" # A,"# &" 1"#;

/181/ - 7
   -  

2 *  
- -
 =$&1$@% &"." $%1 $  &1 ,"%1$@% &" # "E $# #&# -  &1 ,"%1$@% &"
1# -  ".# &" 1$!$11$@% # !$1$"%"#  &",#  =$&"? &" #$#",;
B48DB38D;
1  3   
2 3 

2
" "=J  #$+ $"%"'
0 12$= ,"# &" #$#", &" = $,$;
0 E $# - 1%":$%"#;
0 &"%$!$11$@% - 11"#$1#;
0 %$&&"# &" +"%"&
0 $# &" 1,%"%"# &" #$#",;
0 ","%# 1$1# &" #$#",; ;
0 ","%# &" "+ $&&;
/1  3  
-  


2
" "=J  #$+ $"%"'
0 )"$!$11$@% &" ! %1$%,$"% &" #$#", +"%"&;
0 )"$!$11$@% &" #$#", &" 1%;
0 )"$!$11$@% &" ,#;
0 )"$!$11$@% &" .,.#;
0 )"$!$11$@% &" ,;
51  3  
-E 

2
" "=J " "!$ &"  "? "% % "$& &" 5K &#< # A,"#  "= '
% !#$10E ,$1'
;
"",$%1$@% &" T
.;
"",$%1$@% &" 1%& 1$=$&&
1;
"",$%1$@% &" #@$&# "#
&;
"",$%1$@% &" # #%1$# :$&."#
% ,$1.$@+$1'

*+, -.""#$# / 0
""12# #% &"  * 3G
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

;
"",$%1$@% &" "%&:$%#
.;
"",$%1$@% &" 1+ .1"$%

/1815 2 
  -2 3 

2
&",A# &" 1 ,$ 1% &# # ="$!$11$%"# - # #$#!1$,"%" &# #
 ".# "E "$&#I &# # , "## "1+$&# &" 1%&"%#& &"."% 1 ,$ #
"#"1$!$11$%"# E ,$1# &"  !,1" - # %,#  " +   $!$1& B4CD
B5KD'

$! %F" ""$"G ""$" 

%!"
 # "+$=
 !# "+$=
,%1 A:;' K;4 ,
1$ - +%"#$ "+$=
$ A:; ' K;4 ,
""# "#&# A:; ' K;4 ,
 #%1$# :$&."# "+$=
@$&# "# A:; ' K;KK3W B3,+D
%& 1$=$&& A:; ' 6 #
%2&$& .@%$1 "+$=
T 7;K 0 H;K

4K *+, -.""#$# / 0
""12# #% &"  *
 1 - 2 9- 2

1 - 2 9- 2

1 2 

# ,"$"# - "E $# E " #" ","% "%  =$&1$@% #%'

U ("%"& &" )' X Y    ;;

U "%1$@," ' "2, &" 8G3
U %& 1$," ' "" &" Z Z 55K
U  1="  #"$$?& &" ) ' %12"%S #"$" )4KK40
U "1$$"%"# A#$1#  , &" , "# &" 1%&"%#& &" =  " 1%
#$10 ,$1
U "1$$"%" &" 1" $%:$&."  " , "#" &" 1%&"%#& &" )  "
1% $1.$@+$1;
U
"#$+"%$?&
U ." &" " &"  ,$%$
U .# &" "%#- &" =$&$ 4K : 7K ,, B&"#$+"%&#D
U .# &" =$&$   "11$@%  &" 3K : H7 ,, B&"#$+"%&#D

*+, -.""#$# / 0
""12# #% &"  * 43
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

U $"# &" =$&$ 3KI 7I 4 - 3 ,

U $1$" &" 4K - 4KK 
U !$,
U )$"# &" 1% "#A%& &" "%&:$%#
U )$"# &" -"
U +$& &"  .#

1/ - 2 

  3

51/11 -$""""  &      :$"$

 )!"$  !"1
%#  "% !, $,"#

51/1/ -$""""  &  "!$"    :$"$

 )!"$  !"1
%#  "% !, $,"#

51/15 -$""""  &   !;"    :$"$

 )!"$  !"1
1 - -3
2(
 @#$ &" "#" "# 1$!$11$@% "# 1,.  1$&& &" = & 1$& 
" #$#", +"%"& &" = "% # # A,"# !#$10E ,$1# - ,$1.$@+$1#
& %" 5K &# 1%#"1 $= &" # &" +"%"& &" =;
/1 - 7
  2
(
  1,.1$@% &"  1$&& &" = & 1$& #" "$?A  &"",$%1$@%
&" "!$ &"  "?;
 $",  & 1$@% &"   ".' " "$?A "% % "$& &" 5K &#;
A,"#  "= #"'
"$" &%",F% "(
;
"",$%1$@% &" T
.;
"",$%1$@% &" 1%& 1$=$&&
1;
"",$%1$@% &" #@$&# "#

44 *+, -.""#$# / 0
""12# #% &"  *
 1 - 2 9- 2

&;
"",$%1$@% &" # #%1$# :$&."#
"$" $">":"(
;
"",$%1$@% &" "%&:$%#
.;
"",$%1$@% &" 1+ .1"$%
4;3;%  % $,%"   &"",$%1$@% &" "!$ &"  "? 1"#%&"  
, &" , "# &" = 1%&"%#& "% "  % &" #;
% "#" 1# "  % &" # 1"#%&"  $%+"# &" = "%  1A, &"
"#"$$?1$@% &"   1=" %12"%;
D 2
 
2   
  - -  
2  +
 ,D+ (
  , &" , "# #" &"."A% "%" # #$+ $"%"# 1%#$&"1$%"#'
; # "1$$"%"#   , &" , "# &"."% #" &" ,"$ A#$1;
.; # "1$$"%"# &"."A% "# $,$# - #"1#;
1;  , &" , "# &" #" #$." &"."A "!"1 #"  $,"# 2# &" 
,F% % ="? "%1"%&$& " +"%"& &" = - 2."#" "$?& #  +#
"#"1$=# "% "  1=";
&;  = +"%"& &"."A #" 1% +  &" #,#$# & 1$& "% " &;
";  1%$&& &" , "# &" 1%&"%#& &" =  , &"."A #" &"
:$,&,"%" 4KK ,;
!; % ="? ,&  , "# "#A &"."A #"  & 1%  $&"%$!$11$@%
1"#%&$"%" - "%=$&  .$ &" 1% &" 1$&& $%&$1%& # "%#-# 
"$?#";
+;  &"",$%1$@% &"  1%& 1$=$&& &"."A "$?#" $%,"&$,"%" ,& 
, "#; " &A "# $%&$11$@%  ,,"% &" "%"+  , "#  .$ &"
1% &" 1$&&;
2;
"# 9# &" "!"1 & " %A$#$# E ,$1 #" +"%"A % "" E " #"=$A 
 "= 1$@% 1"#%&$"%";
D 2
 
2   
  - -  
2   73* 
  , &" , "# #" &"."A% "%" # #$+ $"%"# 1%#$&"1$%"#'
; # "1$$"%"#   , &" , "# &"."% #" &" 1" $%:$&.";
.; ## "1$$"%"# &"."A% #" &"#$+"%$?&# "=$,"%" B&> % 2> &"
$,$"? - 1 &" 1% &" 1"# &" &"#$+"%$?1$@%D;
1;  , &" , "# &" #" #$." &"."A "!"1 #"  $,"# 2# &" 
,F% % ="? "%1"%&$& " +"%"& &" = - 2."#" "$?& #  +#
"#"1$=# "% "  1=";
&;  = +"%"& &"."A #" 1% +  &" #,#$# & 1$& "% " &;

*+, -.""#$# / 0
""12# #% &"  * 45
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

";  1%$&& &" , "# &" 1%&"%#& &" = 2 , &"."A #" &"
:$,&,"%" 5KK ,;
!; % ="? ,&  , "# "# &"."A #" "+$& 1 .$9%& 1% " 1."
&" " &"  ,$%$ ","& "% " 1"# &" &"#$+"%$?1$@% &" "%=#"<  
1%  $&"%$!$11$@% 1"#%&$"%" - "%=$  .$ &" 1% $1.$@+$1
$%&$1%& " "%#-  "$?#";
+;
"# 9# &" "!"1 & " %A$#$# $1.$@+$1 #" +"%"A % "" E "
#"=$A   "= 1$@% 1"#%&$"%";
51 
-
7(
; X"!" &" =$&1$%"#< "#%#." &" ". " 1 &" 1$!$11$@% &"
&"#","F;
.; X"!" &" A" &" $%-"1."# E $&#< "#%#." &"  , &" , "#<
$&"%$!$11$@% - "%=$@ &" "##  .$ !#$10E ,$1 - ,$1.$@+$1  #
%A$#$# 1"#%&$"%";
&",A# &"."A "= " 1% &" # ""# -S "# &# +"%"&# 
"$?  "= 1$@% 1"#%&$"%";

" "#"%#" "# & ! " &" "#"1$!$11$%"# &"."A $%,"&$,"%"
1&$% 1% " >"!" &" ,%"%$,$"%< =$&1$%"#< 1% &" 1$&&  " %A$#$#
&" # 1 ## &" "# $%1%!,$&&< , # 11$%"# 1"1$=# " $%&$1 " % "=
, "#";
1; X"!" &" 1% !#$10E ,$1< "#%#." &" " %A$#$# &" # , "## &"
1%&"%#& &" = "%=$&#  .$ &" 1% !#$10E ,$1< &",A# &" 
".1$@% &" # ""# "#"1$=#;
&; X"!" &" 1% ,$1.$@+$1 "#%#." &" %A$#$# &" # , "## &"
1%&"%#& &" = "%=$&#  .$ ,$1.$@+$1< &",A# &"  ".1$@%
&" # ""# "#"1$=#;
"; X"!" &" ,%"%$,$"%S"&' "#%#." &" ! %1$%,$"% -S "1$@%
&" +"%"& &" =;
"."A $%!, #." 1 E $" 1,.$  "="% $&&
& 1$& & %" " 1"# &" "1$@% &" +"%"& &" = E "  "& $%=$& 
, &" , "# &" 1%&"%#& &" =;
61 
-   
<
- 99=(

"$" &%",F% "

!H 7;K [ H;K B 47N  PS0 4N  D
") 3 ,A:$, 3;6 S1,
4 ,A:$, 4;3 S1,;

" " A:$, 3,+S3KK ,

 "I> "+$=

46 *+, -.""#$# / 0
""12# #% &"  *
 1 - 2 9- 2

"$" $">":"
""I "%  K;47 ;";S ,
$: >$  #"%1$

1 
2
(

 2 
 !H  * 
  -

 2 
  2  * 
  -

 2 
3
22
 * 
  -

*+, -.""#$# / 0
""12# #% &"  * 47
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

81  3  
2
(
  "= 1$@% &" "# &# #" 2 1%#$&"&'
1; "# &#  & &$$ &" +"%"& &" =
&; "# &#  &#  !$% &" #",% B6C 2#D;
A1  

(
# , "#"# &" +  &" 1%&"%#& &" = 2% #$& "$?&# & %" 5K
&# .."#I "% "## %A$#$# #" 2% 1%#$&"& # &# &$$# &" +"%"&
&" = - # &# 1"#%&$"%"#  !$% &" #",%B6C 2#D<  =" #
$,$1%1$# &" "# & #."  1$&& &" = +"%"&;
% 1%1 #$@%'

 

2
 
J

+
 ,D+  
 7* 
 
  - G  
D 
- -   -  *   - -  
-2 - 


1
2   H <-2  
  - -=

48 *+, -.""#$# / 0
""12# #% &"  *
*+, -.""#$# / 0
""12# #% &"  * 4H
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

4C *+, -.""#$# / 0
""12# #% &"  *
 1 



1 



 "# &$ 1,"%?@ 1%  ="$!$11$@% &" # $%1$"# #"=$1$# %"1"#$#  "
. "% ! %1$%,$"% &" +"%"& &" = $,$< &# "# ! "% ="$!$1&# "% #
1%!,$&&; % "  # ="$!$11$%"#< #" "$?%  1$.1$@% &" #
$%# ,"%# &" 1%< "%1%A%&#" E " &# "# "#"%.% =$1$%"# &"%
&" %+ &" 1"1$@%;
 1$!$11$@% &" $%#1$@% &" +"%"& &" = 1%#$#$@ "%  "=$#$@% &" &#
# "","%# 1$1#  " 1"1 ! %1$%,$"% &" "E $ 1, #%  1A, &"
+"%"1$@% &" =< " #$#", &" #$& &" =< " 1% &" %$=" &" + < " 1%
&" "#$@%< " #$#", &" #"+ $&&< "%1%%& E " &# # ="$!$11$%"# "$?&#
! "% 1%!,"#;
 1$!$11$@% &" "1$@% &" #$#", +"%"& &" = $,$ #" ="$!$1@ 1% 
#"1 "%1$ &" "%"+$?&< #"1 "%1$ &" "%1"%&$&< #"1 "%1$ &" +& - #"1 "%1$
&" %#" &" = $,$ -  #"1 "%1$ &" #"+ $&&I ! %1$%%&
1%#$#"%","%" - 1 ,$"%& # "#"1$!$11$%"# &" "1$@% 1$%&#  "
!.$1%";
 1$!$11$@% &" &"#","F #" .@ " "E $  &"",$% #$ "!"1$=,"%"
1 ,"  ! %1$@% "#."1$& &" +"%" % =     # 1"## &"
"#"$$?1$@%  1 2J,"&< #" "$?@ " "!$ &"  "?  1%&"%#& &" =
& %" 5K &#; &# # 1%"# !#$10E ,$1# #$"% 1%!," "%1%%& %
&"#=$1$@% "#A%& 1% "#"1  ,"&$ $, $%"% &" K;5 "% " T< K;4  #
#@$&# "#<  1%& 1$=$&& ,A#  "%1%& 3;4 S1, &""1& "% % &

*+, -.""#$# / 0
""12# #% &"  * 4G
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

&" &# &#; # 1%"# ,$1.$@+$1# &" "# &$  &$=$&$,# "% 1+ .1"$%
&" 1%&"%#& &" =< 21$"%& "1 "% &" ".$# =$."# "%1%A%&#" & %"
& " "# &$ ="# ] &" 3 !1S3KK , !"%"  % $,$" &" 3K !1S3KK , E " $%&$1 
 RR< #" "%1%@  #"%1$ &" ; $< $!,"# "#< ,%" -
" &,%# - !$%,"%"   ". &" "%&:$%# "%1%A%&#" ="# ]  K;47
"S, 1%!," #"+J%  RR;

5K *+, -.""#$# / 0
""12# #% &"  *
  


 


3;
& # "# &# ."%$&# "% &# #  ".# "$?&#  # "","%# 1$1#
&" +"%"& &" = $,$ "%  1$!$11$@% &" $%#1$@%< " +"%"& &" =
$,$ "# "% 1%!,$&& 1% # "#"1$!$11$%"# &" !.$1%" - # "E "$,$"%#
$%"%# &" .$;
4;
" 1 "&  # "# &# ."%$&#< "% 9## 5K &#< &",# .#"= E "
% #" & 1" ="# ! " &" # ,$"# &" "#."1$&# #"+J%  RR  "
1%&"%#& &" = & 1$&  " +"%"& &" =;
5; # &# &$$# &" +"%"& &" = # 1, # 1"#%&$"%"#  % !$%
&" #",% % !"1%  1$&& &" = +"%"& 1%!," #" "1$ "% #
"# &# 1"#%&$"%"#  # &#  %"#;
6; " "#."1" &" 1 "&  # "E "$,$"%# &" = "% "  % &" #< E " 
"#$@% &" #$& "% " +"%"& - "#$@% &" "+&    1=" &"."% #" &" 7K -
6K #$ "#"1$=,"%";

*+, -.""#$# / 0
""12# #% &"  * 53
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

54 *+, -.""#$# / 0
""12# #% &"  *
   

  

3; "= % "+$# &" ! %1$%,$"% &" "E $ +"%"& &" =< &"  "#$@% &"
=< &" 1%# , &" "%"+ "91$1< E " #% + # J$"#  &"",$% "
&"#","F &" "E $ " $%&$1% 1% $&"? 1 E $" &$!$1 & E "  "&
&"##";
4; %$%  1%  =$&1$@% &" # #$#",#  1"## E " &$"1 
$%&$"1,"%" $%! -"% "% # %$&&"# & 1$=#;
5;  "%1% + %# ="# "% # ,$"# &" "#"1$!$11$@%< #" 1%#"> %
,%"%$,$"% "="%$= $,"# &" #$#",;
6;  , &" , "# &" 1%&"%#& &" = #" &"." 21" &$$,"%"  
,$#, 2 -  % "$ 1$!$1& "% "#" 1"&$,$"%;

*+, -.""#$# / 0
""12# #% &"  * 55
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

56 *+, -.""#$# / 0
""12# #% &"  *
 77* +

77* +

Murria S. Couper. Quality Control in the pharmaceutical industry. London: Ed. Academic
Press. 1979. Pág. 2-7.
Ylla-Catalá M. La validación un reto actual. Normas para la práctica de una correcta
validación. Ciencia e Industria Farmacéutica. 1983; 2 (1):25-28.
Chemtad C. Principes Généraux de la Validation des Procédés de Validation. STP
Pharma Pratiques 1995 ; 1 (6) : 641-646.
Neal C. Back to the Basics. A Philosophical Overview. Journal of Validation Technology
1997; 3 (3): 281-283.
Chapman K. Worldwide Opportunities though Validation. STP Pharma Pratiques 1992;
2 (5): 415-422.
Gennaro J. Tecnología Farmacéutica. Seminario del Programa Superior de Formación
Farmacéutica. Formación Continuada. Les Heures. Universidad de Barcelona. Marzo
1997. Ponentes: Amelia J., Bas E., Ylla M., Gennaro J.
Salazar R. Introducción al Estudio de la Validación: Concepto y Generalidades.
Validación Industrial. Barcelona: Romargraf; 1999. Pág. 10-18.
Hardman J., Giman P. Investigación y Producción de una Molécula. Madrid: Parmason
S.A.; 1996. Pág. 123-125.
Burghardt M.D. Ingeniería Termodinámica. México: Harla; 1984. Pág. 1-71.
Spilker Z. Industria Farmacéutica y Libre Mercado. Colombia: Grupo Editorial Norma;

*+, -.""#$# / 0
""12# #% &"  * 57
      !"#" $%"   $ &$ '( )!"$ !$ "
&$ '"

1994. Pág. 32-35, 92-96.

Iturralde J.P. Normas Correcta de Fabricación de Medicamentos y Normas de Buenas
Prácticas de Laboratorios. En Faulí C. Tratado de Farmacia Gálenica. Madrid: Ed.
Luzán; 1993. Pág. 105-113.
Baudrand B. Generadores de Vapor Industrial. Madrid: Luzán; 1990. Pág. 5-72.
Remington’s Pharmaceutical Sciences. Sterilization. London: Eighteenth Edition; 1990.
Pág. 1470.
Guía de la OMS sobre Requisitos de las Prácticas Adecuadas de Fabricación (PAF);
Segunda Parte: Validación. Organización Mundial de la Salud. Ginebra 1998.
Palomino E. Calificaciones en la Industria Farmacéutica. Seminario: Validaciones.
Corporación Drokasa. Farmindustria. Lima, Abril 2004. Pág. 1-5.
---------- Validación de Sistemas de Apoyo Crítico y Calificaciones de los Sistemas de
Control Ambiental en Plantas Farmacéuticas. Seminario del Centro de Trabajo e
Investigación en Salud (CETIS). Lima, Abril 2001. Ponentes: Nuñez C., Palomino E.
Olivera J.J. Agua con Fines Farmacéuticos. En: Farmacotecnia Teoría y Práctica.
Joseph Hellman Tomo IV. México: Compañía Editorial Continental S.A.; 1981. Pág.
1363-1377.
Zaebst D. Industria Farmacéutica: Calidad y Validación. Madrid: Continental S.A. 2001.
Pág. 20-22.
Neal C., Rudolph J.S. Sistemas de Ventilación. En: Real Farmacopea Española I Tomo.
Madrid: Primera Edición; 1997. Pág. 303-307, 310-320.
Morris J.M. Principios Básicos de la Ingeniería del Vapor. Lima: Minerva S.A.; 2003.
Pág. 1-92.
Ramírez P. Producción de Vapor. Servicio Nacional de Adiestramiento en Trabajo
Industrial (SENATI). Lima. Marzo 2000. Pág. 1-72.
Da Silva F. Mantenimiento y Reparación de Calderas y Red de Distribución de Vapor.
Técnico de Nivel Operativo. Servicio Nacional de Adiestramiento en Trabajo
Industrial (SENATI). Lima. Marzo 2001. Pág. 1-125.
Palacios M.M. Validación de un Ciclo de Esterilización de Ampollas en Autoclave
Empleando la Ecuación de Arrhenius para la Determinación de la Letalidad. Tesis
para Optar al Título Profesional de Químico Farmacéutico. Lima: Universidad
Nacional Mayor de San Marcos; 2001. Pág. 17-22.
Cameli J. La Validación: Una Filosofía y un Sistema. Seminario: Validación. VI
Jornadas Nacionales de AEFI. Pamplona, Mayo 1995.
Bolton S. Pharmaceutical Statistics. New York: Marcel Decker; 1997.Pág. 490-514.
Caro C.F. Protocolos de Validación de Procesos Estériles (I). Centro de Estudios
Superior de Industria Farmacéutica. Madrid: Comercia; 1996. Pág. 102-120.
The British Pharmacopoeias Commission. British Pharmacopoeia 1999. Vol. II.
Appendices XVIII. 1999. London Inglaterra.
The United States Pharmacopeias Convention. The United States Pharmacopoeia and
the National Formulary 2000. USP XXIII NF 19. Maryland: USP Convection. Inc.
Edition 20º; 2000. Pág. 1326-1328.

58 *+, -.""#$# / 0
""12# #% &"  *
 77* +

Cameli J. La Validación, una Contribución a la Mejora de la Calidad en la Industria.

Seminario: Validaciones. VI Jornadas Nacionales de AEFI. Pamplona, Mayo 1995.
---------- Validación de Proceso y Análisis de Medicamentos. En: Faulí Trillo C. Tratado
de Farmacia Galénica. Madrid: Ed. Luzán; 1993. Pág. 115-123.
Gibson W., Powell-Evans K. Sterilization with Steam. Illinois: Editorial Interpharm Press,
Inc. 1ra. Edition; 1998. Pág. 13-19.
García A. Esterilización en Autoclaves con Vapor. Rev. Industria Farmacéutica
Julio/Agosto. Madrid 1992. Pág. 81-88.
Wallhausser K. La Validación del Procedimiento de Esterilización por Calor en la
Industria Farmacéutica. London: Ed. Hoechst; 1989. Pág. 13-16.
Correa Y.E.; Arrieta S.B. Validación del Proceso de Fabricación de Cápsulas de
Dicloxacilina 500mg. Tesis para optar al Título Profesional de Químico Farmacéutico.
Lima: Universidad Nacional Mayor de San Marco; 2000. Pág. 12-15.
Latham T. Clean Steam Systems. Pharmaceutical Engineering. Journal of ISPE. 1995;
15(3): 20-35.
Berry I. Sterilization with Steam. Suecia: Getinge; 2000. Pág. 1-12.

*+, -.""#$# / 0
""12# #% &"  * 5H