READING  SUPPLEMENT  
 
 
 
CONTROLS  
 
I.      MATERIAL  CONTROL  
 
There   should   be   written   procedures   describing   the   receipt,   identification,   quarantine,   storage,   handling,   sampling,  
testing,  and  approval  or  rejection  of  materials.    
 
RAW  MATERIALS  
 
Raw  materials   are   the   ingredients   intended   for   use   in   the   manufacture   of   drugs   and   cosmetics,   including   those   that  
may  not  appear  in  the  final  product.  
 
Reception  
Upon   receipt   and   before   acceptance,   each   container   or   grouping   of   containers   of   materials   should   be   examined  
visually  for  correct  labeling  (including  correlation  between  the  name  used  by  the  supplier  and  the  in-­‐house  name,  if  
these  are  different),  container  damage,  broken  seals  and  evidence  of  tampering  or  contamination.    
 
Each  container  or  grouping  of  containers  (batches)  of  materials  should  be  assigned  and  identified  with  a  distinctive  
code,   batch,   or   receipt   number.   A   receiving   number   should   have   distinguishing   characteristics   which   will   prevent  
possible  confusion  with  any  number  previously  placed  on  the  container  by  the  supplier.  This  number  should  be  used  
in  recording  the  disposition  of  each  batch.  A  system  should  be  in  place  to  identify  the  status  of  each  batch.    
 
A   receiving   tally   report   (reception   of   materials   report,   incoming   cargo   report,   receiving   report   or   receiving   ticket)  
should  be  prepared  for  every  shipment  by  the  warehouse  personnel,  who  is  also  responsible  for  assigning  a  receiving  
number   to   the   material   (see   Figure   1).   If   the   shipment   consists   of   more   than   one   manufacturing   lot   number,   a  
separate   receiving   number   is   assigned   to   each   lot.  The   receiving   tally   report   (RTR)   is   checked   by   the   QC   inspector   for  
accuracy.   It   should   be   distributed   to   all   groups   concerned   with   the   purchase,   inventory,   use,   and   control   of   the  
materials.   Thus   a   copy   of   the   RTR   is   given   to   quality   control,   warehouse,   purchasing,   and   accounting   departments.  
Manufacturing  firms  may  have  different  entries,  but  the  basic  information  is  quite  similar.  
 
Quarantine  
Materials   should   be   held   under   quarantine   until   they   have   been   sampled,   examined   or   tested   as   appropriate,   and  
released  for  use.  A  quarantine  sticker*  is  pasted  on  the  container  of  the  material  attached  by  the  receiving  warehouse  
personnel  to  indicate  that  a  decision  to  accept  or  reject  is  yet  to  be  made  by  quality  control.    
 
Sampling   methods   should   specify   the   number   of   containers   to   be   sampled,   which   part   of   the   container   to   sample,   and  
the   amount   of   material   to   be   taken   from   each   container.   The   number   of   containers   to   sample   and   the   sample   size  
should   be   based   upon   a   sampling   plan   that   takes   into   consideration   the   criticality   of   the   material,   material   variability,  
past  quality  history  of  the  supplier,  and  the  quantity  needed  for  analysis.    Sampling  should  be  conducted  at  defined  
locations  and  by  procedures  designed  to  prevent  contamination  of  the  material  sampled  and  contamination  of  other  
materials.   Containers   from   which   samples   are   withdrawn   should   be   opened   carefully   and   subsequently   reclosed.  
They  should  be  marked  to  indicate  that  a  sample  has  been  taken.    
 
If   the   test   results   indicate   that   the   raw   material   meets   monograph   specifications,   the   material   is   approved   for   use;  
otherwise,  it  is  rejected.  Decision  stickers  are  then  issued  by  quality  control.  
 

                                                                                                               
*  To  distinguish  the  sticker,  different  color  codes  may  be  assigned  such  as  yellow  for  quarantine,  green  for  approved  and  red  for  

rejected.    A  sticker  may  have  any  other  color  but  it  would  be  wise  to  use  a  color  easily  associated  with  what  it  means.  
  1  
/rpramos2014      
The   decision   stickers   are   either   placed   on   top   of   the   quarantine   sticker   or   the   quarantine   sticker   is   first   removed  
before   the   decision   sticker   is   pasted.   No   two   stickers   of   different   dispositions   must   be   present   on   the   same   container.  
At  this  stage,  the  raw  material  is  transferred  to  either  the  rejected  or  approved  materials  area.  
 
 
 

 
 
Figure  1.  A  typical  receiving  tally  report  
 
 
Rejected  
Rejected   materials   should   be   identified   and   controlled   under   a   quarantine   system   designed   to   prevent   their  
unauthorized  use  in  manufacturing.    A  rejection  sticker  is  pasted  on  the  container.      
 
Approved  
Materials  should  be  handled  and  stored  in  a  manner  to  prevent  degradation,  contamination,  and  cross-­‐contamination.  
Materials  stored  in  fiber  drums,  bags,  or  boxes  should  be  stored  off  the  floor  and,  when  appropriate,  suitably  spaced  
to   permit   cleaning   and   inspection.   Materials   should   be   stored   under   conditions   and   for   a   period   that   have   no   adverse  
affect  on  their  quality,  and  should  normally  be  controlled  so  that  the  oldest  stock  is  used  first.  An  approval   sticker  is  
pasted  on  the  container.  
 
 
 
  2  
/rpramos2014      
Re-­‐evaluation  
Materials   should   be   re-­‐evaluated   as   appropriate   to   determine   their   suitability   for   use   (e.g.,   after   prolonged   storage   or  
exposure  to  heat  or  humidity).  
 
Periodic   testing   is   done   to   re-­‐evaluate   the   material.   Reassay   date   is   given   in   terms   of   month   and   year,   determined  
from  the  last  assay  date.  Based  on  the  stability  of  raw  materials,  the  reassay  dates  can  be  monthly  or  prior  to  use  for  
highly  unstable  materials,  six  (6)  months  for  vitamins  and  flavors,  twelve  (12)  months  for  active  ingredients  and  dyes,  
and  twenty  four  (24)  months  for  active  ingredients  and  excipients.  
 
 
PACKAGING  MATERIALS  
 
Packaging   and   labeling   materials   should   conform   to   established   specifications.   Those   that   do   not   comply   with   such  
specifications  should  be  rejected  to  prevent  their  use  in  operations  for  which  they  are  unsuitable.    
 
Containers  should  provide  adequate  protection  against  deterioration  or  contamination  of  the  intermediate  or  active  
pharmaceutical   ingredient   (API)   that   may   occur   during   transportation   and   recommended   storage.   Physical   and  
chemical   evaluation   of   containers   like   those   made   of   glass,   plastic,   and   metal   have   been   extensive.   Physical  
inspections   generally   include   (1)   Light   Transmission   Test,   (2)   Torque   Test,   (3)   Leak   Test,   and   (4)   Water   Vapor  
Transmission  Test.  The  physico-­‐chemical  tests  include  (1)  Chemical  Resistance,  (2)  Moisture  Permeation,  (3)  Thermal  
Analysis,   (4)   Nonvolatile   Residue,   (5)   Residue   on   Ignition,   (6)   Heavy   Metals,   and   (7)   Buffering   Capacity.   Biological  
Tests  include  (1)  Biological  Reactivity  Tests,  In  Vitro,  and  (2)  Biological  Reactivity  Tests,  In  Vivo.  
 
Light  Transmission  Test  
A  container  intended  to  provide  protection  from  light  or  offered  as  a  light-­‐resistant  container  meets  the  requirements  
for   Light  Transmission,   where   such   protection   or   resistance   is   by   virtue   of   the   specific   properties   of   the   material   of  
which  the  container  is  composed,  including  any  coating  applied  thereto.  
 
Select  sections  to  represent  the  average  wall  thickness  of  either  transparent  or  translucent  glass  or  plastic  material  
used   for   pharmaceutical   containers.   Measure   the   transmittance   using   a   spectrophotometer   of   suitable   sensitivity   and  
accuracy,  adapted  for  measuring  the  amount  of  light  transmitted  in  the  region  of  290  to  450  nm.  
 
Limits   -­‐     The   observed   light   transmission   does   not   exceed   the   limits   given   in   Table   1   for   containers   intended   for  
parenteral  use.  
 
Table  1.  Limits  for  Plastic  Classes  I-­‐VI  and  Glass  Types  I,  II,  and  III  
  Maximum  Percentage  of  Light  Transmission  at  
Any  Wavelength  between  290  and  450  nm  
Nominal   Flame-­‐sealed   Closure-­‐Sealed  
Size  (in  mL)   Containers   Containers  
1   50   25  
2   45   20  
5   40   15  
10   35   13  
20   30   12  
50   15   10  
      [Note  –  Any  container  of  a  size  intermediate  to  those  listed  above  exhibits  a    
transmission  not  greater  than  that  of  the  next  larger  size  container  listed  in  the  table.    
For  containers  larger  than  50  mL,  the  limits  for  50  mL  apply.]  
 
The  observed  light  transmission  for  plastic  containers  for  products  intended  for  oral  or  topical  administration  does  
not  exceed  10%  at  any  wavelength  in  the  range  from  290  to  450  nm.  
 
Torque  Test  (Standard  Test  Method  for  Application  and  Removal  Torque  of  Threaded  or  Lug-­‐Style  Closures)  
This   test   method   covers   the   application   with   a   given   torque   of   a   threaded   or   lug-­‐style   closure   to   a   container,   and  
measures   the   torque   required   to   unscrew   the   closure   from   a   container.   The   values   stated   in   SI   units   are   to   be  
regarded   as   the   standard.   The   inch-­‐pound   units   given   in   parentheses   are   for   information   only.   These   torque  
  3  
/rpramos2014      
measurements  are  of  value  in  rating  the  performance  of  automatic  capping  machines;  in  measuring  any  tendency  for  
threaded   or   lug-­‐style   closures   to   loosen   during   storage   or   shipment   of   the   package;   and   in   measuring   the   force  
required  to  break  hard  plastic  and  overturn  or  “strip”  soft  plastic  and  metal  closures.  
 
Leak  test  
Methods:  
1. Dye  bath  –  containers  are  subjected  to  vacuum  or  pressure  while  immersed  in  bath  
2. Liquid  loss  –  involves  pulling  a  vacuum,  but  without  the  dye,  resulting  in  a  loss  of  liquid  
3. High   voltage   detection   –   involves   very   costly   electronic   equipment,   which   applies   a   high   voltage   across   the  
length  of  the  ampule    
 
Chemical  Resistance  
These  tests  are  designed  to  determine  the  resistance  to  water  attack  of  new  (not  previously  used)  glass  containers.  
The  degree  of  attack  is  determined  by  the  amount  of  alkali  released  from  the  glass  under  the  influence  of  the  attacking  
medium  under  the  conditions  specified.  
 
Glass   Types   -­‐    Glass  containers  for  pharmaceutical  use  are  intended  to  come  in  direct  contact  with  pharmaceutical  
preparations.   Glass   used   for   pharmaceutical   containers   is   either   a   borosilicate   (neutral)   glass   or   a   soda-­‐lime   glass.  
Table  2  shows  of  the  classification  of  these  containers  based  on  this  test  and  the  summary  of  its  characteristics.  
 
 
Table  2.  Glass  Types  
Type   General  Description   Composition   Hydrolytic   Type  of  Preparation   Type  of  
Resistance   for  Use   Test  
I   Highly  resistant,   Boric   oxide,   aluminum   High   parenterals   Powdered  
borosilicate  glass   oxide,   and   alkali   and/or   Glass  
alkaline  earth  oxides  
II   Treated  soda-­‐lime  glass   Soda-­‐lime   glass   that   is   High   acidic  and  neutral   Water  
suitably   dealkalized   parenterals;  alkaline   attack  
(inner  surface)   preparations  (with  
suitable  stability  data)  
III   Soda-­‐lime  glass   Silica   glass   with   alkali   Moderate   not  used  for   Powdered  
metal  oxides   parenterals  (unless   Glass  
with  suitable  stability  
data)  
 
Powdered  Glass  Test  –  Select  six  or  more  containers  at  random,  rinse  thoroughly  with  Purified  Water,  then  dry  
with   a   current   of   clean,   dry   air.   Crush   the   containers   with   the   pestle   and   appropriately   sieve.   Place   in   a  
conical   flask   and   add   High-­‐Purity   Water   then   autoclave.   Decant   the   water   from   the   flask,   add   Methyl   Red  
Solution,   and   titrate   immediately   with   0.020   N   sulfuric   acid   [Refer   to   USP   for   complete   procedure].   The  
volume  does  not  exceed  that  indicated  in  Table  3  for  the  type  of  glass  concerned.  
 
Table  3.  Test  Limits  for  Powdered  Glass  Test  
  Limits  
Type   General  Description   mL  of  0.020  N  Acid  
I   Highly  resistant,  borosilicate  glass   1.0  
III   Soda-­‐lime  glass   8.5  
 
Water  Attack  at  121o    -­‐  This  test  can  be  used  to  qualify  Type  II  glass.  Rinse  thoroughly  3  or  more  containers,  
selected   at   random,   twice   with   High-­‐Purity  Water.   Fill   each   container   to   90%   of   its   overflow   capacity   with  
High-­‐Purity  Water,   then   autoclave.   Empty   the   contents   to   a   conical   flask   then   add   Methyl  Red  Solution,   and  
titrate,  while  warm,  with  0.020  N  sulfuric  acid  [Refer  to  USP  for  complete  procedure].  The  volume  does  not  
exceed  that  indicated  in  Table  4.  
 
 
 
  4  
/rpramos2014      
   Table  4.  Test  Limit  for  Water  Attack  at  121o  
    Limits  
Type   General  Description   Size,  mL   mL  of  0.020  N  Acid  
100  or  less   0.7  
II   Treated  soda-­‐lime  glass  
Over  100   0.2  
 
 
Moisture  Permeation  
Select  12  containers  of  a  uniform  size  and  type,  clean,  and  close  and  open  30  times.  Add  Dessicant  (anhydrous  calcium  
chloride)   to   10   containers   (test   containers)   and   glass   beads   to   the   remaining   2   containers   (controls).   Record   the  
weight  of  the  individual  containers  and  store  in  a  dessicator  at  23  ±  2o  and  75  ±  3%  relative  humidity.  After  336  ±  1  
hours  (14  days),  record  the  weight  of  the  individual  containers.  Determine  the  average  container  volume  by  filling  in  
5  containers  with  water  or  a  noncompressible,  free-­‐flowing  solid,  transfer  the  contents  in  a  graduated  cylinder,  then  
get  the  average.  Calculate  the  rate  of  moisture  permeability,  in  mg  per  day  per  L,  by  the  formula:  
 
(1000/14V)[(TF  –  Ti)  –  (CF  –  Ci)]  
 
in  which  V  is  the  volume,  in  mL,  of  the  container;  (TF  –  Ti)  is  the  difference,  in  mg,  between  the  final  and  initial  weights  
of  each  test  container;  and  (CF  –  Ci)  is  the  difference,  in  mg,  between  the  average  final  and  average  initial  weights  of  the  
2  controls.  
 
For   containers   used   for   drugs   being   dispensed   on   prescription,   the   containers   so   tested   are   tight   containers   if   not  
more  than  1  of  the  10  test  containers  exceeds  100  mg  per  day  per  L  in  moisture  permeability,  and  none  exceeds  200  
mg   per   day   per   L.   For   containers   used   for   drugs   being   dispensed   on   prescription,   the   containers   are   well-­‐closed  
containers  if  not  more  than  1  of  the  10  test   containers  exceeds  2000  mg  per  day  per  L  in  moisture  permeability,  and  
none  exceeds  3000  mg  per  day  per  L.  
 
 
 
II.  MANUFACTURING  CONTROL  
 
Written  procedures  are  extremely  vital  to  the  manufacture  of  drugs  and  cosmetics.  The  procedures  are  embodied  in  
four   important   documents   designed   to   explain   why   and   how   the   products   are   made.   These   are   the   manufacturing  
monographs,  batch  records,  standard  operating  procedures,  and  quality  control  monographs,.  
 
Manufacturing  monograph  
The  manufacturing  monograph  is  the  basic  document  from  where  the  master  formula  and  batch  production  records  
are   based.   This   includes   the   master   formula   records,   master   production   documents,   and   master   packaging  
documents.  
 
A   master   formula   record   is   the   original   document   used   as   key   in   the   production   of   products.   Being   the   prototype,   it   is  
kept   in   a   secured   documentation   room,   duplicated   or   photocopied   only   whenever   a   job   order   is   issued.   It   assures  
identical  reproduction  of  the  product  document.  
 
Batch  records  
Batch  records  refer  to  all  records  generated  during  the  course  of  producing  a  batch  of  quality-­‐controlled  product.  The  
completed  documents  permit  reconstruction  of  the  history  of  the  product.  It  includes  batch  production  records,  batch  
packaging  records,  and  batch  control  records  (RTR,  quarantine  report,  sampling  frequency,  sample  taken,  resample  
request,  testing  frequency,  disposition,  certificate  of  disposal,  stickers).  
 
Standard  operating  procedure  
Standard  operating  procedures  are  generated  to  explain  in  detail  the  reason  behind  a  procedure  and  proper  sequence  
of  steps  to  be  done,  and  how  equipment  are  to  be  operated  for  maximum  performance.  
 
Quality  control  monograph  
The   quality   of   each   and   every   component   used   in   the   manufacture   of   the   product   is   assured   by   testing   these  

  5  
/rpramos2014      
components  in  accordance  with  the  specifications  and  methods  provided  by  the  quality  control  monographs.  
 
Preservation:  Samples  and  Records  
A   reserve   sample   of   components   and   finished   products   consisting   of   at   least   twice   the   quantity   necessary   for   all  
required   tests   of   identity,   quality,   purity   and   strength   is   set   aside   for   preservation.   Complete   records   related   to   the  
control,   use,   production,   distribution   and   complaint   are   maintained   to   permit   reconstruction   of   the   history   of   the  
product.  In  general,  records  and  samples  are  retained  for  a  period  of  five  years.  However,  local  FDA  recommends  the  
following  retention  periods:  
 
  Components:  
1. At  least  two  years  after  the  distribution  of  the  last  lot  of  product  incorporating  the  component  has  been  
completed,  or  
2. One  year  after  the  expiration  date  of  this  last  lot  incorporating  the  components.  
 
Finished  Products  
1. At  least  two  years  after  lot  distribution  is  completed,  or  
2. One  year  after  the  expiration  date  of  the  product.  
 
Records  
1. Drugs:  as  above  
2. Cosmetics:  At  least  three  years  after  manufacture  is  completed.  
 
However,   ICH   Guideline   recommends   that   reserve   samples   of   each   active   pharmaceutical   ingredient   (API)   batch  
should   be   retained   for   one   year   after   the   expiry   date   of   the   batch   assigned   by   the   manufacturer,   or   for   three   years  
after   distribution   of   the   batch,   whichever   is   the   longer.     All   production,   control,   and   distribution   records   should   be  
retained  for  at  least  1  year  after  the  expiry  date  of  the  batch.    For  APIs  with  retest  dates,  records  should  be  retained  
for  at  least  3  years  after  the  batch  is  completely  distributed.  
 
 
Exercise  on  Preservation  of  Records  
 
1. Batch  records  of  the  syrup  manufactured  today  are  to  be  retained.  If  the  product  has  a  shelf  life  of  3  yrs  and  
distribution  will  be  completed  at  the  end  of  next  year,  determine  the  following:  
a. Expiration  date    
b. last  day  when  medication  can  be  taken  
c. 3  possible  retention  periods  for  the  documents  
 
 
IN-­‐PROCESS  QUALITY  CONTROL    
 
During  processing,  the  quality  of  the  product  at  various  stages  of  production  is  audited  by  quality  control.  In-­‐process  
quality   control   (IPQC)   tests   are   performed   to   determine   if   the   product   meets   specifications   throughout   the   entire  
processing  period  and  particularly  during  critical  stages  of  manufacturing.  Any  out  of  range  measurement  can  thus  be  
corrected  before  further  processing  is  continued.  The  audit  also  fulfills  the  primary  objective  of  the  IPQC  which  is  to  
monitor  all  features  of  a  product.  
 
  Solid  Preparation  (TABLET)  
1. Tablet  granulation  
a. Assay  
b. Granule  size  
c. Moisture  content  
2. Compression  
a. Average  weight  
b. Diameter  
c. Disintegration  
d. Dissolution  
e. Friability  
  6  
/rpramos2014      
 f. Hardness  
g. Thickness  
3. Tablet  coating  
a. Average  weight  
b. Color  and  coating  finish  
Liquid  Preparation  
a. Clarity  
b. pH  
c. Solubility  
d. Specific  Gravity  
e. Assay  
f. Viscosity    
Semi-­‐solid  Preparation  
a. Active  material  dispersion  
b. pH  (excluding  ointments)  
c. Viscosity  
 
 
Exercise  on  Bulk  Product  Reconciliation  
 
Production  of  Multivitamin  Syrup  
Batch  size  /  TY:  3000  L  
Manufacturing  Limit:  99%  yield  or  nmt  1%  loss  
Bulk  product:   Actual  yield  =  2990  L  
    QC  sample  =  3  x  250  mL  
1. How  much  is  the  %  gross  yield?  
2. Compute  for  the  %  net  yield.  
3. How  much  is  the  %  total  loss?  
4. Is  the  manufacturing  loss  within  normal  limits?  Why?  
 
 
 
III.  PACKAGING  CONTROL  
 
Packaging   and   labeling   operations   are   controlled   to   assure   that   the   finished   product   is   properly   identified   with   a  
control  code  that  permits  construction  of  the  history  of  the  product  and  to  prevent  mix-­‐ups  and  errors.  Prior  to  use,  
facilities  are  cleared  out  of  package  finished  products  and  packaging  materials  of  the  previous  run.  Products  which  are  
similar   in   appearance,   containers   or   labeling   are   not   processed   simultaneously   on   adjacent   or   nearby   lines   unless  
these   operations   are   separated   by   a   physical   barrier.   Proper   reconciliation   is   done   after   the   packaging   operation   is  
completed.   Discrepancies   between   the   theoretical   yield   and   the   actual   yield   should   be   adequately   explained   before  
the  final  release  of  the  product.  
 
At  regular  intervals,  the  inspector  checks  the  packaging  operation  on  but  not  limited  to  these  important  points:  
1. encoded  batch  and  expiry  date  
2. count  or  measure  in  finished    pack  minimum  fill  
3. label  appearance  and  adhesion  
4. bulk  material  identification  
5. cap  torque  
6. seal  integrity  of  strip  or  blister  pack  
7. correctness  of  first  and  last  packages  
 
 
 
 
 
 
 
  7  
/rpramos2014      
Exercise  on  Packaging  Reconciliation  
 
Production  of  Multivitamin  Syrup  
Batch  size:  3000  L  
Bulk  Product  AY:  2990  L  
Packaging  breakdown:     25000  x  15  mL  
        15000    x  60  mL  
        14375  x  120  mL  
Packaging  Limits:  98%  yield  or  nmt  2%  loss  (cumulative)  
Finished  Product:  
    Fill  Volume   Net  yield   QC  samples  
    14.98  mL   24850  bottles   24  bottles  
    60.25  mL   14390  bottles   12  bottles  
    120.15  mL   14286  bottles   10  bottles  
 
1. What  is  the  %  gross  yield?  
2. How  many  liters  were  lost  during  the  filling  and  packaging  run?  
3. Is  the  packaging  run  within  limits?  
4. Assume  that:  
• 25500  X  15  mL  labels  were  issued  
• one  label  each  is  required  to  be  pasted  on  each  case  of  144  filled  bottles  (whether  complete  or  
not)  
• balance  of  label  is  zero  
• one  label  specimen  for  attachment  to  batch  record  
• maximum  wastage  for  packaging  material  is  3%  
 
a. how  many  cases  are  used?  
b. how  many  loose  bottles  are  there?  
c. how  many  labels  were  used?  
d. what  is  the  %  wastage  
e. did  the  labeling  run  meet  the  specification?  
 
 
 
IV.  DISTRIBUTION  CONTROL  
 
Finished  products  pending  disposition  should  be  separately  stored  from  finished  goods  which  have  been  approved  by  
quality  control  for  distribution.  
 
Finished  goods  warehouse  control  and  distribution  records  should  include  an  adequate  perpetual  inventory  control  
system  or  other  suitable  system  so  that  distribution  of  each  lot  of  product,  identified  by  its  control  code,  can  be  readily  
determined  to  facilitate  recall,  if  necessary,  from  all  consignees  of  the  manufacture  or  repacker.  
 
A  stock  card  (see  Figure  2)  indicates  a  beginning  and  an  ending  inventory  within  a  certain  period.  If  the  stock  goes  
from  the  manufacturer  to  a  single  distributor,  the  stock  card  need  not  indicate  the  name  of  the  recipient.  However,  it  
is  good  inventory  practice  to  write  name  of  the  distributor,  if  there  are  several  involved.    
 
At   the   distribution   level,   it   is   necessary   to   indicate   the   name   of   the   customer.   This   information   is   of   great   value   in  
recalls.  This  documentation  can  be  indicated  in  a  distribution  card  (see  Figure  3).  
 
When  the  stock  is  not  handled  by  a  professional  distributor,  the  stock  card  and  the  distribution  card  can  be  made  into  
only  one  document.  
 
In  both  cases,  separate  cards  are  prepared  per  lot,  and  arranged  in  such  a  way  wherein  the  card  bearing  the  nearest  
expiration  date  is  filled  up.  This  will  ensure  that  the  oldest  approved  stock  is  distributed  first,  whenever  possible.  
 

  8  
/rpramos2014      
  
 
Figure  2.  A  typical  stock  card.  
 
 
 
 

 
 
Figure  3.  A  typical  distribution  card.  
 
 
 
V.  ENVIRONMENTAL  CONTROL  
 
Adequate   ventilation,   air   filtration   and   exhaust   systems   should   be   provided,   where   appropriate.     These   systems  
should  be  designed  and  constructed  to  minimise  risks  of  contamination  and  cross-­‐contamination  and  should  include  
equipment   for   control   of   air   pressure,   microorganisms   (if   appropriate),   dust,   humidity,   and   temperature,   as  
appropriate   to   the   stage   of   manufacture.     Particular   attention   should   be   given   to   areas   where   APIs   are   exposed   to   the  
environment.   If   air   is   recirculated   to   production   areas,   appropriate   measures   should   be   taken   to   control   risks   of  
contamination  and  cross-­‐contamination.  
 
Water  used  in  the  manufacture  of  APIs  should  be  demonstrated  to  be  suitable  for  its  intended  use.  Unless  otherwise  
justified,   process   water   should,   at   a   minimum,   meet   World   Health   Organization   (WHO)   guidelines   for   drinking  
(potable)  water  quality.  If  drinking  (potable)  water  is  insufficient  to  assure  API  quality,  and  tighter  chemical  and/or  
microbiological  water  quality  specifications  are  called  for,  appropriate  specifications  for  physical/chemical  attributes,  
total  microbial  counts,  objectionable  organisms  and/or  endotoxins  should  be  established.  
 
Dedicated   production   areas,   which   can   include   facilities,   air   handling   equipment   and/or   process   equipment,   should  
be   employed   in   the   production   of   highly   sensitizing   materials,   such   as   penicillins   or   cephalosporins.   Dedicated  
production   areas   should   also   be   considered   when   material   of   an   infectious   nature   or   high   pharmacological   activity   or  
  9  
/rpramos2014      
toxicity   is   involved   (e.g.,   certain   steroids   or   cytotoxic   anti-­‐cancer   agents)   unless   validated   inactivation   and/or  
cleaning  procedures  are  established  and  maintained.  Appropriate  measures  should  be  established  and  implemented  
to  prevent  cross-­‐contamination  from  personnel,  materials,  etc.  moving  from  one  dedicated  area  to  another.  
 
 
 
REJECTION  AND  RE-­‐USE  OF  MATERIALS    
 
Rejection  
Intermediates  and  APIs  failing  to  meet  established  specifications  should  be  identified  as  such  and  quarantined.    These  
intermediates  or  APIs  can  be  reprocessed  or  reworked  as  described  below.    The  final  disposition  of  rejected  materials  
should  be  recorded.  
 
Reprocessing    
Introducing  an  intermediate  or  API,  including  one  that  does  not  conform  to  standards  or  specifications,  back  into  the  
process  and  reprocessing  by  repeating  a  crystallization  step  or  other  appropriate  chemical  or  physical  manipulation  
steps  (e.g.,  distillation,  filtration,  chromatography,  milling)  that  are  part  of  the  established  manufacturing  process  is  
generally  considered  acceptable.    However,  if  such  reprocessing  is  used  for  a  majority  of  batches,  such  reprocessing  
should  be  included  as  part  of  the  standard  manufacturing  process.  
 
Reworking  
Before   a   decision   is   taken   to   rework   batches   that   do   not   conform   to   established   standards   or   specifications,   an  
investigation  into  the  reason  for  non-­‐conformance  should  be  performed.  Batches  that  have  been  reworked  should  be  
subjected   to   appropriate   evaluation,   testing,   stability   testing   if   warranted,   and   documentation   to   show   that   the  
reworked  product  is  of  equivalent  quality  to  that  produced  by  the  original  process.    Concurrent  validation  is  often  the  
appropriate   validation   approach   for   rework   procedures.     This   allows   a   protocol   to   define   the   rework   procedure,   how  
it  will  be  carried  out,  and  the  expected  results.    If  there  is  only  one  batch  to  be  reworked,  then  a  report  can  be  written  
and   the   batch   released   once   it   is   found   to   be   acceptable.   Procedures   should   provide   for   comparing   the   impurity  
profile   of   each   reworked   batch   against   batches   manufactured   by   the   established   process.     Where   routine   analytical  
methods  are  inadequate  to  characterize  the  reworked  batch,  additional  methods  should  be  used.    
 
Recovery  of  Materials  and  Solvents  
Recovery   (e.g.   from   mother   liquor   or   filtrates)   of   reactants,   intermediates,   or   the   API   is   considered   acceptable,  
provided  that  approved  procedures  exist  for  the  recovery  and  the  recovered  materials  meet  specifications  suitable  for  
their  intended  use.  Solvents  can  be  recovered  and  reused  in  the  same  processes  or  in  different  processes,  provided  
that  the  recovery  procedures  are  controlled  and  monitored  to  ensure  that  solvents  meet  appropriate  standards  before  
reuse  or  co-­‐mingling  with  other  approved  materials.  Fresh  and  recovered  solvents  and  reagents  can  be  combined  if  
adequate  testing  has  shown  their  suitability  for  all  manufacturing  processes  in  which  they  may  be  used.    
 
Returns    
Returned   intermediates   or   APIs   should   be   identified   as   such   and   quarantined.   If   the   conditions   under   which   returned  
intermediates  or  APIs  have  been  stored  or  shipped  before  or  during  their  return  or  the  condition  of  their  containers  
casts   doubt   on   their   quality,   the   returned   intermediates   or   APIs   should   be   reprocessed,   reworked,   or   destroyed,   as  
appropriate.  Records  of  returned  intermediates  or  APIs  should  be  maintained.  For  each  return,  documentation  should  
include:  
• Name  and  address  of  the  consignee  
• Intermediate  or  API,  batch  number,  and  quantity  returned  
• Reason  for  return  
• Use  or  disposal  of  the  returned  intermediate  or  API  
 
 
 
 
 
 
 

  10  
/rpramos2014      
COMPLAINTS  AND  RECALLS  
All  quality  related  complaints,  whether  received  orally  or  in  writing,  should  be  recorded  and  investigated  according  to  
a  written  procedure.  Complaint  records  should  include:  
• Name  and  address  of  complainant;  
• Name  (and,  where  appropriate,  title)  and  phone  number  of  person  submitting  the  complaint;  
• Complaint  nature  (including  name  and  batch  number  of  the  API);  
• Date  complaint  is  received;  
• Action  initially  taken  (including  dates  and  identity  of  person  taking  the  action);  
• Any  follow-­‐up  action  taken;  
• Response  provided  to  the  originator  of  complaint  (including  date  response  sent);  and  
• Final  decision  on  intermediate  or  API  batch  or  lot.  
 
Records  of  complaints  should  be  retained  in  order  to  evaluate  trends,  product-­‐related  frequencies,  and  severity  with  a  
view  to  taking  additional,  and  if  appropriate,  immediate  corrective  action.  There  should  be  a  written  procedure  that  
defines  the  circumstances  under  which  a  recall  of  an  intermediate  or  API  should  be  considered.  The  recall  procedure  
should  designate  who  should  be  involved  in  evaluating  the  information,  how  a  recall  should  be  initiated,  who  should  
be   informed   about   the   recall,   and   how   the   recalled   material   should   be   treated.   In   the   event   of   a   serious   or   potentially  
life-­‐threatening  situation,  local,  national,  and/or  international  authorities  should  be  informed  and  their  advice  sought.  
 
 
 
 
 
 
References:  
 
ASTM   D3198-­‐97(2007),   Standard   Test   Method   for   Application   and   Removal   Torque   of   Threaded   or   Lug-­‐Style  
Closures,  ASTM  International,  West  Conshohocken,  PA,  2007,  www.astm.org  
 
ICH  Harmonised  Tripartite  Guideline  on  Good  Manufacturing  Practice  Guide  For  Active  Pharmaceutical  Ingredients  
Q7.  In:  International  Conference  On  Harmonisation  Of  Technical  Requirements  For  Registration  Of  Pharmaceuticals  For  
Human  Use.  Step  4  version.  ICH  Expert  Working  Group,  2000.  
 
Lerma,   Norma   V.   and   Marina   O.   Osi.   Drug   and   Cosmetic   Quality   Control   with   Instrumentation,   2nd   ed.   Manila,  
Philippines:  UST  Publishing  House,  1996.  
 
United   States   Pharmacopeia–National   Formulary   (USP–NF)   35/30.   The   United   States   Pharmacopeial   Convention,  
2012.  
 

  11  
/rpramos2014