PHA6122​:​ ​Quality Control Laboratory 

 
TABLET FRIABILITY 
ACETAMINOPHEN TABLETS ➔ Tendency  for  a  tablet  to  chip,  crumble  or  break  following 
Pharmacopeial  tests  are  mandatory. They must be strictly  compression  
followed  because  these  are  official  tests  found  in  the  US  ➔ Normally  confined  to  uncoated  tablets 
Pharmacopeia.  It  includes  UV-Vis  Spectroscopy,  IR  Spectroscopy,  and  surfaces  during  handling  or 
HPLC,  Dissolution,  Disintegration,  Uniformity  of  Dosage  Units  and  subsequent storage 
Deliverable  Volume  to  enumerate  those  tests  that  were  discussed  ➔ A  method  to  determine  the  physical 
previously.  strength,  resistance  to  chipping  and 
  surface  abrasion of uncoated tablets upon 
Objectives:   exposure  to  mechanical  shock  or  attrition 
1. To  prepare  a  specification  sheet for non-pharmacopeial tests for  by  tumbling  them  in  a  rotating  cylinder 
Acetaminophen Tablets  aka ​DRUM 
2. To  understand  principles  on  non-pharmacopoeial  quality  control  ➔ May  also  affect  elegance,  appearance, 
tests of Acetaminophen Tablets  and consumer acceptance of the tablet 
3. To  interpret  the  results  of  the  quality  control  tests  of  ➔ To  perform  this  test,  we  use  a  ​Friabilator​,  which  consists  of  2 
Acetaminophen tablets  parts: (1) Machine, and the (2) Drum 
  ➔ Some  friabilator  models  have  2  drums  on  both  sides  for  2 
NON-PHARMACOPEIAL TESTS  simultaneous determinations of tablet friability  
● Tests  performed  which  are  not  listed  in  official  compendia  and  ➔ Determine  how  well  tablets  will  stand  up  to  coating,  packaging, 
concern a variety of quality attributes that need to be evaluated  shipping, and other processing conditions 
● Some  tests  have  no  officially  set  limits  or  acceptance  criteria  or  ➔ Roche Friabilator ​is most frequently used for this purpose 
rejection  criteria,  and  thus  may  vary  from  manufacturer  to   
manufacturer and from formulation to formulation  Factors Affecting Tablet Friability 
● Are  non-standardized,  therefore,  the  values  are  assigned  by  ❖ Poor condition of punches 
manufacturers  as  “in-process  quality  control  tests”  (which  is why  ○ Tableting  machines  contain  the  punch  and  the  die parts to 
these tests are not mandatory)  form a pressed tablet 
● Must  be  controlled  during  production  and  verified  after  ○ The  poor  condition  of  these  punches  may  lead  to  a  tablet 
production (in-process control)  defect  called  ​WHISKERING  [a  defect  observed  on  the 
  edges of a tablet characterized by a rough surface] 
Most Common Non-pharmacopeial Tests of Tablets  ❖ Moisture Content 
It focuses more on the physical attributes compared to the  Tablet  formulation  with  low  moisture  content  will  make  it 
pharmacopeial tests, which focuses on chemical attributes  hard  for  tableting  machines  to  compress  and  eject  the  tablets 
● General Appearance  readily.  It  may  also  lead  to  tablet  defects  such  as  capping  and 
○ Size  sticking. 
○ Shape  ○ Capping   
○ Thickness and Diameter  ↳ Top  and  bottom  crown  of  the  tablet  is  removed 
Size,  Shape,  and  Thickness  and  Diameter  will  facilitate  completely or partially 
packaging  and  help  the  manufacturers  decide  which  ○ Sticking 
tablet-compressing machine will be used.  ↳ Materials  adhere  to  the  die  which  require  increased 
○ Organoleptic Properties ー includes color, odor, and taste  pressure for ejection of tablet from die 
● Tablet Strength   ↳ Caused by: 
○ Tablet Friability  ✓ Excessive  Moisture  or  high  water content of the 
○ Tablet Breaking Force  tablet formulation 
These  two  will  describe  the  mechanical  strength  of  the  ✓ Improper Mixing 
tablet  to  withstand  fracture  and  erosion  during  manufacturing  and  ↳ May  result  to  ​chipping  ​[it  will  result  to a rough tablet 
handling.  surface] 
● Uniformity  of  Mass  ー  ensures  that  the  tablet  has  the  correct  ❖ Lubricant may be used for easy ejection 
content and weight   Examples of lubricant that may be added: Talc & Stearates 
   
TABLET STRENGTH     
➔ Criterion for product development 
➔ Quality Control (QC) Specification 
➔ Ability  to  withstand  rigors  of  handling  and  transportation 
experienced  in  the  manufacturing  plant  during  coating, 
packaging,  and  printing  in the drug distribution system and in the 
field at the hands of the end users 
 
 
 
 
 
 
 
 

 
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PHA6122​:​ ​Quality Control Laboratory 
 
SAMPLE SIZE REQUIREMENTS  Initial weight:​ 6861.44 mg 
Specifications  Final weight:​ 6859.18 mg 
> 650 mg  10 tablets 
< 650 mg  Should equal to 6.5 g 
The  tablet  should  be  carefully  ​redusted??  prior  to  testing. 
Accurately  weigh  the  tablet  sample  and  place  the  tablets  in  the   
drum,  rotating  it 100 times. Then, remove the tablets after subjecting 
them  to  tumbling  motions.  Remove  any  loose  dust  from the tablets 
as before and accurately weigh.    
At  this  point,  we  have  the  initial  and  final  weights  of  the  Acceptance Criteria​: %weight loss should NMT 1.00% and no obvious 
tablets before and after the tablet friability tests as our data.  broken tablet is present 
➔ 100 rotations  Disposition:​ PASSED 
➔ Effervescent & chewable tablets​ require special stack packing  Interpretation:  
➔ Hygroscopic Tablet​ = 40% Relative Humidity (RH)   The  batch  of  Acetaminophen  Tablets  passed  the  tablet 
An  appropriate  humidity-controlled  environment  is  friability  test  with  a  percent  weight  loss  of  0.03%  which  is  not  more 
necessary for testing  than the acceptance criteria of 1.00% 
➔ Pellets​ = abrasion drum or air stream   
We  also  have  to  take  note  that  tablet  friability  is  a  TABLET BREAKING FORCE  
destructive test, which means that tablets used for determination will  ➔ Formerly known as T ​ ablet Hardness 
not  be  qualified  to  be  used  in  another  test  because  the  quality and  ➔ Another measure of the mechanical integrity of tablets  
integrity of these tablets were already compromised.  ➔ Strength = Stress  
➔ A  destructive  test  [same  with  tablet  friability],  so  tablets  used  in 
  this test are not qualified to be used on other tests 
 

Acceptance Criteria:  BREAKING  Force  required  to  cause  tablets  to  fail  in  a  specific 
● NMT 1.00% of mean weight loss  FORCE  plane 
● New formulation ー ​ NMT 0.8% weight loss  The  load  off  required  to  crush  the  tablet when placed 
● Cracked, cleaved and broken tablet = r​ eject  on its edge  
Tablet 
Generally,  the  test  is  run  only  once.  If  the  results  are 
HARDNESS  Resistance  of  a  surface  to  ​penetration  or  indention 
difficult  to  interpret  or  if  the  weight loss is greater than the targeted 
value,  the  test  should  be  repeated  twice  and  the  mean  of the three  by a small probe 
tests  is  determined.  A  maximum  mean  weight  loss  from  the  three  CRUSHING  Resistance  of  tablets  to  the  application  of  a 
samples  of  NMT  1.00%  is  considered  acceptable  for  most  products  STRENGTH  compressive load 
and  a  maximum  weight  loss  of  NMT  0.8%  is  considered  acceptable  More  fundamental  measure  of  the  mechanical 
for new formulations.   TENSILE  strength of the compacted material 
STRENGTH 
  Considers the geometry of the tablet 
Sample Problem   

Factors Affecting Tablet Breaking Force/Hardness 

Twenty Acetaminophen 500 mg tablets were weighed individually 
❖ Compression of tablet and compressive force  
○ Harder  tablets  are  formed  from  tableting  machines  with  a 
higher force of compression used  
❖ Amount and concentration of binder used 
○ The  more  binder  used  in  the  formulation,  the  harder  the 
manufactured tablets will be  
❖ Method of granulation in tablet preparation 
  ○ Between  wet  and  dry  granulation  procedure,  the  ​wet 
How many tablets will be used for the tablet friability test?  granulation​ method gives harder tablets 
Since  the  individual  weights  are < 650 mg, we compute for  ○ The  ​slugging  method  ​gives  the  best  tablet  hardness  or 
the  number  of  tablets  corresponding  to  6.5  g.  If  we  only  weigh  10  tablet breaking force 
tablets,  the  total  weight  is  6,237.11 mg which is less than the required  ❖ Type and concentration of lubricant used 
weight  (6.5  g  or  6,500  mg).  Therefore,  10  tablets  is  NOT  the sample  ○ Similar to how it affects tablet friability discussed earlier 
size and we have to add another tablet.   
Upon  addition  to  the  11th  tablet,  the  weight  now  becomes  Tablet  Breaking  Force  ​is  determined  by  crushing tablets, 
6,861.44  mg,  which  exceeded  the  minimum  6.5  g or 6,500 mg weight  determining  the  force  applied  to  crush  using  a  hardness  tester. 
of  the  tablet  to  be  subjected  to  the  friability  test.  Thus,  the  sample  Tablet hardness can affect disintegration.  
size for this determination is ​11 TABLETS.  If  the  tablet  is  ​too  hard​,  it  will  not  disintegrate  in  the 
  required period of time stated in the monograph.  
  If  the  tablet  is  ​too  soft​,  it  will  not  withstand  processing 
  such as coating and packaging procedures. 
     
 
 
 
 
 

 
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PHA6122​:​ ​Quality Control Laboratory 
 
There are 5 commonly used Tablet Hardness Tester  Most Commonly Acceptance Hardness Range 
1. Monsanto/Stokes Tester  Force   
➔ 2 jaws facing each other  
4 - 10 kg  Ordinary Compressed Tablets 
➔ A  handy  instrument  used  for  taking  quick  readings  of 
< 2 kg  Chewable Tablets 
tablet hardness 
➔ The  design  consists  of  a  barrel  containing  a  < 4 kg  Sublingual Tablets 
compressible spring held between 2 plungers or jaws  Buccal and Extended/Modified Release Tablets 
10 kg 
➔ The  tablet  is  placed  on  the  lower  plunger  and  the  (Lozenges) 
upper plunger is lowered onto the tablet   
➔ Tablet  hardness  can  be  read using the scale imprinted  ● Sample Size:​ 10 tablets 
in the tester  ● Tablet  Orientation: Score is parallel 
  with the sensing jaw 
2. Pfizer Tester  ● Acceptance  Criteria:  ​No  unit 
➔ Use of hand pliers as aid   outside  +/-10%  of  the  mean 
➔ Requires a spring and a pressure dial   [Acceptance  criteria  varies  but  this 
➔ It  is  ​handy,  tough  and  a  ​direct  dial  reading  is the most commonly used one] 
 
type tablet hardness tester   In  determining  Tablet 
➔ It  works  as  a  pair  of  pliers  and  generated  Breaking  Force,  tablets  are  generally 
breaking force in a single grip   placed  between  2  plates  or  jaws.  The  moveable/sensing  and 
➔ It  compresses  the  tablet  between  a  holding  anvil  and  a  stationary/fixed jaws. 
piston  connected  to  a  force  reading  scale  when its plier-like  Movable  jaw  moves  to  apply  sufficient  force  to the tablet 
handles are gripped  to  cause  fracture.  The  proper  tablet  orientation  is  across  the 
  diameter or parallel to the longest axis. 
3. Strong Cobb Hardness Tester  For  ​scored  tablets​,  scores  are  placed  parallel  to the jaws 
➔ “Manually operated air pump”   to  indicate  the  strength  in  general.  If  scores  are  placed 
➔ The  tablet  breaking  force  was  based  on arbitrary  perpendicular  to the jaws, it can indicate the strength at the weakest 
units referred to as s​ trong cobbs   point  of  the  tablet,  thus  we  place  the  score  parallel  to  the  sensing 
➔ It forces an anvil against a stationary platform   jaw. 
➔ Results  are  viewed  from  a hydraulic scale and the  Units  are  expressed  in  ​kilopond​,  ​kg-force​,  ​newton​,  and 
results are very similar to the Monsanto Tester  strong cobb ​units.  
   
The  first  three  (3)  hardness  testers  discussed  are  Procedure:  
manually  ​operated  where  the  strain  rate  is  dependent on the force  Place  individually  10  uncoated  tablets,  randomly  selected 
exerted by the operator.  between  the  fixed  jaw  and  the  sensing  jaw.  Press  the  test button to 
  move the sensing jaw or movable jaw. 
4. Erweka  The  tablet  fractures  then  the  moving  jaw  stops  and 
➔ Use of suspended weight   retracts slightly. Record the hardness shown on the display panel.  
➔ It  offers  a wide range from manual  If  1  or  more tablets are outside the acceptance criteria, the 
to  fully  automated  tablet  hardness  batch of tablets failed the breaking force test.  
and combination testers    
➔ It  can  measure  units  in  Newtons  Sample Problem 
(N), Strong Cobb, and Kilopond    Tablet  breaking  force  of  10  selected 
➔ It  tests  a  tablet  placed  on  the  lower  anvil  and  they  wait  Acetaminophen  500  mg  tablets  are  as 
moving along a rail transmits pressure slowly to the tablet  determined as follows, in Newtons. 
   
5. Schleuniger ​[Pharmatron Tester]  Mean Breaking Force = 6 ​ 86 N 
➔ Most widely used   Acceptance Criteria: 6 ​ 17.4 - 754.6 N 
➔ An  electric  motor  drives  an  anvil  to 
Lower Limit  Upper Limit 
compress a tablet at a constant rate 
(686 N) 一 [686 N (10%)]  (686 N) + [686 N (10%)] 
➔ The  tablet  is  pushed  against  a 
686 一 68.6  686 + 68.6 
stationary anvil until it fractures  
617.4 N  754.6 N 
➔ A  reading  is  taken  from  a  scale 
indicator  Disposition:​ PASSED 
➔ Eliminated operator variance  Interpretation: The batch of Acetaminophen 500 mg tablets passed 
➔ Horizontally positions  the  tablet  breaking  force  test  because  no  tablet  breaking  force  is 
  outside the acceptance criteria of 617.4 - 754.6 N. 
We take note of the units applicable to all hardness testers where:      
1 kp = 1 kg-force = 9.8 N 
 
Erweka  &  Schleuniger  Testers  are  motor-driven  testers 
where  operator  variability  is  eliminated  unlike  the  first  three 
hardness testers.  
 
 
 

 
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PHA6122​:​ ​Quality Control Laboratory 
 
UNIFORMITY OF MASS [single-dose preparations] 
● Sample Size:​ 20 tablets 
● If all units within specification 
○ PASSED 
● If one or more units are outside specification 
○ Set acceptance limits twice the deviation 
○ No tablet outside twice the deviation   
  Mean Mass = ​623.72 mg 
Tablet  weight  is  the  quantity  of  the  granulation  that  31.19 mg is 5% of the mean mass, 623.72 mg 
contains  the  labeled  amount  of  the  therapeutic  ingredient.  It  is   
influenced  by  the  volumetric  fill  of  the  die  cavity  and dependent on  Acceptance Criteria [​ based on the table] 
the  density  of  powder blend. Tablet diameter and tablet thickness. It  NMT 2 units should be outside the % deviation of 592.53 - 654.90 mg 
is generally applied to uncoated tablets.  Lower Limit  Upper Limit 
In  this  test,  we  are  after  the  correct  dose  and  correct  623.72 一 31.19  623.72 + 31.19 
weight.  The  main  difference  of  uniformity  of  mass  from  uniformity  592.53 mg  654.90 mg 
of  dosage  unit  is  that,  ​uniformity  of  dosage  units​, we are after the 
Disposition:​ PASSED 
content  of  a  drug  in  a  tablet.  For  ​uniformity  of  mass,  ​we are after 
Interpretation:  ​The  batch  of  Acetaminophen  tablets  passed  the 
the  total  weight  of  the  tablets  and  not  the drug content or the label 
uniformity  of  mass  test  because  no  unit  is  outside  the  percent 
claim  
deviation which is 592.53 mg - 654.90 mg.  
 
 
Procedure: 
General Appearance Test: TABLET THICKNESS & DIAMETER 
Weigh  individually  20  units  taken  at  random.  Determine 
● Sample Size:​ 10 tablets 
the  average  mass  for  the  acceptance  criteria,  ​NMT  2  of  the 
● Apparatus: V ​ ernier caliper 
individual  masses  deviate  from  the  average  mass  when  more  than 
● Acceptance Criteria: M ​ ean +/- 5% 
the  percentage  deviation  shown  in  the  table  and  ​none  deviates  by 
 
more than twice​ the percentage deviation.  
The  control  of  tablet  thickness  and  diameter  help  ensure 
 
uniform  tablet  appearance.  It  is  important for physical compatibility 
Acceptance Criteria 
with intended primary containers and tablet packaging processes. 
Pharmaceutical Form  Average Mass  % Deviation  This  test  is  based  on  a  compression  machine  and  the 
≤ 80 mg  10  diameter  of  the  die  is  the  amount  of  fill  permitted  to  enter  the  die 
Tablets  
> 80 mg & < 250 mg  7.5  cavity.  This  is  controlled  by  pressure  and  it  affects  the  tablet 
(uncoated & film-coated) 
≥ 250 mg  5  hardness or tablet breaking force. 
 
Capsules, granules  < 300 mg  10 
(uncoated, single-dose)  Procedure: 
Powders   Using  a  vernier  caliper,  measure  individually  the  tablet 
(single-dose)  ≥ 300 mg  7.5  thickness  and  tablet  diameter  of  10  randomly  selected  tablets. 
Powders for parenteral  Calculate the average tablet thickness and tablet diameter.  
> 40 mg  10  Establish  the  specification  limits  for  the  thickness  and 
use* 
diameter wherein % deviation is Mean +/- 5% of the mean. 
Suppositories & Pessaries  All masses   5 
 
Powders for eye-drops  < 300 mg  10  Sample Problem 
and powders for eye 
lotions   Thickness,  in  mm,  of  10  Acetaminophen  500  mg  tablets  were 
(single dose)  ≥ 300 mg  5  measured individually. 
*When  the average mass is equal or below 40 mg, the preparation is   
not  submitted  to  the  test  for  uniformity  of  mass  but  to  the  test  for  Mean Thickness = 5 ​ .00 mm 
uniformity of content of single-dose preparations  Acceptance Criteria:​ 4.75 - 5.25 mm 
  5% of the mean is 0.25 mm 
Sample Problem  Lower Limit  Upper Limit 
Twenty Acetaminophen 500 mg tablets were weighed individually  5.00 一 0.25  5.00 + 0.25 mm 
4.75 mm  5.25 mm 
Disposition:​ PASSED 
Interpretation:  ​The  batch  of  Acetaminophen  tablets  subjected  for 
tablet  thickness  test  passed  because  no  unit  is  outside  the 
acceptance criteria of 4.75 - 5.25 mm.  
 
   
How many tablets will be used for uniformity of mass?   
20 tablets   

 
TIMTIMAN ​|​ 3H-PHARMACY | 2020-2021
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 100% INSPECTION or INSPECTION  STATISTICAL PROCESS PROCESS CONTROL CHART (SPCC) 
To  check if the finished product manufactured is within  - Involves  the  use  of  process  standard  deviation  and 
specifications  or  standards  before  it  is  distributed  to  the  different charts or graphs located in MS Excel. 
consumers for use. 
 
INSPECTION 
- Comparison  of  certain  attributes  and  dimensions  of  a 
product  against  a  specification  to  find  out  if  the 
product is within prescribed limits 
- We  are  after  the  conformance  of  drug  products  to 
specifications which is to prescribed limits   
- An  activity  to  compare  results  with  specified  We  must draw a graph for us to perform the inspection 
requirements  in  order  to  establish  whether  conformity  by  SPCC.  Then  we  plot  the  different  individual  results  that  we 
is achieved for each characteristic.  gathered from the tests.  
- To  measure,  examine,  test,  or  gauge  one  or  more  BOLD  LINE  to  represent  Mean measure. Then plot the 
characteristics  of  a  product  or  service  and  compare  Upper  limit  (UL)  and  Lower  limit  (LL)  based  on  the  computed 
the  results  with  specified  requirements  to  establish  values  using  broken  lines.  At  this  point  we  can  easily  see 
whether conformity is achieved for each characteristic  whether  the  result  is  within  or  not  within  specifications  or 
  limitations.  
QUALITY CONTROL  Supposedly  your  statistical  process  control  chart  is 
- A  tool  which  gives  assurance  that  a  product  applicable  for  the  test  that  we  conducted  on  your 
conforms  to  standards  and  specifications  through  a  Non-pharmacopeial quality control test. 
system of inspection, analysis, and action   
- Inspection  now  is  really  under  the  scope  of  quality  PROCESS OF INSPECTION 
control   Steps involved: 
  1. Interpretation of the Specification 
2 TYPES OF INSPECTION  - Always  remember  that  limits  and  specifications  are 
1. BY ATTRIBUTES  presented  in  many  ways.  Quality  control  analysts  or 
- Inspection  for  conformity  of  times  as  well  as  for  inspectors  must  be  able  to  identify  and  understand 
non-conformity per hunder items  these  specifications  to  efficiently  interpret  the  results 
- Performed  on  non-measurable  characteristics  such  as  in the test 
color,  odor,  or  any  observable  or  organoleptic  2. Measurement of the Product 
characteristics.  This  inspection  is  done  to  check  for  - This is the actual inspection process. 
conformity and non-conformity of items per 100 items.  3. Comparison of the product with specification 
- Easier to conduct compare to Inspection by Variables  - Compare  results  against  the  Acceptance  &  Rejection 
  criteria.  From  here  now  determine  where  the  results 
2. BY VARIABLES  stand which leads to the fourth step; 
- Magnitude or characteristic of an item; measurable  4. Judgment as to Conformance 
- Performed  on  measurable  characteristics  such  as  - Determine  if  the  product  is  in  conformance  or 
tablet  weight,  diameter,  thickness.  An  inspector  non-conformance  within  or  outside  the  limits.  This  is 
measures  these  characteristics  compared  to  the expression of your judgment before we decide. 
Inspection  by  Attributes,  this  is  more  expensive  yet  5. Disposition of the Product 
give a more accurate result.  - No emotion should be involved in Disposition. 
  - This  step  involved  decision  making  on  the  product 
  whether accept or reject / pass or fail. 
  6. Recording of the results obtained 
  - Process  of  Documentation  and  Reporting  for  quality 
  assurance  and  quality  control.  Wherein  it  plays  a  vital 
  role in quality. Because it signifies proof of work. 
   
   
   
   
   
   
   
   
DEFECTIVE  3.  BASED  ON  SERIOUSNESS/GRAVITY  (SUPPLEMENTAL 
- A unit that contains one or more DEFECT/s  NOTES) FOCUS OF THE LAB COURSE 
- Product that failed to conform to specifications  A. CRITICAL 
  - May  endanger  the  life  or  property  of  those 
DEFECT  who  will  be  using  the  contents  of  these 
- Undesirable characteristic of a product  bottles.  It  may  render  the  product 
  non-functional  since  it  renders  the  product 
  hazardous to the health of the consumers. 
Criteria: Whether the product conforms to the specifications  - EXAMPLES can be seen on the last page  
- Accept/Pass   
- Reject/Fail  B. MAJOR 
- Quarantine  (if  the  product  is not yet rejected, however  - Same  with  critical  defects,  which  render  the 
still not yet accepted)  product  non-functional  or  useless  because  it 
  may  affect  and  alter  overall  product 
CLASSIFICATIONS OF DEFECTS  functionality.  If  these  defects  are  present  in 
1. BASED ON MEASUREABILITY  the  bottles  that  hold  your  medication,  those 
A. VARIABLE   will  now  be  considered  non-functional  or 
- Measured  directly  by  instruments  since  they  useless. 
are numerical)  - EXAMPLES can be seen on the last page 
   
B. ATTRIBUTE   C. MINOR 
- Cannot  be  measured  directly  by  instruments  - Only  minor  defects  are  the  ones  accepted to 
because  they  are  non-measurable,  they  are  be  used  by  consumers  if  present  in  the 
more  on  the  subjective  side  of  the  products  package material. 
and  it  shows  mainly  conformance  or  - It  does  not  endanger  the  life  or  property  of 
non-conformance  only  of  the  materials to the  the  consumer  because the functionality is not 
specification.  affected.  However,  it  is  still  outside  the 
  prescribed  limits.  So  the  overall  product 
2. BASED ON NATURE  acceptability is altered. 
A. OCULAR   - EXAMPLES can be seen on the last page 
- Visible defect, something that can be seen by   
the naked eye)  ACCEPTANCE SAMPLING INSPECTION 
  - In  any  inspection  process  that  is  performed.  We  may 
B. INTERNAL   consider 4 different outcomes. 
- Not  immediately  seen  by  the  eye,  but  it  is  First,  accept  a  LOT  that  confirms  to  standard  and 
present.  It  can  only  be  determined  by further  specifications. This would be the correct and efficient outcome. 
testing.  
- Example:  Sub-potent drugs (drugs that do not 
meet the Label Claim)  
- We  do  not  know  that  a  defect  is  present 
because  it  is not visible. However, a defect of 
a sub-potent drug is present. 
 
C. PERFORMANCE 
- Simple the Function Defect 
- Classified  as  a  Major  defect  based  on  the 
seriousness or gravity.  
- The  drug  product  failed  to  deliver  what  is    
expected to be.   
- Example: Tablet failed to disintegrate     
 
 
 
 
 
 
 Second,  if  we  are  going  to  reject  a  LOT  that  does not  To  not  interchange  the two (Producer and Consumer’s 
conform  to  the  standard.  This  outcome  again  is  proper  and  risk).  Remember  if  a  good  batch  is  rejected,  it’s  the  Producer’s 
efficient.  So  the  first  two  possible  results  of  the inspections are  who  lose.  If  a  bad  batch  is  accepted  it  will  continue  in  the 
correct outcomes.  manufacturing  process and eventually it will be converted into a 
final  product.  It  will  reach  and  be  distributed  in  the  market  for 
consumer use which the Consumer would be at risk. 
 
ACCEPTANCE SAMPLING INSPECTION 
In  addition  to  the ISO sampling plans, which are based 
on  the  mathematical  theory  of  probability.  There  are  several 
practices or types of inspection methods. 
 
1.  SAMPLING  BASED  ON  EXPERIENCE  WITH  THE  PRODUCT, 
THE PROCESS, THE SUPPLIER, AND THE CONSUMER 
- This inspection is conducted based on experience. 
  2. ad hoc SAMPLING 
  - Check fix percentages or occasional random checks. 
The  next  two  possible  outcomes  involve  errors. Errors  3. 100% INSPECTION 
may  arise  when  sampling  is  not performed correctly that will be  - Main topic of Activity # 8 
discussed in the next activity (9).  - Commonly  utilized  for  inspection  of  parenteral 
  preparations.  Because  of  IRREVERSIBILITY  of  the 
Third,  rejecting  a  LOT  that  conforms  to  a specification  reaction which is very crucial. 
or  standards.  An  error occurred because if a LOT conforms why  4. OTHER “SAMPLING” PRACTICES 
do  we  reject  the  BATCH?  This  error  (green  circle)  is  called   
Producer’s risk or Type 1 error or Alpha error.  100% INSPECTION 
- Inspect  all  units  of  sample  disregarding  the  sample 
size 
- Disregards  the  sample  size  which  means 
POPULATION = SAMPLE SIZE 
- Applicable for critical defects and parenterals 
- ADVANTAGE:  
- Know  the  exact  number  of  product  that  was 
inspected 
- DISADVANTAGE:  
- Harder for large scale production 
- Time-consuming 
  - Not applicable for destructive testing 
  - Prone to Personnel error because of Fatigue  
FOURTH,  when  we  accept  a  LOT  that  does  not  - 100%  Inspection  is  not  an  assurance  that  inspection is 
conform  to  specifications  or  standards.  Which  is  classified  as  not  efficiently  performed  even  though  the  main 
Consumer’s error/risk or Type 2 error or Beta error.  advantage  is  that  we  can  determine the exact number 
of defects in a LOT or BATCH. 
 
CONTAINERS 
- “That  which  holds  the  article  (the  drug  product) and is 
or maybe in direct contact with the article” - USP 
 
IMMEDIATE CONTAINER, USP 
- That which is direct contact with the articles at all times 
- Primary packaging 
 
SECONDARY PACKAGING 
  - Materials  that  provide  additional  protection  for  the 
  article  or  the  drug  product such as the Label, Box, and 
  Insert. 
 
   
 TYPES OF CONTAINERS  3. SODA LIME GLASS / SODA LIME SILICA GLASS (per USP) 
LIGHT RESISTANT CONTAINER  - Contains  alkaline  metal  oxides  (mainly  Sodium  oxide)  and 
- Amber glass or Light resistant opaque plastic  alkaline earth oxides (mainly Calcium oxide) 
- Gives  protection  for  Photosensitive  pharmaceutical  - Most common type of industrially produced glass 
products  - Moderate  hydrolytic  resistance  due  to  the  chemical 
- Any  container  that  cannot  be  penetrate  by  UV  rays or  composition of the glass itself. 
Sunlight  - Type 3 glass containers are not usually used for parenteral or 
powders  of  parenteral  use  EXCEPT  for  suitability  testing 
 

TIGHT CONTAINER 
- Protect  content  from  contamination  by  extraneous  indicate that Type 3 glass is the most satisfactory 
liquids,  solids,  or  vapors  from  loss  of  the  article,  from  - Suitable  for  packaging  of  liquid formulations that prove to be 
efflorescence, deliquescence, or evaporation  sensitive to alkali 
- Capable of tight reclosure  - Type  3  cannot  be  used for autoclave but can be used for dry 
- Directly associated with moisture  heat sterilization 
   
HERMETIC CONTAINER  4. GENERAL PURPOSE SODA LIME GLASS 
- Impervious to air  - AKA Type NP 
- Sterile: intended for parenteral administration  - Low hydrolytic resistance 
 

SINGLE UNIT CONTAINER  - Non-parenteral formulation 

- Single  dose  administration  promptly  after  opening  the  - Cannot  be  autoclave  for  it  will  cause erosion reaction rate of 
container  the glass container 
- Promptly  use  after  opening  the  container  such  as  - Capsules, tablets, and topical products 
Ampules   
 

UNIT DOSE CONTAINER  PHYSICO-CHEMICAL TEST 

  CHEMICAL RESISTANCE 
OFFICIAL GLASS TYPES  TYPE  GENERAL DESCRIPTION  TYPE OF TEST 
1. HIGHLY RESISTANT BOROSILICATE GLASS 
- Least reactive  I  Highly resistant, Borosilicate  Powdered glass 
- Contains  significant  amounts of Boric oxide, Aluminum oxide,  glass 
and Alkali and/or Alkaline earth oxides in the glass network 
II  Treated soda-lime glass  Water attack 
- High  hydrolytic  resistance  and high thermal shock resistance 
due to the chemical composition of the glass itself  III  Soda-lime glass  Powdered glass 
- Suitable for Parenteral and non-parenteral uses 
- Used  for  all  applications,  package  water  for  injection,  NP  General-purpose soda-lime glass  Powdered glass 
unbuffered  products,  sensitive  lab  samples,  samples 
Only Type 2 has a different test (water attack).  
requiring sterilization 
Type 1,3,4 are subjected to Powder glass for their Chemical 
- AKA Type 1 Borosilicate glass 
resistance 
   
2. TREATED SODA LIME GLASS 
   
- Treated  in  the  annealing  oven  with  sulfur  to  reduce  alkali 
solubility or basic solubility 
- Suitable  treatment  of  the  inner  surface  of  Type  3  containers 
will  raise the hydrolytic resistance of Type 2 glasses to a high 
level.  This  means  that  Type  2  glasses  are  less  resistant 
compared  to Type 1 but more resistant to Type 3 glasses due 
to  higher  levels  of  Sodium  hydroxide  and Calcium oxide that 
is treated in the glass.  
- Higher level of NaOH and Calcium oxide 
- Less resistant to Type 1 but more resistant to Type 3 
- Products  that  remain  below  pH  7  or  the  most  acidic  product 
for parenteral and non parenteral uses. 
- Type  2  glass  containers  can  be  used  on  alkaline  parenteral 
products. Where stability data demonstrate their suitability for 
use. 
 
 
 
BOTTLE FINISH 
- Area from the mouth to the shoulder of the bottle 
1. HANDLED 
2. THREADED 
- Most common bottle finish 
A. CONTINUOUS - Full turn  
B. LUG - Quarter turn; with breaks 
a. Commonly used for foods (cheezewiz) 
3. BIOLOGICAL - closed through friction 
- Example: Reagent bottle 
4. POUR-OUT - built in funnel-type of mouth   
- Facilitate  pouring  and  transferring  content  from  one  Black cap - Continuous Roll-on 
container to another  Yellow cap - Lug amerseal 
5. SPRINKLE TOP - narrow opening  Blue cap - Pilfer/tamper proof has skirt 
   
Handled bottle finish Continuous & Lug  DIFFERENT WAYS TO DESCRIBE A BOTTLE 
 
TYPES OF BOTTLE 
1. ACCORDING TO SIZE/VOLUME CAPACITY 
2. ACCORDING TO COLOR 
- Flint (Colorless) 
- Amber (Color brown bottle) 
3. ACCORDING TO SHAPE 
- Boston round (bottom portion is round) 
  - Rectangular blake (bottom part is rectangle shape) 
  4. ACCORDING TO METHOD OF MANUFACTURE 
Pour-Out Sprinkle top  - To differentiate, find the Fusion line. If there is a Fusion 
line, that bottle is manufactured by Molding 
- If  no  Fusion  line  is  not  present,  most  probably  it  is 
made by blowing 
A. BLOWING 
B. MOLDED 
 
TEST YOURSELF 

 
BODY 
- Area from the shoulder to the end of the bottle 
 
BOTTLE CLOSURE 
- Bottle  finish  requires  a partner which in Quality control 
it would be the CAP (Bottle Closure)   
1. ROLL-ON - paired with threaded  ANSWER: 
1. Continuous  - 60 mL Boston-round Moulded Amber bottle 
2. Lug amerseal paired with Lug threaded finish   
3. Pilfer proof/Tamper proof - has skirt   
2. FRICTION - biological bottle finish     
- Made up of corks or frosted caps 
3. CROWN - oldest bottle closure 
- Tansan in tagalog 
4. PRESS-ON/SNAP ON 
- Typically used in cosmetic and multivitamin products. 
- Attachment of the cup and the opening 
 UNDER YOUR BOTTLES  
MOLD #: 2019FF 
YEAR MANUFACTURE: 15 (2015) 
CAPACITY/VOLUME: 15-mL 
CAVITY #: 2 
CENTER: Logo of Manufacturer 

 
 
3 MOST COMMON BOTTLE MANUFACTURER IN THE 
PHILIPPINES 
 
ASIA BREWERY 

  
 
UNITED LABORATORIES 

 
 
SAN MIGUEL BREWERY 

 
 PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

APPENDIX A


CRITICAL GLASS BOTTLE DEFECTS



DEFECT DESCRIPTION ILLUSTRATION

Bird Cage (Bird A string of glass expanding across the inside of the
Swing) container.

Spike A small projection of glass in the body of the container.

Overpress/ A finish which has excessive glass projecting upward
Wire edge from the inside edge of the finish.

Split finish A finish which has a crack across the top surface–
extends from the top of the finish down towards the
neck.

Body Checks A crack or fracture through the wall thickness in the
body of the container.

Crizzled Finish A finish with many fine surface fractures, mainly across
the top.

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 PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

Freaks A container so badly formed or squeezed out of shape

that it can be seen at almost any distance.

Uneven or Bad Uneven thickness of the glass.
Distribution

Soft Blister Thin walled bubble in the glass.

Broken Finish A finish which has cracks or actual pieces of glass
broken out of it.

Emhart Glass Hartford Division. (1967). Glass container defects causes and remedies [Photographs and
Descriptions]. Retrieved from
http://old.emhartglass.com/files/TW0738Causes%26Remedies_Secured.pdf

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 PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

APPENDIX B


MAJOR GLASS BOTTLE DEFECTS


DEFECT DESCRIPTION ILLUSTRATION

Chipped Finish A finish from which a small section is broken on the

top or side.

Stones Small pieces of refractory or unmelted batch materials.

Rocker-bottom A bottom which has sagged so that the container is
unstable when placed on a flat surface.

Offset Finish A finish formed out of alignment, either vertically or
Horizontally.

Blank and Mold Relatively large seams extending from the shoulder to
Seams the container base. Blank seams tend to veer off from
the mold seam.

Out-of-Round Finish which is oval-shaped ad which may be pinched
and Off-Gauge or flattened.
Finish

Emhart Glass Hartford Division. (1967). Glass container defects causes and remedies [Photographs and
Descriptions]. Retrieved from
http://old.emhartglass.com/files/TW0738Causes%26Remedies_Secured.pdf

3
 PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

APPENDIX C


MINOR GLASS BOTTLE DEFECTS


DEFECT DESCRIPTION ILLUSTRATION

Sunken A shoulder which is not fully blown up.

Shoulders

Finish Tear A finish which has a light surface crack in the threads
or in the middle.

Washboards A series of horizontal waves or folds on the side of the
container.

Brush Marks Fine vertical lines in the side or neck of a container

Dirty Ware Ware which has carbon or dirty deposits on it.

Wedge Bottom- A localized thick area at one side of the bottom.
Heel Tap- Slug
Bottom

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 PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

Hard Blisters Thick walled bubble in the glass.

Stuck A rough spot left by pulling apart bottles that touched
while still soft and sticky.

Long Neck A neck that has been stretched longer than specified.

Seed Very small bubbles in the glass.

Neck Ring Seam A protruding seam of glass running vertically up to the
finish of the container.

Emhart Glass Hartford Division. (1967). Glass container defects causes and remedies [Photographs and
Descriptions]. Retrieved from
http://old.emhartglass.com/files/TW0738Causes%26Remedies_Secured.pdf

5
  
PHA6122​:​ ​Quality Control Laboratory 
 
SAMPLING PLAN 
SAMPLING INSPECTION OF LABELING MATERIALS ● A specification for sampling inspection 
Objectives:  ● Description  of  the  location,  number  of  units  and/or  quantity  of 
1. Perform inspection on a representation sample of labels  material  that  should  be  collected,  and  associated  acceptance 
 

The  inspection  methods  we  are  focusing  on  in  the  criteria 
laboratory  are  more  on  the  inspection  of  the  packaging  materials.  ○ We  have  to  note  that  all  the  population  should  have  an 
That  is  why  in  100%  inspection,  we discussed containers and bottles.  equal chance to be selected as a sample 
In this activity, the samples are the labels.  ● A  definite  working  rule  regarding  size  and  frequency  of  sample 
and  the  basis  for  acceptance  or  rejection  ​[acceptance  quality 
 

2. Determine  the  size  of  gross  sample and laboratory sample using 

appropriate sampling plan  limit/accepted quality level (AQL)] 
3. Give  a disposition for the sample labels based on conformance to  ○ AQL: maximum percent defective 
regulatory standards  ● Different  sampling  inspection  methods  ​[depending  on  the 
  number of sample groups from a population] 
SAMPLING INSPECTION  ○ Single = 1​ batch of sample and 1 acceptance criteria 
● Process  of  removing  an  appropriate  number  of  items  from  a  ○ Double = ​2 groups of samples and 2 acceptance limits 
population in order to make inferences to the entire population  ○ Multiple =​ several groups and several acceptance criteria 
● Representative units are inspected  ● Requires:   
○ Only  a  representative  sample  of  units  is  inspected.  This  ○ N = lot or batch 
portion  of  the  population  to  be inspected is represented by  ✓ Population 
“n” [sample size]  ✓ The  total  of  all  actual  or  conceivable  items  of  a 
● Based on statistics and law of probability  specific class under consideration for inspection 
● Involves  risks  of  errors  ​because  we  are  only  inspecting  a  ○ n = random sample drawn from lot 
representative  of  the  whole  population  but  despite  the  ✓ Sample size 
possibilities of these errors...  ✓ Small  portion  of  the  batch  from  the  population 
● Better quality assurance than 100% inspection  collected  according  to  a  refined  sampling  plan  or 
  procedure 
RISK OF ERRORS  ✓ There  should  be  equal  chances  of  the  samples  to  be 
represented or selected by random sampling 
Consumer’s Decision 
  ○ c/Ac = acceptance number 
Accept  Reject  ✓ This  number  will  serve  as  the  acceptance  criteria  as 
Lot Conforms  OK  Producer’s Risk  the  maximum  number  of defects a batch can contain 
Producer’s 
Activity  Lot doesn’t  Consumer’s  for it to be still accepted 
OK 
Conform  Risk   
Four  possible  outcomes  in  an  inspection.  Two  outcomes  N = 50, n = 5, c = 1 
are  correct,  that  is  when  we  accept  a  lot  that  conforms  to  Take a random sample of 5 from a lot of 50. If the sample contains 
specifications,  and  rejects  a  batch  that  does  not  conform  to  more than one defect, reject the lot, otherwise, accept the lot 
specifications.    
The  other  two possible outcomes involve  the risk of errors  SAMPLING METHOD 
which  are  producer’s  risk  and  consumer’s  risk.  These  errors  occur  ● Part  of  the  sampling  procedure  dealing  with  the  method 
when sampling is not performed correctly.   prescribed for withdrawing samples 
  ● Most common sampling methods: 
Producer’s Risk  ○ Square Root Method N ​ -plan method 
↳ The probability of rejecting a “good” lot  ○ MIL-STD/ABC/ANSI/ASQZ​1.4 ​Government sampling method 
   
Consumer’s Risk  ABC  stands  for  America,  Great  Britain  and  Canada. These 
↳ The probability of accepting a “bad” lot  are  the  first  three  countries  to  use  the  military  standard  table  in 
  withdrawing  samples.  ​ANSI  stands  for American National Standards 
These  errors  can  be  prevented  by  preparing  and  Institute. ​ASQ​ stands for American Society for Quality. 
implementing an efficient sampling plan.    
  KINDS OF SAMPLES 
  Gross Sample 
  ↳ Number of packages to be opened 
  ↳ Total Sample 
  ↳ We  are after the bigger unit, whether packages, bundles, boxes, 
  or any other quantifiers denoting bigger units 
   
  Laboratory Sample 
  ↳ Sample for QC tests 
  ↳ The  items  to  be  inspected  and  we  are  now  after  the  smaller 
  units, such as labels, inserts, bottle cap, or bottles 
  ↳ Overall, this is the sample size 
     
 
 

 
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PHA6122​:​ ​Quality Control Laboratory 
 
Test Sample  GOVERNMENT SAMPLING METHOD 
↳ Sample  that  has  to  undergo some modifications prior to actual  ● “Military Standards” 
tests  ● Uses a Master table to determine n, Ac, and Re 
  MIL-STD-105D/ABC-STD-105D  sampling by attributes 
Retention Sample 
MIL-STD-414  sampling by variables 
↳ Sample for safekeeping 
↳ Usually  equal  to  twice  the  amount  needed  for  one  complete  ● Normal, Tightened, or Reduced Inspection 
analysis of the sample   
  ACCEPTABLE QUALITY LEVEL (AQL) 
Sampling is the process of removing an appropriate number or  ● Acceptable Quality Limit (AQL) 
items from a population to make inferences to the entire population  ● Maximum percent defective 
  ● Maximum defects per hundred unit 
 

BASIS FOR TIME WITHDRAWAL  It  can  be considered as satisfactory as a process over age 

1. Time Basis  for  sampling  inspection.  The  AQL  can  range  as  high  as  1000  to  as 
↳ Withdrawal  of  samples  is  done  at  a  prescribed  frequency  low  as  0.01.  The  acceptance  criteria  for  serious,  critical,  or  major 
such  as:  per  hour,  every  two  hours,  or any time interval set  defects  should  be  more  severe  than  for  trivial  or  minor  defects, 
by the manufacturers  commonly assigned values of < 10 per 100 units in our inspection. 
2. Portions of a Batch  
 

● Values > 10 

3. Sampling Plan   

Low AQL Values 

↳ Most used basis for time withdrawal 
↳ Given  for  critical  ​(and  major)  defects  because  we  only  allow a 
4. Prescribed Quantity 
minimal number of defective products per 100 items 
↳ Based  on  good  manufacturing  practice  (GMP),  in-house  or 
↳ Type of defects that would have serious consequences 
pharmacopeial requirements of each manufacturing plant 
 
↳ Will  also  be  the  basis  for  withdrawal  for  one  complete 
High AQL Values 
analysis 
↳ Given  for  trivial  defects  because  we  can  allow  a  number  of 
 
defective products  
PREPARATION OF DIFFERENT SAMPLES 
↳ Type of defects that are of little importance 
Gross  Test  Retention   
  Lab Sample 
Sample  Sample  Sample 
Minor defects will not affect the functionality of the product 
<5 = All   
Top, middle, 
6 一 50 = 5  Portion  ● Statistical tools 
end 
Crude Drugs  >50 = 10% of  Quartering  from test  ● Helps  in  determining  how  many  samples  will  be  used,  limit 
(Pooled then 
rounded-up  sample  between acceptability and refusal 
quartered) 
value  0%  For critical defects, unacceptable 
Purified Raw  Square Root  2.5%  For major defects 
2 x OCA  3 x OCA  2 x OCA 
Materials  System 
4%  For minor defects 
Finished 
Based on requirements of the analytical procedure  We  can  interpret  this  as,  every  100  units  inspected,  only 
Products 
four  (4)  minor  defective  products,  only  around  2.5  major  defective 
Packaging  Square Root  MIL-STD for 
products,  and  no  (0)  critical defective products should be present to 
Components  System  attributes 
accept the batch. 
Withdrawn on  Based on GMP,     
In-Process  a time basis  in-house or 
Materials  or portions of  pharmacopeial  In  the  government  sampling  method  or  military  standard 
a batch  reqt.  table,  the  first  step  is  to  use  the  Lot  size  table  to  determine  the 
Summarizes  the  different  preparations  of  samples.  For  sample size code letter depending on the lot size or batch size.  
packaging  material,  the  square  root  system  will  be  used (big units),  For  the  first  column,  we  compute  for  the  total  number  of 
for  laboratory  samples  (smaller  units  aka  sample  size),  the military  population  (smaller  units).  After,  we  determine  the  inspection levels, 
method will be used.  which  can  be special or general. The Special inspection levels can be 
  further  divided  into  four,  which  are  necessary  for  a  relatively  small 
COMMON SAMPLING PLANS  sample size and in cases where large sampling risk can be tolerated. 
● Square Root System/n-Plan Method  For  the  General  Inspection  Level  (I,  II, III), if not specified in 
n = √N + 1   the  problem  we  automatically  use  ​Level  II​,  which  is  the  most 
Example:  common  choice.  ​Level  I  is  used  to  apply  less  discrimination  to  our 
For inspection: 15 bundles of Drug X Label with Batch No. XYZ​123  suppliers, while ​Level III​ is applied for greater discrimination.  
n = √15 + 1   Once  we  were  able  to  determine  the  sample  size  code 
n = 3.87298334621 + 1   letter,  we  now  proceed  to  the  single  sampling  plan  table  of  the 
n = 4.87298334621   specific  general  inspection  level  we  use.  Since  there  are  three 
n = 5 bundles   general  inspection  levels,  there  will  also  be  three  general  sampling 
!! Always round up !!  tables.  
The  acceptance  criteria  are specified by AQL (Acceptance  The  AQL  is  not  standardized  and  is  assigned  by  the 
Quality  Level/Limit).  If  the  population  is  ​≤  4​,  every  container  is  manufacturer.  It’s  more  of  an  in-house  specification  rather  than  a 
sampled.  The  n-plan  method is not statistically based and should be  requirement. 
used only as a guiding principle.     
 
 
TIMTIMAN ​|​ 3H-PHARMACY | 2020-2021
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PHA6122​:​ ​Quality Control Laboratory 
 
If  the  supplier  has  a  good  quality  history  with  the 
manufacturer,  the  general  inspection  level  can  be  reduced.  Lesser 
discriminaiton  may  be  used,  aka  General  Inspection  Level  I 
(Reduced Inspection). 
General  Inspection  Level  III  is  used  for  new  suppliers,  or 
suppliers  with  an  unsatisfactory  history  or  no  recorded  history  of 
transactions  at  all.  It  is  also  called  the  “Tightened  Inspection”  which 
applies greater discriminaiton in an inspection method.  
 
tandaan mo na lang ginawa sa manuf lab for the process 
 
SAMPLE PROBLEM: 
500  boxes  of  labels,  containing  100  pieces  each,  were 
delivered  from  your  supplier.  You  were  tasked  to  inspect  first  the 
batch.  You  found  20  defective  labels.  Since  it  is  just  a  minor  defect, 
you assigned an AQL of 2.5. 
 
What is the gross sample? 
n = √N + 1  
n = √500 + 1  
n = 22.3606797749979 + 1  
n = 23.36  
n = 24 boxes  
 
Gross  sample  is  the  number  of  packages  to  be  opened, 
therefore we are after the bigger unit which is boxes. To compute for 
gross  sample  of  packaging  material  based  on  the  table  before, 
N-plan or the square root method was used. 
 
What is the batch size? 
500 boxes × 100 labels/box  
50, 000 labels  
 
What is the sample size code letter?  
50,000 = N 
 
What is the laboratory sample ​[sample size]​? 
N = 500 
 
What is the disposition? P ​ ASSED 
Ac = 21 
Re = 22 
 
 
 

 
TIMTIMAN ​|​ 3H-PHARMACY | 2020-2021
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 PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

Activity 9
SAMPLING INSPECTION

Table 1. Sample size code letters
















1
 PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

Table 2. Single sampling plans for reduced inspection (Master table)

2
PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

Table 3. Single sampling plans for tightened inspection (Master table)

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PHA6122: PHARMACEUTICAL ANALYSIS 2 LABORATORY
UST – Faculty of Pharmacy

Table 4. Single sampling plans for normal inspection (Master table)

4
 STABILITY STUDY FOR ACETAMINOPHEN TABLET  purpose  or  its  entire  expiry  period  or  retest  period  at 
“Stability  studies  are  a  vital  part  of  the  drug  development  labeled storage conditions 
process  because  this  is  an  important  way  to  assure  that  drug  - Covers  physical,  chemical,  microbiological, 
products/substances  still  remain  at  the acceptance criteria for a  therapeutic, and toxicological attributes. 
given attribute after a period of time.”  - Shall be performed under the following situations: 
  - New  products  or  Existing  products  in  new 
STABILITY  packages 
- The  extent  to  which  a  product retains, within specified  - Change  in  formula,  processing  method,  or 
limits,  and  throughout  its  shelf-life or period of storage  source of raw materials 
and  use, the same properties and characteristics that it  - Batches released by exception   
possessed at the time of its manufacture.  - This  is  possible  in  cases  where  a 
  process  is  well  characterized  in  the 
  critical  process  parameters  and 
quality  attributes  are  well  defined 
TYPE OF STABILITY  CONDITIONS  MAINTAINED  THROUGHOUT 
THE  SHELF-LIFE  OF  THE  DRUG  PRODUCT  and understood already  
(defined by USP)  - Marketed products to confirm assigned shelf-life 
 
Chemical  Each  active  ingredient  retains  its  chemical  SHELF-LIFE DETERMINATION 
integrity  and  labeled  potency,  within  the  - The period of stability of the product 
specified limits and throughout its shelf-life  - The  time  from  the  date  of  manufacture  of  the 
 
formulation  until  its  chemical  or  biological  activity  is 
Example of Chemical Instability 
- When there is a loss of drug through a  NOT  LESS  THAN  90%*  of  the  labeled  potency  or  the 
chemical  reaction  resulting  into  a  lower  limit  is  indicated  in  the  specific  guideline  or 
reduction  of  potency  or  when there is  monograph 
formation  of  higher  risk  of  - We  are  following  the  ASEAN  guidelines  so 
decomposition  or  degradation  the Lower Limit is 95% and not 90% 
products  that  might  be  harmful  when   
ingested 
EXPIRATION DATE DETERMINATION 
Physical  The  original  physical  properties,  including  - It  is  the  time  in  terms  of  month  and  year  calculated 
appearance, palatability, uniformity, dissolution,  from  SHELF-LIFE  +  DATE  OF  THE  LAST PROCESSING 
and suspendability are retained.  STAGE (or Manufacturing date) prior to packaging 
    
- Any  deviation  from  these  original  ASEAN GUIDELINE ON STABILITY STUDY OF DRUG PRODUCT 
physical  properties  can  already  be  a  - Basis of our discussion 
sign of Insufficient stability 
Objective 
Microbiological  Sterility  or  resistance  to  microbial  growth  is  - To  provide  recommendations  on  the  core  stability 
retained  according  to  the  specified  study package required for drug products 
requirements.  Antimicrobial  agents  that  are  - To  propose  shelf-life  based  on  the  stability  data 
present  retain  effectiveness  within  the  generated from the study package 
specified  limits  and  throughout  the  given  Scope: 
shelf-life  - Addresses  information  to  be  submitted  during  the 
Therapeutic  The therapeutic effects remain unchanged  application  for  marketing  authorization  or  registration 
and  variations  of  drug  products  in  ASEAN  member 
Toxicological  No significant increase in toxicity occurs  states  
- The  drug  products  covered  in  this  guideline  include 
“If  any  of  these  stabilities  are  greatly  compromised,  possible 
new  chemical  entity  (NCE),  generics,  and  variation but 
Therapeutic  failure  and  Adverse responses may happen. This is 
exclude  biologicals  and  drug  products  containing 
why  it  is  important  to  do  Stability  studies  to  make  sure that the 
vitamin and mineral preparations 
appropriate  shelf  life  and  expiration  dates  are  assigned  to  the 
Guideline 
product to make sure of its quality and efficiency.” 
- Stability  is  an  essential  factor  of  quality,  safety,  and 
 
efficacy  of  a  drug  product  and  any  insufficiency 
STABILITY STUDIES 
instability  of  a  drug  product  can  result  in  changes  in 
- Order  of  tests  in  order  to  obtain  an  assurance  of  the 
physical as well as chemical characteristics 
stability of a drug product 
- Stability  testing  should  be  biased  towards  more 
- Provide  evidence  that  the  strength,  quality,  purity  of 
stressful  rather  than  less  stressful  conditions  so  as  to 
the  drug  substance  are  suitable  for  its  intended 
provide a margin of error in favor of the patients and to 
 increase  the  likelihood  of  identifying  substances  or  STORAGE CONDITIONS FOR CLIMATIC ZONES (ICH*) 
formulations that post particular stability problems 
CLIMATIC  STORAGE CONDITION  LONG TERM 
- If  the  product  withstands  a  more  stressful  ZONE  STABILITY TESTING 
condition,  it  can  automatically  withstand  the  RECOMMENDED 
less stressful one  CONDITIONS 
- The  objective  of  a  stability  study  is  to  determine  the 
shelf-life as well as the expiration date for a product  Zone I  Temperate  21​o​C / 45% RH 
- Stability  study  consists  of  a  series  of  tests  including 
maintenance  of  the  specifications  of  the  drug  product  Zone II  Mediteranean /  25​o​C / 60% RH 
Subtropical 
packed  in  its  specified  packaging  material  and  stored 
at  the  established  storage  condition  within  the  Zone III  Hot, Dry  30​o​C / 35% RH 
determined time period 
- We  can  only  be  sure  about  the  reliability  of  Zone IVa  Hot-Humid / Tropical  30​o​C / 65% RH 
the  expiration  date  if  the  product  will  remain 
stored  in  its  packaging material and stored at  Zone IVb  Hot / Higher Humidity  30​o​C / 75% RH 
the  established  storage  conditions  as  stated  *ICH = International Council for Harmonization 
in the label  - Regulate  the  technical  requirements  for 
  pharmaceuticals for human use 
STABILITY PROGRAM TESTING FREQUENCY   
STORAGE  SCHEDULE  TESTING FREQUENCY  General  conditions  for  Long  term  Stability  testing  in  the  PH  as 
CONDITION  (months)  well as other ASEAN member states 
- 30​o​C / 75% RH (relative humidity) = Zone IVb 
Long term   Every 3 mos on the 1st year  0, 3, 6, 9, 12, 18, 24, 36   
OR     STORAGE CONDITIONS 
Real-time  Every 6 mos on the 2nd year 
  STUDY / TYPE OF CONTAINER  STORAGE CONDITION 
Every year thereafter until 
the expiration  Long term (for products in  30​o​C ± 2​o​C / 75% RH ± 5% RH 
Primary containers 
Short term  Every 3 mos for 6 mos  0*, 3, 6  SEMI-PERMEABLE to water 
OR   
Accelerated  *initial testing  Long term (for products in  30​o​C ± 2​o​C / RH not specified 
Primary containers 
*mos = months  IMPERMEABLE to water vapor 
LONG TERM / REAL-TIME STABILITY TESTING  
- Stability  studies  under  the  recommended  storage  Accelerated  40​o​C ± 2​o​C / 75% RH ± 5% RH 
condition  for  the  retest  period* or shelf-life** proposed 
(or approved) for labeling  Stress testing*  40​o​C ± 2​o​C / 75% RH ± 5% RH or 
at more stressful conditions 
- Also  known  as  Re-assay  Period:  is  the  that 
after  which  an  active  pharmaceutical  *Stress  testing  is  necessary  for  analytical  method  validation, 
ingredient  should  be  re-examined  to  ensure  pharmaceutical  formulation, identifying and monitoring potential 
that  the  material is still in compliance with the  degradants during stability testing. 
specification  and  thus  suitable  for  use  in  the   
manufacture of the given drug product   SEMI-PERMEABLE / SELECTIVELY PERMEABLE 
- The retest period is for raw materials   - Containers  that  allow  the  passage  of  solvent,  usually 
- **For finished drug product already  water, while preventing solute loss 
  - The mechanism for solvent transport occurs by: 
ACCELERATED STABILITY TESTING  1. Adsorption into one container surface 
- Studies  designed  to  increase  the  rate  of  chemical  2. Diffusion  through  the  bulk  of  the  container 
degradation  or physical change of a drug substance or  material 
drug  product  by using exaggerated storage conditions  3. Desorption from the other surface 
as part of the formal stability studies  - “Moisture,  water,  or  other  solvents  will  get 
  into  contact  with  the  outer  surface  of  the 
  container  and  adsorb  and  then  the  solvent 
  will  be  diffused  through  the  bulk  of  the 
  container  material, then finally the solvent will 
  be  released  by  Desorption  from  the  other 
  surface  of  the  container  or  from  the  inner 
 surface  of  the  container  getting  now  into  the  criteria/specification  as  stated  in  the  individual 
product”  monograph of the product 
- Examples:  a. Take  note:  The  5%  change  in  assay  is based 
- Plastic bags  on  the  initial  value  at  the  first  testing  period 
- Semi-rigid,  low-density  polyethylene  (LDPE)  so  that  is  at  0  month  and  not  based  on  the 
pouches for large volume parenterals (LVPs)  label claim 
- LDPE ampoules, bottles, and vials  2. Any  degradation  product  exceeding  the  acceptance 
  criterion 
IMPERMEABLE CONTAINER  3. Failure to meet the acceptance criteria for pH 
- Containers  that  provide  a  permanent  barrier  to  the  4. Failure  to  meet  the  acceptance  criteria  for  dissolution 
passage  of gasses or solvents and prevents them from  for 12 dosage units ( for capsules or tablets) 
getting into the product  5. Failure to meet the acceptance criteria for: 
- Examples:  - Appearance 
- Sealed aluminum tubes for semisolids  - Physical attributes 
- Sealed glass ampoules for solutions  - Functionality  test  (e.g.  face  separation, 
- Aluminum/Aluminum  blisters  for  solid dosage  resuspendability, caking, hardness, and those 
forms  delivery  per  actuation  of  drug  products  with 
  specialized drug delivery systems) 
STORAGE CONDITIONS  - However,  some  changes  in  physical 
- The  storage  conditions  and  the  lengths  of  studies  attributes  (e.g.  softening  of  suppositories, 
chosen  should  be  sufficient  to  cover  storage,  melting  of  creams)  may  be  expected  under 
shipment,  and  subsequent  use  after  reconstitution  or  accelerated  conditions;  and  as  appropriate 
dilution  as  recommended  in  the  labeling  of  drug  for the dosage form 
product  - Example:  There is face separation of 
  a  semi-solid  dosage  form  that 
SPECIFICATIONS (TESTING PARAMETERS)  occurs  at  accelerated  conditions, 
- Attributes  of  the  drug  product  that  are  susceptible  to  testing  at  the  Long  term  condition 
change  during  storage  and  are  likely  to  influence  the  should  be  performed  and  potential 
quality, safety, and efficacy of the drug product  interaction  effects  should  also  be 
- Testing  should  cover,  as  appropriate,  the  physical,  considered in establishing that there 
chemical,  biological,  and  microbiological  attributes,  is no other significant change 
preservative,  contante  (e.g.  antioxidant,  antimicrobial  - If  there  is  “significant  change”  noted  within  the  first  3 
preservative),  and  functionality  tests  (e.g.  for  a  dose  months’  testing at the Accelerated storage condition, a 
delivery  system,  modified  release,  or  specialized  discussion  should  be  provided to address the effect of 
delivery system)  short  term  excursions  outside  the  label  storage 
- The  analytical  procedure  should  be fully validated and  conditions 
stability  indicating  according  to  the  ASEAN  guideline  - Example: During shipping or Handling 
on analytical validation  - When  evaluating  a  Stability  data,  there  are  2  possible 
- The  studies and parameters themselves must  results of both Accelerated and Long-term data 
be fully validated prior to use  1. First  scenario:  Show  little  or  no  change  over 
- In  general,  appearance,  assay,  and  degradation  time  and  little  or  no  variability  between 
products should be evaluated for all dosage forms  batches 
  2. Second  scenario:  Show  change  over  time 
EVALUATION OF STABILITY DATA  and/or  variability  within  a  factor  or  among 
- “The  focus  of  Activity  10  is  on  the  Evaluation  of  factors 
Stability  Data  gathered  or  the  establishment  of   
Shelf-life and Expiration date from the Stability Data   
- If  there  is  a  “significant  change”  noted  between  3 & 6   
months  testing  at  the  accelerated  storage  condition,   
the  proposed  shelf-life  should  be  based  on  the  real   
time  data  or  should  be  based  on  the  long  term  data   
that is available at the Long term storage condition   
   
THERE IS SIGNIFICANT CHANGE IF:   
1. A  5%  change  in  assay  from  its  initial  value  (not  from   
label  claim),  or  failure  to  meet  the  acceptance   
 
FIRST SCENARIO   
- Statistical analysis is normally unnecessary  SAMPLE PROBLEM 
- Proposed  shelf-life  (Y)  can  be  determined  with  the  A  batch  of  Acetaminophen  tablets  was  subjected  to  stability 
formula “Y = 2x”.   study.  The  study  was  done  initially  for  6  months,  but  due  to 
- Where  x  is  the  period  covered  by  Long-term  observed  significant  change,  it  was  extended  to  30  months. 
data  but  not  exceeding  x  +  12  months*  (x  =  Determine  the  shelf-life  and  expiry  date  based  on  the  data 
period  covered  by  Long-term  data;  minimum  given. Show the following: 
time to conduct stability studies)  - Graph 
- *minimum  time  to  conduct  stability  - Trend line 
studies  - Equation of the line 
- Example: Long term data = 24 months  - Regression statistics table 
Compute for the Proposed Shelf-life:   
Y = 2x  Product: Acetaminophen 500mg tablet 
Y = 2(24)  Batch number: XYZ123 
​Y = 48 months  Specification: 
Compute for the Proposed shelf-life using this formula:  Date of Manufacture: November 16, 2020 
Y = x + 12 months  Expiry Date: 
Y = 24 + 12 months  Shelf-life (months):  
​Y = 36 months   
 
TIME INTERVAL   ACTUAL% LABELLED 
48  >  36.  ​Thus  the  proposed  Shelf-life  that  will  be  (months)  AMOUNT 
followed  is  36  months.  Because  when 
computing/determining  the  Shelf-life  follow  or  go  0  100.8 
towards  a  more  conservative  route.  Since  36  is lesser 
than 48 we then follow 36 months.  3  98.9 
 
6  95.1 
“BUT  for  example  your  value  for  Y  =  2x  does  not  exceed  the 
value for Y = x + 12 months we go ahead and follow Y = 2x.”   9  98.4 
 
SECOND SCENARIO  12  99.1 
- Statistical  analysis  of  the  long-term  data  can be useful 
in establishing  18  98.3 
1. A retest period 
2. Shelf-life  within  the  factor  (e.g.  different  24  100.1 
strengths) 
25  100.5 
 
STATISTICAL APPROACHES TO STABILITY DATA ANALYSIS  26  99.6 
LINEAR REGRESSION 
- Determining  the earliest time at which 95% confidence  27  98.7 
limit  for  the  mean  intersects  the proposed acceptance 
criterion/specification  28  97.1 
 
29  97.8 
POOLABILITY TESTS BETWEEN BATCHES 
- Analysis of Covariance (ANCOVA)  30  97.4 
 
“Assay  is  the  attribute  we  compute  and  based  our  stability 
STATISTICAL MODELING 
study” 
- Multi-factor, Full-design studies 
- Significant  change  in  the  6th  month  by  5%  change 
 
from  its  initial  value  of  100.8%  that  is  why  the  study  is 
 
  also extended. 
 
 
 
 
 
 
 
 
  
  4. After  clicking  OK.  You  will  get  the Summary Output. In 
  this  summary  output, you can see at the last table your 
REGRESSION STATISTICS TABLE (Step by Step using Excel)  Intercept and X variable.  
1. In  your  TOOLS,  make  sure  you  have  an  Analysis 
Toolpak add in  

 
 
5. So  when  we  look at the Coefficient column, the values 
that  you  obtained  for  the  Intercept  and  the  x  variable 
are  the  same  as  what  you  obtain  in  your  Equation  of 
the line 

 
2. Go  to  the  Data  analysis  (red  circle)  and  choose 
Regression 
 
 
6. From  this  table,  we  will use the lower 95% Confidence 
limit.  Because  the  attribute  normally  for  stability 
studies  decrease  with  time  that  is  why  we  use  the 
LOWER 95% 

 
3. First,  input  your  Y-range  (%  Labeled  amount).  Then 
input  your  X-range  (Time  interval  (months).  Then  we 
set the Confidence Level to 95%. Please take note that 
in  ​ASEAN  and  ICH  guidelines  it  is  stricter  thus  it 
should  be  95  not  90  (as  we  all  know  aka  the  T90   
 
value). Then click ok. 
7. Then  we  will  use  this  values  then  use  the formula: Y = 
mx + b to finally get the Shelf-life.  
Where: 
Y = 95% 
m = x variable (from the Lower 95% Confidence limit) 
b = intercept (from the Lower 95% Confidence limit) 
 
 
8. Substitute the values: 
Y = mx + b 
95 = -0.10211792x + 96.743367 
x = 17.0618509 
 
Shelf-life value: 17.0618509​🔺​ months 
 
Remember: 
“We  solve  for  x  because  in  the  data  given  the  X-axis  is  also 
referred  to  as  the  months/Time  interval  and  again  Shelf-life  is 
also measured in months.” 
 
🔺​“Please  take  note  in  shelf-life  analysis  or  Stability  Data 
Evaluation  and  you are trying to determine the Shelf-life, always 
ROUND  DOWN  ignore  the  Rounding-off  rules.  Always  Round 
down  because  it  is  the  more  Conservative  route  towards  the 
safer side. 
 
Expiry date = Manufacturing date + Shelf-life (17 months) 
Expiry date = November 2020 + 17 
Expiry date: April 2022