The document discusses the process for qualifying visual inspectors for pharmaceutical inspection including selecting inspectors based on vision and observation skills, extensive training using mock defect containers, and qualification testing to accurately identify defect types with acceptable error rates. It also reviews inspection parameters, defect categorization, sampling plans, and analytical techniques for investigating particulate matter found during inspection.

1. Qualifying Visual Inspectors
The benchmarking process
• Presented by
• Dr. Yasir Mehmood
• (PhD Pharmaceutics, MBA)

2. Visual Inspection
Visual inspection is a probabilistic process and the specific detection probability
observed for a given product for visible particles that will vary with differences in
Particle characteristics
Package design
Product formulation

3. • Why to inspect?
• To detect and eliminate defective units from the lot.
• Extraneous Particulate matter in solution.
• Product precipitates.
• Sealing / crimping defects.
• Cracks / non-integral container-closure.
• Volume variations
Regulatory requirement – “Injectable products should be
essentially free from any visible particles” USP <1>, <790> & <1790>
Objectives

4. Particulate Matter
Intrinsic
Formulation, Processing Equipment, Primary
Package
Qualified product contact materials (e.g. stainless steel,
aluminum, glass, rubber, silicone oil)
Particulate Matter: Intrinsic element of the manufacturing process

5. Foreign Matter
Extrinsic
Environmental Contaminants
E.g.. Insect Parts, Hair, Fibers, Paint, Rust
Foreign Matter: Foreign particle to manufacturing process. Also called as
Extrinsic Particles

6. • Particles in Vascular System
 Blockages
 Emboli
 Accumulation/Chronic Damage to organs
• Extra vascular Particulate
 Immune Response
 Eye/Tissue Damage
Foreign Matter Concerns

8. Foreign Matter Concerns
Glass fragments in Inhalers
Rubber o Ring pieces in IV solutions
Aluminum Silver in Ophthalmic
Eye Drops
Real Life
Examples

10. 100% Inspection
(USP40–NF35 Supplement I: Chapter1790)
Each unit (container, closure and its content) of Injectables
product should be inspected as part of the routine
manufacturing process
This inspection may be performed at-line or in-line with
filling or packaging or in a separate, off-line inspection
department
This inspection should take place at a point when and
where defects are most easily detected (e.g. before
printing)

11. InspectionProcess Flow
Filling 100%
Inspection
After
Reconstitution
Acceptance,
Sampling, and
Testing
Packaging
Analyse and
Trend Rejects
Supplemental
Testing
Rejected Units
Accepted Units

12. • Critical Defects:
That cause serious adverse reaction or death of patients & any non
conformity that compromise the integrity of container and
thereby risks microbiological contamination of the sterile product.
• Major Defects:
That carries the risk of a temporary impairment or medically
reversible reaction, or involves a remote probability of a serious
adverse reaction.
• Minor Defects:
These defects do not impact product performance or compliance;
they are often cosmetic in nature, affecting only product
appearance or pharmaceutical elegance.
Types of Defects

13. AQL Sample Testing
Defect Category Nature of Defects AQL Range
Critical
Before Reconstitution:
 Broken or cracked glass vial
 Seal on vial broken, missing or
jagged
 Presence of any visible particle
 Precipitation inside the vial
0.01-0.1
Major
After Reconstitution:
 Particle/spot/smudge inside vial,
adhered to glass/stopper
 Cap broken / over crimped/under
crimped
 Presence of Invisible particulate
matter
0.10-0.65
Minor
 They include defect on outside of the vial,
scratch, or glass defect.
1.0-4.0
AQL: Acceptance Quality Limit

14. Light
Intensity
NLT 2,000-
3,750 lux for
clear glass
container
10,000 lux For
translucent
plastic container
Background
Black / White
18% Gray
Inspection
Time
10 sec per
container
Additional time
for complex
containers
Critical Process Parameters

15. Apparatus
• Vertical matte black panel
• Vertical non-glare white panel next to black panel
• Adjustable lamp holder with shaded, white light source and a
diffuser (two 13W fluorescent tubes, each 525 mm (20.7 in) in length
is suitable), illumination at the viewing point is between 2,000 and
3,750 lux for clear glass ampoules.
• Higher values are preferable for colored glass and plastic containers.

16. Selection Criteria
• Prerequisites
oPre-employment Health check
oPre-employment eye test – requirement > 90 % corrected
All operators should have a near vision visual acuity/ color
blindness test prior to inspector training. The achievement
of 14/14 acuity is required

18. Selection Criteria
• Character
• The inspector should realize the importance of his task.
• The inspector should be able to perform repetive work
• Ability to learn and adapt new ideas.
• The inspector should have good observation skills and should also
be patient

19. Training of Visual
Inspectors
• Training of relevant SOPs and Work-Instructions
• Introduction to defects using training kits
• Learning individual defects using training kits and defect
libraries
Basic qualification:
• Additional qualification in small teams more
complicated products
• Requalification once a year

20. Training Phase 1
 All training is defined in a SOP
 Classroom instruction
 Product specific physical characteristics
 Small number of defect vials with Large particle
 Move to real inspection station
 Practice manipulation, timing & detection
 Seeded containers no blanks-familiarization.

21. Training Phase 2
• Seeded containers diluted with blanks-familiarization.
• Distinguish particle types.
• Distinguish bubble forming Drug Products.
• Timing.
• Use of tools (e.g. clip)

22. Training Phase 3
• Best inspectors offer 'tricks', methods, advice
• Visual inspection under supervision and 100 % re- inspection
• Further introduction to defects using test kits
• Qualification using test kits
• Requalification once a year

27. Overall
Accuracy
Total no. of inspections that matches for standard  100
Total no. of inspections
Overall
Error Rate
Inspector
Accuracy Rate
Unit Specific
Error Rate
Total no. of inspections don’t matches for standard  100
Total no. of inspections
No. of correct matches by the inspector  100
No. of Inspections
No. of incorrect matches on specific unit  100
No. of inspection done on the specific unit
Calculations

28. Lot Size
Special Inspection Levels
S-1 S-2 S-3
501 -1200 C C
E
1201 -3200 C D E
320 -10000 C D F
10001 -35000 C D F
35001-150000 D E G
150001-500000 D E G
500001-Over D E H
•Sample size code letters (Table 1 ISO2859-1))
Note: In case of critical defects only S1 sampling plan is use; which means person should be able
to inspect 100% defects. However, for major & minor defects we can shift towards S2 & S3
inspection levels.
Sampling Plan Of Vials For
Reconstitution / Optical

29. Sample
size code
letter
Sample
size
Acceptance quality limit, AQL in percent nonconforming items and
nonconformities per 100 items (normal inspection)
0.010 0.65 4.0
Ac Re Ac Re Ac Re
C 5 0 1
D 8
E 13 1 2
F 20 0 1 2 3
G 32 3 4
H 50 5 6
J 80 1 2 7 8
K 125 0 1 2 3 10 11
Single Sampling Plans For
Normal Inspection
(Table 2A ISO-2859-1)

30. Sample
Size
Code
Sample
Sample
Size
Cumulative
Sample Size
Acceptance quality limit, AQL in percent nonconforming items
and nonconformities per 100 items
(normal inspection)
0.01 0.65 4.0
Ac Re Ac Re Ac Re
C
First
Second
3
3
3
6
* *
D
First
Second
5
5
5
10
E
First
Second
8
8
8
16
0
1
2
2
F
First
Second
13
13
13
26
* *
0
3
3
4
G
First
Second
20
20
20
40
1
4
3
5
H
First
Second
32
32
32
64
2
6
5
7
J
First
Second
50
50
50
100
0
1
2
2
3
9
6
10
K
First
Second
80
80
80
160
* *
0
3
3
4
5
12
9
13
Double Sampling Plans For Normal
Inspection
(Table 3A ISO2859-1)

31. ID of
Vial
Std.
Vials
First Inspection Trial Second Inspection Trial Third Inspection Trial
1 G G G G G G G G G G
2 B B B B B B B B B B
3 G G B G B G G G G G
4 G G G G G G G G G G
5 G G G G B G G G G G
6 G G G G G G G G G G
7 G G G G G G G G G G
8 B B B B B B B B B B
9 B B B B B B B B B B
10 G G G G G G G G G G
Visual Inspection Trials
Data For 10 Out Of 100 Vials

32. Breaks
• Time away from the lamp
Eye break
• Minimum of 8 minutes per hour
eye break
Time

33. Lunch
Discussions
Trainings
Breaks

34. Visual Acuity........................ 92%
Color Vision ......................... 76%
Education............................ 42%
Training.............................. 94%
Test of Inspection Ability........ 90%
Experience.......................... 32%
22% have different selection and training Production and QA inspectors?
Survey 2014 Results

35. How Frequently Inspectors Take A Break Or Rotate To A Non
Inspection Task?

36. Qualification with kit shall be carried in designated
visual inspection area for routine product
Trained visual inspector to perform visual inspection of
characterized qualification kit.
Record the number details of rejected & good units in
format.
Qualified inspector shall check number details of rejected &
good units & quantity & quantity segregated by the trainee
visual inspector
Trainee able to
identify the entire
rejects & good units
pass
Fall in 1st attempt
Identify defects (container/closure
and particulate matter) and good units
By comparing container
numbers with ‘Master List for
Qualification Kit’
Fall in 2nd attempt
Fall in 3rd t attempt
Disqualified
Qualification of Visual Inspector

37. • Part iculat e mat t er can b e def in ed b y s iz e :
• Vi s i bl e p ar t i c l es : ≥ 1 00 μm
• S ub - v i si b l e p ar t i c l es : < 1 00 μm
• N o v i s i b l e p a r t i c l e s a r e a l l o we d
• U S P c o n t a i n s l i m i t s f o r s u b - v i s i b l e p a r t i c l e s
≥10 μm ≥5 μm
Small Volume Injections 6000 600 per container
Large Volume Injections 25 3 per mL

38. The technique involves
directing a laser through a
dilute solution
I n s t r u m e n t c o u n t s a n d s i
z e s p a r t i c l e s Shadow
Flow
Detector
Laser Diode
Light obstruction Method

39. Light obstruction
Method

40. Pr o s
• 1 - 6 0 0 m i c r on s
• F a s t a n d r e p e a t a b l e
• R e c om m en d ed b y U S P
C o n s
• Pr o v i d e s “ a v e r a g e ” p ar t i c l e s i z e
• I n s t r u m e n t a c c u r a c y
• B u b b l es
Th e m et ho d s ho ul d b e v er i f i ed f o r t h e
s p e c i f i c p r o d u c t a n d a n y u n u s u a l s a m p l e p r e
p a r a t i o n
N O TE :
Light obstruction Method

41. Test Volume (ml) Average Number of particles
Test1.A More than 100ml
 NMT 25 per ml for equal to greater
than 10um.
 NMT 3 per ml for equal to greater than
25um.
Test1.B
Less than or equal to
100ml
 NMT 6000per container for equal to
greater than 10um.
 NMT 600 per container equal to or
greater than 25μm.
Acceptance Criteria
Note: If the average number of particles exceeds the limits, test the preparation by the Microscopic Particle
Count Test.
Light obstruction Method

42. An i n v e s t i g a t i o n i s r e q u i r e d t o d e t e r m i n e t h e n a t u
r e a n d s o u r c e o f t h e p a r t i c u l a t e
I n v e s t i g a t i v e a n a l y s i s :
• Va l i d a t e d m e t h o d s a r e n o t r e q u i r e d
Investigation

43. Concomitant Analysis
Identification of particulate
Particle may be visible or sub visible
How
particles
found
Inspection
of Raw
Material
QC
inspection
of final
product
Operators

44. • F i l t r a t i o n ( U S P < 7 8 8 > M e t h o d 2)
• C e n t r i f u g a t i o n
• M a n u a l r e m o v a l wi t h l i g
h t m i c r os c o p e a nd s c
a l p e l
• S o l v e n t
e x t r a c t i o n s / r i n s i n g
Sample Preparation

45. Sample Preparation

46. Te c h n i q u e s m u s t b e s u i t a b l e f o r a n a l y z i n g m i c ron s i ze d
p a r t i c l e s t y p i c a l l y we i g h i n g l e s s t h a n a f e w m i c r o g r a m s
Th es e i nc l u d e :
• Li g h t m i c r os c o py
• S E M a n d S E M / E D S
• M i c r o - FT I R
s p e c t r o s c o p y
Analytical Method

47. •Colour and size of a contaminant
•Physical nature of the contaminant:
•Gel-like
•Solid (crystal, amorphous or fiber)
•Heterogeneity of the contaminant
•Chemical nature of the contaminant:
•Organic material
•Polymeric material
•Inorganic (e.g. salt or metal)
•Recommendations for analysis
starting point
Light Microscopy

48. Light
Source
Stationary Mirror
Beam
Splitter
Sample
Detector
Moving Mirror
FTIR Spectroscopy

49. • H e r e i s a n e x a m p l e Po l y e t h y l e n e s p e c t r u m
-(-CH2-CH2-CH2-)n-
Scissoring
of H’s
Rocking
of H’s
C-H stretching
FTIR Spectroscopy

50. • S E M s a r e t r a d i t i o n a l l y
u s e d t o o b t a i n m o r ph ol o gy o f
c o n d u c t i v e m a t e r i a l s
( i . e . m e t a l s )
• Th i s i s p e r f or m e d b y c o
l l e c t i n g e m i t t e d
s ec o nd ar y e l e c t r o ns
e m i t t e d f r o m a s u r f a c e
• C o l l e c t i o n o f e m i t t e d X - r a
y s a l l o ws f o r t h e
d e t e r m i n a t i o n o f t h e s o
u r c e e l e m en t
Electron Beam
e-
Backscattered
Electron
Detector
EDS

51. Fe Cr
Mn
Fe
Ni Al
Fe
Stainless Steel
EDS

52. SEM

53. W h at i s t h at p ar t i c l e i ns i d e o f t h e p r e - f i l l ed s y r i
n g e ?
• U p on i ni t i a l e x a m i n at i o n we c ou l d s e e a g r e y i s h p a r t
i c l e i n s i d e o f a p r e - f i l l e d s y r i n g e .
• Th e p l a s t i c s y r i n g e wa s c u t o p e n a n d e x a m i n e d b y l i
g h tm i c r o s c o p e . Th e p a r t i c l e wa s o b s e r v e d s i t t i
n g o n t h e b a r r e l s u r f a c e .
• We p r op o s e d t o o bt a i n p ho t o s o f t h e p ar t i c l e a n d
t h e n a n a l y z e i t b y FTI R a n d S E M / E D S .
Case Study 1

54. Light grey particle on syringe wall Magnified
Li g h t m i c r o s c o p y a n d m a n u a l p r o b i n g s h o we d t h e p a r t i
c l e t o b e g r ey, o pa qu e a nd e l a s t o m e r i c .
Case Study 1

55. Grey Particle
Talc
Butyl Rubber
FT I R s h o we d t h e p a r t i c l e t o m a t c h t h a t o f a f i l l e d b u t y
l r u b b er
Case Study 1

56. Si
Mg
C
O
An al y s i s b y S E M / E D S s ho wed C , O , M g a nd S i a s pr e d
o m i n a n t e l e m e n t s
C as eS t u d y # 1
Case Study 1

57. The light grey particle is talc filled butyl rubber
Syringe plunger septum
The septum is a black rubber, so it is ruled out as a potential source of
particles
Audit the manufacturing process with respect to light grey rubber source
(e.g. gasket o-ring septa)
They could also approach their supplier as particles have upstream
source
Case Study 1:
Conclusion

58. W h a t i s t h a t f l o a t i n g i n t h e v i a l ?
• D u r i n g r o u t i n e Q C t e s t i n g b y U S P < 7 9 0 > , a r e j e
c t e d v i a l was s et a s i d e f o r s ub s eq ue nt i n v e s
t i g a t i o n
• I n i t i a l e x a m i n a t i o n r e v e a l e d a f i b
e r
• We p r o p o s e d t o a n a l y z e
t h e f i b er b y m i c r o - FT I R
Case Study 2

59. Fiber Spectrum
Polystyene Spectrum
Li g h t m i c r o s c o p y - f i b e r wi t h a f l a t p r o f i l e
FT I R a n a l y s i s i d e n t i f i e d t h e f i b e r a s p o l y s t y r e n e .
Case Study 2

60. Th e f i b e r wa s i d e n t i f i e d a s p o l y s t y r e n e
Th e p l a s t i c v i a l wa s a n a l y z e d a n d f o u n d t o b e p o l y
s t y r e n e
Th e v i a l i s t h e l i k e l y s o u r c e
Case Study 2:
Conclusion

61. W h a t a r e t h o s e p a r t i c l e s I c a n ’t e v e n s e e ?
• D u r i n g Q C t e s t i n g b y U S P < 7 8 8 > M e t h o d 1 , p a s s
i n g r e s u l t s w e r e o b t a i n e d, howe ver t he c ount s we
r e h i g h e r t h a n e x p e c t e d .
• Th e p r o d u c t wa s f i l t e r e d . E x a m i n a t i o n o f t h e f i l t e
r s h o we d d a r k p a r t i c l e s wi t h s i z e s i n t h e r a n g
e o f 2 5 m i c r o n s .
• We p r o p os e d t o a n al y z e t h e p a r t i c l es b y FTI R
a n d S E M / E D S .
Case Study 3

62. W e we r e n o t a b l e t o o b t a i n a u s e f u l FTI R s p e c
t r u m
T h e p ar t i c l e i s h i g hl y a bs or bi n g o r r e f l e c t i v e
Case Study 3

63. S E M c on f i r m e d t h e p ar t i c l e s i z e s
a n d s h a p e s .
Filtered
Particulate
Reference Charcoal
C as eS t u d y # 3

64. C
Filtered
Particulate
Reference Charcoal
O
E l e m e n t a l c o m p a r i s o n
Case Study 3

65. B a s ed o n FTI R s pe c t r o s c o p y, S E M a nd E D S
a n a l y s i s t h e s u b - v i s i b l e p a r t i c l e s we r e i d e n t i f i e d a s c
h ar c o al
Ac t i v a t ed c h a r c o al i s u s e d i n t h e i r p r oc e s s e s a s a f i l t e
r i n g a i d
Th e m a n u f a c t u r i n g p r o c e s s d i d n o t f u l l y r e m o v e t h e
c h a r c o a l f r o m t h e i r p r o d u c t
W h y ? ?
Case Study 3:
Conclusion