One of the mandatory and critical process in parenteral product manufacturing.

1. Visual Inspection of Parenteral Products
Prepared by: Sambhujyoti Das

2. General Process Flow
DISPENSING RMs MANUFACTURING
FILTRATION
(STERILIZATION)
FILLING &
SEALING
VISUAL
INSPECTION
DISPENSING OF
CONTAINERs /
CLOSUREs
WASHING
STERILIZATION /
DEPYROGENATION
100% filled
containers are
inspected.
Slide No. 2

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> , EP, JP.
Slide No. 3

4. The Particle Family
VISIBLE
PARTICLES
EXTRINSIC INTRINSIC INHERENT
o Not part of product (or non
product contact).
o From foreign and unexpected
sources.
o Fibers (e.g., cellulous), clothing
fragments, hair, rubber, metal,
plastic, and paint.
o Bioburden is unknown and
uncontrolled.
o Greater risk.
o Part of product / package
(product contact surfaces).
o Known sources.
o Glass, stainless steel, rubber
from stoppers, and gasket
material.
o Can change in the product
over time.
o Intrinsic to extrinsic.
o Expected from the drug
formulation.
o Adjuvant material in
suspension products, certain
excipients in serum albumin,
proteinaceous aggregates.
o Patient safety impacts should
be analysed.
o Should be in specification.
Slide No. 4

5. Guess the particle type
Polyester fibre Elastomer particle
(From aseptic gown) (From Rubber Stopper)
Slide No. 5

6. The Irony
REGULATION
PRACTICAL
SITUATION
Probabilistic
inspection
process
Unrealistic
Particle free
process
100%
Elimination of
Particle
100% Particle
free
Confused?
Slide No. 6

7. Visual Inspection System
Slide No. 7

8. Manual Inspection
 Visual inspection against black & white
background.
 Illumination at the inspection point by two
13-W / 15-W fluorescent lamps.
 Intensity between 2000 and 3750 lux.
 Gently swirl and/or invert each unit.
 Ensure that no air bubbles.
 5 s against each of the backgrounds.
 Presence of any particles should be
recorded. Slide No. 8

9. Automated Inspection
 Similar optical inspection like manual.
 Same or greater sensitivity (not all).
 Better consistency.
 Better efficiency with higher output.
 Often higher false rejection rate.
 High cost, limited adaptability.
 Standardization / validation intensive.
Slide No. 9

10. Particle Catalogue
Inspector’s ViewMagnified View
Slide No. 10

11. Particle Size vs Detectability
Particle Size % POD
>200 µm 100%
<100 µm 25% - 70%
<50 µm <5%
Detection Variables: Illumination (intensity, glare), contrast, duration
(inspection time, rate), agitation, number of particle, product type, container
type. Slide No. 11

12. Post Inspection Sampling
 Mandatory sampling and inspection after
100% visual inspection.
 Sampling plan as per ANSI/ASQ Z1.4 –
2008 (or ISO 2859-1): General Inspection
Level – II, Single sampling plans for Normal
inspection with an AQL of 0.65%.
 Batch releasing criteria: NMT the specified
number of units contains visible particulates.
 Special level sampling (reduced sample
quantity) for destructive inspections (for
powder filled, lyophilized products, coloured
containers, etc.).
AQL Failure
Is the test
Destructive
?
Investigation
Re-inspection
of 100% units
Batch
Rejection
Yes
No
PerformAQLinspection
Slide No. 12

13. Particle Separation, Identification and Characterization
 Manufacturers should have knowledge on their particulate matter rejections.
 Type of particles.
 Source of each particle type.
 Routine trend / capability of particulate rejections.
 Morphology of each type of particle.
 Chemistry of each particle type.
 Manufacturers should have comprehensive particle control and monitoring
strategies in place.
Slide No. 13

14. Particle Separation, Identification and Characterization
Detection by
Inspection
(Optical visual
inspection)
Verify & Isolate
(Capillary
withdrawal /
Filtration)
Characterization
(Size, shape,
morphology,
colour, etc.)
Identification
(FTIR, Raman,
EDS, etc.)
Remediation /
Control
(Investigation,
CAPA)
Slide No. 14

15. Particle Isolation
Capillary withdrawal method Filtration method
Slide No. 15

16. Characterization (Microscopic study)
Cardboard Tyvek Rayon
Human Hair Polyester
Slide No. 16

17. Identification (FTIR Spectra)
Cardboard
Tyvek
Rayon
Human Hair
Polyester
Slide No. 17

18. Product Recalls
Lack of Sterility
Assurance
22%
Visible
Particles
22%
Impurities / Degradation
9%
Other
47%
USFDA STERILE INJECTABLE DRUG RECALLS (2008 – 2012)
Slide No. 18

19. • Sagent Pharmaceuticals, Inc. has initiated the voluntary recall of one lot of
Oxacillin for Injection, USP, 10 g to the user level due to the receipt of a
product complaint for a single vial containing small, dark particulate
matter found within the solution after reconstitution. (Date: 18 Aug. 2016).
• Hospira issues a voluntary nationwide recall for one lot of 0.25% Bupivacaine
Hydrochloride Injection, USP due to the presence of particulate matter
within a single vial. (Date: 8 Aug. 2016).
• Teva Pharmaceuticals initiates voluntary nationwide recall of 7 lots of Amikacin
Sulfate Injection USP 500 mg/2 mL and 1 Gram/4 mL vials due to potential of
glass particulate matter. (Date: 2 Aug. 2016).
• PharMEDium issues voluntary nationwide recall sterile preparations
(Bupivacaine HCl) due to the presence of glass particulate matter. (Date: 5
May 2016).
Product Recalls
Slide No. 19

20. • Must establish a maximum allowable reject rate.
• Must control re-inspection of product, including when appropriate, inspection
conditions and number of re-inspections permitted.
• Inspectors must be trained and training documented.
• Inspectors must be periodically recertified.
• Training and certification conditions must align with routine 100% inspection
conditions.
• Address inspection fatigue during qualification.
• Must conduct thorough investigations. Identify particulate matter when
performing investigations.
• Must use statistically sound sampling plan(s) for AQL inspection.
USFDA 483 Trends
Slide No. 20

21. Any Questions?
Every closed eye is not sleeping, and every open eye is not seeing.
Slide No. 21

22. • Particulate Matter in Injections – USP 39, General Chapter <788>.
• Visible Particulates in Injections – USP 39, General Chapter <790>.
• Visual Inspection of Injections – Draft USP Chapter <1790>.
• Recall Data, Steven Lynn, FDA Office of Manufacturing and Product Quality, March,14,
2013.
• Warning Letters 2016 - www.fda.gov.
• PDA Visual Inspection Forum, by John G. Shabushnig, Ph.D. Pfizer Global Quality
Operations March 9, 2011.
• A Global Association PDA Update on Technical Reports, recent Projects 2015.
• Manual Visual Inspection Scientific Approach to Determine Particles Probabilistic
Detectability – by Luis Aviles at Interphex, Puerto Rico, 2016.
References
Slide No. 22