Visual Inspection of Injectable

Products:
More than Sorting Good
from Bad …

John G. Shabushnig, Ph.D.

Insight Pharma Consulting, LLC

johnshabushnig@aol.com
September 2022

© 2022 John G. Shabushnig

 Agenda
• Why inspect?
• What we are looking for
• How to inspect
• Acknowledgements
• References and resources

© 2022 John G. Shabushnig

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Why inspect?

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 Why Inspect?
• Patient Risk
– Physiological Implications
• Particles
– Chemical and Microbiological Implications
• Particles, Container Integrity
• Compendial Requirements
– Pharmacopeias
• Regulatory Requirements
• Process Knowledge and Continuous Process
Improvement

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 FDA Sterile Injectable Drug Recall
Notices 2017-2021
Visible Particles
Lack of Sterility Assurance
35% Labeling
Container
Other*

15%

33% 3%
* Incl. incorrect potency
14% or dose, discoloration,
impurities/degradation
products and storage
temp excursions.
Data obtained from the FDA Recall and Safety Alerts Archive,
https://www.fda.gov/Safety/Recalls/default.htm

© 2022 John G. Shabushnig

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 Visible Particulate Recall Notices
30
25

21
20
Recall Events

12 12
11 11
10
10 9
8 8
6 6

Year
Data obtained from the FDA Recall and Safety Alerts Archive,
https://www.fda.gov/Safety/Recalls/default.htm

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 Recent FDA Recalls

• 12-3-2021 Gilead Issues a Voluntary Nationwide Recall of Two Lots of

Veklury® (Remdesivir) Due to Presence of Glass Particulates
– Glass particles
• 9-3-2021 Hospira Issues a Voluntary Nationwide Recall of Aminosyn II
0.15%, an Amino Acid Injection, Sulfite Free IV Solution Due to the
Presence of Particulate Matter
– Fibers, hair and proteinaceous material
• 6-30-2021 Teva Initiates a Voluntary Nationwide Recall of One Lot of
Topotecan Injection 4 mg/4 mL (1 mg/mL) Due to Presence of
Particulate Matter
– Grey silicone particle, cotton fiber
• 5-8-2021 ICU Medical Issues a Voluntary Nationwide Recall of
Lactated Ringer’s Injection, USP Due to the Presence of Particulate
Matter
– Iron oxide

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 US FDA 483 Themes

• Must establish a maximum allowable reject rate.

• Must control reinspection of product, including
when appropriate, inspection conditions and
number of reinspections permitted.
• Inspectors must be trained, and training
documented.
• Inspectors must be periodically requalified.
• Training and qualification conditions must align
with routine 100% inspection conditions.
• Address inspection fatigue during qualification.
• Must use statistically sound sampling plan(s) for
AQL inspection. © 2022 John G. Shabushnig 8
 Pharmacopeial Requirements

USP <790> EP 2.9.20 JP 6.06

Illumination 2,000-3,750 2,000-3,750 2,000-3,750 lux
Intensity (lux) (8,000-10,000)*
Inspection 10 sec 10 sec 10 sec
Time (sec)
Background Black/White Black/White Black/White
Acceptance “essentially free “clear and “free of readily
Criteria from visible practically detectable
particulates” particle-free” foreign insoluble
ANSI/ASQ Z1.4 matter”
AQL=0.65%

* Illumination intensity for plastic containers

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 United States Pharmacopoeia USP 43
• USP <1> Injections and Implanted Drug Products
(Parenterals) – Product Quality Tests
– Foreign and particulate matter: Articles intended for
parenteral administration should be prepared in a
manner designed to exclude particulate matter … Each
final container of all parenteral preparations should be
inspected to the extent possible for the presence of
observable foreign and particulate matter (hereafter
termed visible particulates) in its contents. The
inspection process should be designed and qualified to
ensure that every lot of all parenteral preparations is
essentially free from visible particulates …

© 2022 John G. Shabushnig

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 United States Pharmacopoeia USP 43
• USP <1> Injections and Implanted Drug Products
(Parenterals) – Product Quality Tests
– Qualification of the inspection process should be
performed with reference to particulates in the visible
range and those particulates that might emanate from
the manufacturing or filling process. Every container in
which the contents show evidence of visible
particulates must be rejected. The inspection for visible
particulates may take place during examination for
other critical defects such as cracked or defective
containers or seals or when characterizing the
appearance of a lyophilized product.

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 United States Pharmacopeia USP 43
• USP <790> Visible Particulates in Injections
– Inspection conditions defined
• Harmonized with EP
• 2,000-3,750 lux
• Black and white backgrounds
• No magnification
• 5 sec viewing against each background
• Swirl and/or invert sample
– Applies to Extrinsic and Intrinsic particles
– Inherent particles addressed in individual
monographs or approved regulatory filings

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 USP <790> Acceptance Criteria
• At Time of Batch Release
– 100% inspection followed by acceptance sampling
– ANSI/ASQ Z1.4 or ISO 2859
– AQL= 0.65%, UQL= 2.3-3.3% typical
– Alternate and equivalent plans acceptable
• For Product in Distribution
– n = 20, a = 0
– AQL= 0.26%, UQL= 10.9%

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 USP <790> Supplemental Inspection
• Supplemental Inspection
– Where the nature of the contents or the container–
closure system permits only limited capability for
inspection of the total contents, the 100% inspection of
a batch shall be supplemented with the inspection of
constituted (e.g., dried) or withdrawn (e.g., dark amber
container, suspensions, highly colored liquids) contents
of a sample of containers from the batch. The
destructive nature of these tests requires the use of a
sample smaller than those traditionally used for non-
destructive acceptance sampling after 100% inspection.

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 USP <1790>
• <1790> Visual Inspection of Injections
– Information Chapter
– Key elements of an inspection process
• Patient Risk
• Elements of a good inspection process
• Lifecycle / Continuous Improvement
• Visible Defect Types
– Extrinsic, Intrinsic and Inherent
• Inspection Technologies
– Published in USP 40 1st Supplement
• Official Aug 2017, Updated May 2022

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 USP <1790>

Accepted
Units
Acceptance
100%
Filling Sampling Packaging
Inspection
and Testing

Rejected
Units

Analyze and Supplemental

Trend Rejects Testing

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 Other International Standards
• EU
– EMA Annex 1 Manufacture of Sterile Products
– EP 2.9.20 Particulate Contamination: Visible Particles
– EP 5.17.12 Recommendations on Testing of Particulate
Contamination : Visible Particles
• Japan
– JP 6.06 Foreign Insoluble Matter Test for Injections

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What we are looking for.

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 Typical Defects found by Visual
Inspection (Abbreviated List)
• Particles
• Product
– Gross over- or under-fill
– Cloudy or discolored (solution)
– Melt or collapsed cake (lyo)
• Container (for vials)
– Cracks
– Chips
– Scratches
– Dirt on exterior

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 Typical Defects found by Visual
Inspection (Brief List cont.)
• Closure (for vials)
– Leaking
– Missing or damaged stopper
– Loose or torn overseal
– Scratched or dented overseal
– Missing overseal or flip-cap button
– Incorrect flip-cap button color

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 Particulate Matter Definitions

• Extrinsic (from outside the process,

uncontrolled)
– Environmental Contaminants
• insect parts, hair, fibers, paint, rust
• Intrinsic (from within the process, unplanned)
– Processing Equipment, Primary Package
• qualified product contact materials (e.g. stainless steel,
glass, rubber, silicone oil)
• Inherent (part of the formulation, controlled
and expected)
RISK
– Protein agglomerates

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 Particulate Size Ranges

<100 nm 100 - 1,000 nm 1 - 100 µm >100 µm

Nanometer Submicron Subvisible Visible

• SEC (Size Exclusion • Light Obscuration • Manual / Human

Chromatography) • Microscopy • Semi-Automated
• FFF (Field Flow • Flow Microscopy • Automated
Fractionation) • Coulter Counter
• SDS-Page Gels
• AUC (Analytical Ultra-
Centrifugation)
Narhi, et al. J Pharm Sci, 2012

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Defect Classifications

Critical defects are those which make the

product unfit for use. This defect may pose a
risk to patient safety.

Major defects are those which may impair

functionality, processing, or handling that
may lead to a loss of performance.

Minor defects are those which represent a

general lowering of perceived quality (i.e.
appearance) but do not limit the function of
the product or make it unsafe.

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How to inspect.

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 Common Visual Inspection Methods
• Manual Inspection (MVI)

• Semi-Automated Inspection (SAVI)

• Automated Inspection (AVI)

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 Critical Inspection Parameters

• Lighting
– Illumination Intensity
– Uniform, Flicker-free
• Fluorescent, Incandescent, LED
– Tyndall (dark-field)
• Background
– Black / White
• Presentation and Manipulation
– Swirl and/or invert
• Pace
– 10 sec / container reference

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Manual Inspection Booth

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 Human Inspection Sensitivity
100
Probability of Detection (%)
90
Borchert
80 Knapp
70 Ryan

60 Androver
Borchert
50
Melchore
40
30
20
10
0
0 50 100 150 200 250
Particle Diameter (µm)

From Shabushnig, Melchore, Geiger, Chrai and Gerger, PDA Annual Meeting 1995

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 Inspector Selection

• Visual Acuity Testing

– Must pass exam with 20/20 near
vision
• Vision may be corrected with
prescription lenses or contacts
– Tested annually

• Color Impairment Testing

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Training

30
© 2022 John G. Shabushnig
 Training
• Manual Inspection Training Process
– Defect identification/categorization
• Defect Reference Manual or Library
• Defect Samples
– Demo of inspection procedure by
– Practice in non-production training environment
– Inspect training set with good and defective units
• Typical training time two weeks

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 Qualification Test Kits
• Inspect Qualification Test Kit with representative
defects
– Typical test kit contains 300-500 units with 30-50 defect
examples (≤10% defect rate).
– Can be made with product or surrogate and contain
production rejects or simulated defects.
– Test kits may be prepared internally or purchased.
– Test kits should have an expiration date (typically 1 year,
does not need to match expiration of product) after which
they can be critically inspected, and the expiration date
extended (typically done annually).
– They should be reviewed and approved by Quality.
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 Qualification Testing (1)
• Qualification Testing
– Knapp RZE method based on probability of rejection (PoD)
may be used to calibrate test kit and set acceptance
criteria.
– False reject rate (FRR) should be ≤5%.
– Conduct tests at end of day/shift for maximum fatigue.
– Set a time limit for completion of inspection of test kit to
align with routine inspection rate (e.g., 3-4/min for MVI).
– Initial qualification should require three (3) consecutive
successful inspections of the test kit.

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 Qualification Testing (2)
– Separate qualifications should be performed for each
family of products (e.g., clear solution, colored solutions,
suspensions, lyophilized powders, etc.) and containers
(e.g., clear, amber vials, syringes, cartridges, bags, etc.).

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 Requalification
• Requalification should be performed at least
annually.
• It can be done with a single inspection of a
representative test kit to demonstrate maintenance
of proficiency.
• It is a good practice to requalify inspectors who have
not done inspection for an extended period of time
(e.g., 3-6 months).

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 Other MVI Considerations
• Various types of breaks help keep the inspector alert
and focused.
– Shift change and lunch breaks (2x/shift)
– 5 minute ‘eye breaks’ (each hour)
– Micro-breaks during the inspection process
– Shift to non-inspection task (e.g., loading, unloading,
documentation)
• Reduced ambient light recommended.

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 In Process Control
• Control alert and/or action limits should be
established and applied to 100% inspection rejection
rates to identify atypical lots.
– Mean + 3σ (for critical, major, minor and particle defects)
is often used for these action limits.
– Limits are reviewed (and recalculated as needed) at least
annually and when significant process (manufacturing and
inspection) changes are made.
– Typical actions when these limits are exceeded include
investigation, tightened AQL, and reinspection.
• Inspection results should be trended and assessed
for adverse trends.

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 Acceptance Sampling / AQL Inspection
• After 100% inspection, a sample of accepted units is
sampled and reinspected.
– Sampling plans and acceptance criteria follow ANSI/ASQ
Z1.4 or ISO 2859.
– Acceptable Quality Limits (AQL) are chosen for each defect
category based on risk (critical, major and minor).
• Industry mean values are 0.065%, 0.65% and 2.5%, respectively
• These are used to determine the accept number or number of
defects of each category permitted in the sample. Normally, no (0)
critical defects are permitted.
– If the number of defects found exceed the accept number,
investigation and reinspection are required.

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 Important Points to Remember

• Inspection is probabilistic; it can not be relied upon

to detect and remove all defects.
• Therefore, defect prevention through continuous
process improvement should be part of your
control strategy.
• While particles are most often associated with
visual inspection, container and closure defects
must also be detected and removed.
• Inspector training and qualification is critical to
successful manual visual inspection.

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 Acknowledgements
• USP Visual Inspection Expert Panel
- D. Scott Aldrich - Ultramikro
- John Ayres - Pharma Safety Solutions
- Roy Cherris - Bridge Associates International
- Mary Lee Ciolkowski - Bausch & Lomb
- Desmond Hunt - USP
- Steve Langille - ValSource
- Russell Madsen - The Williamsburg Group
- John Shabushnig (Chair) - Insight Pharma Consulting
- Deborah Shnek - Alder Biopharmaceuticals
- Hailin Wang – FDA
- Neal Zupec - Baxter

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 References and Resources (1)
• FDA Draft Guidance for Industry (2021): Inspection of
Injectable Products for Visible Particulates
• USP <1> Injections and Implanted Drug Products (Parenterals)
– Product Quality Tests
• USP <790> Visible Particulates in Injections
• USP <1790> Visual Inspection of Injections
• EMA Annex 1 Manufacture of Sterile Products
• EP 2.9.20 Particulate Contamination: Visible Particles
• EP 5.17.12 Recommendations on Testing of Particulate
Contamination : Visible Particles
• JP 6.06 Foreign Insoluble Matter Test for Injections

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 References and Resources (2)
• Generalized Methodology for Evaluation of Parenteral
Inspection Procedures, Knapp and Kushner, J. Parent. Sci &
Techn., 34 (1) (1980)
• Implementation and Automation of a Particle Detection
System for Parenteral Products, Knapp and Kushner, J. Parent.
Sci & Techn., 34 (5) (1980)
• Industry Perspective on the Medical Risk of Visible Particles in
Injectable Drug Products, Bukofzer, et al, PDA J Pharm Sci and
Techn., 69 (2015)
• Particulate Matter in Injectable Drug Products, Langille, PDA J
Pharm Sci and Techn., 67 (3) (2013)
• PDA Survey – 2014 Visual Inspection, Shabushnig, Parenteral
Drug Association, October 2015

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 References and Resources (3)
• Visual Inspection and Particulate Control, Aldrich, Cherris and
Shabushnig, DHI Press ©2016, PDA Bookstore
• Guide to Acceptance Sampling, Taylor, Taylor Enterprises, Lake
Villa, IL, ©1992
• PDA Technical Report No. 43 (Revised 2013): Identification
and Classification of Nonconformities in Molded and Tubular
Glass Containers for Pharmaceutical Manufacturing: Covering
Ampoules, Bottles, Cartridges, Syringes and Vials
• PDA Technical Report No. 76 (2016): Identification and
Classification of Nonconformities in Elastomeric Components
and Aluminum Seals for Parenteral Packaging
• PDA Technical Report 79 (2017): Particulate Matter Control in
Difficult to Inspect Parenterals

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Questions?

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