Best Practices:

CCIT in Manufacturing

Oliver Stauffer, CEO

PTI Inspection Systems
Pharma’s Future 2

• Antibody-Drug Conjugates (ADC’s)

• Advanced gene therapy (RNA)
• Personalized therapy (CAR-T)
• Target therapy (mAbs)

LARGE MOLECULE
PARENTERAL DELIVERY

COPYRIGHT © PDA 2020

Shift in CCI 3

• FDA Guidance for Industry (2008)- Container and Closure

System Integrity Testing in Lieu of Sterility Testing
• USP Chapter 1207 (2019)– Package Integrity Evaluation –
Sterile Products
• EMA Annex 1 (2020)– Manufacture of Sterile Medicinal
Products

COPYRIGHT © PDA 2020

Package Integrity 4

Smallest leak to allow ingress determination

Lee Kirsch, et al, PDA J Pharm Sci & Technol, Vol. 51, No. 5, 1997

108 to 1010 P. diminuta E. Coli

From: MicrobeWiki From Wikipedia

• Glass micro-pipettes through wall of stoppered glass vial

• 0.1 to 10μm diameter (Sized via helium mass spec)
• Microbial challenge by immersion + liquid tracer element
• Challenge conditions
• Water bath immersion 60ºC 2hr, then 25ºC 1hr
• 24 hr immersion, ambient pressure
Most bacteria are 0.2 µm in diameter and 2-8 µm in
length. The three basic bacterial shapes are coccus
Ingress Risk Dropped: Log -3.8 sccs (Leak < ~1μm) (spherical), bacillus (rod-shaped), and spiral (twisted),
however pleomorphic bacteria can assume several
No Ingress: Log -5 to -5.8 sccs (Leak ~0.3 to 0.2μm) shapes.

COPYRIGHT © PDA 2020

Naturally Occurring Defects 5

Sample leak rate Visual Size

-5
10 Sample 6
mbar·l/s
mbar·l/sec
sccm um Sample 2
1 0.00095 95 0.05700 Large crack 2.67
Medium
2 0.0000021 0.21 0.00013 0.13
crack
Medium
3 0.000014 1.4 0.00084 0.32
crack
Small
4 0 0 0.00000 0.00
Scratch
6 0.00067 67 0.04020 Large crack 2.24 Sample 3 Sample 16
7 0.015 1500 0.90000 Large crack 10.61
0.0000002
9 0.029 0.00002 Small crack 0.05
9
10 0.00029 29.0 0.01740 Large crack 1.47
11 0.074 7400 4.44000 Large crack 23.56
12 0.055 5500 3.30000 Large crack 20.31
16 0.0014 140 0.08400 Small crack 3.24
Small
18 0 0 0.00000 0.00
Scratch
Small
19 0 0 0.00000 0.00
Scratch
20 0.016 1600 0.96000 Large crack 10.95

COPYRIGHT © PDA 2020

A Complex System 6

• CCI and Component Performance

➢ Dimensional tolerances
➢ Stopper and tip-cap
➢ Barrel barrier properties
• Barrel – Plunger(piston)
• Needle Shield - Needle Tip & Barrel
• Plunger Ribs
• Headspace Criticality

COPYRIGHT © PDA 2020

Dye Ingress Test Methods 7

ISO 8362-5
Test Method [Link]. 3.2.9 Modified ISO Modified ISO
USP 31 <381> USP/PhEur

Dye Solution 1 g/L (0.1% w/v) 1 g/L (0.1% w/v) 0.1% w/v 0.1% w/v
Methylene Blue Methylene Blue Methylene Blue Methylene Blue
Aqueous Solution Aqueous Aqueous Aqueous
Solution Solution Solution
Vacuum -27 kPa -37 kPa 75 ± 5 kPa1 63 kPa2

Time Vacuum 10 minutes 10 minutes 30 minutes 30 minutes

Time 30 minutes 30 minutes 30 minutes 30 minutes

Atmospheric
Pressure ➢ Package characteristics
1 equivalent to drawing a vacuum of about -25 kPa
2 equivalent to drawing a vacuum of about -37 kPa
➢ Surfactant concentration
➢ Vacuum level
➢ Vacuum dwell time
➢ Ambient pressure dwell time
➢ Operator capability
➢ Operating conditions
COPYRIGHT © PDA 2020
 8
Vacuum Decay Dye Ingress

Leak Test Results Visual Inspection Results2

Defect Type ID Code1
dP Pa P/F Inspector 4 Inspector 5 Inspector 6
B6 8 P N N N
B7 8 P N N N
Controls Tested
B8 8 P N N N
for Ingress
B9 8 P N N Y
B10 8 P N N N
111 64 F Y Y Y
112 54 F N N Y
5μm hole 113 88 F Y Y Y
114 56 F N N N
115 46 F N N Y
126 192 F Y Y Y
127 184 F Y Y Y
10μm hole 128 186 F Y Y Y
129 301 F Y Y Y
130 194 F Y Y Y
141 352 F Y Y Y
142 356 F Y Y Y
15μm hole 143 346 F Y Y Y
144 445 F Y Y Y
145 371 F Y Y Y

1 Holed syringes are identical to those used for Part 1, ASTM precision and bias studies.
2Y = dye seen, N = No dye seen

COPYRIGHT © PDA 2020

Dye Ingress Research 9

Vacuum Decay Container/Closure Integrity Testing Technology. Part 2. Comparison to

Dye Ingress Tests
Heinz Wolf, Tony Stauffer, Shu-Chen Y. Chen, Yoojin Lee, Ronald Forster, Miron
Ludzinski, Madhav Kamat, Brian Mulhall and Dana Morton Guazzo; PDA Journal of
Pharmaceutical Science and Technology September 2009, 63 (5) 489-498

Development of a Dye Ingress Method to Assess Container-Closure Integrity:

Correlation to Microbial Ingress
Lana S. Burrell, Mary W. Carver, George E. DeMuth and William J. Lambert; PDA
Journal of Pharmaceutical Science and Technology November 2000, 54 (6) 449-455

Comparing Physical Container Closure Integrity Test Methods and Artificial Leak
Methodologies
Sarah S. Peláez, Hanns-Christian Mahler, Christoph Herdlitschka, Toni Wertli, Matthias
Kahl, Atanas Koulov, Anja Matter, Satish K. Singh, Martina Widmer, Oliver
Germershaus and Roman Mathaes; PDA Journal of Pharmaceutical Science and
Technology May 2019, 73 (3) 220-234

Container Closure Integrity Testing—Practical Aspects and Approaches in the

Pharmaceutical Industry
Helen Brown, Hanns-Christian Mahler, James Mellman, Alejandra Nieto, Daniel
Wagner, Matthias Schaar, Roman Mathaes, Juergen Kossinna, Franz
Schmitting, Sascha Dreher, Holger Roehl, Markus Hemminger and Klaus Wuchner;
PDA Journal of Pharmaceutical Science and Technology March 2017, 71 (2) 147-162

COPYRIGHT © PDA 2020

 10

Vacuum
Decay
Leak
Detection

COPYRIGHT © PDA 2020

Vacuum Decay Test Cycle 11

The gold standard for test method reliability.

M5 Test Cycle
Cycle 1 (step1 -2) Cycle 2 (step 3-5)
900.0 Large Leaks Small Leaks
800.0
700.0
1 2 3 4 5
Absolute Pressure, mb

600.0
500.0
Test Cycle Pass
400.0
Large Leak
300.0
Small Leak
200.0
100.0
0.0
0 1 2 3 4 5 6 7 8 9 10
Test Cycle – Time in seconds

COPYRIGHT © PDA 2020

Liquid Defect Amplification 12

450
400
350
300

dP (Pa)
250
Leak size (um)
200
0.86
150
100
50 0.22
0.05
0
0 2 4 6 8 10 12
MC 500 mbar Real 500 mbar
Flow Rate (ccm)

COPYRIGHT © PDA 2020

1mL Prefilled Syringe Case Study 13

COPYRIGHT © PDA 2020

 14

High Voltage
Leak
Detection
(HVLDmc)

COPYRIGHT © PDA 2020

Functional Principle of HVLDmc Test 15

Good Sample Leak

C1 – volume btw. C1
inspection electrode I1 I2
& the product V
V V R R

C2 C2
R – Liquid in the
C2 – volume btw. detection vial/syringe
electrode & the product
2 capacitors 1 capacitor

V – High Voltage Source

R – Electric Resistance of the product
C1 – Capacitor 1: Glass between the inspection electrode and product
C2 – Capacitor 2: Glass between the detection electrode and product
I1 – current produced when product container is sealed
I2 – current produced when product container is defective

COPYRIGHT © PDA 2020

High Voltage Leak Detection (HVLDmc) 16

e-

Inspection
Electrode
C1  Glass
Wall
C1
R  Liquid
Contents
C2
 Glass Wall

Detection
Electrode

COPYRIGHT © PDA 2020

MicroCurrent HVLD - Benefits 17

10 minutes test
Outside the product

COPYRIGHT © PDA 2020

1mL Prefilled Syringe Case Study 18

COPYRIGHT © PDA 2020

 19

PTI’s Robotic
Platform
• Highly flexible
• Indexing accumulator
• Adaptive handling or nested
presentations
• Multi-format rapid changeover
• Modular concept throughout
• Defects preserved
• HVLDmc or Vacuum Decay

COPYRIGHT © PDA 2020

 20

Advanced
Applications
• Auto-injectors
• Cartridges
• Combination devices
• Complex geometries
Vacuum Decay Platform 21

COPYRIGHT © PDA 2020

Data Integrity 22
 23

MicroCurrent HVLD Vacuum Decay

➢ Liquid fill • Small molecule liquid and
➢ MALL Sensitivity (<1 micron) lyophilized
➢ Low exposure voltage • MALL Sensitivity (<1 micron)
➢ Dynamic product range • Large leak capture, no
➢ No Ozone generated contamination
➢ Defect position ID • Quantifies leak size
➢ Detects clogged defects • Adaptive leak testing capabilities
➢ 0.2mL to 500mL containers • Any size container

COPYRIGHT © PDA 2020

Next Generation Sensitivity 24

COPYRIGHT © PDA 2020

Conclusions 25

• Critical defect size is below 10 microns

• Dye ingress is not effective for many parenteral applications
• Understanding product and package dynamics is critical
• Data integrity: a focal point of regulatory action
• Next generation technologies are quantitative and deterministic
• Reliability, Sensitivity, Practicality
• Robotic automation provides distinct advantages
• Vacuum Decay and HVLD are powerful technologies for automated
parenteral CCIT

Uncompromised flexible quality assurance.

COPYRIGHT © PDA 2020

 26

Thank you!
[Link]@[Link]

COPYRIGHT © PDA 2020

 27

COPYRIGHT © PDA 2020

 28

Supplemental Slides

COPYRIGHT © PDA 2020

Tortuous Defects 29

50 Micron 30 Micron
Power (50 Micron) Power (30 Micron) 30µ Pinhole – ~3.26 sccm
5
30µ 20mm Channel – ~0.16 sccm
Flow Rate (sccm)

2
30µ 40mm Channel – ~0.08 sccm
1

0
0 10 20 30 40 50 60
Capillary Length (mm)

COPYRIGHT © PDA 2020

 30

“Proteinaceous
106
product may
interfere with defect
detection.”1

➢ Pipettes draw liquid through the calibrated defect

➢ Naturally occurring defects and laser defects are into the pipette cavity ahead of test.
susceptible to blockage when testing. ➢ Volume of liquid exposed to vacuum with low
➢ Solutes may be deposited internal to the defect potential for solute blockage before test.
passage during testing due to liquid ➢ Ideal condition for detection.
107vaporization. ➢ Not representative of naturally occurring
defects.
1 Li,
Lei. American Pharmaceutical Review. February 20, 2013. Container Closure Integrity Testing Method Development and
Validation for Prefilled Syringes.

COPYRIGHT © PDA 2020

Statistical Quality Limits 31

Reject Limit Set % Known % Known # of good samples 1 False

Point good will good will that will fail per Reject Per
Pass Fail 10,000

Avg +1 Std Dev 84.13% 15.87% 1587 6

Avg +2 Std Dev 97.72% 2.28% 228 44
Avg +3 Std Dev 99.87% 0.13% 13 769
(1x Noise)
Avg +4 Std Dev 99.99% 0.0033% .33 31,574
Avg +5 Std Dev 99.9972% 0.000028% .0028 ~3,500,000
Avg +6 Std Dev 99.999% 0.00001% .001 ~10,000,00
(2x Noise) 0

COPYRIGHT © PDA 2020

Realistic Defects 32

COPYRIGHT © PDA 2020

Naturally Occurring Defects 33

Sample leak rate Visual Size

-5
10 Sample 6
mbar·l/s
mbar·l/sec
sccm um Sample 2
1 0.00095 95 0.05700 Large crack 2.67
Medium
2 0.0000021 0.21 0.00013 0.13
crack
Medium
3 0.000014 1.4 0.00084 0.32
crack
Small
4 0 0 0.00000 0.00
Scratch
6 0.00067 67 0.04020 Large crack 2.24 Sample 3 Sample 16
7 0.015 1500 0.90000 Large crack 10.61
0.0000002
9 0.029 0.00002 Small crack 0.05
9
10 0.00029 29.0 0.01740 Large crack 1.47
11 0.074 7400 4.44000 Large crack 23.56
12 0.055 5500 3.30000 Large crack 20.31
16 0.0014 140 0.08400 Small crack 3.24
Small
18 0 0 0.00000 0.00
Scratch
Small
19 0 0 0.00000 0.00
Scratch
20 0.016 1600 0.96000 Large crack 10.95

COPYRIGHT © PDA 2020

 34

Traditional TargetLeak
He Certified Leak Sizes He Certified Leak
Rate Rate
67.0 10-5 29.0 10-5
Sample 6 mbar·l/s Sample 3 mbar·l/s
0.04020 sccm 0.01740 sccm
2.24 ~µm 1.47 ~µm

10.0V 10.0V

COPYRIGHT © PDA 2020

 35

He Leak Rates
He Certified Leak He Certified Leak
Rate Rate
Sample 2 0.21 10-5 Sample 3 1.40 10-5
mbar·l/s mbar·l/s
0.00013 sccm 0.00084 sccm
0.13 ~µm 0.32 ~µm

10.0V 7.6V

COPYRIGHT © PDA 2020

MicroCurrent HVLD 36

Good Sample Leak

C1
I1 I2

V R V R
V

C2 C2

Ozone Creation Exposure Voltage Product Range

COPYRIGHT © PDA 2020

Deterministic CCI 37

➢ A package’s ability to prevent product loss, maintain product sterility, and in

some cases, prevent oxygen ingress or maintain sub-atmosphere headspace
pressures.
➢ Not defined as absence of microbial ingress, liquid ingress, or loss of
sterility.
Deterministic: the leakage event is based on phenomena that follow a predictable
chain of events, and leakage is measured using physicochemical technologies
that are readily controlled and monitored, yielding objective quantitative data.

Deterministic methods
• Electrical Conductivity and Capacitance
(HVLD)
• Laser-Based Gas Headspace Analysis
• Mass Extraction
• Pressure Decay
• Tracer Gas Detection, Vacuum Mode
• Vacuum Decay

COPYRIGHT © PDA 2020