Container Closure

Integrity Testing (CCIT)

Solutions for the
pharmaceutical industry
The quality and effectiveness of drugs signifi-
cantly depends on their proper packaging:
Sterile products and moisture/oxygen sensitive
drugs require excellent barrier during the shelf
life of the product (up to a couple of years) to
protect them from biological contamination,
water and oxygen ingress. Otherwise, serious
consequences might occur. This was proven
by a grave incident in the 1970's: During this
period, contaminated intravenous fluids pack-
aged in glass bottles – which were typical at
the time for packaging such dosage forms –
caused an estimated 2,000 to 8,000 episodes
of bloodstream infection, resulting in the
deaths of about 10 % of the patients. This
severe package-integrity failure incident has
triggered a heightened awareness of package
integrity in the life science industry.

The key risks for contamination are by humidity, oxygen or ■■ 1207.1: Package Integrity and Test Method Selection
microbiological ingress, which can impact the drug stability ■■ 1207.2: Package Integrity Leak Test Methods
throughout the product life cycle. To prevent the risks of stabil- ■■ 1207.3: Package Seal Quality Test Methods
ity failure of highly moisture sensitive drugs (e.g. dry powder The USP <1207> thereby does not claim to describe all possi-
for inhalation) or the risk of biological ingress of sterile paren- ble methods, but gives a good overview and general guideline
teral drugs, integrity tests with a high sensitivity are required. for the evaluation of various popular potential methods.

Regulated market Test methods and detection limits

The high risk in regards to pharmaceutical Container Closure An initial list of the various test methods used for package
Integrity Testing leads to a strictly integrity testing was already pub-
regulated environment. Key authori- lished in the late 90s. The report
ties are the FDA (United States) and Sensitive drugs require packaging back then was very narrow in
the EMA (Europe). scope and recommended to vali-
for prevention of moisture or date chemico-physical leak test
In 2008 the US FDA published a
new guideline for the whole life sci-
oxygen or microbial contamination methods by comparing them
directly to a microbiological ingress
ence industry (pharmaceutical com- test. This probabilistic test method
panies, veterinarian drugs and com- relies on a series of sequential and/
panies that manufacture sterile medical products) that obliges or simultaneous events with random results. The findings are
the sector to perform reliable physical measurement to ensure associated with uncertainties that demand large sample sizes
proper CCI. and precise test condition controls. Some publications on
microbiological ingress tests show that the method detects
In practice, the regulations of the FDA as well as the Europe- leakage pathways the size of a single microorganism. The
an Guideline for Good Manufacturing Practice with Annex 1
for the Manufacture of Sterile Medicinal Products are often 100
Microbial Ingress Failure Rate (%)

interpreted quite broadly and without specific recommenda-

tions. The main obligation given to the manufacturers is that 80
they must ensure “the container-closure system to maintain
the integrity of its microbial barrier, and, hence, the sterility of 60

a drug product throughout its shelf life” (US FDA).

40

What the official regulations often do not describe in detail is 20

how the CCI testing should be performed. They usually only
stipulate to use appropriate methods and procedures. The 0
United State Pharmaceopia, the government body in-charge -7
-6 -5 -4 -3 -2 -1
of standards and guidelines for the pharmaceutical industry – Log orifice size
which typically are internationaly accepted – dealt with Mean leak
diameter (microns)
this issue and in 2016 presented a new guideline: the 0.1 0.2 0.3 0.4 0.7 2 6 8
USP <1207>. This guideline focuses on sterile and critical
pharmaceutical products (e. g. vials and syringes) and is Figure 1: Microbial ingress failure rate in relation to leak size
divided into 3 chapters: (source: Kirsh, PDA J Pharm Sci & Technol, 54,4, 2000 p. 305-314)

2
 below chart describes the risk related to different orifice sizes: chart below gives an overview of corresponding deterministic
As shown in figure 1, the critical leak size is at 0.2 µm, test methods, mainly based on PDA USP <1207>:
respectively 6·10-6 mbar l/s. This value is widely used as the
so-called MALL (maximum allowable leak level). Furthermore, The broad range of different methods can be traced back to
the chart says that a leak of 2 µm already poses a risk of the different challenges for CCIT within the pharma market.
close to 70 % for the contamination of the drug. Those are related to the different process steps, the different
packaging types and the different drug types.
This must be kept in mind when looking at other studies,
which have proven that classical probabilistic test methods
Liquid Solid
could miss leaks, resulting in an impairment of product sterili-
filled filled
ty. Specific examples are Microbiological Ingress Testing as
well as Blue Dye Test Methods. Rigid
100
packaging
(%) of vials with dye ingress

80 Flexible
Detection probability

packaging
60

Figure 5: Drug/container configuration matrix

40

dye ingress
20 microbial ingress
While in the early development stage of a packaging (“pack-
0 aging design phase”), the supplier is obliged to ensure that
0
10 20 30 40 50 60 70 80 the packaging is by design capable to ensure the sterility.
Microtube inner diameter (µm) Therefore the packaging needs to be tested for defects in the
range of 0.2 µm, respectively 6 · 10-6 mbar l/s (MALL). These
Figure  2: Detection probability in relation to microtube inner are the current requirements for stability and quality control of
diameter (source: Burrell L.S. (et. al PDA J Pharm Sci Tech 54, containers filled with drugs. Integrity tests are mainly per-
p. 449-455), Figure  3) formed in the range of 2 to 20 µm defect size. The main rea-
son for this is the feasibility of the available methods to detect
As shown in figure 2, a dye ingress test has only an about smaller defects in a reasonable test time. When dealing with a
70 % chance to detect a 10 µm leak. Any leaks below 5 µm 100  % inspection of the production line that operates at
are more or less non-detectable. speeds for 120 to 600 parts per minute, the allowed defect
size is sometimes even increased to a significantly higher lev-
It is therefore recommended to apply a deterministic integrity el. The Limit of Detection (LOD) for production units is defined
test method whenever leakage measurements are based on as a risk-based decision between cost, technology and prod-
phenomena that follow a predictable chain of events. The uct. To compensate on this risk-based approach, additional
off-line sample testing is performed to a tighter spec in the
range of 1 to 10 µm. This also applies to stability testing
Leak test method Measurement Row Detection which is performed in laboratory tests. Here again the sensi-
outcome range tivity is more important than the test time.
Tracer gas
Helium flow < 0.1 to Figure 5 gives a rough differentiation between the broad
(Helium mass 1
(mbar l/s) 10 µm range of different packaging and drug types within the
spectrometry)
pharma industry. Not all test methods can be used for all
Laser-Headspace [O2] and/or [CO2] kinds of packaging as well as all drug types.
< 0.1 to
(Frequenzy modulated Gas pressure 2
> 50 µm
spectroscopy) (%) Besides the below-mentioned characteristics of packaging
AMI1 Leakage (N2, Ar, types, also characteristics such as transparency of the pack-
< 0.2 to aging and its electrical conductivity play an important part in
(Optical emission CO2, H2O...) 21
> 50 µm regards to the selection of the right integrity test method.
spectroscopy) (mbar l/s)
Table 1 below gives a more detailed overview of available
Mass Extraction CCIT methods and also provides as a guideline for the
Mass flow < 1.0 to
(Micro/Mass flow 32 selection by pointing out specific characteristics as well as
(µg/min) > 50 µm
sensors) limitations of the different test methods:

HVLD Electrical current < 1.0 to Pfeiffer Vacuum test methods

3
(Leakage current) (µA) > 50 µm Pfeiffer Vacuum offers a wide range of different leak testing
methods to adress the multitude of challenges within the
Pressure rise < 1.0 to pharmaceutical industry as there is no one solution that fits
Vacuum decay 3 all different challenges connected to a specific product.
(mbar/s) > 50 µm
Pfeiffer Vacuum can support you during the complete CCIT
1 USP <1207> "Emerging Technology" process definition and integration and also provide GMP sup-
2 ASTM Standard F-3287-17 proves capability to detect 1.0 µm defect, port in regards to IQ/OQ (Installation Qualification/Operational
qualifies for USP <1207> row to rating
Qualification) including the needed documentation for all our
test methods. The following overview gives you an impression
Figure  4: Overview of different leak test methods of Pfeiffer Vacuum´s portfolio of leak testing methods.

5
 Helium Mass O.E.S (Optical Emission Mass Vacuum
Spectrometry Spectroscopy) Extraction Decay
Deterministic Yes Yes Yes Yes
(Yes)
Non-Destructive Yes Yes Yes
only for open containers
Quantitative Yes Yes Yes Yes
He charging Plausability
Sample preparation No sample preparation
test
Test pressure Vacuum
Detection range
0.01< Q < 10 µm > 0.2 µm > 1 µm > 5 µm
(Sharp edge orifice)
Lyophilized (dry) or liquid drugs
Drug Product Limitations
Plugging risk for small defects for protein based drugs
Container must handle 1 bar differential pressure
Container Non-porous material
Limitations He Permeation High outgazing

Require gas headspace or liquid inside the container

Difficult to set-up Outgazing of the container and the drug type will impact the
■■ Requires proper He gas test duration and the detection limit
management
■■ Requires plausability
test to valid the test
result.

Method Not practical for mass

Limitations production testing

Detection limit is Free volume inside the test chamber can limit
depending on packaging sensitivity --> Test chamber must be optimized
and drug type for each format parts.

Detection limit depends Sensitive to temperature and/or volume variations

on the gas used for the
detection
High selectivity (He) Selectivity: can detect High sensitivity detection Simple
simultaneously gas spe- of water leakage
High sensitivity test cies (N2, H20, Ar, CO2,…)
Method
Robust technology
Advantages
Possibility to localize the Can test multiple contain-
leak position with sniffing. ers with high sensitivity at
the same time.
Mainly used for the design Highly verstaile and sensi- Highly verstaile and sensi- Older production test
and qualification phase tive test for different drug / tive test for different drug / method.
of the packaging's, packaging systems packaging systems
Comments
not practical for mass Can be used in laboratory In-line option available. Reduced reliability for
production testing. or as IPC in production. measurements at limit of
detection.

Table 1: Available CCIT methods and selection guideline

Helium Mass Spectrometry

Pfeiffer Vacuum helium leak detection solutions are perfect

for MALL testing in the pharmaceutical industry. In order to
ensure a correct measurement, it is very important to man-
age the tracer gas concentration during the measurement.
This is especially tricky when handling vials or other sealed
packages. Therefore, Pfeiffer Vacuum offers complete solu-
tions including tracer gas handling and charging, as well as
adaptations for your packaging and test chambers.

Figure 6: Leak detector for MALL testing from Pfeiffer Vacuum

(Conceptionally design)
3
Vision HSA HVLD Dye Microbial
(Deflexion) (Head Space Analysis) (High Voltage) Ingress Challenge
Yes Yes Yes

Yes Yes Yes

Yes

Storage time No sample preparation Immersion in dye or microbial media

Atmospheric Pressure Shallow Vacuum Atmospheric Pressure

> 5 µm > 0.01 µm 10-40 µm > 20 µm > 0.2 µm

Lyophilized drugs
Conductive liquid drugs Light colored drugs –

Rigid & Transparent Non-conductive Non-porous material

material
Container Design
(Semi-rigid or flexibe)
Require gas headspace Test only at the point of Destructive Long (few weeks) and
Sensitivity depends on the Requires waiting time electrode contact, with liq- Expensive
product design: before actual testing uid behind. Probabilistic
■■ Headpsace volume (hours up to weeks)
■■ Size of the cavity Limited usage for flexible Poor sensitivity
Waiting time depends on packaging's.
■■ Shape of the container
the gas headspace and Operator & multi-
detection limit. No real quantitative mea- parameters dependant
Headspace needs to surement
be either vacuum or
100 % Nitrogen Risk due Ozone generation
Requires positive control to calibrate the equipment

Identification of the leaky High selectivity (O2) Very fast, high thorughput Low cost equipment Direct measurement of the
cavity or container. can be acheived biological contamination
Very fast, high thorughput Easy to understand
Can test multiple contain- can be acheived
ers with high sensitivity at
the same time.

Mainely used for blister Indirect leak test, we Very fast method for pro- Widely-used for decades
packs. measure the consequence duction test, limited usage
of oxygen ingress through for flexible packaging's. Industry & regulatory familiarity
defects.

Mass Extraction
Our USP <1207> and ASTM (F-3287-17) recognized Mass
Extraction Technology works on the principle of rarefied gas
flow. Testing takes place in vacuum conditions to attain higher
sensitivity. This patented technology type of testing is particu-
larly suitable for pharmaceutical packaging such as IV-bags,
pouches or glass vials. Larger defect and defects as small as
1 μm can be detected with this method. The technology is
thereby suitable for laboratory applications as well as for the
use in production environment allowing stability control as
well as automated 100 % testing (also in inline machines).
FDA laboratories in the US and major pharmaceutical compa-
nies have been using the Mass Extraction instruments for over
10 years. Figure  7: Mass Extraction system from Pfeiffer Vacuum

4
Optical Emission Spectroscopy
The Pfeiffer Vacuum Optical Emission Spectroscopy Instru-
ment used in the AMI test systems measures leak tightness
using a patented process that does not require a tracer gas.
Instead, this method uses the existing gas mixture in the cavi-
ties inside the packaging to perform high-sensitivity testing
over an extended measuring range. Thereby the AMI has the
ability to differentiate gas species that are typical to pharma-
ceutical products. The procedure offers great flexibility and
can test a variety of different packaging types such as blister
packs, pouches, vials and plastic bottles and can also test
multiple samples at the same time.
The wide measuring range of the AMI offers higher sensitivity
Figure  8: Compact leak test system AMI from Pfeiffer Vacuum
than conventional tests, starting from 0.5 μm (and smaller)
respectively leak rates of down to 1·10-6 mbar l/s, but can also
identify gross leaks as for example a completely open contain-
er. As a result, the AMI device can perform gross and fine USP 1207.1. It can be used in laboratory testing as well as
leak testing in just one device. The procedure delivers deter- IPC (In Process Control) during production testing. Depending
ministic test results with high repeatability, irrespective of the on the packaging, also the simultaneous testing of multiple
user, and with reliability and accuracy that within the range of parts at the same time is possible.

All data subject to change without prior notice. PI0479PEN (October 2018/1)

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