Understanding Container and Closure System Integrity … 1_Booth_pres.pdf · Understanding...

Understanding Container

and Closure System

Integrity Testing

Crystal Booth, M.M.

Masters of Microbiology from North Carolina State University

Former Associate Director of Microbiology at Novartis

Understanding Container and Closure System Integrity

Testing

Application of the Assay

What is the test used for?

Regulations governing the test

Review some regulatory observations regarding Container and Closure System

Integrity Testing (CCIT)

Examining some of the various testing methods

Developing and Validating the Method

Developing a method

Performing the validation

Establishing acceptance criteria

Performing the test

Stability Testing

Interactive Exercise

Using an interactive game, participants review information pertaining to

monitoring microbial metrics.

Application of the Assay

What is the Test Used For?

Container closure systems should maintain the sterility

and product quality of sterile final pharmaceutical,

biological, and vaccine products throughout their shelf-

life.4

Contaminants may include microorganisms, reactive gases, and

other substances.13

Container closure systems consist of primary packaging

components and secondary packaging components.13

Primary packaging components are those components that come

into direct contact with the product, such as a glass vial or

syringe.

Secondary packaging components, according to USP <1207> are

those components that are vital to ensure correct package

assembly, such as aluminum caps over stoppers.13

What is the Test Used For?

What is Container Closure Integrity Testing (CCIT)?

CCIT is an assay that evaluates the adequacy of

container closure systems to maintain a sterile barrier.

http://www.accuratuslabs.com/wordpress/wp-content/uploads/2015/05/container-closure-integrity-testing-300x300.jpg

Some Regulations Governing the Test 21CFR211.94 Drug Product Containers and Closures2

(a) Drug product containers and closures shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements.

(b) Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product.

(c) Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes shall be validated.

(d) Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties shall be written and followed for drug product containers and closures.

Some Regulations Governing the Test

European Commission EudraLex- The Rules Governing

Medicinal Products in the European Union

Annex 1- Manufacture of Sterile Medicinal Products

• 117. “Containers should be closed by appropriately validated

methods. Containers closed by fusion, e.g. glass or plastic

ampoules should be subject to 100% integrity testing. Samples of

other containers should be checked for integrity according to

appropriate procedures.”1

• *Repeated in PIC/S PE 009-12 (Pharmaceutical Inspection

Convention)12

Volume 4- Part II Basic Requirements for Active Substances

used as Starting Materials

• 9.20. “Containers should provide adequate protection against

deterioration or contamination of the intermediate or API that

may occur during transportation and recommended storage.”3

Some Regulations Governing the Test ICH Harmonized Triplicated Guideline, Quality of Biotechnological

Products: Stability Testing of Biotechnological/Biological Products

Q5C10

Sterility testing or alternatives (e.g. container/closure integrity testing)

should be performed at a minimum initially and at the end of the

proposed shelf-life. 10

Other Guidance Material

Guidance for the Industry “Container and Closure System Integrity Testing in

Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile

Products.9

USP <1207> Sterile Product Packaging- Integrity Evaluation, and the new

updated drafts <1207>13, <1207.1>14, <1207.2>15 and <1207.3>16 Series

PDA Technical Report 27

PDA White Paper: Container Closure Integrity Control versus Integrity Testing

during Routine Manufacturing4


FDA Compliance Program Guidance Manual, Chapter 56-

Drug Quality Assurance Program 7356.002A- 09/11/155

(5) Verification of Container and Closures. The physical and

chemical characteristics of containers and closures can be critical

to the sterility and stability of the finished product. Many

containers and closures look alike (color and dimensions), but are

made of different materials or have a different surface treatment

such as silicone on stoppers and ammonium sulfate on Type I glass.

Evaluate the firm’s procedures for assuring containers and closure

consistently meet appropriate specifications.

Determine what tests and examinations are done to verify the

containers and closures are made of the correct materials with the

correct dimensions (critical to ensuring continuing container-

closure integrity) and are free of critical defects.


FDA Compliance Program Guidance Manual, Chapter 56-Drug Quality Assurance Program 7356.002A- 09/11/155

(6) Container / Closure Integrity. The integrity of the container / closure system is critical to assuring that all units of drug products remain sterile through shipment, storage and use. Leaking containers or closures lead to product contamination.

Reference: FDA’s 1994 Guidance for Industry for the Submission of Sterilization Process Validation in Applications for Human and Veterinary Drug Products.

Evaluate the tests and studies performed to demonstrate the integrity of container / closure systems for all sterile drugs, including:

• Verify that all incoming container-closure components meet specifications, including all appropriate dimensions.

• Determine studies adequately simulate the stress conditions of the sterilization process, handling and storage.

• Verify that the units tested in validation are appropriate (e.g., for terminally sterilized drug product, the units selected should be exposed to the maximum sterilization cycles using the production process).

• Sensitivity of the test is specified.

• Container-closure integrity is demonstrated during validation and as part of the stability program (in lieu of sterility testing), over the shelf life of the product.

A Few Regulatory Observations

Regarding Container and Closure

System Integrity Testing

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A Few Regulatory Observations Regarding

Container and Closure System Integrity Testing

FDA Warning Letter Dated 24Jun09:

This is a repeat violation of the February 2007 inspection.

Your QCU failed to establish an adequate stability testing

program designed to evaluate the integrity of the container-

closure system. Specifically, SOP-QC-XXXX does not include

the storage orientation for liquid products. The stability

samples for liquid products should be stored in an upright or

inverted orientation in order to test and evaluate the integrity

of the bottle seal.



FDA Warning Letter Dated 20Jan11:

Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product [21 C.F.R. § 211.94(b)].

• For example, your firm identified 542 incidences through consumer complaints of product defects such as, leaks, bursts, and premature activation during the period of January 2008 to August 2010. These are critical defects that can impact sterility and stability of your product. Your firm identified that the probable cause was the result of defective materials used in the manufacture of the container closure system.

• Your response is not adequate since the sampling plans described are not based on appropriate statistical criteria to sufficiently identify these known potential defects, especially given the history of the supplier for this container closure system.

• Furthermore, your final product inspection procedure and use of a (b)(4) does not appear to be effective in preventing shipments of product with critical defects to the marketplace. Additionally, our data indicates there may be other cases of foreign substances in products manufactured at your facility such as an insect found in the intravenous solution of XXXX and dirt reported inside of (b)(4) and the (b)(4) of XXXXX®. Please provide an evaluation of the suitability of any of these potentially affected lots.



FDA Warning Letter Dated 31May13:

Your firm failed to ensure your container closure system

provided adequate protection against foreseeable external

factors in storage and use that can cause deterioration or

contamination of the drug product (21 CFR 211.94(b)).

For example, you received consumer complaints identifying at

least ten (10) membrane leaks and one hundred fifty-five

(155) inadequately-fitting blue caps during the period of

November 2011 to March 2013. These are critical defects that

can impact the sterility and stability of your products.

This is a repeat violation



FDA Warning Letter Dated 02Nov15:

FDA investigators also noted CGMP violations at your facility,

causing your drug product(s) to be adulterated within the

meaning of section 501(a)(2)(B) of the FDCA. The violations

include, for example:

• Your firm failed to establish adequate written procedures designed to

assure batch uniformity and integrity of drug products that describe

the in-process controls, and tests, or examinations to be conducted on

appropriate samples of in-process materials of each batch (21 CFR

211.110(a)).

• Your firm failed to ensure container closure systems provide protection

against foreseeable external factors in storage and use that can cause

deterioration or contamination of the drug product (21 CFR 211.94(b)).



FDA Warning Letter Dated 21APR16:

Puncturing a container compromises the integrity of the container closure

system, and each puncture increases the chances of contamination.

In response to our observation regarding (b)(4), you indicated that you

developed a container closure integrity test for the (b)(4) and plan to

demonstrate the sterility of the (b)(4) throughout its expiry. However, this

test only confirms the sampled portion is sterile and does not validate the

integrity of the container. Additionally, the tested portion may not have

detectable microbial contamination after the (b)(4) container loses

integrity, but the amount of bacterial endotoxin may still increase. Your

proposed corrective action is not adequate to demonstrate container

closure integrity. Therefore, your response does not indicate how you will

ensure your finished product is sterile and the amount of endotoxin is

within an acceptable limit after multiple punctures to the (b)(4)

containers.

Examining Some of the Various Testing Methods

Container closure integrity testing can be performed in

many different ways.

All methods have pros and cons.8

Some containers, such as ampoules, require 100% integrity

testing.4

New proposed changes to USP Chapter <1207> describes

several methods the user and experiment with.

The proposed update removes the requirement to

compare the results of other container closure integrity

(CCI) assays to the microbial ingress challenge.

The updated chapter series is expected to become official

in August 2016.


The chapter (proposed USP <1207>) divides the tests

into two major categories.

Deterministic- less subject to error and provide

quantitative results8

Probabilistic- more uncertainty in assay results,

includes traditional methods8

Testing methods included in the chapter were chosen

from peer reviewed articles and are supported by the

American Society for Testing and Materials (ASTM) 8

The user may choose from the methods listed or even

methods not listed as long as the final method is properly

validated and optimized for the closure system.8


Deterministic methods include:

Electrical Conductivity and Capacitance Test

(HVLD)

Laser-based Gas Headspace Analysis

Mass Extraction

Pressure Decay

Tracer Gas (vacuum mode)

Vacuum Decay

http://www.cincinnati-test.com/pressure-decay-test-systems.html

Examining Some of the Various Testing MethodsDeterministic

Leak Test

Technologies

Package Content

Requirements

Package

Requirements

Leak Size Class

(Detection Range)Measurement Outcome and Data Analysis

Effect of Method

on Package

Test Time

Order of

Magnitude

Electrical

conductivity and

capacitance

(high-voltage leak

detection)

Liquid (with no combustion

risk) must be more

electrically conductive

than package.

Product must be present

at leak site.

Less electrically

conductive than

liquid product.

3 to 6

Range varies with

product–package,

instrument, test

sample fixturing,

and method

parameters.

Quantitative measure of electrical current

passing through the test sample: provides an

indirect determination of leak presence as

shown by a drop in test sample electrical

resistivity, with a resultant increase in voltage

reading above a predetermined pass/fail limit.

Nondestructive,

although product

stability studies

are recommended

to verify effect of

exposure.

Seconds

Laser-based gas

headspace

analysis

Gas volume, path length,

and content must be

compatible with

instrument’s detection

capability.

Transparent or

translucent,

amber or

colorless.

1 to 6

Detection of

smallest leakage

rates is a function

of time span

between analyses.

Quantitative measure of gas headspace

content of the test sample by laser-based gas

analysis, for product requiring a headspace of

low oxygen concentration, low moisture vapor

concentration, and/or low absolute pressure.

To calculate the leak rate of the test sample,

one can use results compiled as a function of

time.

Nondestructive Seconds

Mass extraction Gas or liquid must be

present at leak site.

Presence of liquid at leak

site requires test

pressures below vapor

pressure.

Product must not clog leak

path.

Rigid, or flexible

with package

restraint

mechanism.

Porous package

requires masking

to limit gas flow

through porous

material.

3 to 6

Range varies with

product–package,

instrument, test

fixtures/chamber,

and method

parameters.

Quantitative measure of mass flow rate

resulting from test sample headspace escape

or liquid product volatilization within an

evacuated test chamber housing the test

sample.

Leak rate of the test sample may be estimated

by comparing the mass flow results of the test

sample to tests performed using leak rate

standards and positive controls.

Quantitative measure of pressure provides an

indication of larger leak presence.

Nondestructive Seconds to

minutes

Examining Some of the Various Testing MethodsDeterministic

Leak Test

Technologies

Package Content

Requirements

Package

Requirements

Leak Size Class

(Detection Range)Measurement Outcome and Data Analysis

Effect of Method

on Package

Test Time

Order of

Magnitude

Pressure

decay

Gas must be present

at leak site.

Product (especially

liquids or semi-

solids) must not

cover potential leak

sites.

Compatible with

pressure detection

mode.

Rigid, or flexible with

package restraint

mechanism.

3 to 6

Range varies with

product–package,

instrument, and

method parameters.

Quantitative measure of pressure drop within a

pressurized test sample; pressure drop results

from escape of gas through leak paths.

Results that are compiled as a function of time are

indicative of leakage rate of the whole test sample.

Nondestructive,

although means

used to access

test sample

interior may

compromise test

sample barrier.

Minutes to

days,

depending

on package

volume and

required leak

limit of

detection

Tracer gas

detection,

vacuum mode

Tracer gas must be

added to package.

Tracer gas must

have access to

package surfaces to

test package for

leaks.

Able to tolerate high-

vacuum test conditions


package restraint

mechanism.

Limited tracer gas

permeability

1 to 4

Detection of larger

leaks is a function of

instrument capability

and test sample

fixturing.

Quantitative measure by spectroscopic analysis of

tracer gas leak rate while tracer gas is being

drawn out of a tracer-flooded test sample into a

vacuum chamber.

Leak rate of the total sample can be calculated by

normalizing the measured tracer leak rate by

tracer concentration in the test sample.

Nondestructive,

although access

to package interior

for tracer gas

introduction may

compromise test

sample barrier.

Seconds to

minutes

Vacuum decay Gas or liquid must

be present at leak

site.

Presence of liquid at

leak site requires

test pressures below

vapor pressure.

Product must not

clog leak path.


package restraint

mechanism

Porous package

requires masking to

limit gas flow through

porous material.

3 to 6

Range varies with

product–package,

instrument, test

sample chamber,

and method

parameters.

Quantitative measure of pressure rise (vacuum

decay) within an evacuated test chamber housing

the test sample; vacuum decay results from

headspace escape from the test sample, or liquid

product volatilization.

Leak rate of the test sample may be estimated by

comparing vacuum decay results for the test

sample to results of tests performed using leak

rate standards and positive controls.

Nondestructive Seconds to

minutes

a The leak size class detection range cited for each technology allows for method-to-method comparison. The leak sizes actually detected by a fully developed and validated

deterministic method may deviate from these ranges, as noted.


Electrical Conductivity and Capacitance Test (also known as High Voltage Leak Detection HVLD)

Leak detection in walls of nonporous, rigid or flexible packaging containing liquid or semi-liquid product (e.g. ampoules) 15, 17

• High voltage/high frequency charge is applied across the container-closure system17

• A leak will cause an increase in current across the high voltage electrodes, triggering the reject mechanism for the leak detector17

Key factors include voltage level, probe positioning, container-closure system geometry and wall thickness, and product formulation17

Advantages Disadvantages

• Automation of the integrity test17

• Rapidity of the test procedure

(seconds) 17

• Can be used online17

• Nondestructive15

• Could potentially detect leak

locations15

• Quantitative Electrical Conductance

Measurements15

• Testing under normal atmosphere11

• High voltage/high voltage field could

potentially affect potency and stability

of some protein-based therapeutics. 17

• Requires conductive liquid fills11


Laser-based Gas Headspace Analysis Typically performed using non-contact methods, such as frequency

modulation spectroscopy17

• Near infrared diode laser light passes through the gas headspace region15

• Light is absorbed as a function of gas concentration and pressure15

• Absorption information is processed using phase-sensitive detection techniques15

• A microprocessor analyzes the data and yields the test results15

Can be used for lyophilized products or oxygen-sensitive liquid products17

Headspace gas analysis is rapid (seconds)—allows 100% inspection of oxygen sensitive products or products packaged under vacuum17

Nondestructive and provides quantitative results15

Key parameters: Headspace Volume, Package Temperature, Headspace Pressure and Vacuum, Sensitivity of the Headspace Analysis Instrumentation17


Mass Extraction Nondestructive and Quantitative15

Can be used for detecting leakage in nonporous, rigid or flexible packages15

• Packages with a porous component can be tested by masking the porous package component15

The test sample is placed inside a test chamber that is pneumatically connected to a mass extraction leak test system equipped with a vacuum generator package15

• The chamber is quickly evacuated for a predetermined time to reach a predetermined vacuum level. A series of evacuation cycles are performed, each intended to identify smaller leakage rates15

• After each cycle, the test system is isolated from the vacuum source and measurements of absolute pressure, pressure decay rate, and/or gas mass flow rate are captured15

• Readings greater than predetermined limits that were established using negative controls are indicative of container leakage, triggering test cycle abort15

• For those test samples passing all previous larger leak vacuum cycles, a final vacuum is drawn15

• With all flow from the test chamber directed through the mass flow sensor, the mass flow rate is measured. Mass flow above a predetermined limit established using negative controls is indicative of container leakage15

Advantages• Rapidity of the test

procedure 17


• Quantitiative15

Disadvantages• Requires fixtures for

each container

closure system 17

• Proteinaceous

products may

interfere with defect

detection11

Examining Some of the Various Testing MethodsPressure Decay

Intended for integrity testing of the gas headspace region of the test sample (nonporous, rigid, or flexible packages) 17

• For this test, the container-closure system is placed in a test fixture that is either pressurized or evacuated17

• The test chamber is allowed to stabilize, and then the change in pressure or vacuum is measured over time17

• Pressure or vacuum can be measured directly or by differential pressure between the test chamber and a reference chamber17

Key test parameters include temperature, package geometry, test fixture geometry, volume of package headspace, water vapor pressure inside the package, stabilization time, and test time17

Advantages Disadvantages

• Rapidity of the test

procedure 17

• Can be used online17


• Quantitiative15

• Requires fixtures for each

container closure system 17

• Proteinaceous products

may interfere with defect

detection11


Tracer Gas Detection (Vacuum Mode) Detects leakage from nonporous, rigid or flexible packages15

The test requires the presence of tracer gas inside the test sample package15

• Helium is the most commonly used tracer gas, and hydrogen is also used15

The leakage rate of tracer gas is quantitatively measured using a spectrometric analytical instrument specific for the tracer gas15

To perform the vacuum-mode test, test samples that have been fully or partially flooded with tracer gas are placed inside an evacuation chamber15

• The instrument's vacuum pump evacuates the test chamber or fixture, drawing any leaking tracer gas through the analyzer15

• The absolute leak rate of the test sample may be calculated by normalizing test results by the partial pressure of the tracer gas within the test sample at the time of test15

• Test sample leakage is judged acceptable if the absolute leak rate is below that which has been reported to put product quality at risk15

Advantages

• Rapidity of the test

procedure 17


• Quantitiative15

• Sensitivity11

Disadvantages

• Requires helium-

containing

headspace (for

helium leak

detection) or

modified atmosphere

packaging (for

headspace oxygen

testing)11


Vacuum Decay

Nondestructive and quantitative15

Detects leaks in nonporous, rigid or flexible packages. Packages with a porous component can be tested by masking the porous package component. 15

• The test sample is placed in a closely fitting evacuation test chamber, which is equipped with an external vacuum source. 15

• The test chamber plus test system dead space are evacuated for a predetermined period of time. 15

• The targeted vacuum level chosen for the test is predetermined on the basis of the test sample type under evaluation. 15

• The rise in dead space pressure (i.e., vacuum decay) is monitored for a predetermined length of time using absolute and/or differential pressure transducers. 15

• A pressure increase that exceeds a predetermined pass/fail limit established using negative controls indicates container leakage. 15

Advantages• Rapidity of the test

procedure 17


• Quantitiative15

Disadvantages• Requires fixtures for

each container

closure system 17

• Proteinaceous

products may

interfere with defect

detection11


Probabilistic Methods Include:

Microbial Challenge by Immersion

Tracer Liquid Tests (e.g. Dye Ingress)

Bubble Tests

Tracer Gas (Sniffer Mode)

Microbial Challenge by Immersion and Dye Ingress

are the most recognized leak test methods.

USP <1207> Series is encouraging a move toward

the deterministic methods.


Probabilistic

Leak Test

Technologies

Package Content

Requirements

Package

Requirements

Leak Size Class

(Detection Range)

Measurement Outcome and Data

Analysis

Effect of Method

on Package

Test Time

Order of

Magnitude

Bubble emission Gas must be present at

leak site.

Product (especially liquids

or semi-solids) must not

cover package surfaces to

be leak tested.

Rigid, or flexible

with package

restraint

mechanism.

4 to 6

Range varies with

product–package,

test sample fixturing

and positioning,

method parameters,

and analyst technique

and skill.

Qualitative measure by visual inspection of

bubble emission caused by escape of test

sample headspace while sample is

submerged and exposed to differential

pressure conditions. Alternatively, sample

surfaces may be exposed to surfactant.

Continuous bubble emission indicates

presence of a leak, its location, and its

relative size.

Destructive Minutes

Microbial

challenge,

immersion

exposure

Growth-supportive media

or product.

Presence of liquid at the

leak site required for

method reliability.

Able to tolerate

pressure and

immersion

challenge.

Rigid, or flexible

with package

restraint

mechanism.

4 to 6

Range varies with

container-closure,

test sample fixturing

and positioning,

challenge condition

severity, and inherent

biological variability.

Qualitative measure by visual inspection of

microorganism growth inside test samples

filled with growth-supportive media or

product, post immersion in heavily

contaminated challenge media while

exposed to differential pressure conditions,

followed by incubation to encourage

microbial growth.

Growth in the test sample indicates the

presence of test sample leak site(s)

capable of allowing passive or active entry

of microbes.

Destructive Weeks

Examining Some of the Various Testing MethodsProbabilistic

Leak Test

Technologies

Package Content

Requirements

Package

Requirements

Leak Size Class

(Detection Range)

Measurement Outcome and Data

Analysis

Effect of Method

on Package

Test Time

Order of

Magnitude

Tracer gas

detection, sniffer

mode

Tracer gas must be added

to package.

Tracer gas must have

access to package surfaces

to be tested for leaks.

Leak site

accessible to

probe.

Limited tracer gas

permeability.

3 to 6

Range varies with test

sample, method

parameters, test sample

fixturing, and analyst

technique and skill.

Smaller leak detection

may be possible under

optimum test conditions.

Quantitative measure by spectroscopic

analysis of tracer gas near the outer

surfaces of the tracer-flooded test

sample, sampled using a sniffer probe.

Tracer presence above a pass/fail limit

indicates presence and location of a leak

site.

Nondestructive,

although access to

package interior for

tracer gas

introduction may

compromise test

sample barrier.

Seconds to

minutes

Tracer liquid Contents must be

compatible with liquid tracer.

Product must not clog leak

path.

Rigid, or flexible

with package

restraint

mechanism.

Compatible with

liquid tracer

detection mode.

4 to 6

Able to tolerate liquid

immersion.

Smaller leak detection

may be possible under

optimal test conditions

employing chemical

analysis tracer detection.

Range varies with

container-closure, test

sample fixturing and

positioning, challenge

condition severity, and

tracer liquid content.

Measure of tracer in test sample

previously submerged in tracer-charged

liquid while exposed to differential

pressure conditions. Alternatively, tracer-

charged test samples may be submerged

in tracer-free collection fluid.

Tracer presence indicates leak site(s)

capable of allowing tracer passage, and

tracer magnitude may indicate relative

leak size (assuming a single-leak

pathway).

Tracer migration measurement may be

quantitative (by chemical analysis;

preferred approach for small leak

detection) or qualitative (by visual

inspection).

Destructive Minutes to

hours

a The leak size class detection range cited for each technology allows for method-to-method comparison. The leak sizes actually detected by a fully developed and validated deterministic method

may deviate from these ranges, as noted.



Suitable for any container-closure system that can withstand immersion and pressure changes.17

Test article is immersed in a broth containing the test organism. 17

• Brevundimonas diminuta, Serratia marcescens, Escherichia coli and other organisms have been used for this test. 17

This test may be static (no pressure or vacuum) or dynamic (pressure and vacuum are applied, typically to simulate air transport) 17

Key test factors include: bacterial size and motility, differential pressure, challenge media, exposure time, and viable count in the challenge media. 17

Advantages• Widely used for

decades11

• Industry and

regulatory

familiarity11

• Readily incorporated

into media fills11

Disadvantages• Less sensitive11

• Detection

probabilistic for

small-size defects

(i.e. <20 µm) 11

• Destructive11



The dye leak test is the most common liquid tracer test.15

• The container is immersed in a methylene blue solution and pressure and vacuum are applied to the container. 15

• The container inspected visually or via spectrophotometry (preferred method). 15

Key factors include differential pressure, compatibility of the dye with the product, liquid viscosity and surface tension, inspector training and experience (for visual inspection) or assay sensitivity (for spectrophotometry). 15

Qualitative and destructive17

Advantages• Widely used for

decades11

• Industry and

regulatory

familiarity11

Disadvantages• Less sensitive11

• Detection

probabilistic for

small-size defects

(i.e. <20 µm) 11

• Destructive11


Bubble Tests

The item under test is pressurized to about 3 psig and

immersed in a bath containing water or water and

surfactant (e.g., polysorbate 80).15

• This test can detect leaks as small as 10-5 mbar-L/sec.15

Key test factors include differential pressure, test

time, immersion fluid surface tension, visible

inspection conditions (e.g., light intensity,

magnification, and background), and visual

inspector training and experience.15

Qualitative and destructive17

http://flexpakinc.com/gallery/


Tracer Gas (Sniffer Mode)

Test samples are flooded completely or partially with the tracer gas via one of several options. 17

• Piercing a closed test sample to introduce pressurized tracer gas (sealant is applied to close the puncture site) 17

• Flooding the test sample before package closure17

• “Soaking” a closed test sample by pressurizing with tracer gas (most applicable to larger leak detection) 17

Test samples are checked for leakage by scanning the outer package surfaces using a vacuum wand17

The use of negative and positive controls along with the test samples provides evidence of test method limit of detection.17

The sniffer mode is generally chosen when the leak location must be identified. 17

Developing and

Validating the Method

Developing a Method

Package integrity verification occurs during three product

life cycle phases:14

1. The development and validation of the product-

package system

2. Product manufacturing

3. Commercial product shelf-life stability assessments

Testing needs to show the complete picture of container

CCI over the lifecycle of the product.

Any leak test requires optimization for each product-

package application.13

Developing a Method

All methods have limitations, but the following aspects should be considered.11

Methods must be suitable for its intended use

Methods must be applicable to the specific drug product-package (e.g. drug products can interact with CCI defects)

Methods must detect leaks effectively

Non-destructive CCI testing

Choose a preliminary method following vendor’s recommendations or literature research.

Choice of method depends on specific desired outcomes14

1. Detecting the presence of leak paths

2. Determining the location of leak paths

3. Measuring leak rate for the whole package

4. Evaluating the potential for microbial ingress

Other Criteria• Liquid or solid product?

• Headspace gas?

• Headspace vacuum?

• No Headspace?

• Package design?

• Rigid or flexible package?

• Moveable components?

• Polymeric materials?

• Metallic materials?

• Transparent or Opaque

materials?

• Porous materials?

• Multi-dose systems?

Developing a Method

Positive and negative controls need to be created for the assay.

Positive controls are needed to simulate defects.

• Leaks that occur naturally are rarely uniform holes or channels. They are generally complex tortuous paths.13

The controls will be tested along with intact samples under different testing parameters. 11

Negative and positive controls are designed and assembled appropriately with consideration of container–closure design, materials of construction, characteristics of anticipated package leaks, and impact of product contents on test results.14

Developing a Method

Many methods are available to create positive controls

Positive Control Type Advantages Disadvantages

Micro-pipettes11

Easy sample

preparation

Fragile

Broken tips may not be

easily detected

Laser drilled

holes11

Sample geometry can

remain unchanged

Better resemble natural

defects in glass (cracks)

and polymer (pinholes)

Cost

“Hole” size of laser-

drilled effects needs to

be calibrated

Microtubes11

Easy sample

preparation

Robust

Easy to use

The length of the

microtube defects

usually longer than that

of the typical “real-world”

defects

Wire

Easy to prepare

Easy to use

Can create a tenting

effect where the size of

the control is not

accurate

Developing a Method

In addition to choosing a preliminary method, creating

positive and negative control samples, acceptance

criteria must be predetermined.

• All negative controls must pass

• All positive controls with leaks at or above the claimed

limit of detection must fail

• A lower limit of detection must be established

• An upper limit of detection should be established

http://www.rxpax.com/training-services/

Developing a Method

USP <1207.1> and ICH Q2 (R1) describes how to determine and establish a limit of detection (LOD) for the method chosen. 14

The LOD is the smallest leakage rate or leak size that the method can reliably detect, given the product-package of interest.14

During method development trials all negative controls must pass and all positive controls with leaks at or above the claimed limit of detection must fail. 14

The LOD for a given method is defined as the smallest-leak positive control subset that consistently demonstrates leakage in 100% of the positive-control subset units at that defect size and larger. 14

• The percentage of positive controls to be detected must be specified in the validation study protocol by the end user. 14

Multiple methods are available to determine limit of detection criteria.

Developing a Method

USP <1207.1> also describes the need to verify the

largest leak detection capability or upper limit of

detection.

All analytical methods have optimum measurement ranges. 14

All leak test method selection should also take into account the largest

leak sizes likely to occur in the sample population. 14

Once an optimized method is created, multiple lots

should be tested representing the package integrity at

the extremes of finished product-package profiles. 14

e.g. relevant product variations, including various packaging component

sources/lots, drug products batches, as well as packaging sites and

lines.11

The quantities to be tested should be sufficient to provide adequate

assurance of package integrity. 14

Developing a Method

At this point

A method has been chosen

Target acceptance criteria has been established

Positive and negative controls have been created

Leak test method parameters have been developed

and optimized through experimentation to ensure

sensitive, accurate, robust, and reproducible leak

detection for specific product–package systems.14

And successful qualification(s) have been performed

A validation protocol should be written outlining

the successful trials and parameters created

during the method develop phase.

Performing the Validation

Container closure integrity methods need to be validated for

specific drug-product packages

Various components, such as the drug product, can affect the

testing outcome.

Validation of the final leak test method is required to

demonstrate test method detection limit, accuracy, range,

robustness, and precision.11, 13

Method accuracy is the ability of a leak test to correctly identify or size

leaks (as per the intended leak test outcome).14

Method precision is a measure of test result reproducibility and is proven

during method validation by testing a randomly mixed population of

negative and positive controls over multiple days by multiple operators

and, when possible, using multiple test instruments.14

USP <1225> Validation of Compendial Procedures and ICH Q2(R1)

provide good guidance on method validations


The established validation protocol should be followed when

performing the validation.

Validations are typically performed in triplicate by performing

the method created in the method development phase.

USP <1207.1> recommends randomly mixing negative and positive

control populations over multiple days by multiple operators and, when

possible, using multiple test instruments.14

Quantities of samples to be tested must be sufficient to

provide adequate assurance of package integrity and will likely

vary on the basis of:

1. The complexity of the product–package 14

2. The specifics of the user specification requirements14

3. The prior experience of the producer. 14


The method validation protocol should be written to describe introducing a number of defects of known size or leak rate as controls

Acceptance criteria for leak test method validation should include the following:

1. All negative controls pass (no leaks are identified) 14

2. All positive controls with leaks at or above the designated limit of detection fail (leaks are detected). 14

3. An integral package is one that conforms to specific product-package maximum allowable leakage limits.13

For some test methods (e.g. liquid tracer leak detection by mass spectrophotometric analysis), test blanks are also included as part of method validation and routine testing. 14

Blanks are not equivalent to, and should not substitute for, negative controls. 14

New USP <1207>

series removes the

requirement to

compare to microbial

ingress


After the successful validation, a report should be written

describing the acceptable parameters, acceptance criteria,

validation results, and the method to be used for routine

testing and stability testing.

Establishing Acceptance Criteria Acceptance criteria was established in the method development

phase.

A lower limit of detection was established and demonstrated

An upper limit of detection was established and

demonstrated

Positive and negative controls were created

• All positive controls must fail

• All negative controls must pass

Leak test method parameters were developed and optimized

through experimentation (e.g. amount of vacuum to pull)

Units that test to be non-integral need to be investigated

Performing the Test After the method is develop and validated, a routine testing SOP

(standard operating procedure or test method) should be

established.

The routine SOP should lock down all the parameters and

acceptance criteria for the specific product/container-closure

system so that the test is performed the same way every time.

“The manufacturer should be able to justify the amount of testing

required on the basis of statistical process control results generated

during the validation phase, and later, on the basis of routine

manufacturing product-quality trending analyses.”14

Quantities of samples to be tested must be sufficient to provide adequate

assurance of package integrity.14

Package integrity should be re-evaluated when changes are

required in package design, package materials, or

manufacturing/processing conditions.14

Stability Testing

The routine testing SOP should be utilized when performing

CCIT for stability testing.

Container-closure integrity should be demonstrated as part of

the stability program over the shelf life of the product for

new and existing products.5

Sterility testing or alternatives (e.g. container/closure

integrity testing) should be performed at a minimum

initially and at the end of the proposed shelf-life. 10

Container-closure integrity testing can be used to replace

sterility testing in stability protocols.4, 9

CCIT may not replace the sterility test for release

testing.4, 9

Stability Testing

If a non-destructive test has been validated for the specific

container-closure system, it is useful during stability studies.

The same container can be used throughout the stability

period.

This saves money and allows for more meaningful profiles

of container-closure integrity.17

Where the same strength and exact container/closure system

is used for 3 or more fill contents, the manufacturer may

elect to place only the smallest and largest container size into

the stability program, i.e., bracketing.10

Summary Container Closure Integrity Testing evaluates the adequacy of

container closure barrier systems to maintain a sterile barrier.

Some guidance documents and regulations that discuss CCIT include

FDA 21CFR211.94

European Commission EudraLex Annex 1 and Volume 4- Part II

ICH Q5CC

Guidance for the Industry “Container and Closure System Integrity Testing in

Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile

Products”

USP <1207>

PDA Technical Report 27

PDA White Paper- “Container Closure Integrity Control versus Integrity Testing

during Routing Manufacturing”

FDA Compliance Program Guidance Manual, Chapter 56- Drug Quality

Assurance Program 7356.002A

Summary Container Closure Integrity Testing is currently reviewed by

regulators

Many different methods are available to perform CCIT.

The proposed USP <1207> update divides the methods into deterministic

and probabilistic.

There is a move to move toward more deterministic methods.

The USP <1207> revised guidance series is expected to become

effective in August 2016 and removes the recommendation to

compare CCIT methods to microbial ingress testing

Methods described in the proposed USP <1207> update include:

Electrical Conductivity and Capacity Test (HVLD)

Mass Extraction

Pressure Decay

Tracer Gas (vacuum mode)

Vacuum Decay



Bubble Tests Tracer Gas (Sniffer

Mode)

Summary

Package integrity verification occurs during

three product life cycle phases:14

1. The development and validation of the product-package

system

2. Product manufacturing

3. Commercial product shelf-life stability assessments

CCIT needs to show container integrity over the

life cycle of the product.

CCIT methods require optimization for each

product-container/closure application.

All methods have limitations

Summary

During method development, a preliminary method is

chosen, optimized, and qualified.

Target acceptance criteria will be established

Positive and negative controls will be created

Leak test method parameters will be developed and

optimized through experimentation.14

Qualification(s) trials will be performed

Quantities for testing should be sufficient to provide

adequate assurance of package integrity. 14

Summary Container closure integrity needs to be validated for

each specific drug-product package.

Validations are typically performed in triplicate.

USP <1207.1> recommends to randomly mix negative and positive control populations over multiple days, with multiple operators, and if possible, using multiple test instruments.

Acceptance criteria should include the following:

1. All negative controls pass (no leaks are identified) 14

2. All positive controls with leaks at or above the designated limit of detection fail (leaks are detected). 14

3. An integral package is one that conforms to specific product-package maximum allowable leakage limits.13

4. Upper and lower limits of detection should be established as well as any key testing parameters.

Summary

Routine and stability testing should be performed per

an approved standard operating procedure or

method.

Package integrity should be re-evaluated when

changes are required in package design, package

materials, or manufacturing/processing conditions.14

CCIT can be used in place of sterility testing during

stability studies.

Non-destructive CCIT methods save product and

money.

Bracketing strategies can be utilized during stability

studies when appropriate.10

Using an interactive game, participants review information pertaining to

monitoring microbial metrics.

BINGO1. Container closure systems should maintain the ___________and

product quality of sterile finished products.

Sterility

2. All methods have pros and __________.

Cons

3. Some container, such as ________, require 100% integrity testing.

Ampoules

4. The proposed USP <1207> revisions remove the requirement to

compare CCIT results to the ___________ingress challenge.

Microbial

5. The proposed USP <1207> divides the test into _______ major

categories.

Two

BINGO6. _____________ assays are less prone to error.

Deterministic

7. The microbial ingress challenge is a ______________ assay.

Probabilistic

8. The _______ leak test is the most common liquid tracer

test.

Dye

9. Testing should show the complete CCI picture over the

___________ of the product

Lifecycle

10. All __________ controls with leaks at or above the claimed

limit of detection must fail.

Positive

BINGO11. A lower limit of _______________ must be established.

Detection

12. Quantities of samples to be tested must be ____________ to provide

adequate assurance of package integrity.

Adequate

13. Package integrity should be ______________ when changes are

required in package design.

Re-evaluated

14. All __________ controls must pass.

Negative

15. CCIT can be used to replace sterility testing in ___________

protocols

Stability

BINGO16. Container __________ integrity methods needs to be validated for

specific drug product packages.

Closure

17. Revisions to USP <1207> series are expected to become official in

__________ 2016.

August

18. Package integrity verification occurs during ________ product life

cycle phases.

Three

19. ____________ drilled holes can be used to create positive controls.

Laser

20. Choose a preliminary method following vendor’s recommendations or

____________ research.

Literature

BINGO21. The vacuum decay method is _____________ and quantitative.

Nondestructive

22. The dye leak test is destructive and _______________.

Qualitative

23. CCIT can be performed in ___________ different ways.

Many

24. _____________ may not replace the sterility test for release testing.

CCIT

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