Genesis Packaging Technologies

Impact of Cold Storage Conditions on Parenteral Vials

Roger Asselta, Vice President of Technical Affairs

HIV Env Vaccine Manufacturing Workshop September 15, 2016Rockville, Maryland

Selection and Utilization of Parenteral Container Closure Systems

• Container Closure Systems for Packaging Human Drugs and Biologics (USFDA Guidance 1999)

• Description

• Suitability for the Intended Use

• Protection

• Compatibility

• Safety

• Performance• CSS Functionality

• Drug Delivery

• Quality

• Physical Characteristics

• Chemical Composition

2

A Parenteral Package must be Suitable for its Intended Use

• The recently revised <USP 1207> states;• CCI or package integrity is defined as “the absence of

package leakage greater than the product package maximum allowable leakage limit (MALL).”

• An “Integral Package” must:• Prevent microbial ingress (ensure sterility)

• Maintain drug quality • Limit loss of product contents

• Prevent entry of debris or detrimental gasses

*become effective August 2016

Definitions

• Leak: a hole, crack or porosity through a component of the CCS, or a gap at an interface of the components capable of allowing a gas or liquid ingress or egress the CCS

• Leakage: the movement of the liquid or gas through the leak

• Maximum Allowable Leakage Limit (MALL): the smallest gap (leak) or leak rate that puts product quality at risk (sometimes called the ‘critical leak’)

CCI is proven when…

The package meets the

Maximum Allowable Leakage Limit

required to ensure product quality attributes of sterility and physicochemical stability through expiry.

Those package requirements include:

Sterility preservation

Formulation loss prevention

Critical gas headspace preservation

Vacuum, Low O2, Low H2O vapor

Parenteral Vial Integrity Failures

• Loss of Potency

• Potency Rise, Increase in Concentration

• Increase in Moisture Content of Lyo Cake

• Deterioration of Cake Quality

• Oxidation of API due to Changes in Headspace

• pH Shift due to CO2 Ingress

• Gravimetric Change

• Vacuum Loss

• Loose Seals Noted

• Sterility Failure

• Not Robust in Deep Cold

• CCI Testing Failure

Root Causes of CCI Failures

• Component Quality• Poorly Designed, Specified, Controlled

• CCS Components Improperly Matched

• Seal Quality• Lack of Sufficient Process Validation (Understanding of Variation)

• Suboptimal equipment or operation

• Improper Equipment Set-Up, Variation in Set-up

• Lack of Process Monitoring and Control

• Improper Handling, CCS Not Sufficiently Robust

Inherent Package Integrity

• The leakage rate of a well-assembled (sealed) container/closure system using defect-free components

• Deviations from inherent package integrity • Aberrant components- out-of-specification, defective

• Poorly assembled, inadequately sealed packages

• Damage to assembled packages

• Exposure to harm conditions post assembly that affect the seal, component materials (including there properties) and/or component fit

Components of a Vial Seal

Stopper Flange

Vial Sealing Surface

CrimpVial

Stopper

Aluminum Ferrule Ferrule

Stopper Plug

Parenteral Vial Seals

1

2

3

• 1 Valve (Plug) Seal

• 2 Transition (Ring) Seal

• 3 Land Seal

Elastomeric Closure

• Elastomers are amorphous polymers that exist above their Glass Transition Temperature (Tg) and exhibit viscoelastic behavior. Rubber Formulations for closures to seal pharmaceutical containers have Tg s that are usually below -50° C.

• Interchangeable with the Term Rubber• Rubber more properly used for vulcanized (cross-linked) elastomers

• Viscoelastic Properties in response to an applied energy (force)• Elastic in that it can store energy.

• Viscous in that it dissipates energy

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Elastomeric Closure (continued)

• In sealing rubber components, the elastic property is the more important. An applied stress (sealing force) induces a corresponding strain which creates a contact stress. This stored internal energy is the Residual Seal Force (RSF).

• As the polymer chains rearrange to reduce this internal energy (hysteresis), stress relaxation occurs with a reduction in RSF.

• The viscous property of rubber, too, is important. It allows considerable segmental motion or flow. This movement can fill gaps and voids in the sealing surface.

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Land Compression Seal

• Is the Primary Seal

• Achieved by Vertical Deformation (Applied Force)

• It is:• Reliable

• Controllable

• Measurable

EMEA Annex 1: Manufacture of Sterile Medicinal Products118: The container closure system for aseptically filled vials is not fully integral until the aluminum cap has been crimped into place on the stoppered vial. Crimping of the cap should therefore be preformed as soon as possible after stopper insertion.

Dimensional Relationships

• Components are Independently Developed by Suppliers

• Dimensions and Tolerances Developed Long Ago• Based on Suppliers’ Manufacturing Capability, Not Necessarily Fit and

Functionality

• Standards are wide and vague, allowing for poor fit

• Differing dimensional measurement techniques

• Formulation development does not necessarily focus on physical properties, Recent the focus is more on E & L concerns

Mismatch of Components

• Machinability Challenges

• Raised Stopper Issues

• Failure to Achieve CCI

• Failure to Maintain CCI• Under Ambient Conditions

• Under Stressed Conditions (e.g. very low storage temperatures)

Stopper Varieties

ISO 8362-1 Blowback Variation

GPI 2710

Stopper Plug/Vial Fit

Minimum Interference 0.2mm

Maximum Interference 0.8mm

Raised Stoppers

So...

• What happens to CCI during deep cold storage?

• How does vial seal tightness correlate to maintaining CCI?

• What should you do if you have product requiring deep

cold storage (live viral vaccines, gene/cell therapy)?

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Glass transition temperature Tg

• Only polymers have a glass transition temperature.

• When the polymer is cooled below this temperature, it loses elasticity and becomes hard and brittle, like glass.

• ‘Rubbery state’ vs. ‘glassy state’

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If container closure integrity depends on the elasticity

of the rubber stopper, one might expect potential

sealing issues below Tg of the rubber stopper.

Identified CCI issues in deep cold storage

Because deep cold storage (-80 ˚C to cryo) is colder than the Tg of most rubber stopper formulations (-55 to -70 ˚C), there is an increased risk of losing CCI if:

•An appropriate vial / stopper combination is not used- Vial / stopper design (blowback, non-blowback, etc.)

- Vial / stopper fit (relative dimensions stopper plug, inner vial neck)

•Capping / crimping is not done properly- ‘Tight’ vs. ‘Loose’

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REF: Container/Closure Integrity Testing and the Identification of a Suitable Vial/Stopper Combination for Low-

Temperature Storage at -80 CBrigitte Zuleger, Uwe Werner, Alexander Kort, Rene Glowienka, Engelbert Wehnes, Derek Duncan

PDA J Pharm Sci and Tech 2012, 66 453-465

Considerations

• “Critical factors for the maintenance of CCI included appropriate design of the vial and stopper plug, relative dimensions … giving a tight fit, as well as an appropriately tight capping and crimping process.”

• “Dimensional variation … as well as (manufacturer’s) different specifications … motivates a careful selection of packaging components for storage at -80°C”.

Brigitte Zuleger, et al. “Container/Closure Integrity Testing and the Identification of a Suitable Vial/Stopper Combination for Low-Temperature Storage at -80°C”; PDA J Pharm Sci and Tech, 2012

Objectives follow up -80 ˚C studies

• Quantify capping & crimping parameters• Three capping pressures defined

• Measured with Residual Seal Force

• Direct comparison of RT, -20˚C, -80 ˚C, and cryogenic (-178 ˚C) storage

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Experimental parameters

• Stopper/vial combinations• Five different stopper/vial combinations

• Crimping parameters• Genesis RW-50 capper (sealing rail)

• Crimping pressures (applied force differentials):

• Low: 45N; Med: 98 N; High: 151 N

• Correlation of applied forces to RSF

• Stoppered empty vials

• Storage at RT, -20˚C, -80 ˚C, liquid nitrogen

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• Air filled vial at 1 atm at room temperature

• In cold storage the initial headspace condenses and creates underpressure

• The stopper can lose its elastic properties and closure can be lost

• Cold dense gas from environment fills headspace

• Warming container to room temperature regains stopper elasticity and reseals closure

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Initial

headspace

1 atm

Air/N2/CO2

Air/N2/CO2

Air/N2/CO2

Air/N2/CO2

Air/N2/CO2

Leakage in deep cold storage:Air vial goes into storage on dry ice

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• Cold dense gas now trapped inside, expands as temperature increases, creating overpressure

• Maintenance of this overpressure can be monitored over time to verify that the leak was temporary.

Air/N2/CO2

Air/N2/CO2

Leakage in deep cold storage:Air vial goes into storage on dry ice

Quantifying the physical headspace conditions with Laser-based Headspace Analysis enables identification of CCI dynamics during deep cold storage

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The analytical tool

Laser diode

Detector

Example: CCI of media filled vials stored on dry ice

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• 2R clear tubing vials containing media.

• Initial headspace conditions: 1 atm of air

• Stored on dry ice for 7 days.

• Thawed to room temperature (RT).

• Headspace conditions analyzed.

• Any change in the headspace conditions is a direct

sign that closure was lost during dry ice storage

resulting in headspace gas exchange.

Example: CCI of media filled vials stored on dry ice for 7 days

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Example: CCI of media filled vials stored on dry ice

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Some important comments on these results:

• The maintenance of overpressure in the leaking

samples over time at RT means the vial has

resealed at temperatures above the Tg of the

rubber stopper.

• Leaks during deep cold storage are temporary!

• Other methods (blue dye, microbial ingress,

pressure decay) that test these vials after thawing

will NOT identify these vials as having leaked.

Quantifying vial seal tightness

Residual seal force

• RSF is the stress a compressed elastomeric closure flange continues to exert on a vial land Sealing surface after application of an aluminum seal (crimping)

• Sufficient compression is essential to seal integrity.

• Quantifying the RSF is a test method for the indirect estimation of elastomeric closure compression

• There is an Optimum Window of Closure Compression

• Poor Compression Cannot be Visually Detected

• RSF testing is recognized in the recently revised USP <1207> Sterile Product Packaging – Integrity Evaluation in section <1207.3> Package Seal Quality Test Methods

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Measuring RSF

The compression curve (red) is a combination of the viscous and elastic responses to the stress from tester load. “The knee”(yellow) is where additional deformation occurs. An algorithm is applied, using the 1st (blue) and 2nd (green) derivatives to accurately identify that knee.

Ludwig J, Nolan P, Davis C, Automated method for determining Instron residual seal force of glass vial/rubber stopper closure systems, PDA J Pharm Sci & Technol 47, (1993) 211 – 218

-1000

-500

0

500

1000

1500

2000

2500

3000

0

5

10

15

20

25

30

35

40

5 25 45 65 85 105 125

DE

RIV

AT

IVE

S x

10

00

RESIDUAL SEAL FORCE ANALYSIS

FORCE

KNEE

1 DER.

2 DER.

Compressive Force (Distance)

Co

mp

ress

ive

Load

(Fo

rce

in lb

s.)

Correlation of RSF to Compression

50454035302520

25

20

15

10

5

0

S 2.47516

R-Sq 82.6%

R-Sq(adj) 82.3%

COC West % Comp

CO

C W

est

RS

F

Fitted Line PlotCOC West RSF = - 13.70 + 0.7835 COC West % Comp

Per cent Compression

Res

idu

al S

eal F

orc

e (R

SF)

3cc Vial with 13mm halobutyl serum stopper

Correlation of RSF to Leak Rate

Results: X-ray imaging

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Low crimping pressure Nominal crimping pressure High crimping pressure

Images by MicroPhotonics Inc. Using Bruker Micro CT SkyScan 1173

Results: Failures

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40

Results: Overpressure vs Temp

Stopper

13mm serum

Vial

2 ml EU BB

3 crimping

pressures (RSF)

Results: Failure rate vs. RSF

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LOW RSF CLEARLY

CORRELATES TO HIGH

CCI FAILURE DURING

DEEP COLD STORAGE

THREE crimping pressures

FIVE vial/stopper

combis

FOUR storage

temps

Results: Storage at -80°C

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• There is risk for CCI failure at storage temperatures below the Tg of the rubber stopper formulation.

• CCI failures can be mitigated by ensuring appropriate vial / stopper combination and capping & crimping parameters

• RSF measurements can be a useful tool in quantifying seal tightness and predictive of CCI failure at low temps

• Laser Headspace Analysis is a suitable non-destructive method to detect (temporary) leaks in cold storage

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Conclusions

Duncan, D.; Asselta, R. “Correlating Vial Seal Tightness to Container Closure Integrity at Various Storage Temperatures” proceedings of PDA Parenteral Packaging Conference, Frankfurt,

Germany; (2015)

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