11MARCH/APRIL 2020PHARMA INDUSTRY

PHARMA INDUSTRY Case study: Activ�Blister ™

solutions providesuperior protectionof a model drugproduct over cold�form foil

EXECUTIVE SUMMARY

F reeThink Technologies, Inc., AptarCSP Technologies, and PCI PharmaServices compared the efficacy ofActiv-Blister™ packaging

configurations with cold-form foil inmaintaining the stability of a model tableteddrug product. An Accelerated StabilityAssessment Program (ASAP) study wascarried out and growth of the main degradantof the active ingredient was quantified. Thedata were modeled using the ASAPprime®

software and includedfour different packagingconfigurations: cold-formfoil blisters, thermoformincorporating Activ-Blister™ technologywith molecular sieve,thermoform incorporating Activ-Blister™technology with silica gel and thermoformblisters alone. Four typical ICH storageconditions were also evaluated: 25°C/60%RH, 30°C/65% RH, 30°C/75% RH and40°C/75% RH. Two different initial relativehumidities were modeled to assess theimpact of starting water content on shelf-life.To confirm the modeling results, tablets werepackaged and stored under these conditionsfor up to 6 months prior to analysis. Aspredicted from the ASAP study, the packagingconfigurations can be ranked from most

protective to least protective towardsdegradation in the following way: Activ-Blister™ technology with molecular sieve> Activ-Blister™ technology with silica gel > coldform foil > thermoform blister alone. The advantage of Activ-Blister™ solutions overcold-form foil was particularly pronouncedwhen the drug product had a high initialwater content. ASAPprime® predictions ofdegradant growth within packaging agreedwith the data generated from the stressedblistered tablets at all packaging, storage andinitial water conditions. ASAPprime® caneffectively model packaging configurations

incorporating molecular sieve and silica gelversions of Activ-Blister™ packaging andpredict the shelf-life of a product using Activ-Blister™ technology.

OBJECTIVES

• To compare the efficacy of Activ-Blister™packaging configurations with cold-form foilin maintaining the stability of a modeltableted drug product.

MARIA KRISCH¹, CRAIG VOELLMICKE², STEVE MEDFORD³, PHILIP WATERMAN¹, AUSTIN ZISKA¹,

¹FreeThink Technologies, Inc.,Branford, CT;

²Aptar CSP Technologies, Auburn, AL;

³PCI Pharma Services, Rockford, IL.

Table 1. Modified Arrhenius parameters for the sample drug producttablet.

12 MARCH/APRIL 2020 PHARMA INDUSTRY

• To examine the role of starting watercontent in the efficacy of Activ-Blister™packaging configurations.

• To demonstrate that ASAP and theASAPprime® software can accuratelymodel packaging configurationsincorporating molecular sieve and silicagel versions of Activ-Blister™ packagingand predict the shelf-life of a productusing Activ-Blister™ technology.

ASAP STUDY

• A model tablet drug product wasproduced and an Accelerated StabilityAssessment Program (ASAP) study wasconducted at FreeThink Technologies.

• Tablets were stressed (open) over atemperature range of 35°C - 60°C and arelative humidity range of 11%RH - 75% RH.

• Related substances were quantified byHPLC and the growth of the maindegradant modeled using the moisture-modified Arrhenius equation, assuminga 3% specification limit.

• A good model was obtained with Ea

(activation energy, i.e. temperaturesensitivity) and B (moisture sensitivity)values in the average range for similarproducts (Table 1). The model wasused to predict product shelf-life underdifferent storage conditions.

Moisture-Modified Arrhenius Equation:

PRODUCT PACKAGING ANDSTORAGE

• Blister packaging of the drug producttablets was performed by PCI PharmaServices.

• Tablets were divided into two categories:1. Low % RH: Stored in presence of

silica gel desiccant until blistering.2. High % RH: Equilibrated in a

25°C/60% RH stability chamber for24 hours before blistering.

• Materials used:1. Molecular sieve desiccant film, Aptar

CSP Technologies (M-0035, 0.8 mmthickness, 8 mm x 8 mm).

2. Silica gel desiccant film, Aptar CSPTechnologies (M-0020, 0.8 mmthickness, 8 mm x 8 mm).

Figure 1. Probability of passing with a 2-yr shelf life at 25°C/60% RH, 30% dosage RH: Molecular sieve: 99%, Silica gel: 95%, Cold-form foil: 71%,Thermoform alone: 24%. Activ-Blister™ with molecular sieve results in the lowest degradant growth. The impact of Activ-Blister™ packagingconfigurations is highest with high dosage RH (60% RH).

Molecular SieveActiv-Blister™ Packaging

Silica GelActiv-Blister™ Packaging

Cold-form Foil

Thermoform Blister

40

°C/7

5% R

H30

°C/6

5% R

H25

°C/6

0%

RH

25°C

/60

% R

H30

°C/6

5% R

H4

0°C

/75%

RH

Thermoform Blister

Cold-form Foil

Silica GelActiv-Blister™ Packaging

Molecular SieveActiv-Blister™ Packaging

Figure 3. The 40°C/75% RH conditions have differing scales due to the wide range of degradation.

Molecular sieve Activ-Blister™ Solutions

Silica gelActiv-Blister™ Solutions Cold-form foil Thermoform> > >

MOST PROTECTIVE TO DEGRADATION LEAST PROTECTIVE TO DEGRADATION

Figure 2.

13MARCH/APRIL 2020PHARMA INDUSTRY

3. Thermoform, Tekniplex (Tekniflex®

VPA10400 triplex with PVC, PE, 4 milPCTFE (Aclar® UltRx4000)).

4. Aluminum foil lidding, Amcor Flexibles(20 µm thickness).

5. Cold-form foil.

• Blistered tablets were stored in reach-instability chambers (Darwin PH030) atFreeThink Technologies (Table 2).

• At initial set-up, the dosage RH wasdetermined for a subset of tablets.

• Afterstressing,growth of theprimarydegradant wasmeasured byHPLC..

RESULTS

Growth of the main degradant in tabletsstored under ICH stability conditions underdifferent packaging configurations isshown in Figure 1.Selected ASAPprime® predictionscompared to degradant growth in tabletsstored under ICH stability conditions isshown in Figure 3.

CONCLUSIONS

The packaging configurations can be rankedin the following way as shown in Figure 2:• The advantage of thermoform

combined with an active desiccant film(Activ-Blister™ Solutions) over cold-formfoil is particularly pronounced for drugproduct with a high initial water content.

• The ASAPprime® program can be used toeffectively model packaging configurationsincorporating molecular sieve and silicagel versions of Activ-Blister™ packagingto predict the probability of passing witha particular shelf-life.

• Activ-Blister™ packaging combines thepractical advantages of thermoformblisters with the moisture protectionprovided by desiccant in order toprovide a thermoform option formoisture-sensitive drug products.Table 2. Blistering and storage conditions used for the stability study.

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