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November 2014

Prescription Packaging In-Use Stability Study Research Report

A study conducted by the Healthcare Compliance Packaging Council, through the assistance of Bilcare Research, Inc. Legacy Pharmaceutical Packaging, LLC, Constantia Flexibles, and Klöckner Pentaplast of America.

Prescription Packaging In-Use Stability Study Research

Table of Contents

Sec on Page

1.0 Execu ve Summary 1

2.0 Introduc on 3

3.0 Methodology 6

3.1 Nomenclature 6

3.2 Study Variances 6

3.2.1 Drug Molecules 6

3.2.2 Packaging 6

3.2.3 Storage Condi on 7

3.2.4 Product Parameters 7

3.2.5 Tes ng Frequency 8

3.2.6 Study Matrix 9

3.3 Tes ng Methods 12

3.3.1 Moisture Gain 12

3.3.2 Tablet Hardness 12

3.3.3 Disintegra on Time 13

3.4 Equipment & Instruments 13

3.5 Study Methodology 14

4.0 Results & Discussion 14

4.1 Simvasta n Moisture Gain Results & Discussion 14

4.1.1 Simvasta n MG Results ‐ 30 Count 14



4.2 Simvasta n Hardness Results & Discussion 21

4.2.1 Simvasta n Hardness Results – 30 Count 22

4.2.2 Simvasta n Hardness Results – 60 Count 24

4.2.3 Simvasta n Hardness Results ‐ 90 Count 26

4.3 Simvasta n Disintegra on Time Results & Discussion 28

4.3.1 Simvasta n DT Results – 30 Count 28



4.4 Lisinopril Moisture Gain Results & Discussion 34

4.4.1 Lisinopril MG Results – 30 Count 34

4.4.2 Lisinopril MG Results – 60 Count 36

4.4.3 Lisinopril MG Results – 90 count 38

4.5 Lisinopril Hardness Results & Discussion 40

4.5.1 Lisinopril Hardness Results – 30 Count 40



4.6 Lisinopril Disintegra on Time Results & Discussion 46

4.6.1 Lisinopril DT Results – 30 Count 46




Sec on Page

4.7 Me ormin Moisture Gain Results & Discussion 52

4.7.1 Me ormin MG Results – 30 Count 52



4.8 Me ormin Hardness Results & Discussion 58

4.8.1 Me ormin Hardness Results – 30 Count 58



4.9 Me ormin Disintegra on Time Results & Discussion 64

4.9.1 Me ormin DT Results – 30 Count 64



Conclusion 70

Table of Contents

Executive Summary

Prescription Packaging In-Use Stability Study Research Report

Prescription Packaging In-Use Study conducted and coordinated by: Bilcare Research, Inc.

Products packed and supplied by:

Legacy Pharmaceutical Packaging, LLC

Blister Packaging Materials provided by:

Bilcare Research, Inc.,

Klöckner Pentaplast of America,

Constantia Flexibles, and

Honeywell, Inc.

IMS Health calculates that the average U.S. patient filled more than 12 retail

prescriptions in 2013 with those 65 and over filling an average of 28 prescrip-

tions annually. Most of these prescriptions are solid oral dose drugs dispensed

through retail pharmacies. That’s quite a lot of pills.

Drug manufacturers conduct stability studies on their drug and its package to

assure that the drug’s formulation is safe and effective for the shelf life indicated

on the package. The package also functions as physical protection for the drug

as it journeys from manufacturer to point of dispense. These standard stability

studies are conducted on sealed containers. In the U.S., this is most often a bulk

container intended for pharmacy use only and not intended to reach the patient.

In most parts of the world, however, solid oral dose products are provided in unit

dose packaging protecting each solid dose individually until used by the patient.

Unit dose packaging is not prevalent in the U.S. retail setting. The original manu-

facturers’ packaging only protects the product until it reaches the pharmacies or

other distributors, as they must repack the drugs into patient-ready formats. The

most common form of re-packing in the pharmacy or mail-order environment is

either the HDPE bottle or traditional amber polypropylene vial. It is the opinion of

many in the industry, including the HCPC, that these multi-dose packaging

modes offer little product protection since they are opened on a daily basis, al-

lowing repeated environmental exposure.

The HCPC, through the assistance of Bilcare Research, Legacy Pharmaceutical

Packaging, Constantia Flexibles, and Klöckner Pentaplast of America, devel-

oped a study investigating potential degradation of three commonly used chronic

condition prescriptions during normal patient use when packed in different pack-

A study conducted by the Healthcare Compliance Packaging Council, through the assistance of Bilcare Research, Inc. Legacy Pharmaceutical Packaging, LLC, Constantia Flexibles, and Klöckner Pentaplast of America.

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aging formats. The three products (Simvastatin, Lisinopril, and Metformin) were packed in

five different packaging formats:

amber polypropylene pharmacy vials,

HDPE white bottles,

PVC blisters (to be referred to as low barrier blister)

PVC/PE/PVdC (250/25/90) blisters (to be referred to as medium barrier

blisters), and

PVC/Aclar® UltRx 2000 (10 mil/2 mil) blisters (to be referred to as high barri-

er blister).

All blister formations were sealed with a 25 micron push-through foil lidding.

Aclar® and PVdC film blisters are designed to provide more protection against moisture

than mono-PVC blisters.

Each of the packaging formats were tested in three different environmental conditions:

25°C/75%RH,

25°C/90%RH, and

40°C/75%RH.

In addition, all vials and bottles were tested using differing numbers of doses (30, 60, and

90) to compare how the length of a prescription and increased exposure impacts the deg-

radation of a drug.

The study focused on the physical degradation happening to the product during the in-use

time by assessing any changes to the drug products in:

Moisture Gain

Tablet Hardness

Disintegration Time

The study results demonstrated the effect daily exposure to the home environment

can have on non-coated tablets. The results support the theory that drug products

dispensed in packaging with minimal moisture and oxygen protection have an in-

creased risk of physical degradation during normal use. More specifically, the prod-

ucts tested in polypropylene vials, HDPE bottles or PVC blisters, showed higher

physical degradation than those packaged in PVC/Aclar® or PVC/PVdC blisters.

Degradation increased when drugs were tested in higher humidity, simulating bath-

room conditions, versus those tested in 25°C/75%RH. The degradation results indi-

cate that Simvastatin, Lisinopril and Metformin when dispensed in vials, HDPE bot-

tles or PVC, undergo changes through daily exposure to typical home environ-

ments because bulk packaging does not provide protection to individualized dose.

Whether these changes can affect these drugs’ specific efficacy or their absorption

rates needs further investigation.

The results of this study are not intended to challenge the manufacturers’ stability criteria

for primary bulk packages, nor state that the products failed in anyway, but the data does

indicate that current prescription packaging does not protect the physical characteristics of

these products during normal use. The HCPC believes the next step would be to broaden

the scope and include chemical assay tests on drugs exposed to these or similar study

conditions in order to determine the potential impact on efficacy. Chemical assays can

determine if the drugs still meet the +/-10% acceptable change limit as documented by the

Packaging formats used in the HCPC Research Study.

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Regardless of the drug form, all medicinal products need to be protected through distribution and pharmacy until used by the patient.

FDA. The HCPC invites other organizations concerned with patient safety and improved

outcomes to evaluate the research results contained herein and further investigate in-use

stability, not only for the drugs depicted here, but for the many other pharmaceuticals

used and trusted by patients in their homes.

Additional research needs to be conducted to determine the most effective packaging for

the thousands of drug products on the market, each with their own environmental sensitiv-

ities, as they relate to moisture and oxygen ingress and exposure during “in-use” condi-

tions. Packages need to be designed to protect drug products during their entire life cycle

and, as shown in this study, packages using high barrier materials and unit dose can ac-

complish that goal. Once we move closer to protecting the products appropriately, we

ensure that patients will receive effective products to treat their conditions.

Introduction

The U.S. market for pharmaceuticals was $310 billion as of 2013, with a significant portion

remaining in traditional solid dose pills dispensed through retail pharmacies. Increasing

access to health care through the Patient Protection and Affordable Care Act, as well as

continued improvement in the U.S. economy, will drive growth in pharmaceutical spending

over coming years, with a projected 3-5% increase in total drug expenditures.

Regardless of the drug form, all medicinal products need to be protected through distribu-

tion and pharmacy until used by the patient. With the growing number of channels through

which drugs travel, traditional retail pharmacy, mail-order, or third-party repackager, par-

ticular attention must be paid to protect drug products from temperature, humidity, oxygen

and light.

The right primary packaging selection will protect the product from these environmental

influences with the exception of temperature and time. The correct packaging choice must

provide protection for the product against moisture, gases and light while not leaching

foreign substances onto or into the drug product and thereby ensure the safety and effica-

cy of the product when it is to be consumed by the patient. The extent of protection in

these various aspects, however, depends on the product’s properties, as well as climatic

variables during transportation and in-use time. Recommendations in Pharmacopoeia and

guidelines set forth by the U.S. Food and Drug Administration (FDA) via the International

Conference on Harmonisation (ICH) are merely advisory. Precise quantitative standards

must be locally determined through rigorous testing. The wide variety of packaging materi-

als and the highly technical nature of medicinal products often create significant challeng-

es for pharmaceutical manufacturers to determine the appropriate protection mechanisms.

Primarily, drug packaging must:

Protect against all adverse external influences that can alter the parameters

of the product, i.e., moisture, light, and oxygen.

Protect against biological contamination.

Protect against physical damage.

Carry the proper product information and present it in a clear and concise

fashion

Support effective use of the medication by the patient within their daily life-

style

The correct packag-ing choice must pro-vide protection for the product against moisture, gases and light, while not leach-ing foreign substanc-es onto or into the drug product and thereby ensure the safety and efficacy of the product when it is to be consumed by the patient.

The common form of repacking in the pharmacy is either HDPE bo les or tra-di onal amber poly-propylene vials.

The packaging material must be selected in such a way that:

It does not have an adverse effect on the product.

Its protective qualities maintain the stability and efficacy of the product until it

gets consumed by the patient.

The core purpose of drug manufacturing is to create safe and effective products that deliv-

er maximum clinical benefit when properly used. Poor drug stability can directly impact

product efficacy and consumer safety. As such, stability is an essential part of the drug’s

protocol. Drug manufacturers establish a formulation’s shelf life through stability studies.

These studies monitor the amount of time it takes for the active ingredients to drop below

an assigned level, as well as the time it takes for unknown or dangerous impurities to ac-

cumulate beyond safe limits. Unfortunately, it can take many years for a formulation to

reach its shelf life, making it unfeasible for drug manufacturers to track degradation in a

real world time scale.

Drug manufacturers conduct extensive product stability studies to determine product

needs during packaging, storage and transshipment. Standard stability studies are typical-

ly valid for sealed containers. In most parts of the world, solid oral dose protection is pro-

vided through unit dose packaging, where each unit is individually protected through pack-

aging, desiccants and other scavengers. Such individually protected products are consid-

ered “good” until they have been finally consumed by the end user.

In the U.S., unit dose packaging is not a prevalent form of packaging for retail pharmacy.

U.S. solid dose distribution typically uses bulk packaging requiring the repacking of the

drugs into patient ready or unit-of-use formats. The protection provided by the original

manufacturers’ package is effective only until it reaches pharmacies. The common form of

repacking in the pharmacy environment is either HDPE bottles or traditional amber poly-

propylene vials. It is the opinion of many in the industry, including the HCPC, that the con-

tainer integrity of these multi-dose packages is compromised when they are first opened to

consume the product. These forms typically require the patient to open the closure at least

once every day to consume the drug, thereby exposing all the remaining tablets to the

home atmosphere. Even if the patient puts the closure back on the bottle/vial, the

product’s immediate atmosphere is flushed with air and moisture. This exposure repeats

every time the patient opens the bottle/vial to consume a tablet.

This poses a potential problem for the multitude of moisture sensitive solid dose products.

They absorb moisture from the surrounding atmosphere which can trigger and accelerate

product degradation. The amount of moisture reaching the product is dependent upon the

atmosphere in the area where the packages are opened. Some home environments may

have high humidity levels, such as a bathroom, which could increase product degradation.

There is not much control over how patients store and consume their medications and

many are not aware of the implications from poor storage.

Pharmacies dispense products to patients with the assumption that the product will main-

tain the same level of potency/efficacy during the in-use period which is typically 30, 60 or

90 days. However, it is a known fact that drug substances, like other perishable products,

are susceptible to environmental conditions. Though there has been sporadic information

supporting this fact, no systematic study has been available to show the extent of drug

product degradation occurring during typical use, i.e., after dispensing from pharmacies

and submitted to typical patient usage and storage. This aspect of potential product

degradation during home use has not received appropriate attention. Therefore, the HCPC

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5

Mul -dose contain-ers typically require the pa ent to open the closure at least once every day to consume the drug, thereby exposing all the remaining tablets to the home atmosphere.

initiated a scientific study evaluating the degradation of physical properties of three com-

monly used drugs during normal use.

There are thousands of prescription solid dose products on the market. The HCPC decid-

ed to focus on three products widely prescribed for millions of Americans with chronic

conditions: Lisinopril, Simvastatin and Metformin.

Lisinopril, the generic form of Astra Zeneca’s Zestril® and Merck’s Prinivil®, is prescribed

for those suffering from high blood pressure/hypertension. The American Heart Associa-

tion estimates that 77.9 million (1 out of every 3) adults have high blood pressure and that

approximately 75% are under treatment for the disease.

Simvastatin is known as a HMG-CoA reductase inhibitor (statins). It is a common pre-

scription for patients suffering from high cholesterol.

Metformin is the generic form of Glucophage® from Merck and is used to treat many of

the 16.1 million people diagnosed with Type 2 diabetes.

The generic pharmaceuticals used in the HCPC research were non-coated tablets which

can be environmentally sensitive to air and moisture.

The results provided within this study are not intended to challenge manufacturers’ stabil-

ity criteria for the drugs listed, nor state that the products failed in anyway. The data does

indicate more research is necessary on the stability of drugs during normal patient use. In

particular, the HCPC highly recommends further study be conducted, including chemical

assay, on drugs exposed to HCPC research conditions. This can more fully evaluate the

true efficacy of drugs exposed to the home environment and determine if the drugs still

meet the +/- 10% acceptable change limit for chemical assay as documented by the FDA.

The HCPC invites other organizations focusing on patient safety and improved outcomes

to consider the results of the research contained herein and further investigate in-use sta-

bility, not only for the drugs depicted here, but for the many other pharmaceuticals used

and trusted by patients in their homes.

3.0 Methodology 3.1 Nomenclature

This section explains the methodology employed to study the degradation possibilities of the three drugs during the

patient usage period when the product is packed in different packaging formats under the scheme of this study. The

three products (Simvastatin, Lisinopril, and Metformin) were packed in five different packing modes - amber polypro-

pylene pharmacy vials, HDPE white bottles, PVC blisters (to be referred to as a PVC blister or low barrier blister),

PVC/PE/PVdC (250/25/90) blisters (to be referred to as PVdC blister or medium barrier blister) , and PVC/Aclar®

UltRx 2000 (10 mil/2 mil) blisters (to be referred to as Aclar® blister or higher/highest barrier blister). All blister for-

mations were sealed with a 25 micron push-through foil lidding. All the packaging formats were exposed to three

different environmental conditions, 25°C/75%RH, 25°C/90%RH, and 40°C/75%RH. In addition, all vials and bottles

were tested using differing numbers of doses (30, 60, and 90) to compare how the length of a prescription impacts

the degradation of a drug.

Abbreviation Description

USP United States Pharmacopeia

DT Disintegration Time (Measured in Seconds) LHM Climatic Condition at 25°C and 75% RH

HHM Climatic Condition at 25°C and 90% RH

ICH Climatic Condition at 40°C and 75% RH

RH Relative Humidity measured in %

3.2 Study Variances 3.2.1 Drug Molecules Selected for the Study

As previously mentioned, three commonly used medication molecules were selected for study. They are:

Simvastatin Tablet

Lisinopril Tablet

Metformin Tablet

3.2.2 Packaging

Different packages provide different levels of protection to the product due to differences in barrier properties. There-

fore, the degradation possibilities of the product in different packaging will naturally be different. The main objective of

the study was to understand the influence of packaging to control possible drug degradation during the in-use stage.

The study was conducted for the three molecules in the following commonly used primary packs.

Amber Polypropylene Pharmacy Vials - 37.4 mils average wall thickness

HDPE Bottles - 35.4 mils average wall thickness

Blister packs (3 blister films sealed with 25 micron push-through foil lidding)

PVC (10 mil)

PVC/PE/PVdC Clear (250microns/25 microns/90 gsm)

PVC/Aclar® UltRx 2000 Amber (10 mil/2 mil)

The three blisters provide different levels of moisture barrier properties. PVC blisters provide a very low moisture

barrier. The PVC mono film used to make the blisters has the WVTR (water vapor transmission rate) of ~3.5 g/m2/

day. The PVdC blister used film with a WVTR of ~0.28 g/m2/day and the Aclar® blister film has a WVTR of 0.11

g/m2/day. All these WVTR values are at 38o C/90% RH.

The five packaging variations were packed in 30 day, 60 day and 90 day counts.


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Table 3.1-1: Key description for the common abbreviations used

3.2.3 Storage Conditions

Storage conditions significantly affect the product stability and hence the study was performed in 3 different condi-

tions representing normal/low humidity-ambient temperature, high humidity-ambient temperature (indicating a possi-

ble bathroom condition) and the ICH accelerated conditions as follows:

LHM - 25oC & 75% RH

HHM - 25oC & 90% RH

ICH - 40oC & 75% RH

3.2.4 Product Parameters Studied

This study was mainly focused on the physical degradation happening to the product during the in-use time. There-

fore, this study monitors the following product parameters:

Moisture Gain

Tablet Hardness

Disintegration Time

Moisture Gain - Moisture absorbed by a drug product is one of the main reasons of product degradation.

Therefore, moisture sensitive products are packed in moisture barrier packaging to better protect the product from

moisture. The efficacy of the packaging, storage conditions, and dispensing method can all cause moisture ingres-

sion into the package which will be absorbed by the product and cause product degradation. The moisture absorp-

tion by the product will depend on the moisture absorption tendency of the product (water activity of the product),

temperature and humidity conditions of storage, type of packing, head space available in the packing, the time of

exposure, etc. This study is conducted to understand the moisture absorption by the three drugs when they are

packed in different types of packaging and exposed to various storage conditions while being consumed by/or dis-

pensed to the patient.

Hardness - Moisture absorption/desorption affects the physical property of the drug, especially the hard-

ness of the product. Changes in physical degradation can be an indication of other alterations occurring, calling into

question the efficacy of the product.

Disintegration Time - Disintegration time is an important property of oral tablet formulation as it measures drug

release which correlates with bioavailability of the active ingredients. DT is the time required for a tablet to complete-

ly disintegrate into small particles. Each formulation is made in such a way that the tablet will be disintegrated within

a specified time. However, as with tablet hardness, the DT can also be affected by moisture and temperature. Either

DT increases due to the influence of these parameters, which results in a longer time for the tablet to release the

ingredient, or DT can decrease, causing tablet to release the ingredient faster than expected. Neither situation may

be acceptable. It is possible that not enough drug would be absorbed, reducing the therapeutic effect, or too much of

the drug would be absorbed too soon, with potential harmful effects.

As the study was focused to determine the changes happening on the product from when the patients receive it until

it is consumed, the percentage change occurring to each of the pharmaceutical products for all the above properties

was monitored and recorded.

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3.2.5 Testing Frequency

In the case of the vial and bottle, the 30 day count, 60 day count and 90 day count were separately studied. The blis-

ters were studied in continuum.

Moisture gain was measured at 0, 3 , 5 , 10, 15/20, 30 days for the 30 count bottle; 0, 3, 5, 15, 30, 45, 60 days for the

60 count bottle; and 0, 5, 30, 45, 60 and 90 days for the 90 count vial/bottle.

Tablet hardness was measured at 0, 3 , 5 , 10, 15/20, 30 days for the 30 count bottle; 0, 3, 5, 15, 30, 45, 60 days for

the 60 count bottle; and 0, 5, 30, 45,60 and 90 days for the 90 count vial/bottle.

Disintegration time was measured at 0, 15, 30 for the 30 day count bottle; 0, 15, 30, 60 day count for the 60 count vial/

bottle; and 0, 30, 60 and 90 days for the 90 count vial/bottles.


8

3.2.6 Study Matrix

Following is the final study matrix for each product:

9

Storage Condi on

Packing Mode

Product Parameter

30 Count 60 Count 90 Count

Day of Tes ng Day of Tes ng Day of Tes ng

0 3 5 10 15 30 0 3 5 15 30 45 60 0 5 15 30 45 60 90

25oC/75% RH

PP Vial

Moisture Gain (%)

x x x x x x x x x x x x x x x x x x x x

Hardness x x x x x x x x x x x x x x x x x x x x

(N)

D T (Secs) x x x x x x x x x x x x

HDPE Bo le

Moisture Gain (%)



(N)


PVC

Moisture Gain (%)

x x x x x x x x x x x x x x x x x


(N)


PVC/PE Moisture Gain (%)


/PVdC Hardness x x x x x x x x x x x x x x x x x x x x

(N)


PVC/ Moisture Gain (%)


Aclar® Hardness x x x x x x x x x x x x x x x x x x x x

(N)


3.2.6 Study Matrix Continued


10

Storage Condi on

Packing Mode

Product Parameter



0 3 5 10 15 30 0 3 5 15 30 45 60 0 5 15 30 45 60 90

25oC/90% RH

PP Vial

Moisture Gain (%)



(N)


HDPE Bo le

Moisture Gain (%)



(N)


PVC

Moisture Gain (%)



(N)



x x x x x x x x x x x x x x x x x x


(N)



x x x x x x x x x x x x x x x x x x


(N)


3.2.6 Study Matrix Continued

11

Storage Condi on

Packing Mode

Product Parameter



0 3 5 10 15 30 0 3 5 15 30 45 60 0 5 15 30 45 60 90

40oC/75% RH

PP Vial

Moisture Gain (%)



(N)


HDPE Bo le

Moisture Gain (%)



(N)


PVC

Moisture Gain (%)



(N)





(N)





(N)


a. As blister samples are continuous measurements common for 30 day count, 60 day count and 90 count studies, common time points will have the same data for blisters samples.

b. Some of the data was collected on day 20 instead of day 15 (due to holidays/vacation). The appropriate data points are shown in the same way in the graphs.

c. The 15/20 day moisture gain data for the blister sample is suspected to have a recording error and hence dropped from the report, but it does not affect the end result.

3.3 Testing Methods 3.3.1 Moisture Gain

Moisture is one of the main causes of drug degradation and thus the main function of packaging is to prevent the

product from absorbing moisture and prevent any degradation of the product. Measuring the moisture gained by

product during the usage period can be indicative of possible degradation in the product. Moisture gain is calculated

gravimetrically by weighing the samples before and after the exposure. The difference in the product weight is taken

as the moisture gain. Tablet-to-tablet weight variation was determined by taking the weight of 10 tablets of each of

the products and standard deviation (SD) and relative standard deviation (RSD) were calculated and found as below.

Parameter Drug Product

Simvasta n Lisinopril Me ormin Weight Standard Devia on (g) 0.0020 0.0030 0.0050

Weight Rela ve Standard Devia on (%) 0.98 1.35 0.83

Minimum Weight (g) 0.2025 0.2200 0.5926

Maximum Weight (g) 0.2082 0.2292 0.6089

Average Weight (g) 0.2053 0.2230 0.5994

Table 3.3.1.1: Initial Average weight of each product and its standard deviation determine to assess the tablet-to- tablet variation

The vial, bottle and blister containers were weighed immediately after receipt and placed into their respective envi-

ronments. To simulate real life use, a dose was removed each day from each vial and bottle. At the intervals de-

scribed below, the sample containers were weighed and the increase in weight for each dose was compared to the

average dose weight for that drug.

To avoid error caused by weight loss from damaged packaging, blister packs were tested in a slightly different man-

ner. Instead, a blister pack (hereafter “blank”) with all doses removed was weighed before exposure and at the

standard test intervals. The test blister packs were weighed at the test intervals below and any weight gained by the

blank was subtracted from the weight gain of the test blister.

3.3.2 Tablet Hardness

Tablet hardness shows the physical integrity of the solid dosage product. Therefore, maintaining the required hard-

ness is important for the tablet. A second set of test containers was kept in the appropriate environments, tested in

triplicate, and the data was averaged to reach a final result for each time point. The equipment and test method con-

formed to USP <1217> “Tablet Breaking Force”.

Tablet-to-tablet variations in hardness were determined by measuring the hardness 20 times using different tablets of

the same product in the received condition. The following chart shows the standard deviation calculated.


Simvasta n Lisinopril Me ormin Hardness Standard Devia on (N) 5.9 7.2 13.9

Hardness Rela ve Standard Devia on (%) 7.7 15.3 8.5

Minimum Hardness (N) 66.3 36.6 143.5

Maximum Hardness (N) 85.6 61.1 197.9

Average Hardness (N) 76.5 46.9 162.9

Table 3.3.2.1: Initial Average Hardness of each product and its standard deviation determined to assess the tablet-to-tablet variation

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3.3.3 Disintegration Time


Simvasta n Lisinopril Me ormin DT Standard Devia on (Sec) 10.7 2.14 12.2

DT Rela ve Standard Devia on (%) 4.00 5.11 1.30

Minimum DT (Sec) 260 37 921

Maximum DT (Sec) 283 46 934

Average DT (Sec) 268.3 41.8 924.9

Table 3.3.3-1: Initial Average Disintegration Time of each product and its standard deviation determined to assess the tablet-to-

tablet variation

3.4 Equipment and Instruments

All the equipment and instruments are installed and qualified for the usage. All equipment and instruments are under

regular maintenance and have valid calibration certificates to signify that they provide accurate and reliable data for

all the studies. Calibration reports and certificates are issued upon calibration via internal methods or via calibration

by a qualified service contractor using NIST standard materials. Table 3.4.1 shows the equipment and instrument

listings from Bilcare testing labs performed on this formulation.

Equipment No.

Equipment Description Model

No. Manufacturer

Calibration Status

Certificate of Calibration/ Validation?

1064 Hardness Tester HT-300 Key

International Calibrated Yes

1066 Disintegration Tester LIJ 2 Vanguard

Pharmaceutical Machinery

Calibrated Yes

1401 Environmental Chamber #1 6010 Caron Calibrated Yes




1077 Analytical Balance PW 120 Adam Calibrated Yes

Table 3.4-1: List of equipment and instruments used in the study and their calibration status

13

Disintegration Time is an important measurement to determine the drug release property of the product. It is the time

required for the tablet to disintegrate completely in the aqueous medium which is kept at 37.8o C, equivalent to body

temperature. This indicates the time taken by the tablet to disintegrate within the intestinal system making the active

ingredient available to be absorbed by the bodily system.

A third set of test containers was kept in appropriate environments, tested in duplicate, and the data were averaged

to reach a final result for each time point. The equipment and test method conformed to USP <701> for

“Determination of Disintegration time of Tablets and Capsules”. To understand the variations, DT was repeated 5

times using different tablets of the same product at the received stage. The variations observed are shown below:

3.5 Study Methodology This study is intended to simulate the “in-usage” scenario of patients at home. The products were packed in a GMP

packaging area of Legacy Pharmaceutical Packaging, LLC, including the polypropylene amber vials which were

packed by a licensed pharmacist to replicate the packing and distribution system of typical pharmacies. The pack-

aged products were then wrapped in foil to ensure no exposure to outside atmospheric conditions during shipping to

the BilcareOptimaTM Lab, where the study was performed.

Initial readings of the product properties were measured and recorded and measurement variations were determined.

The packages were then labeled for the stability study conditions and study parameters. All the packaged variances

were then kept in Bilcare environmental chambers using the specified temperature/humidity conditions previously

stated. Separate packages were kept for the study of each property, Moisture Gain, Tablet Hardness and Disintegra-

tion Time (DT).

Separate bottles and vials of 30, 60 and 90 counts were kept for the study and properties of each of these counts

were determined separately. Blister samples were kept as common pool samples for 30, 60 and 90 count studies.

To simulate actual use conditions, bottles and vials were opened every working day and kept open for one minute at

the respective environmental chambers and then closed tightly. From the bottles and vials kept for the moisture gain

study, one tablet each was removed from the respective packs to simulate the effect of emptying the bottle/vials.

However, from the packs kept for hardness and DT, only the tablets required for the measurement were removed at

the time of measurement. The study continued for 30 days, 60 days and 90 days separately for the respective count

vials and bottles. All three types of blister samples were kept for 90 days and readings were taken at same frequency

as in the case of vials and bottle study.

4.1 Simvastatin Moisture Gain Testing Results & Discussion

Simvastatin is a very popular cholesterol medication which has comparatively lower moisture sensitivity, i.e., it is not

very hygroscopic. This pharmaceutical is normally dispensed in 30 count, 60 count and 90 count packs.

4.0 Results and Discussion

4.1.1 Simvastatin MG Testing - 30 Count Packaging

Figure 4.1.1-1: % Moisture Gain of 30 count products over a period of 30 days under LHM conditions (25°C/75%RH)

14


25oC/75% RH is the mildest condition studied. Even so, the product packed in vial, bottle and PVC low barrier blister

increased in weight slightly over time. Product packed in PVC/PVdC (medium barrier) and PVC/Aclar® (higher barri-

er) absorbed little to no moisture.

Figure 4.1.1-2: % Moisture Gain of 30 count products over a period of 30 days under HHM conditions (25°C/90%RH)

When the product was exposed to higher humdity (90%RH), the product in vial, bottle and low barrier blister showed

increased moisture absorption while the product packed in the medium and high barrier blisters exhibited little

change.

Figure 4.1.1-3: % Moisture Gain of 30 count products over a period of 30 days under ICH conditions (40°C/75%RH)

15

An accelerated testing condition commonly used for stability studies is 40oC/75%RH. This condition tests both the

effect of elevated temperature and humidity on the product. As before, Simvastatin in the higher barrier blister packs

absorbed less moisture compared to all other packaging. Overall, Aclar® offered the best protection, followed closely

by PVdC.

Figure 4.1.1-4: % Moisture Gain of Simvastatin after 30 days in different packing, under all studied conditions.

This bar chart depicts how much the product can absorb moisture in a 30 day time period of simulated patient in-

home use. Thirty-count is the standard minimum dispensing amount by the pharmacy for these products when it is

dispensed in different types of packaging. The chart indicates the extent of moisture-induced degradation which can

occur to the product when the product is in different storage conditions. It is very obvious from the graphs that prod-

ucts packed in high-barrier blisters absorb less moisture compared to the vial, bottle or PVC blister sample. There-

fore it is logical to conclude from this data that it is possible for more degradation to occur if the product is packed in

vials, bottles or in PVC blisters, compared to the product packed in medium and higher barrier blisters.

As mentioned, the product Simvastatin is not a very hygroscopic product and hence the amount of moisture absorp-tion depicted is not high as can be the case with products that have a higher moisture sensitivity.

16





17

Figure 4.1.2-4: % Moisture Gain by the Simvastatin in 60 days under all studied storage conditions


The 60 count Simvastatin study closely mirrors the 30 count study. It is interesting to see that the moisture absorp-

tion by the product for the same days while it is in the 30 count vial/bottle pack and 60 count vial/bottle packs are not

always same. This difference is due to the following:

1. Available head space for moisture to be filled in when the pack is opened every day,

2. Amount of tablets available in the pack to absorb the moisture contained within the head space, and

3. Difference in the surface area of the package available for moisture permeation.

18




19

These parameters are different in a 30 count pack versus a 60 count pack. The moisture absorption of the same

product, in this case Simvastatin, packed in the same type of packing, but of different sizes and counts, will tend to

be different because of the variants in head space, number of tablets in the package over time and the different

surface area. While these differences are notable, the key takeaway is that Simvastatin packed in vials, bottles or

low barrier blisters absorbed significant quantities of moisture, while the samples packed in the medium and higher

barrier film blisters did not. This is true regardless of the condition tested.



Figure 4.1.3-4: % Moisture Gain of Simvastatin in 90 days 30 count products over a period of 30 days under all conditions

20


The 90 count Simvastatin study yielded similar results to the 30 and 60 count studies with regards to the 25°C/90%

RH and 40°C/75%RH environments; Simvastatin absorbs moisture most readily in bottles and low barrier blisters and

is best protected by the medium and higher barrier blister packaging.

For the vial packed product, the 30 count and 60 count for the 25°C/75%RH condition indicated a small loss of mois-

ture in the final days of each test period. It may be possible for the tablet to dehydrate, but it is not clear if the results

were due to lost moisture or tablet weight variation. A more detailed evaluation of the chemical make-up of the tab-

lets (chemical assay) might point to the reason for this change. This study was not designed to evaluate "why" the

changes were taking place but simply to measure the physical change itself. Further work should be done to under-

stand why these tablets lost weight in the final days of the study even though the moisture available to each tablet

actually increases as the tablet count decreases in the container.

Regardless of the count, (30, 60 or 90) and storage condition, the product dispensed in bottles, vials and PVC blisters

absorbed more moisture at the end of the day while the product packed in the medium and high barrier blisters ab-

sorbed very little moisture and hence may be more stable.

4.2 Simvastatin Hardness Results & Discussion

Moisture absorption/desorption affects the physical property of the drug, especially the hardness of the product.

Changes in physical degradation can be an indication of other alterations occurring, calling into question the efficacy

of the product. The following section shows the changes to the tablet hardness of Simvastatin during the in-use

stage when in different packaging formats.

There is always the possibility of variation in tablet hardness. The relative standard deviation (RSD) determined for

Simvastatin is marked in each chart, so the percent change shown is more than inherent hardness variations. The

absolute value of each product’s hardness is given in the table 3.3.2.1 provided in the earlier pages.

21

Figure 4.2.1-1: Hardness of 30 count products over a period of 30 days under LHM conditions (25°C/75%RH)

4.2.1 Simvastatin Hardness Testing - 30 Count Packaging

Figure 4.2.1-2: Hardness of 30 count products over a period of 30 days under HHM conditions (25°C/90%RH)

22


Figure 4.2.1-3: Hardness of 30 count products over a period of 30 days under ICH conditions (40°C/75%RH)

Figure 4.2.1-4: Summary of Hardness of 30 count products over a period of 30 days under all conditions

23

Moisture absorption by the product potentially decreases the tablet hardness. The original hardness values of each

product is given in the table 3.3.2.1 previously provided. All the graphs shown in the Figures 4.2.1 are the % change

from the original value. The results show that when the tablet is dispensed in the medium and higher barrier blisters

there is minimal change. When the product is dispensed in the low moisture barrier package, the hardness is drasti-

cally reduced. Normally a 40% change from the initial value is considered to be a signficant and objectionable

change, which is evident from the graph depicting when Simvastatin is dispensed in a low barrier package like PVC

or HDPE bottle, even in 30 days of use.




24




25




26




The 60 count and 90 count packs show a similar trend to the 30 count packs (with a few exceptions), but the differ-

ence is magnified due to longer duration, especially in the high humidity conditions. The data suggests that high hu-

midity causes the tablets to soften in an extreme fashion. As before, PVC and bottles provide the least protection,

vials and the medium barrier film offer moderately better protection, and the highest barrier film prevents almost all

softening in all conditions.

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4.3.1 Simvastatin DT Testing - 30 Count Packaging

Figure 4.3.1-1: DT of 30 count products over a period of 30 days under LHM conditions (25°C/75%RH)

4.3 Simvastatin Disintegration Time Results & Discussion

The following highlights the DT results for Simvastatin. DT is the time recorded for a tablet to completely disintegrate

into small particles, which correlates to the bioavailability of a drug’s active ingredients.

Figure 4.3.1-2: DT of 30 count products over a period of 30 days under HHM conditions (25°C/90%RH)

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Figure 4.3.1-3: DT of 30 count products over a period of 30 days under ICH conditions (40°C/75%RH)

Figure 4.3.1-4: Summary of DT of 30 count products over a period of 30 days under all conditions

It is clear from the data that products undergo significant change in Disintegration Time (DT) when not packed in a

barrier blister in all conditions studied. The product shows significant reduction in DT within 30 days when packed in

vials, bottles, and PVC blisters. Product packed in the higher barrier blisters of either Aclar® or PVdC remain almost

unchanged under all conditions.

29




30




The 60 count study indicates that the Simvastatin degrades over time regardless of environment. There is a decrease

in DT in all packages, but product in the higher barrier blister packages exhibits minimum change. This again reiter-

ates the fact that higher barrier blisters provide better protection.

31




32




The trend in DT is consistent for 30, 60 or 90 count packs. The results are a clear indication that, regardless of stor-

age condition or container count, sensitive products should be packed in higher barrier blisters.

33


4.4.1 Lisinopril MG Testing - 30 Count Packaging


4.4 Lisinopril Moisture Gain Results & Discussion

Lisinopril is a regularly prescribed medicine for treatment of high blood pressure. Lisinopril is not very hygroscopic. It

was tested for moisture gain, tablet hardness, and disintegration time using the same packaging and storage condi-

tions as Simvastatin during the same period of time. The results of the testing are provided and discussed on the

following pages.

34



Figure 4.4.1-4: % Moisture Gain of 30 count products from the initial value after 30 days of exposure under all conditions

Lisinopril 30 count samples reacted in a similar way to the Simvastatin in all three environments. It is very clear from

the results that the tablets packed in the medium and higher barrier blisters absorbed little moisture while product

dispensed in the PVC blisters, the vial and the bottles absorbed the greater moisture. As the Lisinopril tablet is less

hygroscopic than Simvastatin, the overall moisture gain is lower.

35

Figure 4.4.2.-1: % Moisture Gain of 60 count products over a period of 60 days under LHM conditions (25°C/75%RH)



36



Figure 4.4.2-4: f % Moisture Gain/loss after 60days in the 60 day count pack under all conditions

When compared to the 30 count study, the 60 count Lisinopril samples reveal a more complete picuture of how Lis-

inopril reacts to adverse evironmental conditions; Lisinopril absorbs little to no moisture at 25°C/75%RH, significant

moisture at 25°C/90%RH, and loses significant moisture at 40°C/75%RH. Products losing moisture when exposed to

elevated temperatures is not uncommon and the fact that dehydration can be observed at 40°C/75%RH is not sur-

prising. However, the basic trend which is being observed in the study has not changed. Regardless of the condition,

the medium and higher barrier blisters provide the highest level of protection for the Lisinopril tablet, much like for

Simvastatin.

37




38



Figure 4.4.3-4: % Moisture Gain/Loss after 90 days in the 90 count packs under all studied condition conditions

The trends shown in the 60 count study are expanded in the 90 count study. Lisinopril changes little in weight even

after 90 days. It can be seen that the product loses moisture when it is exposed at higher temperature conditions.

This result again proves that the product packed in higher barrier blisters is least affected even after the 90 day in-

use period.

39


4.5.1 Lisinopril Hardness Testing - 30 Count Packaging


4.5 Lisinopril Hardness Results & Discussion

40




Lisinopril hardness variation shows interesting results. The figures clearly indicate that not only the humidity, but the

temperature adversely affects the tablet hardness. It is understandable that higher barrier packaging can protect the

product against moisture, gases and light, but not against temperature. This explains the fact that the higher barrier

blister package is able to protect the product completely against hardness changes at 25oC/75% RH and 25oC/90%

RH, but significant hardness reduction happens in all packaging at 40oC/75% RH. This indicates that Lisinopril, nor-

mally not hygroscopic, is sensitive to humidity and temperature, when measuring tablet hardness. Since Lisinopril is

41




often delivered to patients by mail, there is a need to understand the relationship between hardness and safety and

efficacy given the uncontrolled temperatures involved in mail delivery. This evidence suggests that Lisinopril might

require higher barrier blister packaging and ambient storage conditions.

42




The 60 count study expands on the trend established in the 30 count study. Lisinopril softens over time whether or not

a significant amount of water is absorbed. Furthermore, heat increases the amount of change and the type of pack-

aging utilized has little impact.

43




44




The 90 count data confirms the trend hinted above: Lisinopril decreases in hardness over time and no level of protec-

tion can prevent this outcome. That being said, the softening can be slowed by keeping humidity and heat to a mini-

mum.

45


4.6.1 Lisinopril DT Testing - 30 Count Packaging


4.6 Lisinopril Disintegration Time Results & Discussion

46




Lisinopril shows an interesting but concerning result. The product shows an increase in Disintegration Time when it is

not effectively protected. This means the product can have less release of the active ingredient if it is not dispensed in

a barrier blister and stored under ambient conditions. The changes are quite drastic at the ICH accelerated conditions.

47




48




49




50




As with the hardness results, the DT properties of Lisinopril are influenced by temperature. The changes occur irre-

spective of packaging. When stored at elevated temperatures, DT increased significantly. These observations call into

question the mail-order process which frequently exposes products to higher temperatures.

Like Simvastatin, Lisinopril received the best moisture protection in a barrier blister. The lowest change in hardness

due to moisture/humidity is observed from the tablets packed in Aclar® or PVdC blister. This was a consistent obser-

vation throughout the study. However, when a product is temperature sensitive, like Lisinopril, primary packaging can-

not prevent damage, as shown in the hardness changes observed at 40oC/75% RH.

51


4.7.1 Metformin MG Testing - 30 Count Packaging


4.7 Metformin Moisture Gain Results & Discussion

Metformin is a frequently prescribed medicine to treat diabetes. It is known to be moisture sensitive. Like Simvastatin

and Lisinopril, it was tested for moisture gain, hardness and disintegration time using the same methods and packag-

ing, during the same testing period.

52



Figure 4.7.1-4: Summary of % Moisture Gain of 30 count products over a period of 30 days under all conditions

Of the three drugs tested, Metformin showed the greatest absorption tendency and the 30 count study shows the ear-

liest hint of this trend. The trend it depicts is very typical of moisture sensitive products, as it shows small moisture

gain at the milder conditon of 25°C/75%RH, while it shows high moisture gain under high humidity/ high temperature

conditions. Significant changes can be seen in the 25°C/90%RH and 40°C/75%RH samples when they are packed in

vials, bottles, and low barrier PVC. It is very clear that the medium and higher blisters provide the most effective

moisture protection to this moisture sensitive product.

53




54



Figure 4.7.2-4: % Moisture Gain after 90 days in the 90 day count packs under all conditions

As 60 days of exposure approached, the Metformin moisture absorption trends became very clear. Product packed in

vials, bottles, and PVC blisters started absorbing significant moisture. Those same samples show a greater change

at 25°C/90%RH and 40°C/75%RH. Regardless of the environment, product dispensed in the higher barrier blisters

were least affected at all storage conditions studied. In a more hygroscopic drug like Metformin, even the differences

in the moisture barrier blister films is becoming evident. In earlier cases with comparatively low moisture sensitive,

less hygroscopic products, the difference in the protection level between Aclar® and PVdC is not as evident as both

55




provide high moisture protection. On comparative ground between the two barrier blisters studied, Aclar® film offered

a higher moisture barrier than the PVdC film. Therefore, moisture absorption, or the lack thereof, by Metformin in the

highest barrier blister is clearly better than the PVdC blister, though both provide excellent protection compared to the

other packaging modes.

The results echo those seen in the earlier data for Simvastatin and Lisinopril, higher barrier blisters are the best

packing formats to protect the product from moisture while during the in-use stage.

56



Figure 4.7.3-4: % Moisture Gain by Metformin after 90 days in the 90 count packs under all conditions

The study conducted on the 90 count Metformin packs repeats the same trend observed in the other counts, except in

the case with 40oC condition. It is possible the elevated temperature is causing the moisture gain differences for the

vial, bottle and barrier blisters to be less significant than in the ambient temperature conditions. However, it is still

evident that highest barrier provides the best protection overall. This applies to all conditions.

57


4.8.1 Metformin Hardness Testing - 30 Count Packaging


4.8 Metformin Hardness Results & Discussion

58




59

The Metformin hardness results are typical of moisture sensitive products where the characteristics remain unaltered

with moisture protection (i.e., packed in barrier blister).




60




After 60 days, Metformin continues to soften when improperly protected. In particular, the data in the 60 count hygro-

scopicity and hardness studies show that PVC and HDPE bottles allow moisture to soften the tablets, especially at

high humidity.

61




62




One can see here that Metformin softens drastically when improperly protected at high humidity conditions. Regard-

less of the environment, PVC and the bottle packed Metformin show the greatest change, although contrary to the

earlier results, Metformin dispensed through vials show better results.

63


4.9.1 Metformin DT Testing - 30 Count Packaging


4.9 Metformin Disintegration Time Results & Discussion

64




Compared to the other two drugs, Simvastatin and Lisinopril, Metformin showed less DT change across all formats

but still highlighted that higher barrier blister packaging provides better stability during the in-use stage.

65




66




The figures from 4.9.2-1 to 4.9.2-3 exhibit an interesting phenomenon, called time lag effect, which is not uncommon

in pharmaceutical formulations. Initially, when the product absorbs some moisture, it makes the product particles loos-

en up and this helps the product to disintegrate faster. Therefore, initially DT is reduced. However with time, the mois-

ture causes the “binding effect” (which is very familiar for us in the case of common salt (without the addition of an

anticaking agent) and becomes hardened in moist conditions. A similar process is experienced with cement used in

building construction. Therefore, DT shows an increase. Again, the graphs are self-explanatory. Such changes are

almost non-existent when the product is dispensed through a barrier blister.

67

Figure 4.9.3.-1: DT of 90 count products over a period of 90 days under LHM conditions (25°C/75%RH)



68




The time lag effect of the Metformin tablet’s DT is evident and consistent in the 90 count packs, as well. This is an

important observation of the study. This explains why some DT results with longer duration are different from short

term results. This is a common dilemma that pharmaceutical formulators/packaging engineers face in the stability

study where the initial trend shown by the product is not concurrent with long term stability results.

Again the overall results undoubtedly confirm that the product dispensed in the higher barrier blister remain more sta-

ble throughout the in-use period.

69

The results obtained throughout the study are consistent with the theory that considerable physical degradation of

drugs occurs during normal use if the drug products are dispensed in packaging which does not provide effective

moisture protection. More specifically, if the products are dispensed, either through polypropylene vials, HDPE

bottles or PVC blisters, they show higher physical degradation while products dispensed through PVC/Aclar® or

PVC/PVdC blisters remain stable. Such degradation can increase if drugs are stored in places of higher humidity,

like bathrooms, rather than cool and dry places.

It is important to understand why products dispensed through barrier blisters provide better “in-use” stability com-

pared to product dispensed through vials, bottles or PVC blisters.

When drugs are stored in conditions with higher humidity than their originally manufactured condition, they tend to

absorb moisture to reach equilibrium. Moisture is a primary cause of drug product degradation and drug manufac-

turers try to protect the product from absorbing more moisture from its environment to maintain stability.

Pharmaceutical producers evaluate a product’s moisture sensitivity during the stability study conducted during drug

development. Based upon the needs of the product, packaging is designed so that it remains devoid of extra mois-

ture during original packing, transit and storage, until it reaches retail pharmacies. Moisture absorption becomes a

problem when the original bulk container is first opened for dispensing in pharmacy, whether retail or institutional.

There are two principal methods of moisture ingress into packaging. The first method is when the pack is opened in

a humid environment and the available head space is filled with the surrounding humid air which can then be ab-

sorbed by the product. The second is by moisture permeation through the package.

The first type of moisture ingress happens each time a patient opens the package to take a pill. This is a primary

source of the moisture available for product absorption in vial or bottle packaging. These containers, intended for

daily use, are repeatedly filled with humid air which can be absorbed by the remaining tablets in the pack. This

continues until the last pill is consumed. Blister packs, by design, prevent this kind of moisture ingress as every

tablet is individually protected until use. This is the reason why moisture gain by the products in vials and bottles

were higher and the degradation observed was higher. The second type of moisture ingress (moisture permeation

through the container surface) happens even if the package is never opened and depends on the moisture barrier

property of the packaging material, its thickness and closure system. Vials used for this project are made of poly-

propylene (PP) while the bottles are high density polyethylene (HDPE). PP is a much better moisture barrier mate-

rial than HDPE. Therefore, while the moisture ingress into the pack by the first type, i.e., opening and closing the

container in a humid environment, is the same for both vials and bottles, the second type of moisture ingress is

significantly more in HDPE bottles compared to PP vials. This is the reason higher degradation in bottles versus

vials is seen.

As stated above, blister packs are designed to give moisture protection to individual tablets. Therefore, the first

kind of moisture ingress does not happen when the product is dispensed in a blister pack. However, the second

type of moisture ingress can happen if the film used for making the blister pack is moisture permeable. PVC mono

film is a poor moisture barrier and therefore moisture can permeate through the PVC blister. This is the reason the


70

5.0 Conclusion

71

moisture absorption and related degradation is higher in the products packed in mono PVC blisters. However, when

the blister is made using high moisture barrier polymer films like PVC/Aclar® or PVC/PVdC Films, the moisture per-

meation is minimal. This means each tablet is protected from moisture until it is consumed by the patient. This is

the reason drug products in the study packaged in the PVC/Aclar® and PVC/PVdC blisters were minimally affected

by the conditions. The PVC/Aclar® film in this study provides greater moisture barrier than the PVC/PVdC film, and

should protect the products better, but in some cases when products are not highly moisture sensitive there will be

nominal performance difference between these two films.

The study demonstrates that the moisture-influenced degradation is dependent upon the storage environment. If the

drug is stored and opened in high humidity areas, like bathrooms, the chances of degradation are increased. In

addition, while a package can provide effective protection against degradation caused by moisture, gases and light,

it cannot provide temperature protection. This is why temperature-influenced degradation occurred in many cases

across all packaging types. It is important to keep drug products in a cool place even when dispensing in barrier

blisters to remain stable and effective throughout the usage period.

The quantity of product and volume of head space in any container can also influence the rate of degradation. For

example, the 30 count, 60 count and 90 count vials and bottles vary with volume of head space, surface area of the

pack and the number of tablets competing to absorb available moisture. Therefore, moisture absorption rates for an

individual product in different size packs may vary. For instance, on day 30 the moisture absorption rate for a 30

count container may look different than day 30 of a 60 count container. This is because of the difference in the num-

ber of products absorbing the available moisture.

Each drug is unique and product sensitivity is studied extensively by pharmaceutical manufacturers. However, once

drugs reach the pharmacy, manufacturers lose control over the package form utilized to carry the drug to the end

user. It is important to dispense product in packaging which is able to protect the drug throughout normal use to

maintain its effectiveness. The data in this study suggest it is best accomplished when dispensing drugs in higher

barrier blisters.

The study results demonstrate the different rates of physical drug degradation during normal patient use when dis-

pensed in vials or bottles, the most common method in U.S. pharmacies. This study focused on the physical degra-

dation of the drug product relative to packaging and further chemical degradation and dissolution studies should be

done to understand the potential reduction of actual drug potency during normal patient use.

It is the opinion of the HCPC that the ultimate goal of drug packaging is to:

Protect the product from the environment.

Protect the patient, help the patient take the drug through adherence reminder systems.

Protect the product AND the patient from unscrupulous players in the supply chain.

and

Protect our healthcare system from unwanted cost and unnecessary patient harm.

This is the ultimate benefit that appropriately designed packaging can provide. This study demonstrates that more

research needs to be conducted on the most appropriate packaging for the thousands of drug products on the mar-

ket, each with their own environmental sensitivity, during the normal use cycle. If we successfully protect drug prod-

ucts when in the hands of the end user, as well as throughout distribution, we have moved one step closer to pro-

tecting patients by ensuring drug efficacy.

2711 Buford Road, #268 Bon Air, VA 23235

804‐338‐5778 Fax: 888‐812‐HCPC

Email: [email protected]

www.hcpconline.org

Sources:

IMS Health Incorporated; Special Data Request, 2014. American Heart Association Statistical Fact Sheet 2013 Update National Diabetes Information Clearinghouse Am J Health Syst Pharm. 2014 Mar 15;71(6):482-99. doi: 10.2146/ajhp130767. National trends in prescription drug expenditures and projections for 2014.Schumock GT, Li EC, Suda KJ, Matusiak LM, Hunkler RJ, Vermeulen LC, Hoffman JM.

Note: Aclar® is a registered trademark of Honeywell International.

The Healthcare Compliance Packaging Council

is a not‐for‐profit trade associa on whose

mission is to promote the greater use of

compliance‐promp ng packaging to improve

pa ent adherence and pa ent outcomes.

www.hcpconline.org. For more informa on

on the Prescrip on Packaging In‐Use Re‐

search Study, please contact us.

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