WHAT'S INSIDE · blister, Figure 4 shows increased moisture absorption under high humidity. The...

• Results of HCPC packaging study

• Anti-counterfeiting/brand protection

• Best practices in pharma blisters

• Addressing extractables/leachables

• Avoiding glass delamination

• Sterilization and ISO 11607

• Vendor resource guide

…and much more!

TIPS, TRICKS AND BEST PR ACTICES FOR LIFE SCIENCE PACK AGING MATERIALS.

WHAT'S INSIDE

ACKNOWLEDGEMENTS3 A list of experts contributing to this playbook

INTRODUCTION5 Rx for best practices

FEATURES7 Study: Drug degradation a function of packaging design, method

16 Best practices in implementing anti-counterfeiting/brand protection systems

20 Tips for successful design of pharmaceutical/medical device labels

24 Best practices when designing folding cartons, inserts, outserts

28 Nine tips for more effective medical device bags, pouches and lidding

32 Best practices in pharmaceutical blister packaging

34 Making the migration connection—addressing extractables and leachables

43 Making the call—digital or conventional printing in healthcare packaging?

49 Packaging for terminally sterilized medical devices—five FAQs about ISO 11607

54 Label material advancement, printing tech, improves safety safety

61 Eliminate glass delamination—pre-screen to keep vials lamellae-free

69 Packaging labels take a bite out of needlestick, sharps injuries

TABLE OF

CONTENTS

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DESMOND G. HUNT, M.S., PH.D.Senior Scientific LiaisonUSP (U.S. Pharmacopeia)

ACKNOWLEDGEMENTS Playbook Advisors

EDWARD J. BAUERSenior Associate - Packaging Technology Integrated Solutions PTIS, President - Edward Bauer and Associates LLC

TAMAL GHOSHSenior Category Head - Packaging Development Dabur

ROBERT L. ARGENTERO CPPPackage Engineering ManagerMaquet Cardiovascular LLC

RAJIV DUAFormulation & Fill-Finish Coordinator Lupin Ltd (Biotech, Div.)

ETIENNE FUNGPlant ManagerProlacta Bioscience

VARUN BAJAJResearch ScientistRanbaxy Laboratories Ltd.

3 / 753 / 75LIFE SCIENCE PACKAGING MATERIALS PLAYBOOK 3 / 75


ACKNOWLEDGEMENTS Contributors, by Company

Individual Contributors, by Country

ARGENTINAGustavo Grobe

INDIARajiv DuaTamal GhoshVarun BajajAvinash Ballal

PUERTO RICOOmar Torres

UNITED KINGDOMTim Sandle

USADesmond G. Hunt, M.S., Ph.D.Edward J. BauerRobert L. Argentero CPP

Tamal GhoshDABUR INDIA LTD

Edward J. BauerEDWARD BAUER AND ASSOCIATES LLC

Rajiv DuaLUPIN LTD (BIOTECH, DIV.) INDIA

Robert L. Argentero CPPMAQUET CARDIOVASCULAR LLC

Tim SandleMICROBIOLOGY SOLUTIONS

Edward J. BauerPACKAGING TECHNOLOGY INTEGRATED SOLUTIONS PTIS

Etienne FungPROLACTA BIOSCIENCE

Varun BajajRANBAXY LABORATORIES LTD., INDIA

Omar TorresSTRYKER PUERTO RICO

Desmond G. Hunt, M.S., Ph.D.USP (U.S. PHARMACOPEIA)



BY MELISSA LARSON,Contributing Editor

INTRODUCTION Rx for best practicesIt isn’t easy to deal effectively with packaging materials in your quest for efficient product protection. Government standards and regulations, supply chain management, and innovations in the materials themselves, make it challenging to stay up to date. We’re offering this Playbook—designed to be read either on the screen, or printed out— as a way to tap into the wisdom of the experts.

To help you rethink the way you choose and use healthcare packaging materials, we reached out to the readers of Healthcare Packaging, and came away with a wealth of advice on best practices and pitfalls to avoid. From choosing and using blister packs and labels to folding cartons and anti-counterfeiting systems, you’ll find nuggets of wisdom from those who’ve been there.

Have you ever wondered whether or not tablets degrade over time, when consumers open and close the amber vial once or twice a day? The Healthcare Compliance Packaging Council did, and they, along with some of their member companies, recently completed a study which looked at the stability of three highly prescribed products: Simvastatin, Lisinopril and Metformin, packed in typical patient-ready formats. The results are fascinating and should serve as a wakeup call on this topic to the pharmaceutical industry.


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We also spotlight sterilized medical device packaging systems in an article that demystifies ISO 11607-1, and sheds light on common misconceptions. In another article, we talk about best practices in guarding against glass delamination in vials and other glass specialty medical packaging, asking the experts how and when to be testing for delimitation both before and after the fact.

And addressing another hot topic in healthcare packaging circles, we enumerate best practices in testing for extractables and leachables with USP. Some migration is unavoidable, so knowing what to expect through careful material characterization is key.

A final word. The entire cost of producing and distributing this playbook has been underwritten by the companies who have sponsored it. We thank them for their support, and we thank you for reading. ✪

continued

Rx for best practices






Study: Drug degradation a function of packaging design, methodThe Healthcare Compliance Packaging Council (HCPC) recently published their report, “Prescription Packaging In-Use Stability Study Research,” revealing some surprising implications about traditional pharmaceutical packaging. Along with Bilcare Research, Legacy Pharmaceutical Packaging, Constantia Flexibles, and Klöckner Pentaplast of America, the HCPC set out to study how drugs were affected by various temperature and humidity conditions in different types of packaging. They included three drugs (all non-coated tablets) and tested how they held up over 30, 60 and 90 days in the following packages:

• Amber polypropylene pharmacy vials

• HDPE white bottles

• PVC blisters (low barrier blisters)

• PVC/PE/PVdC (250/25/90) blisters (medium barrier blisters)

• PVC/Aclar® UltRx 2000 (10 mil/2 mil) blisters (high barrier blisters)

They tested the drugs under three climatic conditions: 1. Ambient temperature-normal/low relative humidity (25°C/75%

Relative Humidity (RH))2. Ambient temperature-high relative humidity (25°C/90%RH)3. High temperature-normal/low relative humidity (40°C/75%RH)

01 Simvastatin Hardness 25ºC/90%RH 90Ct vs. 40ºC/75%RH 90Ct

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The study confirmed that drugs in packaging with minimal moisture and oxygen protection undergo changes much more rapidly than those in medium and high barrier blister packs. The HCPC did not intend to challenge pharmaceutical companies’ stability data, but suggests that the right blister packaging could offer better protection than traditional packaging.

Note: It is important to note that only drug degradation, and not efficacy, was tested.

When do high barrier blisters make the most difference?Because moisture is one of the main causes of drug degradation, a major function of pharma packaging is to prevent the product from absorbing moisture.

High barrier blister outperformed medium barrier blister in the following:

• Simvastatin Hardness: High barrier film offered more protection in 90-count containers of the cholesterol drug under high temperature and high humidity, as seen in Figure 1.

• Simvastatin Disintegration Time (DT): Disintegration time changed the least in high barrier film in 90-count packs, Figure 2. (This trend was clear at all three container counts.)

• Metformin Moisture Absorption: The moisture-sensitive diabetes drug showed less moisture gain in high barrier blisters by the 60-day mark (Figure 3).

How do humid storage conditions affect tablets?It’s important to study the effects of humidity on tablets because they’re often subjected to

continued

Study: Drug degradation a function of packaging design, method






high humidity under normal use, being kept in bathrooms where frequent showers take place.

When Simvastatin was packed in bottles, vials and low barrier blister, Figure 4 shows increased moisture absorption under high humidity. The product in the medium and high barrier blisters at high humidity exhibited little change. Many other parts of the study confirmed that high humidity had a significant affect on products stored in packaging with a low moisture barrier.

How do high temperatures affect tablets?Lisinopril testing showed that not only the humidity, but also the temperature has a major effect on tablet hardness and disintegration time. High barrier blister protects products from moisture, gases and light, but not from temperature.

Hardness As shown in Figure 5, the higher barrier blister package is able to protect the product in 30-count containers against hardness changes under ambient temperature at both low and high humidity, but hardness is reduced in all packaging at high temperature.

Note: Lisinopril also undergoes hardness reduction over time, regardless of the packaging used.

continued


02 Total Change in Simvastatin DT 90Ct

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03 Total Metformin % Moisture Gain 60Ct

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After 90 days, changes of 20% or more were observed in all packaging types, including medium and high barrier blisters.

Drugs like Lisinopril, which are often delivered by mail, may benefit from both the highest barrier blister and heat protection. Time effects should be considered as well.

Disintegration TimeThe DT results also confirmed that Lisinopril is greatly affected by temperature, regardless of packaging. Elevated temperatures increased DT significantly, even in high barrier blister packs (Figure 6).

Like Simvastatin, Lisinopril was better protected from moisture in a medium or high barrier blister at ambient temperatures. However, when a product is temperature-sensitive like Lisinopril, primary packaging cannot prevent damage, as shown in the hardness and DT changes observed high temperatures.

What were the most alarming results at 30 days?Even in bottles and vials, it’s expected that products will be relatively unchanged in a short usage period. But the study uncovered some surprising results in the 30-day containers…

1. Trend: Simvastatin packed in bottles and PVC blister had hardness changes nearing or exceeding 40% under all temperature and humidity conditions (Figure 7).

Why it’s significant: In general, a 40% change in hardness from the initial value is considered to be a significant and objectionable change. Simvastatin, a drug with low

continued







04 Simvastatin % Moisture Gain 25ºC/90%RH 30Ct

Days of Exposure

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eigh

t Gai

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Vial Bottle

876543210

-1-2-3

0 5 10 15 20 25 30

PVC PVdC Aclar®

06 Total Change in Lisinopril DT 90Ct

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05 Total Change in Lisinopril Hardness 30Ct

% Ch

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07 Total Change in Simvastatin Hardness 30Ct

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25ºC/75%RH 25ºC/90%RH 40ºC/75%RH

continued







moisture sensitivity, had significant hardness (and DT) changes at only 30 days of normal use, even under ambient temperature and normal humidity.

2. Trend: As seen in Figure 8, Metformin absorbed much more moisture when packed in vials, bottles and PVC blister under high temperature and high humidity conditions.

Why it’s significant: Metformin is a moisture-sensitive drug, and the moisture gain in the 30-day period suggests that sensitive drugs should be packaged in high barrier blister.

3. Trend: Lisinopril, a temperature-sensitive drug, showed a considerable increase in DT when packaged in bottles and PVC blisters, while the medium and high barrier blister offered better protection under the high temperature condition Figure 9.

Why it’s significant: Disintegration time is the time recorded for a tablet to completely disintegrate into small particles. This correlates to the bioavailability of a drug’s active

continued


25ºC/75%RH 25ºC/90%RH 40ºC/75%RH

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08 Total Metformin % Moisture Gain 30Ct

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09 Lisinopril DT 40ºC/75%RH 30Ct

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ingredients, and means the product may release less of the active ingredient if it’s not dispensed in a medium or high barrier blister and stored under ambient conditions. Because Lisinopril is temperature-sensitive, the changes are extreme at the high temperature condition.

Why does disintegration time decrease before it increases in some cases?Figure 10 shows that Metformin DT initially decreases (around 30 days of exposure) and then increases significantly by the 60th day. Why? The time lag effect.

Time Lag Effect• Decrease in DT: The product absorbs moisture, causing

product particles loosen. The loosening helps the product to disintegrate faster, so initially DT is shorter. This could mean that too much of the drug will be absorbed too quickly, with potential harmful effects to the consumer.

• Eventual Increase in DT: With time, moisture causes a binding effect in the tablet. The product hardens, and DT increases. This could result in not enough of the drug being absorbed,

continued


Days of Exposure

% Ch

ange

15

10

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10 Metformin DT 25ºC/75%RH 60Ct


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11 Total Change in Simvastatin DT 30Ct

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Vial Bottle Aclar®






reducing its therapeutic effect. Again, efficacy due to increased hardness wasn’t specifically tested.

• Blister Matters: It’s important to note that the products remained more stable in the medium and higher barrier blister.

Vials and bottles vs. high barrier blistersMany of the study’s results showed strong benefits to using high barrier blisters over vials or bottles:

• Even at only 30 days, Simvastatin’s decrease in DT exceeded 40% in vials and bottles at all conditions, while the product in high barrier blister remained relatively unchanged (Figure 11).

• At high humidity, high barrier blisters protected Lisinopril tablets from changes in DT much more effectively than vials and bottles in 30-, 60-, and 90-count containers (Figure 12).

• In all conditions in Figure 13, Metformin was clearly more stable in 60-count packs with regard to DT changes.

SummaryThis study showed that appropriately designed packaging can have a great impact on the stability of tablets under a range

continued


12 Total Change at 25ºC/90%RH

% Ch

ange

Lisinopril DT 30Ct Lisinopril DT 60Ct Lisinopril DT 90Ct

200

150

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50

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} RSD

Vial Bottle Aclar®

13 Total Change in Metformin DT 90Ct

% Ch

ange

Vial Bottle Aclar®

20ºC/75%RH 25ºC/90%RH 40ºC/75%RH

} RSD

141210

86420

-2-4






of different usage conditions. While it presented some very compelling findings, the HCPC recommends that more research be conducted on the effects of packaging on specific drugs, as each one has its own environmental sensitivity. It’s clear from the study that medium and high barrier blister packaging can help to protect patients by maintaining drug efficacy throughout the usage period. With more research, pharma companies can further develop their packaging strategies to uphold drug quality in the many distribution channels and storage conditions that products now face. ✪

continued







Best practices in implementing anti-counterfeiting/brand protection systems

Pharmaceutical anti-counterfeiting experts had the following advice for implementing anti-counterfeiting and other security systems for pharmaceutical and medical packaging.

1. Acquire an agile and flexible approach to brand protection. This includes acquiring a deep understanding of all the different geographic markets where your products are sold, and building in an ability to react to legislative or geographical requirements as they come up.

2. Consider the overall cost of your anti-counterfeiting/brand protection program in proportion to the underlying problem. Be

mindful that anything you put in place can to some degree be replicated within a 12 month cycle. Work with the marketers to produce a strategy that constantly evolves the brand protection to stay ahead.

3. Match the cost of protection to the value of the product. It’s foolish to protect an inexpensive product with expensive brand protection. Costs must include setup, application, quality control, surveillance and detection, and any lab costs (not to mention costs of failure in terms of market or reputation).






4. Use ‘smart’ technology on an Internet-based platform. Given the growing sophistication and size of worldwide counterfeiting efforts, it’s wise to look for an alternative to such devices as holograms, watermarks, special inks, etc. which counterfeiters are increasingly able to copy. Instead, consider a system in which information pertaining to your product can be changed at a moment’s notice, remotely. This way you are always many steps ahead of any counterfeiter, using techniques they cannot copy.

5. When implementing security features, use a reputable vendor that is accredited with a recognized group like the North American Security Products Organization (NASPO). NASPO is an ANSI-accredited standards development organization based in Washington, D.C. Its members include Fortune 500 companies, commercial, industrial, government and non-governmental organizations (NGOs).

6. Be ready with the questions. Ask a prospective vendor the following:

• What are your security accreditations?

• Will our information and plates be secure and password protected?

• What is your destruction policy? (Expensive security plates have been known to be stolen from dumpsters)

continued







• Do you have a head of brand protection? (Is it something they actively work with or are they just trying to recommend expensive features to profit?)

• Are there security features which can be offered at little or no cost?

Last, talk to the technical sales reps at respected anti-counterfeiting technology firms (makers of inks, holograms, or similar products.) Ask whom they have successfully worked with, and if they can recommend a vendor for you.

7. Resist adding an overt measure to a pack that does not also contain covert measures, since the overt feature alone will not be sufficient to assure the authenticity of the pack. Consider inexpensive covert features, such as microtext, but increase their usefulness by applying them in more than one location. This makes it more likely that a counterfeiter will overlook some of the measures you have taken.

8. Align the protective features with the packaging. Aesthetically, the color and texture must match. Stability testing may include temperature, humidity, light, gamma radiation and more. Feature alignment is more challenging with covert protection.

9. Consider that the leading solutions in anti-counterfeiting/brand protection may be offered by a strategic combination of vendors rather than a single vendor. It is key for manufacturers to understand the landscape, and to work with the correct selection of experienced vendors.

continued







10. Make sure your electronic security platform interfaces with your current and proposed technologies and IT/ERP/CRM systems. Data can be collected and analyzed to provide ‘real-world, real-time’ information, and evidence of pre- and post- purchasing customer behavior and satisfaction. This data, in turn, can be used to shape sales and marketing strategies, and future distribution channels.

11. Consider what a unique package code can do, other than deter counterfeiting. The same unique package codes that you are considering for security can also be used to open up one-to-one, interactive communications with: the patient, their caregiver, and with healthcare professionals, etc. This can improve market access, increase product use, and even improve health outcomes. The package can also be tracked and traced through the distribution and sales process. ✪

continued







Tips for successful design of pharmaceutical/medical device labelsDetailed specifications are a must in healthcare labels. Use your specs as a blueprint for success.

1. Don’t get stuck with the “default” label stock. It's a common mistake, when faced with a new labeling project, to contact a friendly package printer and ask for a suitable material for the application. Packaging printers usually offer to their clients those materials they have in their warehouse at the moment, or their most convenient commodity. These "default set label stocks" are rarely the same for all printers.

A good label material development process should end with an accurate specification that indicates all alternative materials that have been tested and are suitable for the application. If you have a vendor change, any new material combinations should be subjected to development tests, to ensure they are compliant with the product and processes requirements you’ve already established.

2. Don’t leave the total pressure sensitive label structure to the materials manufacturer or converter. Specify not only the facestock, but the adhesive and liner. The spec should indicate all alternate facestocks, adhesives and liners, branded or generic, which are commercially available. Adhesives have different properties depending on the substrate. Not all alternate facestocks have the same performance in cold-chain requirements. An alternate liner material may not run as well as the original in a particular labeling machine.






3. Design your labels to interface with your current and proposed technologies and IT/ERP/CRM systems. Use smart codes that can perform multiple functions, such as one-to-one customer communication, anti-counterfeiting and track and trace. When patients scan the unique codes on the now ‘smart’ packs, de-identified data can be collected and analysed from specific patient cohorts to provide ‘real-world’ data and evidence. This can be used to further improve treatments, care pathways, healthcare and health outcomes. Similarly, data can be collected and analyzed with regard to improving anti-counterfeiting, product authentication and track and trace.

4. Measure your label specs against a high standard. Ask a trusted supplier for examples of the best specifications that have been provided to them, and to ask for a critique of your specification against that standard. Good specifications are critical to achieving consistent and accurate printed labels. Particular attention should be paid to:

• Specifying stock and adhesive (sufficient detail),

• Dimensions, including a die outline,

• Unwind direction,

• Inner and outer roll diameters (so that the labels perform on the packaging line),

• Allowed splicing,

• Inspection method,

• Proper handling of defective labels, and

• Packing method for finished rolls.

continued

Tips for successful design of pharmaceutical/medical device labels






5. Show, as well as tell. By including drawings or graphics prominently displayed on the packaging, you can creatively communicate your most important information at a glance. The FDA has a number of requirements for what is required on medical device labeling, including its instructions for use, and these must be included. However, the labeling is most often not read, or kept, making it difficult to communicate to the user. And if the user learns something by glancing at your graphic, he or she may be more likely to read on.

6. Conduct “usability” tests of your label. Validate your label communication by asking a user to open the package, without asking them to read the copy on the label, and then ask questions to test whether or not they picked up your graphic's key message when handling the package.

7. Beware label material obsolescence. Have you ever been in a situation where your label material is linked to your NDA and you get a letter that your material or adhesive will be obsolete in three months? Here is another reason why a label vendor experienced in

continued




MORE INFORMATION

Number of requirements: For more on the FDA’s medical device labeling regulations

CLICK HERE »



http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/DeviceLabeling/ucm2005422.htm




healthcare applications should recommend more than one compatible material, and a good label spec should always include an alternative material. Having a "back-up" plan is low-cost insurance which could save you time and money in the future.

8. Give preference to label vendors who work exclusively in pharma and healthcare. An experienced label vendor for healthcare will know more about all of the various challenges you work with everyday, including FDA requirements, than a general label vendor that happens to have made pharma labels.

9. When translating labels to be used in overseas markets, take the time to have the labels correctly proofread. This is not only important to avoid any clinical complications, but also to avoid any cultural confusion that might arise where different phrases might be wrongly interpreted.

10. When designing in-house label printing systems, serious consideration should be given to "print one, apply one" processes, otherwise known as "on-demand" label printing. It is often tempting to print labels in batch processes to capitalize on speed, however the risk of inaccurate label reconciliation increases in batch printing. Additionally, "on demand" printing is often more efficient and less costly overall than batch printing since there is less handling and label scrap. ✪

continued





Print quality, efficiency and handling of graphics were important considerations in folding cartons and outserts for healthcare packaging even before the advent of serialization and new types of coding. Here’s some practical advice.

1. Be aware of standards for machine-readable codes on pharmaceutical packaging. Attributes such as the percentage of china clay (Kaolin) in the cartonboard, the consistency of physical

dimensions, and surface energy levels—that were less important with human readable text—have a big impact on the readability of codes such as ECC200 2D Datamatrix.

Cartons printed with a ECC 200 2D Datamatrix ideally need to be 100% white with a 100% black print to get the best possible grade with ISO 15415; or the inverse for black cartons with white printing. Generally cartons are 85% white and printed codes are 85% so the maximum score can only be 73% before there is any impact on quality caused by on-line variations.

2. Don’t underestimate the importance of prepress when auditing print suppliers. Many pharmaceutical companies do not have extensive knowledge of how artwork is manipulated in order to produce printing plates. Auditors should be able to assess the following:

Best practices when designing folding cartons, inserts, outserts



MORE INFORMATION

ISO 15415: For more about this bar code standard

CLICK HERE »



http://www.iso.org/iso/catalogue_detail.htm?csnumber=54716


• whether the prepress operators are well-trained,

• whether state-of-the-art methods are used for plate production,

• how secure the storage of electronic files is, and

• whether the supplier’s own artwork is prepared in a manner that reduces the need for extensive manipulation to achieve the desired appearance and quality on the final printed material.

Also, the pharma company's own artwork development should be especially attentive to the use of die outlines that are provided by the print supplier, in order to avoid the chance of missing text when cartons or inserts are cut for folding.

3. Strive for standardization. Each product's design usually starts with the dosage and package size. The smaller the packaging, the more economical packaging and shipping costs will be in the future. The problem is if you have a limited number of packaging lines and

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a much larger number of SKUs, all with different sizes, you spend a lot of set up time between runs customizing and adjusting your packaging line.

Try to see if your new products can match size with an existing product. You might save money in bottle purchases. You might save time in packaging line set-up time. It may be more efficient for you to order a larger size outsert than what you require and leave half of one side blank. Standardizing your packaging sizes will uncover hidden efficiencies on your packaging line and allow you to get more product out the door faster than in an ultra-customized plant. You may even see faster service from your outsert vendor since they won't have to change their folders into different configurations.

4. Always consider how the package will be used in the field. Many packages are used in a clinical setting and an opened carton is disposed of when the patient leaves the facility or room, for example. Was the carton necessary?

5. Ensure that the carton bending line (crisping line) is well perforated for easy folding. This is very critical for effective folding operations.

When using any Protective Packaging (PP) material on the Packaging System (PS) it is important to account for the variability of these components. It is not cost effective and

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sometimes impossible to require to the supplier components that are on the limit of the specification and basically impossible to request samples with different attributes on the limits of the specification on specific combination, e.g. length at maximum with width and minimum. To account for this variability run a Component Qualification with several lots (three recommended) and split, through the length of each lot run, into samples to be measured for the CQ and samples for Packaging System Design Performance testing. Using all lots from the CQ, combine the samples for Packaging System Design Performance testing to make the product samples for this test. In this way you have challenge the performance of the components including the natural variability of the manufacturing process of the components and their materials. In addition, in this way you may justify any deviation of the attribute of the component using the Packaging System Design Performance testing results as the support data since both come from same lots. ✪

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Flexibles are more and more prevalent in effective healthcare packaging. Here is some advice regarding testing, design and converting.

1. When implementing a seal process for a pouch, ensure that the Low Specification Limit (LSL) of the seal strength is as close as possible to the seal strength actually tested. It should be based on samples that were challenged in Packaging System Design Performance testing. Since the equipment to measure the seal strength in the industry is usually of high resolution and precise, there is not a value to choose but a statistical distribution. Choose a value around the minus 2 to minus 4 Sigma from the average to be selected as the LSL for the sealing process.

If this is close to -2S it is safer for the customer, but tighter for production. If it is closer to -4S it will be less tight for production, with more space for process variation, but more risk is passed along to the customer. The decision should be made based on risks and consequences analyses. Avoid using the one-size-fits-all 1.00 lbs/in as the final LSL.

2. Take the time and effort to observe how your medical packaging is treated at the point of use. The integrity of sterile barrier systems is well regulated and controlled from the device manufacturer to the healthcare facility. In contrast, training in proper handling, storage and use at the end-user, i.e. healthcare establishments, needs some serious attention.

Nine tips for more effective medical device bags, pouches and lidding



DEFINITION

Low Specification Limit: The lowest level of process performance or product quality that is within an acceptable range defined by customer standards and measurements of defects in the process or product itself.




Sterile supplies are all too often handled like pre-packed meat, sausage, cheese at a local retailer. A sterile barrier system must not be opened like a food pack, by aggressively tearing the packs open at one edge. As an example, in a dentist’s treatment room, one can see untrained technicians break the packed instrument through the porous fibrous paper backing of a pouch that has been sterilized in steam or in gas. What a waste of effort for the manufacturer to guarantee the integrity of the pack through its life cycle. The solution is better training at the point of use.

3. In contrast to the above, design in ease of opening the package in a clinical or sterile room setting. Your end users will be opening the pouch or tray with gloves on, and in potentially moist environments. Vertical or horizontal perforations ease opening for end users.

4. Establish your roll size constraints. Due to space constraints, you may prefer small roll quantity, or you may prefer more bags per roll to reduce labor. Also consider whether your facility can accommodate the space a larger roll takes up.

5. Guard against smudging. On rollstock material that is thermally imprinted during processing, make sure the bag is converted with a varnish coat to keep the direct print on the bag from smudging. Add another layer of print protection if using a resin-based print ribbon on the bagger.

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6. Test for migration of low-molecular-weight particles to the surface of film. The film surface layer is enriched with low-molecular-weight particles, like plasticizers, polysiloxanes, and oligomers. You must ensure that the product inside the bag is not changed or affected by contact with these particles.

7. If your lidding material is unprinted, be sure to design in a distinctive radius in one of the corners to prevent operators from placing the adhesive side up on the tray. Another option is to pre-print a corner peel mark, logo, or label "tick mark" on the lidding so that there is a clear visual indicator as to what side is "up". This precaution will prevent manufacturing downtime when the lidding sticks to the seal platen and shuts down the line.

8. Become educated on all the ways lidding can potentially fail during distribution testing. Seal "creep" or "lift" during a distribution test may occur under the following situations:

• Device movement inside the tray impacts the seal or lid causing the seal to prematurely begin to peel.

• Flexing of the tray during drop testing causes the tray to buckle or fold in regions which transmits to the seal flanges.

• Environmental extremes may cause the lidding sealant to become brittle (cold drop) or soften (hot drop) and fracture loose from the tray flange.

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DEFINITION

Seal platen: The flat metal plate mechanism by which an impression is made in the lid.




• Sterilization using EtO or Gas Plasma may cause significant pressure changes within the package causing seal creep during vacuum cycles.

• Air shipment of non-porous packages will experience internal pressure changes that can stress seals.

9. Don’t assume flexible packaging, plastics or fibrous webs are fit for all uses and sterilization methods. It is important to validate the performance of a final pack configuration,

including the sterile item folded in a sterile barrier system. Leaks, breaks, discoloration, or other failures might not occur because of a failing packaging material, but because it has failed to interface with the packed item, storing conditions etc. ✪

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DEFINITION

EtO: One of the most popular methods of sterilization of medical devices is through exposure to Ethylene Oxide gas (EtO/EO).

Gas Plasma: Gas Plasma (vaporized hydrogen peroxide) provides low-heat sterility cycles with non of the off-gassing concerns present with EtO.




There’s a science to good design and manufacture of blister packaging. Here’s what the experts recommend.

1. Trust the cold form foil manufacturer to do the cavity design. They understand the material much better than machine shops, and will not over-size the cavity. Cold form foil can be less expensive than certain barrier plastic thermoforming films, depending on the cavity size.

2. Understand the difference between physical and chemical properties of a barrier material. Amorphous versus crystalline materials

exhibit significantly different barrier properties. Consider coatings like PVDC to improve barrier performance before jumping to a more expensive material, and make the appropriate cost/benefit judgment for the product.

3. Don’t neglect the effect of different temperatures (20, 40, 60 degrees), on stress and shrinkage of primary plastic packaging, which can appear during long-term stability tests.

4. Ensure the product recipe is completely finalized before engaging the packaging development process. As tempting as it may be to begin beforehand, if the product requirements change mid-stream, it can create more work rather than save time.

Best practices in pharmaceutical blister packaging



DEFINITION

Cold form foil: The alumi-nae foil shape is formed by simply pressing into a mold by means of a stamp.




5. Traditional 25-micron push-through lidding foils can pose problems in dispensing to elderly patients. This has been overcome by reducing the gauge to a more senior-friendly 17 micron and 20 micron foil, reducing the push-through force.

6. Watch for solvent-based heat seal lacquers to be gradually supplanted. As we move towards more patient sensitive and environmentally friendly world, experts predict that waterborne coatings will become the new standard in the field. ✪

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Best practices in pharmaceutical blister packaging






Adapted from "Assessment of drug product leachables associated with pharmaceutical packaging/delivery systems and Assessment of extractables associated with pharmaceutical packaging/deliver systems," by Desmond Hunt, USP

Through the course of a pharmaceutical product’s life, from initial manufacture to final administration in the field, it will come in contact with a variety of components, materials of construction, and primary/secondary/final drug product packaging systems. Such contact may result in interactions between the pharmaceutical products and these components and materials.

These interactions can be classified either as additive, reductive, or transformative:

• Additive interactions - If the interaction is additive, a constituent of the packaging system is added to the product due to the interaction.

• Reductive interactions - If reductive, a product constituent is reduced, in either level or action, due to its uptake into the packaging system.

• Transformative interactions - If the interaction is transformative, the product is transformed (for example, loss of stability) due to a physicochemical interaction with the packaging system.

Making the migration connection—addressing extractables and leachables






An additive, and sometimes transformative, interaction can reflect a process where some substance - extractables - migrate out of the packaging system and accumulate - leachables - in the product, with subsequent delivery to the patient during drug administration. Leachables in a pharmaceutical product can affect safety and/or efficacy.

• Extractables are organic and inorganic chemical entities that can be released from a pharmaceutical packaging/delivery system, packaging component, or packaging material of construction under laboratory conditions, sometimes aggressive.

• Leachables are organic and inorganic chemical entities that migrate from a packaging/delivery system, packaging component, or packaging material of construction into an associated drug product under normal conditions of storage and use or during accelerated drug product stability studies. Leachables are typically a subset of extractables or are derived from extractables.

Ascertaining riskIn order to assess these risks and manage the potential issues posed by leachables, it is necessary to know:1. The identities of the leachable compounds. 2. The levels to which leachables will accumulate in the finished drug product

over its shelf life.

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continued


Degree of Concern Associated with the Likelihood of Packaging Component-Dosage Form Interaction

Route of Administration High Medium Low

Highest Inhalation Aerosols and Sprays

Injections and Injectable Suspensions; Inhalation Solutions

Sterile Powders and Powders for Injection; Inhalation Powders

High Transdermal Ointments and Patches

Ophthalmic Solutions and Supensions; Nasal Aerosols and Sprays —

Low Topical Solutions and Suspensions; Topical and Lingual Aerosols; Oral Solutions and Suspensions

—

Oral Tablets and Oral (Hard and Solf Gelatin) Capsules; Topical Powders; Oral Powders

Safety Thresholds Examples of Packaging Concerns for Common Classes of Drug Products

* While this table provides a convenient overview of the general level of regulatory concern with various dosage forms regarding leachables, it should not be inferred that "low-risk" dosage forms (e.g. oral tablets) by that defination carry no risk from leachable issues.

** Although low-risk dosage forms (e.g., solid orals, topical powders) typically do not rigorously require leachables studies as part of the drug prodcut registration process, it it is possible that leachables could appear in drug product impurtiy profiles either during registration stability studies or in marketed products.






These two pieces of information can be used to establish the magnitude of patient exposure (dose), and therefore the safety risk posed by an individual leachable. It can also establish the likelihood of any compatibility issues involving the drug product.

Although leachables represent a particular class of drug product impurity, current regulatory guidance for drug product impurities specifically considers leachables to be out of scope. Thresholds that have been specifically proposed for drug product leachables are based on either patient safety considerations or the current capabilities of analytical technology.

Safety thresholds are particularly important in a leachables assessment because current analytical technology allows detection of trace organic and inorganic chemical entities at extremely low levels (i.e., ng/mL; ng/g). Identification and risk assessment (or qualification) of every individual chemical entity in a typical leachables profile at the limits of current analytical technology is neither necessary from a toxicological perspective nor feasible in a typical drug product.

These safety thresholds allow for a science and risk-based determination of acceptable levels of leachables, and can be based on results from preclinical exposure studies, as well as additional safety risk factors that consider, among other things, route of administration, daily exposure, and treatment duration.

Because safety thresholds are derived from exposure data they are considered in terms of units of exposure, such as Total Daily Intake (TDI). Thus, any safety threshold must be

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converted into units of concentration (e.g., μg/mL) so that it can be applied as an analytical threshold in the laboratory. The analytical threshold is a guide as to which chemical entities in the leachables profile should be considered for chemical characterization (i.e., confirmed identification) and safety evaluation and qualification.

Two assessments complement one anotherRegulatory guidelines and various best-practice recommendations all state that assessment of the potential impact of contact between a component or material and the final drug product involves testing the final drug product for leachables.

• Leachables assessment - This assessment includes a migration study with a purpose to discover, identify, and quantitate leachables that have migrated from the contacted system, components or materials and accumulated in the drug product. However, a leachables assessment cannot stand alone as the single means of assessment.

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USP RESOURCES

Download full recommendations and best practices chapters on Extractables and Leachables from US Pharmacopeia

CLICK HERE »





http://www.usp.org/sites/default/files/usp_pdf/EN/meetings/workshops/m7126.pdf


• Extractables assessment - Since the pharmaceutical packaging/delivery system is the primary source of potential leachables, any leachables assessment should be preceded by an extractables assessment performed on the packaging/delivery system, its primary and certain critical secondary packaging components, and/or packaging and delivery system materials of construction; consistent with regulatory guidelines and best-practice recommendations.

Such an extractables assessment can also be performed on particular components and/or materials of construction of manufacturing and packaging equipment, as well as certain

tertiary packaging components, that are deemed of high leaching potential or have been implicated in an identified leachables problem with a particular drug product.

Both the extractables and leachables assessments are exercises in producing analytical data about the composition of an extract or pharmaceutical product. This body of data is not, in and of itself, an indication of the potential safety or quality impact of the extractables or leachables. Rather, these data must be interpreted to infer their safety or quality implications.

Establish the link between assessmentsA leachables-extractables correlation is established when actual drug product leachables can be linked both qualitatively and quantitatively with extractables from corresponding extractables assessments of individual packaging components.

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Leachables-extractables correlations are important for several reasons, including justifying the use of routine extractables release tests of packaging components as an alternative to leachables testing during stability studies for high-risk drug products, establishing the source of a leachable producing an OOS result for a low-risk drug product, change control, and ongoing quality control, etc.

Where’s the link?A qualitative correlation is demonstrated when a leachable is linked either directly or indirectly to an extractable (i.e., potential leachable). For an appropriate quantitative leachables-extractables correlation to exist, the quantity of any individual leachable over the shelf life of a drug product must be mathematically related to the quantity of the corresponding extractable. One of the more simple mathematical relationships between an extractable and a leachable is that the quantity of the leachable in the drug product should be less than or equal to the quantity of the corresponding extractable.

For high-risk drug products, leachables-extractables correlations may be established over multiple batches of drug product (accelerated or at end of shelf-life) and multiple batches of packaging components. Extractables studies should ideally be conducted on lots of components that were used to manufacture the drug product batches used in primary stability studies (and therefore on the drug product batches on which leachables testing was conducted to establish leachables-extractables correlations).

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Not making the connectionConsider the following case:1. The maximum level of a specific leachable in the formulation during stability studies was

substantially greater than the calculated maximum potential accumulation levels of that same leachable as established by the extraction study.

2. The extraction studies were conducted on the same lots of components used to make the primary drug product stability batches.

Considering those two facts, it must be concluded that the extraction study was inadequate. Therefore a leachables-extractables correlation for that specific leachable cannot be established. In this case, either a more complete extraction study must be performed in which the extractable level exceeds the maximum level of the leachable, or the leachable must be controlled as such in the drug product specifications for shelf-life stability testing, and release testing as an extractable at the component level is inadequate to control this leachable.

If a leachable-extractables correlation cannot be established, possible explanations include: inadequate extractables assessments of packaging components; unreported changes in packaging component composition or manufacturing processes; or unreported changes in the identity of packaging components.

Get everyone on boardTo successfully manage leachables throughout the drug product lifecycle, it is critical to establish close and regular communication among those stakeholders throughout the development and drug product lifecycle responsible for the quality of the drug product:

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• Chemists

• Toxicologists

• Packaging engineers

• Manufacturing operations

• Procurement

• Materials

• Think even further upstream and downstream

With respect to leachables, communication between the analytical chemist and toxicologist is critical. For example, if a leachable is found to be above an accepted limit, or a new leachable is found, a safety evaluation will need to be performed. The chemist will need to provide the toxicologist with information that will help to qualify the leachable, including: the identity of the leachable, which may include compound class or more specific information, such as chemical formula and structure; and the amount and concentration of the leachable in the drug product.

Information sharing between packaging component manufacturers/suppliers and drug product developers/manufacturers is also important in order to guide packaging component and materials of construction selection, and facilitate leachables-extractables correlations via knowledge of packaging component chemical compositions. ✪

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Making the call—digital or conventional printing in healthcare packaging?

Tips for choosing the right printing methodTwenty years ago, only a few small niche markets used digital printing. With advances being made everyday in technology, one could speculate that most printing presses will eventually become digital, at least in some form. In the meantime, digital and conventional printing will coexist, and healthcare manufacturers will need to make a choice and match the right technology to the job. Here are some tips for making those choices:

* These numbers depend on the overall size of the label or carton.



Conventional Printing Digitial Printing

• Carton runs are in excess of 50,000* • Label runs are in excess of 500,000* • Changes are infrequent • Variable printing is not needed

• Runs are short: less than 50,000 for cartons and up to 500,000 for labels*.• Copy changes are frequent. • Lead time is short. • Serialization or variable coding is needed for anti-counterfeiting protection,

track-and-trace initiatives, or pedigree requirements. • Inventory must be limited due to space constraints or concerns about obsolescence

and waste.

Coventional Printing vs. Digital Printing Advantages

DEFINITION

Digital printing: Digital printing refers to methods of printing from a digital-based image directly to a variety of media, as opposed to offset printing, where an image is transferred via plate or rubber blanket.




Sometimes the answer to the question “digital or conventional?” is “both.” Both printing technologies typically are used in situations where multiple stock keeping units (SKUs) of a product are sold, offering consumers different strengths or dosage counts, or addressing the needs of a particular market.

For example, a brand’s 100-count bottle may involve a run in the millions, while its 25-count bottle only requires a couple hundred thousand. In this situation, it makes sense to print the label for the 100-count SKU on a conventional press, while the label for the 25-count container is digitally printed.

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Making the call— digital or conventional printing in healthcare packaging?

SHOULD THIS JOB BE CONVERTED TO DIGITAL PRINTING–A CHECKLIST If the response to some or all of the following questions is “Yes,” digital printing should be considered. C

HECKLIST

✓ Would you like to meet changing market demand almost immediately for lower volume SKUs without carrying excess inventory?

✓ Would you like to compress cycle time and receive labels and folding cartons within days instead of weeks? Would you like to reduce costs in key operations areas such as prepress, ordering, ware- housing, product obsolescence and distribution?

✓ Would you like to protect your brands by adding security features such as microprinting, layered optical watermarks, taggants or color-shifting ink?

✓ Would you like to prepare for electronic pedigree requirements by individually serializing each label or folding carton with a unique number, bar code or radio frequency identification tag?

✓ Would you like to have more consistent quality of color and bar codes in your printed packaging, cartons and labels?

Source: Nosco






Considerations in digital printing implementationHealthcare packaging professionals are still on the fence about whether or not they will be implementing digital printing into their process. If you are one of those professionals, here are some things to consider in your digital printing journey:

Keep big picture in focus when crunching numbersExperts say that there remains a general impression among brand owners that digital printing will cost more than traditional printing methods. Often, this is due to the fact that prospective customers are taking too narrow a view of comparative pricing. The digital print provider you choose has the resources to help you crunch numbers, using your costs, to determine if your products are a cost effective fit for the digital model.

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0 10 20 30 40 50

01 Top advantages of digital printing (respondents checked up to three choices)

Reduce overhead cost of inventory

Speed to market

Lower unit printing and prep costs

Variable data/serialization

Minimize obsolenscence

Color consistancy

None of the above

46%

44%

43%

38%

33%

19%

3%

Source: Healthcare Packaging survey, gauging attitudes about the use of digital printing technology. Completed, July 2013. 122 respondents.






Reducing inventory costs had the most appeal among digital printing advantages, followed closely by speed to market.

Over and above the cost per thousand of each print method, the following costs need to be taken into account:

• Prepress and plate cost

• Inventory management

• Label or carton obsolescence

• Quality complaints/rejections

• Cycle time

• Color management

Value proposition is key Some experts suggest that instead of attempting to compare costs, prospective customers should focus on the value proposition: not having obsolete inventory, speed to market, reduced cycle times, and the elimination of several steps in the printing process.

Substrate changes require attention, reasoning It’s important to evaluate and test any effects on the substrate that arise as a result of changing printing methods. Re-qualify your substrate, including topcoat or varnish, especially when cold chain conditions will apply.

Don’t neglect your supply chainDigital printing will transform all parts of the workflow, not just the printing method. Be ready for changes in how you track and move product. Can your distribution system handle two-day

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turnaround? Experts say new digital customers need to rethink their entire supply chains, including what happens after printing, and start putting the pieces in place early on in the process.

Digital printing has limitationsDigital printing is great for short to medium runs, incorporating variable information, and being able to provide just-in-time orders. At this time, digital printing equipment doesn’t have sufficient speeds for long runs and only has the ability to match 97% of the PMS colors. Also, fluorescent and pearlescent effects cannot be achieved inline and must be performed as a finishing step.

Dealing with packaging lead times causes the most distress for healthcare packaging users.

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0 10 20 30 40 50 60

Lead times on packaging material orders

Short-run costs

Obsolescence of packaging materials due to package graphic changes

Inventory storage costs

Color consistancy

Pre-press costs

56%

46%

45%

34%

26%

18%

02 Experiencing issues with labels, �exible packaging, folding cartons, and/or inserts

Source: Healthcare Packaging survey, gauging attitudes about the use of digital printing technology. Completed, July 2013. 122 respondents.






How user groups can helpUser groups for digital print professionals are one of the most efficient ways for OEMs to disseminate information, gather user feedback, and give digital printers the opportunity to network with each other. One example is Dscoop (Digital Solutions Cooperative, http://www.dscoop.org), which bills itself as an independent global community of graphic arts business owners and technical professionals who use HP Indigo and Scitex equipment and related solutions.

Education is the aim of this organization, which was founded in 2005 and boasts 8000 members worldwide. Dscoop serves North America, Asia-Pacific, Europe, the Middle East, Africa and Latin America. It “walks the walk” on that global focus, as it holds annual conferences not only in the United States, but worldwide.

Also available to Dscoop members are a print directory, committees organized according to the members’ type of usage (Commercial, Grand Format, Labels and Packaging, etc.), and partner opportunities for vendors who sell ancillary equipment like substrates, soft-ware and equipment. ✪

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http://www.dscoop.com


Adapted from material supplied by DDL

Developing and implementing a packaging system for terminally sterilized medical devices is daunting. Packaging system design and material choice is a function of the nature of the medical device itself, expiration date, the intended sterilization methods, the intended use, mode of transportation, as well as storage.

The ultimate objective of a packaging system for terminally sterilized medical devices is to enable the sterilization, physical protection and preservation of sterility up to the point of use and to provide an aseptic presentation. The sterile barrier system is essential for the safety of terminally sterilized medical devices.

International Standard ISO 11607-1 lists what is required of materials and pre-formed systems designed for use in terminally sterilized medical device packaging.

ISO 11607-1 consists of four key areas: 1. Stability Testing (accelerated aging and real time aging) 2. Performance/Dynamics Testing3. Package Strength Testing4. Package Integrity Testing

Packaging for terminally sterilized medical devices—five FAQs about ISO 11607






This ISO standard also addresses packaging materials by presenting requirements for their physical properties and material performance as well as requirements for sample size, labeling, and documentation.

Here are five of the most frequently asked questions with answers based on our experience.

1. Why is testing performed at every step of the packaging validation process? Performing package strength and package integrity tests throughout the validation process helps to more easily determine the root cause of any failures. If testing were left until the end of the process and a failure were to be found, it would be very difficult to determine the point at which failure actually occurred in order to take corrective action and as a result would cost the developer valuable time and money.

2. Why does the standard separate accelerated aging and real time aging from performance/dynamics testing? ISO 11607-1 defines stability testing (i.e. accelerated aging and real time aging) and performance testing (i.e. environmental and distribution simulation) as separate entities, evaluating different aspects of the sterile barrier package. This allows the tests to be carried out separately and not as a sequential series of tests on the same packages. This separation allows the evaluation of the effects of aging via whole package integrity and seal integrity testing at time intervals specified by accelerated and real time aging protocols. Test samples are pulled from the aging populations in order to evaluate

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DDL WHITE PAPER

For the entire document, including six more FAQs on ISO 11607, download the full white paper from DDL

CLICK HERE »



http://info.testedandproven.com/11_frequently_asked_questions_about_iso_11607_1-2-1-0-0


physical package integrity over time. An example of a whole package integrity test is ASTM F2096, “Standard test method for detecting gross leaks in porous medical packaging by internal pressurization (bubble test).” An example of a seal integrity test is ASTMF1929, “Standard test method for detecting seal leaks in porous medical packaging by dye penetration.” Seal strength can be characterized by executing a test such as ASTM F 88, “Standard Test Method for Seal Strength of Flexible Barrier Materials”. In addition, having some advance knowledge of the behavior and performance of the selected packaging materials through an accelerated aging protocol helps the packaging engineer anticipate potential negative effects of extended high temperature exposure on materials and seals. This separation also allows the interaction between the packaging system and the protected product(s) to be evaluated as they respond to the stresses imposed by the manufacturing processes, sterilization processes and the handling, storage and shipping environments. This interaction can be evaluated via packaging system performance testing such as ASTM D4169 followed by whole package and seal integrity testing on the same packages. The data obtained as a result of separating stability and performance testing provides the packaging engineer with valuable information on the packaging materials’ integrity performance over time and the packaging system’s integrity performance throughout the manufacturing process, sterilization process and the subsequent handling, storage and shipping environments.

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MORE INFORMATION

ASTM F 88: Find out more about the standardization leader ASTM and read about seal strength standards for flexible barrier materials

CLICK HERE »



http://www.astm.org/Standards/F88.htm


Creating a sequential aging and package performance protocol will create a very rigorous validation of the packaging process. However, choosing not to perform sequential testing and carry out stability and performance testing as separate entities still allows for compliance with the ISO 11607-1.

3. Is environmental extremes testing considered a requirement of ISO 11607-1? It is not accurate to say that environmental extremes testing is a requirement. However, the standard indicates in several sections (6.2.3 (h), 6.2.3. (j), 6.3.5 and 6.4.4 (NOTE)) that the package design shall consider the effects of distribution, storage and handling; this is where environmental extremes should be taken into account.

4. What is a reasonable rationale for sample size selection?

The selection of sample size is a difficult question, as it depends upon the level of risk severity and risk probability associated with the process. If the process

of making a package causes many defects in itself, and the process cannot be refined to reduce the defects, then the sample size may need to be higher. Likewise, if the result of a defect may cause significant harm to a patient, then more testing will be required to ensure that the defect is found before it can cause harm. For packaging, the process can usually be refined by compliance to standards like ISO 11607 to produce packages that have a high probability of withstanding hazards and reaching their intended destinations without failure. Also, a well-established quality control process ensures that the packaging process is in control within its specified limits of operation as defined in the process validation.

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5. Is it true that dye penetration is unreliable for packages using Tyvek? No, this is not true. However, it takes special care and training to identify the difference between a true channel versus a permeation of dye fluid through the Tyvek. If a channel leak is present, the dye will migrate through in a matter of seconds. If the dye is allowed to be in contact with an area of Tyvek for too much time, it will permeate through. The usual length of time to allow the dye to be in contact with a seal is about ten seconds. ✪

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Adapted from materials provided by Schreiner MediPharm

Among the many challenges the pharmaceutical industry is facing today, patient safety remains key. Packaging techniques are increasingly relying on advanced labeling materials, with unique capability to deliver important drug messages, to improve adherence and bolster safety. Within a complex regulatory landscape as well as diversified markets and medications, it is even more important to ensure safe drug administration for healthcare providers and consumers alike. Sophisticated label materials provide solutions that can play an important role in supporting product and patient safety.

Initially, the label serves to clearly and reliably mark the pharmaceutical product by providing information on the product, its administration, batch number, expiration date, etc. However, dosage forms and drug delivery methods can vary widely, so the label design has to be optimally tailored to meet the specific requirements of the medication. Ideally, the label provides additional functionalities that add value to the product by enhancing user friendliness and product safety.

Helping Avoid Medication Errors: Labels with Detachable PartsIn June 2010, the FDA held a public workshop to receive comments on the topic of medication error reduction. This resulted in a Draft Guidance “Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors,” published in April 2013.

Label material advancement, printing tech, improves safety safety






One of the recommendations included in the FDA’s draft guidance refers to “transferrable or peel-off labels for injectable medications,” emphasizing the fact that refilling injection solutions from, e.g., a vial or ampoule into an unlabeled disposable syringe harbors a particularly high risk of medication errors, since this might lead to administration of the wrong drug or wrong strength. By equipping the primary container with a label, including an integrated peel-off part, such instances could be avoided. The peel-off part is instantly available at the point of product preparation and can be easily and reliably attached to the unmarked syringe. Besides, it cannot be accidentally discarded as in the case of auxiliary labels provided with the carton.

A cost-effective, yet intelligent solution to meet the above recommendations could be a single layered peel-off label, which due to its special design, is particularly suited for labeling small containers for single-dose applications, such as ampoules and vials. The label can be easily wrapped around the container and provides sufficient space for all critical information, as well as for the inscription of variable data and printing of barcodes. The detachable part contains the product name, the barcode, an area for post-printing of variable data, as well as space for manual inscription of dose, date and administrator’s signature. Thus, it is ensured that all crucial information is directly available at the disposable syringe after reconstitution. The detachable part can be applied to the syringe like a flag without covering the graduation lines. The product information is easy to read and scanning of the code is simple. For greater ease of use when wearing gloves, the detachable part slightly lifts, so it can be easily peeled off when the label is opened.

continued

Label material advancement, printing tech, improves safety






More sophisticated solutions of peel-off labels feature multiple layers to accommodate several detachable parts and are mainly suited for multi-dose containers. They can be adapted to all kinds of primary containers and specific customer applications and demand extensive know-how in material and advanced printing technologies.

High-efficiency multi-functional labelsEfficient and safe drug administration plays an important role in daily healthcare practice. Intelligent, multi-functional label solutions can help optimize processes in healthcare environments and thus contribute to patient safety. Only to mention one example: A hanger label for infusion bottles, which provides extended space for text information and additional detachable parts.

Due to the multi-layered design, the label offers enough space for detailed product descriptions, while the integrated hanger allows the administering caregiver to quickly and easily hang the infusion bottle on a bedside rack. With the help of additionally integrated detachable label parts, the infusion can be documented in the patient’s medical records as well as the hospital files, thus ensuring reliable documentation and traceability of the medication. An alternative, even more sophisticated approach would be the addition of a paper booklet with many pages for texts in different languages.

Label-integrated needle protectionA growing number of injectables are administered in prefilled syringes, which are ready to use and easy to handle. However, needlestick injuries harbor a high risk for healthcare personnel to be infected by contaminated blood after the injection. Roughly 3.5 million work-related needlestick injuries occur globally every year. Regulatory requirements by the U.S. FDA and

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NIOSH demand that sharps instruments have to be equipped with safety devices. Also, in the European Union, member states had to implement directive 2010/32/EU on the prevention of sharps injuries into national legislation in May 2013.

By integrating the safety mechanism into the syringe label, regulatory demands can be met in a smart and user-friendly manner. The compact design of the needle trap label allows the blood-contaminated needle to be simply and safely secured after the injection, and can be easily operated by healthcare personnel in a controlled, single-handed fashion. After the needle is locked into the plastic trap, it is irreversibly protected.

Additional features to cover patient safety aspects may be integrated into the label, like peel-off parts for documentation of the administered injection, graduation lines for delivery of the right dose or anti-counterfeiting features for product security and brand protection.

Ensuring product integrityPackaging and labeling are critical to product authentication and should provide a reliable hurdle against counterfeiting and tampering. Due to international regulations, serialization and tracking of a product through the complete supply chain becomes a growing issue. Following the recently signed Drug Quality and Security Act (DQSA), FDA has started work on a US-wide track and trace system. Also, in Europe, directive 2011/62/EU will have an impact on packaging and labeling. The ultimate goal is to find solutions to clearly authenticate and secure drugs through the supply chain. Labels including, for instance, 2D matrix codes or alphanumeric codes for online authentication ensure traceability and authentication on the unit level.

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In general, integrated security concepts should ideally combine several security technologies in a multi-layered approach including overt and covert features. Thus, a customized solution could for instance include overt technologies like holograms, color-shifting inks, guilloche, micro-text printing or thermochromic inks. Covert technologies, like voiding effects, special pigments that can only be seen by a special reader, or luminescent digital watermarks, etc., would only be visible for informed experts. Ultimately, the objective should be to work closely with the pharmaceutical manufacturer in a consultative approach in order to find the ideal solution that suits his specific security requirements, while integrating easily into the usual brand appearance.

Reliable self-medication and user comfortUser safety and comfort is the primary concern in the development of pens and autoinjectors for self-injection. Multi-functional label solutions can be individually customized to further enhance reliability and ease of use of these injection devices. The range of functionalities that can be realized includes a temperature indicator producing a reversible color shift that shows when a defined room or cooling temperature has been reached. A special varnish coating improves grip and feel of the surface and helps patients to safely use the pen. In addition, integrated tactile elements make it easier to tell apart similar systems containing different active ingredients through touch.

If the pen has a transparent window to check the medication, the contents can be protected against UV rays by a double-layered label which can be easily opened and closed again. Alternatively, the transparent window included in the label can be equipped with UV protection.

continued







Integrated peel-off parts serve to remind the patient to regularly check the contents. First-opening indication as well as anti-counterfeiting features can be integrated as well.

Ensuring patient complianceSophisticated label solutions can also support patient safety by the integration of printed electronics as well as RFID and NFC technologies (radio-frequency identification, RFID, and near-field communications, NFC). Noncompliance to prescribed drugs can harbor severe risks for patients, particularly in case of chronic diseases. With the help of a label that features printed electronics and is attached to a tablet blister, it is possible to document patience compliance. When an individual cavity is opened to remove a pill, the printed conductor path is destroyed, which diverts the flow of current provided by the battery. This results in a higher resistance level that is read and electronically stored. Labels including RFID or NFC chips can also add interactive functionalities which benefit the end user, for instance authentication features, product information, medication warnings or general customer communication.

Addressing the healthcare environmentOften, the concern with high-performance labels is that they cost more, on a unit basis, than conventional labels. While this might be true in many instances, a true economic evaluation would include the value to healthcare providers in safer operations during drug administration, the enhanced supply-chain security, and, above all, the higher level of consumer satisfaction. A higher level of patient adherence to medication regimen can have clear economic value. In an era where patient outcomes are becoming a more direct measurement of both drug efficacy and healthcare operational performance—“value-based healthcare”—these issues will become only more important going forward.

continued







Sophisticated label solutions can offer much more than just product marking. They integrate multiple functions in the label that are optimally tailored to the specific product and its application. Thus, they help to optimize processes in healthcare practice, enhance user comfort and ensure patient safety as well as product security. Also the label should not only support brand appearance of the pharmaceutical product, but also add value to it by clearly differentiating it from the competition. Last but not least, it has to be easily and efficiently integrated into the production processes at the pharmaceutical manufacturer. ✪

continued


1 Aspden P, Wolcott JA, Bootman JL, Cronenwett LR, eds. Preventing Medication Errors. Institute of Medicine, The National Academies Press: Washington DC. 2006.






Eliminate glass delamination— pre-screen to keep vials lamellae-freeAdapted from "Evaluation of the inner surface durability of glass containers," by Desmond Hunt, USP

Glass, in the form of ampules, bottles, cartridges, vials, and prefillable syringes, is the container material of choice for parenteral products. This is especially true for the biopharmaceuticals that have increased the demand for small-volume glass cartridges, vials, and prefillable syringes.

Glass delamination, which ultimately results in the appearance of glass particles and lamellae, is a serious quality issue and can result in a product recall. Delamination is a lagging indicator of structural instability. Although lamellae is the most obvious visual indicator, it represents the final stage of a seriously weakened glass surface structure, and can be observed only at a point where prevention is no longer an option.

Exacerbating the problem, mechanical energy from shaking or vial-to-vial contact, which occurs in packaging and during transport, may dislodge the lamellae from the weakened internal surface.

Tests for delamination combine an examination of the vial inner surface and exposure to aggressive test solution to predict the likelihood of the vials’ delaminating. Indicators include the appearance of a pitted, fractured surface instead of a smooth surface, as well as a number of changes in the test solution, including increases in SiO2 concentration, the ratio of SiO2/B2O3 or Si/Al, the number of subvisible particulates in the solution, and a fall in pH.



DEFINITION

Glass delimitation: Glass delamination occurs when top layers of a glass surface separate and flake off, typically at a scale invisible to the naked eye.

Lamellae: A thin layer, membrane, scale, or platelike tissue or part - in this case, a tinny glass chip.

Subvisible: Too small to see without magnification.




Factors that influence inner surface durabilityFactors like glass composition, the conditions under which the containers were formed, subsequent handling and treatments, and the drug product in the container all have the potential to influence the durability of the inner surface of glass containers (Table 1).

Not all listed factors influence surface durability to the same degree, and their effects can be additive. Because of the range of variables, end users should examine all relevant variables for an individual drug product and assess the degree of risk for delamination and formation of subvisible and visible glass particles.

continued

Eliminate glass delamination— pre-screen to keep vials lamellae-free



ContainerContainer storage, handling, processing Drug Product

Glass composition

Molded or tubing container

Tubular Manufacturing process• Converting speed• Converting temperature

Post-formation treatments• Ammonium sulfate• Washing• Depyrogenation

Storage conditions• High humidity

Drug substance

Formulation• Acetate, citrate, phosphate buffers• Sodium salts of organic acids• High ionic strength, e.g. >0.1M • Complex agents, e.g. EDTA• High pH (>8)

Terminal sterilization

Labeled storage conditions (controlled room temp. or refrig)

Shelf life

Table 1: Factors that Influence the Inner Surface Durability of Glass

USP RESOURCES

Download full recommendations and best practices chapters on glass delamination from USP

CLICK HERE »



http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/c1660.pdf


Testing is a good first step, but can’t predict delaminationEach lot of Type I glass containers received by a pharmaceutical manufacturer must comply with the Surface Glass Test (designated in in chapter 660 - USP). This test provides an indication of surface durability, but does not appear to provide a clear, direct correlation with the propensity to form glass particles or to delaminate.

For instance, low surface alkalinity value can be obtained from containers treated with ammonium sulfate; but the treatment itself may reduce the inner surface durability, and the amount of alkalinity comes from the sum of all the internal surfaces.

Molded vs. tubing - Although the above example is representative for all internal surfaces of molded glass containers, tubing glass containers can have different degrees of surface durability, depending on inner surface location (e.g., just above the heel vs. the side wall).

Interaction with drug - The most important variable that affects the surface durability is the drug product itself, and because it uses water as the extracting medium, the Surface Glass Test does not take this into consideration.

Therefore, the Surface Glass Test represents only a first step in quality control of surface durability, and additional screening methods should be used to demonstrate the suitability of vials for a formulation from a particular source before formal stability studies begin.

continued






https://mc.usp.org/sites/default/files/documents/GeneralChapterPDFs/660ContainersGlass.pdf


Screening methods to evaluate inner surface durabilityI. Predictive screening methods Screening methods help evaluate glass containers from different vendors (molded or tubular), glass formulations (COE 33 or 51), and post-formation treatments. Screening also establishes lot-to-lot variation from individual vendors during the drug development process, as well as lot-to-lot variations for products that have been shown to have a particular propensity to

form glass particles or to delaminate.

Screening methods can use a number of different technologies to examine three key parameters: 1. Visual examination and chemical profile of the

inner surface layer.2. The amount and identity of extracted elements in solution.3. The number of subvisible and visible particles in solution

Taken together, these elements are assessed by predictive tests for formation of glass particles and delamination, which in turn reflect reduced durability.

Predictive tests should look for precursors that lead to delamination rather than flakes themselves, and should be able to quickly provide predictive indication of surface durability. This makes the tests useful not just for vendor selection, but also for evaluation of individual lots if necessary. Some commonly used analytical methods for evaluating the three key parameters are shown in Table 2.

continued


GLASS CONTAINER TYPES* & PHARMA USEFULNESS

Type I – Borosiicate glassThese glass containers are suitable for most products for parenteral and nonparenteral use.

Type II – Treated soda-lime-silica glassThese glass containers are suitable for most acidic and neutral aqueous products for parenteral and nonparenteral uses, and can be used for alkaline parenteral products when stability data demonstrate their suitability.

Type III - Treated soda-lime-silica glass on the basis of the hydrolytic resistance of the glassThese glass containers usually are not used for parenteral products or for powders for parenteral use, except when suitable stability test data indicate that Type III glass is satisfactory.

* This feature focuses primarily on Type I glass, because it is the most widely used in the biopharmaceutical industry

KEY

CONCEPT






II. Aggressive screening conditions In selecting an appropriate primary glass container for pharmaceutical liquids, analysts should consider two approaches:

1. Accelerated temperature exposures - The first approach is a series of accelerated temperature exposures using aggressive conditions that establish, in rank order, the chemical durability of the container without any specific reference to a given compound.

continued


Parameter Test Parameter Instrumentation

Glass inner surface • Degree of surface pitting• Chemical composition as a

function of depth

• DIC Microscopya or EMb • SIMSc• Conductivity/pH meter• IC–MSd or ICP–OESe

Extracted elements in solution

• Conductivity/pH• SiO2 concentration• Presence of lamellae and

visible particles• Lamellae or particle number and size• Lamellae or particle morphology

and composition

• Visual inspection• Particle size analyzer• SEM–EDXf

Lamellae and visible and subvisible glass particles

a. Differential interference contrast microscopy.b. Electron microscopy.c. Secondary ion mass spectrometry.d. Inductively coupled plasma–mass spectrometry.e. Inductively coupled plasma–optical emission spectrometry.f. Scanning electron microscopy–energy-dispersive X-ray spectroscopy

Table 2: Analytical Techniques for Screening Studies






Such testing can be helpful when selecting a packaging kit for which the most chemically durable glass is desired. This testing also can be helpful in determining if changes in glass quality have occurred or in assessing processing changes that have been made by the primary container manufacturer. Table 3 provides some model systems that could be used for this assessment.

continued


Formulation 0.9% KCl pH 8.0

3% Citric Acid pH 8.0

20 mM Glycine pH 10.0

Conditions 1 h at 121° 1 or 2 cycles

24 h at 80° 24 h at 50°

Table 3. Formulations and conditions used to accelerate delamination

2. Link accelerated conditions to conditions for given product–If the purpose of the glass screening is to determine the suitability of a given glass container for a specific product, the testing proposed in Table 3 is insufficient. The exposure conditions are too harsh and do not provide a direct link to the product itself. In these instances, accelerated conditions are still relevant, but they must link to the relevant conditions for the given product.

For example, if a product will be stored at 5° and accelerated conditions are 30°, then testing should occur at 30°. Many products or formulations cannot withstand the elevated temperatures shown in Table 3. In addition, false positive testing results could be obtained because the unusually high temperatures shown in Table 3 could cause signs of delamination, but moderate exposure at 30° would produce no evidence of glass incompatibility.






Because lower temperatures are required for actual product testing, the duration of testing must be longer, ranging from weeks to months. A larger number of vials also is appropriate for this scenario because the goal of the testing is to ensure the results are representative of the quality of the glass that will be used for the drug product.

Table 4 shows some of the conditions that could be used for testing with a specific product.

SummaryEvaluation of the inner surface of glass containers begins with the Surface Glass Test, which uses water as the extracting medium. A low value is not always an indicator of a durable inner surface because the glass could have had a surface treatments (e.g., ammonium sulfate). Such treatments can lead to a silica-rich surface layer that represents a weakened glass structure, and risk of delamination increases when the vial is filled with formulations that contain aggressive agents such as organic acids, EDTA, or solutions that have high ionic strength or

continued


Stress Test Water Control Drug Product Control

• Vials: washed, depyrogenated• Filled with Stress Test solution• Accelerated time and temperature

treatment conditions

• Vials: washed, depyrogenated• Filled with Water for Injection• Autoclave if applicable to

Drug Product• Accelerated Drug Product stability

storage conditions

• Vials: washed, depyrogenated• Filled with Drug Product• Autoclave if applicable• Accelerated Drug Product stability

storage conditions

Table 4: Screening Strategy for Glass Vials



DEFINITION

Depyrogenation: Depyrogenation is the act of removing fever-causing substances (pyrogens) from solution, most commonly from injectable pharmaceuticals.




pH. The screening methods and strategies described here can assist in the evaluation of glass containers from different suppliers, and can provide an indication of the propensity of the selected formulation to cause delamination over time. Selection of glass vials intended to contain a drug product with one or more of the formulation risk factors identified in Table 1 should undergo particular scrutiny. ✪

continued


GLASS SUPPLY CHAIN BEST PRACTICES–A CHECKLIST

Before considering treatment of glass containers, manufacturers must consider the upstream origins of the containers they purchase. To maintain and improve container quality over time, manufacturers should take the following steps in selecting a glass container vendor:

CHECKLIST

✓ Audit supplier (glass manufacturer or converter)

✓ Obtain glass formulation from the supplier

✓ Designate 33 or 51 COE for Type I glass

✓ Determine tubing glass source(s) for converters

✓ Determine production site(s)

✓ Determine if the tubing converting equipment varies in age, design, and manufacturer from site to site

✓ Evaluate in-line electronic inspection systems for quality control of glass tubing and for glass containers

✓ Determine whether the containers have been treated with ammonium sulfate

✓ Establish acceptable quality levels for incoming lots with the vendor

✓ Monitor and trend the quality of incoming batches by monitoring the values obtained by the Surface Glass Test [in USP 660]





https://mc.usp.org/sites/default/files/documents/GeneralChapterPDFs/660ContainersGlass.pdf


Packaging labels take a bite out of needlestick, sharps injuriesAdapted from materials provided by Schreiner MediPharm

Every year, more than two million needlestick injuries occur in hospitals and the health care sector, due to faults in needle packaging, ultimately exposing healthcare workers to blood borne pathogens. However, a new packaging label for syringes may hold a solution.

Global regulationsTo improve the protection of employees in hospitals and the healthcare sector, intergovernmental organizations such as the Food and Drug Administration, World Health Organization and the National Institute for Occupational Safety and Health have proposed guidelines outlining proper processes and procedures for dealing with sharps injuries.

Most recently, The Council of the European Union published the Directive 2010/32/EU in 2010, which sets specified rules and minimum requirements to increase the prevention against sharps injuries for their employees.






Active and passive safety systemsThe results of current research demonstrate that approximately 85% of all needlestick injuries may be avoided by using modern safety products. Safety systems are generally divided into active and passive systems.

As the EU Directive only addresses employers in the healthcare sector, pharmaceutical manufacturers are principally not obligated to reduce the risk of needlestick injuries when designing their products. However, the pharmaceutical industry has already launched several products with passive or active safety systems.

A packaging solution A needle trap protection system consists of a needle trap that is integrated into the syringe label, securing the blood-contaminated needle after injection. The system is activated in a controlled

continued

Packaging labels take a bite out of needlestick, sharps injuries

HOW TO PREVENT SHARPS INJURIES

To prevent sharps injuries, the Directive 2010/32/EU lists the following actions in descending order regarding their effectiveness:

• Avoidance of any unnecessary use of sharp instruments, e.g. elimination of unnecessary injections

• Definition and implementation of safe procedures for handling sharp instruments and contaminated waste as well as their disposal, e.g. through provision of medical devices with integrated safety mechanisms

• Definition of regulations and provision of training programs

• Observance of standard precautions, e.g. no recapping of used syringes

• Use of personal protective equipment such as gloves

EFFE

CTI

VEN

ESS

MORE

LESS






single-handed method. When the needle locks in the trap. The needle protection system can be adapted to all conventionally used syringe dimensions, utilizing existing secondary packaging. Due to the simple design, the needle trap, like conventional labels, can be easily processed on commonly used labeling equipment with a few, minor modifications.

ProcessPrepare: The trap is bent toward the side by approximately 90 degrees.

Remove: The cap is removed.

Inject: Healthcare staff performs the injection as usual.

Secure: The needle is secured by placing the trap against a hard, stable surface and then pressing it down. This activation can easily be performed using one hand.

Snap: The user bends the trap by approximately 90 degrees until the needle audibly clicks into the plastic part.

continued

Packaging labels take a bite out of needlestick, sharps injuries SAFETY SYSTEMS

The result of current research confirms that approximately 85% of all needlestick injuries

can be prevented through the use of modern safety systems. Safety engineers recommend that safety systems have the following properties:

• The safety mechanism is a component of the system and compatible with other accessories.

• Its activation must be possible by using one hand.

• Its activation must be possible immediately after use.

• The safety product must not jeopardize the safety of the patient.

• The safety mechanism excludes its reusability.• The safety product requires no change in the

application technique.• The safety mechanism must be marked by a

clear, tactile or audible signal.






Dispose: The syringe with the secured needle can be disposed in the nearest sharps container.

The injection is administered without any risk of injury to the patient, contrary to automatic (passive) activation systems. The activation process to secure the needle can be controlled 100%. Furthermore, the needle-trap may be activated at any time after administration, even when the syringe is only partially emptied.

Additional functions such as graduations or anti-counterfeiting features may be integrated into the label. Needle-trap also allows reliable documentation of injections that have been administered. For this purpose, the label is equipped with peel-offs to facilitate documentation in the patient’s medical file or vaccination card.

IntegrationThe number of stock keeping units does not increase due to this device’s two-in-one combination of a label and needle trap and can be adapted to all standard syringe dimensions. Due to the simple design, this needle protection system, may be easily processed on all commonly used labeling equipment at the same speeds. Minor modifications to

continued


SAFETY SYSTEMS

Other aspects play a role in the selection of suitable safety systems as well:

• Acceptance by employees: The less the application of the system differs from the handling to which the employee is accustomed, the higher the acceptance will be. Furthermore, it is important that the system does not impair the view of the injection area.

• Acceptance by patients: The system must not pose any health risks to the patient or cause anxiety.

• Acceptance by administration: Cost aspects are to be considered as well. Besides the purchasing price, they include costs for storage, particularly in the case of refrigerated products, and disposal.






continued


RISK by amount of blood exposure to

deviceFREQUENCY of needlestick injuries in healthcare ector

Riske.g. central

venous cathetere.g. peripheral vein catheters

e.g. blood drawing needle

e.g. butterfly for blood drawing

Serious e.g. intramuscular injection

e.g. porth catheter e.g. scalpel blade

MediumTransdermal

Ointments and Patches

Ophthalmic Solutions and

Supensions; Nasal Aerosols and

Sprays

e.g. subcutaneous

injection

e.g. lancet, heparin injection

Low e.g. accupuncture e.g. insulin injection

Rarely Occasionally Frequently Very frequently

Safety Thresholds Examples of Packaging Concerns for Common Classes of Drug Products

LEGEND

Source: Wittmann Andreas, Risk Assessment Matrix, University of Heidelberg, 2011

Risk is not acceptable. Action to address the risk is very urgently required.

Risk is not acceptable. Action to address the risk is required.

Risk is acceptable. Standard precautions are appropriate.






continued


existing labeling equipment and processes are required. Qualification or re-qualification of the slightly modified manufacturing process provides needlestick safety with minimal capital investment. Due to the flexibility of the device label’s materials, there is no risk of the syringes breaking during the application process. The syringe label meets the requirements of the monitoring authorities for safety and quality and has been awarded 510(k) clearance

by the Food and Drug Administration (FDA) for marketing in the United States. The prefilled syringe equipped with a needle trap maintains the familiarity of the instrument (the prefilled syringe) in its original form, thereby ensuring continuity of the brand design and a high user-acceptance. ✪

Prepare.

The trap is bent toward the side by approximately 90 degrees.

Remove.

The cap is removed.

Inject.

Healthcare staff performs the injection as usual.

Secure.

The needle is secured by placing the trap against a hard, stable surface and then pressing it down. This activation can easily be performed using one hand.

Snap.

The user bends the trap by approximately 90 degrees until the needle audibly clicks into the plastic part.

Dispose.

The syringe with the secured needle can be disposed in the nearest Sharps Container.






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