Blister packaging is not rocket science – or is it? Good blisters are the result of an optimized interaction between materials, equipment/tooling, and processing conditions. Neglecting just one is inviting trouble. Paying attention to all three cornerstones of this magic triangle will keep your line operators, purchasing personnel and customers happy.
Cornerstone #1: Materials
Forming Webs – Poly-Vinyl-Chloride (PVC) films have been the primary blister packaging material for over 40 years. Forgiving, easy to thermoform and low-cost, PVC is a good choice for any pharmaceutical packaging application that does not require any barrier.
If any of the active pharmaceutical ingredients (APIs) or excipients are sensitive to moisture, light, oxygen or other gases, barrier materials come into play. All have their pros and cons; ultimately, the drug and its desired shelf life dictate the type and level of barrier. One choice for low- to mid-barrier needs is PVdC coated films, available in several MVTR (Moisture Vapor Transmission Rate) options. In the mid- to high-barrier market, laminates of PVC/PCTFE (Aclar® and VapoShield™) or PVC/PE/PCTFE are widely used. Pharmaceutical packagers can choose from a range of films offering various degrees of protection from moisture ingress or egress. Oxygen barrier also can be incorporated.
The various MVTR rates of common barrier blister materials.
For ultra-high barrier requirements, thick-gauge PCTFE or Cold-Form Foil (CFF) structures are used. The foil layer in CFF provides ultimate protection, but requires special tooling, usually runs at slower line speeds, and typically results in larger package formats than thermoformed blisters. In order to avoid costly over-packaging, CFF should only be chosen if the highest achievable amount of oxygen, moisture and light barrier is required. Thermoformable barrier materials allow for more flexibility and easier down-gauging in the post-launch phase, once long-term stability data are available – an option that often comes with considerable cost savings over the lifetime of the drug.
Bridging the gap between PCTFE laminates and Cold-Form-Foil are ALU-LOOK™ thermoformable films that mimic the metallic looks of CFF. Available in multiple barrier options, they offer all the benefits of thermoformable materials plus the high-quality image of foil packages.
Going Green – The environmental discussion continues over the benefits and challenges of PVC; the quest for PVC-free materials by large retailers such as Wal-Mart and repeated efforts in California to ban PVC in packaging have expedited the development of PVC-free forming materials.
While Polypropylene (PP) has been used as a blister material for over two decades, it has mostly remained a niche application. Cyclic Olefin Copolymer (COC) films are gaining traction, offering moisture barrier, clarity, and excellent performance in challenging deep-draw applications. Most recent developments have focused on polyester-based films that can either be used as a replacement for mono PVC (non-barrier), or in PCTFE laminations for barrier packaging. In addition to being PVC-free, these films potentially offer immediate energy savings on blister lines due to lower onset forming temperatures.
Lidding Foils – Any forming web needs to be matched with lidding that seals to the product contact side of the formed blister. As long as the product contact side is PVC (e.g. mono PVC, PVdC coated films, PCTFE laminates, CFF), the choices are plentiful. Foils come with permanent or peelable heatseal coatings, depending on the opening mechanism of the package (e.g. push-through, peelable, child-resistant peel-push).
Sealing to materials other than PVC is getting easier, too. Lidstock sealing to PP has become standard, and most foils designed to seal to PVC also bond to PET-based forming webs. Materials with “universal” heat-seal layers offer increased flexibility in the regulatory setting and for any type of change, including post-approval changes.
Any heat-seal coating should be glossy, clear, and resistant to abrasion. It should not block in the roll, and be uniformly applied. The right amount is key: too little heatseal coating might compromise seal integrity, but overly thick coatings should be avoided, too. Especially when packaging moisture-sensitive products, thick layers of heat-seal can allow additional moisture to diffuse into the package through the cross-section.
Some sealing layers are prone to mature, especially over the first few days after processing. A peelable seal might become harder to peel or even permanent; conversely, a seal found satisfactory during in-process control can become loose. While in-process quality assurance (QA) is critical, so is long-term control.
When using unsupported aluminum lidstock, the temper of the metal foil (soft vs. hard) can play a crucial role in the package’s performance. Depending on package and tooling design, soft-temper foil can considerably reduce blister curl, especially when working with multilayer barrier webs.
The caveat with soft-temper foil is not to compromise the functionality of the typical push-through blister pack. Soft foil will usually work well as long as the contents are solid and sturdy (e.g., coated tablets, hard lozenges, chewing gum). Soft gel capsules, effervescent, or fragile tablets may not be suitable for soft foil packaging; due to its higher elongation at break, damage can occur to the tablet or the soft shell of the capsule before the foil ruptures.
Cornerstone #2: Equipment and Tooling
Design is Key – Good design principles for forming and sealing tools are not only in line with U.S. Food and Drug Administration’s move toward Quality by Design (QbD), but also make plain sense for getting the process right. Investing in good tooling right from the start, including stability tooling, pays off over the drug’s lifetime.
Forming tools should start with dedicated, matched tooling for top-to-bottom mold, and have the necessary coatings or treatment to allow easy release of the formed web from the female tool. Good blister geometry has rounded radii instead of chamfers and, depending on the draw ratio, typically has drawing angles of at least 3 degrees for non-barrier and 8-10 degrees for barrier webs. Proper placement of evacuation holes also allows the web to fully form into cavities with optimal material distribution.
Good blister design for solid oral dose drugs, especially moisture-sensitive products, keeps a minimum 3mm of area between the product-containing cavities; likewise to the outer edge of the blister, date stamps, or perforations. This minimizes moisture ingress through the side (cross-section) of the package, and limits the effect of micro-channeling.
Good knurl pattern – Sealing tools have considerable impact on lidding foil. An overly aggressive sealing die combined with high pressure and high line speed can lead to stress cracking of the lidding foil and compromise seal integrity. Even worse, this may become apparent only in the long-term. Even though the in-process testing for seal integrity (in pharma, usually a methylene blue bath) may find the seal acceptable, microscopic fractures in the foil can compromise the shelf life of the product over time.
Key characteristics of a platen sealing tool should be good flatness and the appropriate knurl. Use pressure-sensitive tape to assure planarity of the tool. For best results, vary the type of knurl depending on the type of lidding and web width. Smaller knurls work well on a narrow web, since air can escape more easily. On a wider web, use a slightly larger knurl to allow space for entrapped air to go.
Finally, be sure to inspect and clean sealing die surfaces regularly. Dirt or residues from over-lacquers, inks, and paper particles can build up, absorb heat, distort the knurl pattern, and lead to an uneven seal.
Platen vs. Rotary sealing – Both types of sealing tools have their place. Platen sealing works especially well on wide web widths where sealing temperatures can be lower and dwell times are usually higher. It offers uniform seal pressure – especially important for paper-backed structures. However, platen sealing machines often mean massive mechanical systems which, in turn, can mechanically challenge foil.
Conversely, blister machines with rotary sealing systems are frequently high-speed equipment that operates with narrow webs. The nature of sealing by means of a rotating drum inherently means short dwell time; the sealing area is a thin line rather than a flat area. Since the heat-seal coating needs a certain temperature to bond, it may take more pressure, higher temperature, and possibly even a foil preheating station to get a satisfactory seal, especially for multilayer structures such as CR lidding. Novel foil structures that combine paper and PET into a white PET layer help to reduce this effect.
Cornerstone #3: Processing
Forming – Preheating the forming film to the appropriate temperature will ensure even and complete cavity forming. Understand the material characteristics, start at the lower temperature end, and adjust the temperatures accordingly. Use an even multiple (usually, 2 or 3 times the length of the forming mold) as the length of the web preheating section.
Avoid stress forming. All polymers, including PVC, have a “memory” - they tend to relieve any stress introduced in the forming station (e.g. from too much or too little heat, or by using universal top molds) when reheated during the sealing process. This might cause movement of material, excessive curling, and micro-channels that can form weeks or even months later and may result in leakages and compromised shelf life for the drug product.
A simple way to visually check “stress” in sealed blisters is with polarized PET. Held over the formed blister at a 45-degree angle, a distinct coloration of the formed web will indicate stressed areas.
Sealing – Different lidding structures require different machine settings (seal temperature, dwell time, and pressure), even if the heat-seal layer is identical. Unsupported aluminum foil usually seals faster than paper-backed or child-resistant (CR) structures where the heat must travel through the paper, possibly the PET film, and the aluminum foil before reaching the heat seal coating.
Materials with a wide sealing window are a plus, allowing for more flexibility in the production process and change between equipment, set-ups, etc.
Whenever possible, seal at lower temperatures and use shorter dwell times. Not only does this promote higher line speeds, but also avoids unnecessary exposure of the drug product to heat –, especially important when packaging drugs containing large-molecule APIs (such as proteins), heat-sensitive excipients, or novel drug delivery systems. Applying less heat to paper-backed structures also avoids “scorching” of the paper.
Finally, lower sealing temperatures mean less energy consumption – one more step toward a more environmentally sustainable packaging process.
Cooling systems – During a typical production day, cooling systems are subject to varying temperatures. To minimize variation in the processing parameters and maximize control, provide separate cooling areas for forming and sealing stations.
About the Author
Angela Roggenhofer is Sales & Marketing Manager for the pharmaceutical packaging business unit of Tekni-Plex, a global manufacturer of a diverse range of technically-sophisticated and value-added packaging products primarily serving the healthcare, food and consumer industries.
Tekni-Plex is headquartered in King of Prussia, PA and operates more than 20 sites strategically located around the world. For more information, visit www.tekni-plex.com or call (484) 690-1520.
Aclar® is a registered trademark of Honeywell International.
VapoShield™ and ALU-LOOK™ are trademarks of Tekni-Plex, Inc.