Pharmaceutical packaging requires high attention to detail due to the critical nature of the materials required to protect the active product throughout its shelf life. Types of packaging material and design can also be influenced by the respective markets and heavily regulated by the authorities.
The pharmaceutical pack must protect the product against light, humidity and oxygen, as well as mechanical, climatic, microbiological and human hazards. It may need to be child and/or pilfer-resistant and it must also be compatible with the product and its contents.
These factors - coupled with the need to reduce costs for emerging markets, supply products for compassionate use, and compete with other competitors products on the market, only serve to complicate the development process. Further challenges facing pharmaceutical companies include making their products more patient-compliant, features to prevent counterfeiting, barcoding and verification systems to ensure product authentication, and integrating systems to allow for track and trace through the supply chain. This is also complicated by international and local market regulations.
Legislation governing child-resistant packaging
Pharmaceutical packaging may need to be child-resistant. This depends on the nature and toxicity of the active product and its ability to meet market and legislative requirements.
A European standard for non-reclosable packaging (EN 14375) has been drafted, and the current guidelines indicate that all products containing paracetamol, aspirin and iron will be affected.
The European standard mirrors very closely the old British Standards Institute (BSI) legislation, whereby an entry criterion of eight blister pockets accessed from ten constitutes a failure during child panel testing. However, the consumer lobby within the European Union (EU) opposes the eight-unit entry criterion of the draft CEN standard, and instead seeks to introduce an entry limit based on the toxicity of the individual product or compound.
A World Health Organisation (WHO) report assessing the predicted toxic dose of various products and compounds in relation to children supports this proposal. If toxicity is brought into the equation then this may impact the vast majority of products within the pharmaceutical industry.
Due to the uncertainty surrounding what will become legislation, some companies have now adopted their own standards, in that all new products must be packed into child-resistant packaging, regardless of the harmful nature and toxicity of the drug product. Again, this has a massive impact on their resources and financial commitment in implementing such a strategy.
At one time, packaging development was considered a separate topic tagged on to the end of the development programme, almost as an afterthought, but now the development approach is totally integrated. This situation has changed in recent years, with research and development (R&D) expenditure increasing rapidly.
However, the number of innovative new drugs in the pharmaceutical sector that have been approved by the Food & Drug Administration (FDA) each year has not shown a comparative upturn.
At the same time, other factors have conspired to complicate the registration situation, increasing the amount of data that has to be supplied, which, again, slows down the development process. The manufacturer could reclaim this additional development cost by increasing the cost of the product, but given the current economic climate, this is not possible, and many pharmaceutical companies are finding that their prices are being reduced rather than increased. In light of this, manufacturers can:
- reduce the testing carried out - however, the requirements to develop and introduce a new pack are forever increasing.
- speed up development through better planning and by optimising the development approach; the pressure is therefore on to make the development process more effective and this means integrating all aspects overlapping the development wherever possible.
Glass, being particularly inert, does not present a very interesting problem to the packaging technologist. However, once plastics are involved the situation changes, and regulatory authorities are much more interested in the composition and performance of the package.
New chemical entities (NCEs) are so few and far between these days that companies regularly look at their aging products with a view to revamping them. One way to do this is to repackage the product in a more sophisticated way.
Occasionally, the pack and product administration system cannot be separated; an example is a pump container for aerosols or a powder dispenser such as the spin-haler. Thus, one cannot separate the pack and the product (just as one cannot physically separate the product and the pack) and, therefore, they cannot be separated in regulatory terms. A drug is affected by the packaging, both in practice and in the eyes of the regulatory authority.
In the US a parental drug produced in a plastic container, even an old drug such as sodium chloride (saline) does not fall within the category of generally recognised as safe (GRAS), but is regarded as a new drug according to the Federal Food and Drug Cosmetic Act S201(P). If you cannot separate the product and the pack while the products are becoming more sophisticated, it is not surprising there is increased regulatory attention focused on the pack.
In packaging development the aim must be to try and develop a pack for worldwide use. At the same time, pharmaceutical development departments will be busy trying to develop one product worldwide. This trend, however, is being countered by marketing departments, which are trying to obtain precisely the right product for each market.
Just as market needs differ, local regulatory agencies may also have different requirements. Marketing departments are reducing the number of variants required and standardising the packaging components to reduce the number of presentations in the marketplace.
Advances in technology and pharmaceutical packaging
There have been many new developments in recent years, such as covert and overt anti-counterfeiting features, more child-resistant materials, and advanced forming technology designed to reduce the amount of material used and achieve more complex pocket designs. There have also been developments in blister sealing tool designs to achieve a tighter, stronger blister pack. Research is also ongoing into pure aluminium-only base laminates to reduce cost, and cyclo olefin co-polymers (COC) and PVC/PCTFE films that offer improved moisture barriers. There have also been developments in desiccated base films, by introducing a desiccant scavenger as a coated film under the product contact layer (heat seal lacquer) within the base laminate.
These new advances in technology have led to more complex designs and a need for tighter control over specifications and test requirements. Any failure of the packaging system may result in the ultimate failure of the active product to administer its required dose. For these reasons, careful consideration of materials, equipment and design is essential. One of the most significant advances in pharmaceutical packaging is the unit-dose blister pack.
Given the accelerated pace of globalisation, pharmaceutical companies are faced with notable increases in the complexity of their organisations and processes. Therefore, the need to create packaging strategies, and implement them swiftly and efficiently has become ever-more demanding. Coupled with the increasing regulatory, technical and marketing challenges, packaging innovation has become a critical factor in the future growth and success of the pharmaceutical industry.
The basic requirement of maintaining product integrity and patient safety still remains the top priority within the industry. However, this is becoming increasingly difficult given the worldwide distribution of pharmaceutical products in extreme climatic and environmental conditions, and pressure to reduce the cost of goods. Furthermore, balanced against increasing costs in the fight against counterfeiters, as well as enhancing patient compliance, child-resistant packaging, tamper evidence and the need for higher barrier films, the old blister packs, bottles and cartons may no longer be suitable for the new market requirements.
Protection and use
In order to obtain a full pharmaceutical pack evaluation it is necessary to consider a number of requirements. For instance, a pack may have to provide protection against:
- ingress from the atmosphere which may result in product deterioration, such as oxygen, moisture, carbon dioxide and micro-biological hazards
- migration of product ingredients from within the product to the outside atmosphere
- migration from the pack into the product, such as discoloration and softening of the heat seal lacquer
- mechanical damage to the pack or the product.
The pack must also provide a convenient means for removing the product without exposing other units to the atmosphere or problems to the user. Furthermore, the pack must retain the product in good condition throughout its shelf life.
Hermetically sealed packs
Another challenge is the requirement for a totally sealed pack: airtight, with virtually no exchange between the product and the external atmosphere. In reality, few pharmaceutical packs actually meet this latter definition.
The aforementioned points need to be established by performing formal stability testing over a range of temperatures and humidity. As with all pack selections, detailed knowledge of the product, the packaging materials and the process to be employed are essential requirements.
An ever-increasing demand for protective functions, mainly with regard to moisture and UV light, is being made in the field of pharmaceutical packaging. This is caused by:
- a high sensitivity of the product to light, moisture and oxygen
- the demand for a barrier against the diffusion of components and active product
- substances such as essential oils and alcohol
- the use of various products in tropical regions
- the need for the products to have an extended shelf life.
The challenge of non-compliance
Pharmaceutical non-compliance or adherence is a worldwide problem. In the US alone, the annual cost of patients not taking their medications approaches $300 billion. It is also estimated that 20-50% of patients worldwide are not adhering to their medication regimens.
The many reasons for non-compliance range from forgetfulness to off-putting side effects, a complex dosing regimen when taking other types of medication, social and personal reasons, and the frequency of administration (for instance, more than once a day). Whatever the reason, an alarming number of patients are suffering and not getting the benefits out of their medication, an increased number of patients are being admitted to hospital for emergency treatments, a tremendous amount of good medication is being wasted and countless working days are lost. Medication providers and healthcare professionals must collaborate to educate patients about how better to take their medication, while packaging technologists must conduct research into new designs and processes in order to help this process along.
More efficient packaging will help; unit dose packaging in particular can be designed in formats that remind people when to take their medications. Birth control pills, certain antibiotics, hormone-replacement therapies and steroids are already being dispensed in unit dose packaging, which has proven highly effective in helping people to manage their pharmaceutical regimens. The pharma industry strongly believes that if more products were packaged in a unit dose format, the non-compliance problem would be greatly reduced.
Furthermore, innovative packaging has been shown to improve patient compliance and is fast becoming an integral part of product and marketing strategy. Compliance packaging helps a patient adhere to a medication plan; it can also enhance the patient's knowledge of the product and give them increased confidence in its benefits, as the package is in constant use.
Generally, a compliance package is a pre-packaged, ready-to-use dispensing system that contains unit doses for one treatment cycle, along with compliance aids, and information to educate, motivate and remind the patient to take the medication correctly. An effective compliance package should be designed with the patient's needs, abilities and requirements in mind, resulting in a final product that is aesthetically pleasing, safety conscious and user-friendly, one that incorporates a process that gives valuable feedback to the healthcare provider; basically, a package that is advantageous to all parties.
How smart packaging can help
Technologies are now available that provide both a compliance pack and adherence monitoring, giving pharmacy services valuable information about the patient and their dosage regimen.
One such solution is the smart pack, a blister pack that contains a microchip in the form of printed circuitry. This device can be used to capture information and incorporates an audio alarm that reminds the patient at predetermined times to take their medication. The technology can also communicate warnings, expiration dates and product authentication. Smart packs can also be tailored to local market requirements, the type of illness and the age of the patient. This information can then be sent via a mobile phone to the health provider using short messaging system (SMS) technology, and data can be generated over time to track the patient's response to the treatment.
This type of technology has also been used in blister wallet packs - such as the Aardex MEMS cap - bottle packs with the circuitry incorporated into the cap. However, this has limitations in that it only detects when the cap has been opened and not when the patient has removed a tablet.
No one style of compliance packaging works for all medications. Packages must be developed on a case-by-case basis, and some of the more complex treatment regimens being developed by pharmaceutical manufacturers today require more innovative packages and design expertise. All of them, however, must make it easier for the patient to remember to take the proper dosage at the prescribed time, and should take advantage of pack space to communicate the brand message clearly and build brand equity.
Track and trace the pharma value chain
Further complications within the design process include the need to track and trace a product throughout the supply chain. Experts estimate that 5% of all drugs sold worldwide are counterfeits; in some countries this figure is an unprecedented 50%. Counterfeit drugs and product diversion risk lives, undermine revenues and threaten company reputations. The pharmaceutical industry needs to ensure supply-chain security and gain the ability to authenticate the ePedigree, or lifecycle analysis (LCA) of a product.
Track and trace solutions are an essential part of this strategy, identifying the origins of a pharmaceutical industry product and verifying its authenticity. Track and trace solutions also help to combat product diversion, whereby legitimate products are diverted from one market to another, which has implications for licensing obligations and distribution agreements, as well as for revenues.
There are many solutions in the market for this purpose, some of which include the ability for reimbursement. So it makes sense where possible to combine technologies for counterfeit, traceability and reimbursement purposes.
In summary, then, designing pharmaceutical packaging is more complex and challenging than ever before. Companies are under pressure to simplify the supply chain, use more environmentally friendly materials and invest in a sustainable business, while at the same time developing low-cost products for third-world and emerging markets, as well as designing superior barrier packs for tropical regions, and moisture and oxygen-sensitive products.
More recently, there has been local and international market demand for the following:
- more child-resistant and senior-friendly packaging
- incorporating compliance solutions into primary and secondary packs
- an increase in tamper-evident and pilfer-proof features
- applying track and trace technologies to the finished pack to simplify the supply chain
- including a number of overt and covert anti-counterfeit features within the pack design.
Smart technology: the latest pharmaceutical packaging innovations
- Dosepak - a proven commercial success, this features an outer carton, a fold-over inner blister card, an attached insert for patient education and printed directions, and unit dose packaging for improved patient compliance. It is proven to be effective in titration and combination therapy, and can include a micro CD containing patient education materials or for information in a sample or trade package. Dosepak is senior friendly and carries the highest possible child-resistance rating (F=1).
- The Proteus Biomedical: the Raisin System - the patient swallows a digestible sensor adhered to a tablet and an electronic patch senses that the tablet has passed into the stomach. Data is stored on the patch, and then transmitted to a physician, pharmacist or clinical study coordinator via mobile phone using bluetooth technology.
- Medication reminder wristwatch/pager - the features include up to 12 daily alarms and an alpha reminder message. The system also includes a medical 'snooze' facility (every three minutes until the medication is taken) and alert buttons. It also carries medical information to be used in a databank. The system has so far been used in clinical trials, which have shown to improve patient compliance and medication adherence.
- Dose recognition system - the patient uses a mobile phone as a camera to take an image of their blister pack when a tablet has been dispensed and sends the image to a health provider.
- Vitality GlowCap - a tiny battery-powered wireless computer is fitted to the top of a pill bottle, which reminds the patient to take their medicine. The GlowCap is set (via telephone conversation) to take one or more pills at different times of the day. The patient can then return the call to their health provider when their medication is taken.
- Remind cap - when the closure is removed from the bottle and the tablet or capsule is taken, a button is pressed to set the time for the next dispensation. A light will flash and beep 24 hours later and continues until the cap is removed. The beep stops after 12 hours if the cap is not removed and repeats the cycle again at the original set time.