Enhanced safety features for sensitive drugs

Growth in the pharmaceutical and biotechnology industry continues at a dynamic pace. A large number of new diagnostic and therapeutic formulations are exiting from the development pipeline. 49 drugs which were placed on the German market in 2014 are based on new active ingredients. Besides innovative R&D and production techniques, advances in packaging technology are also needed for these products. In particular, the primary packaging material which comes into direct contact with the product ingredients has a crucial influence on product safety. Some producers are attempting to put advanced quality assurance systems in place to support development of primary packaging and to monitor the filling process. “Intelligent” packaging is another significant trend. Pre-filled disposable syringes and packaging with built-in quality detectors and dose administration aids provide additional functionality. At ACHEMA 2015, exhibitors in Hall3, in the Forum and in the Pavillon Agora presented their innovations in the field of pharma packaging.

Protection of high-value ingredients and formulations, quality assurance and unrestricted functionality are top priorities during selection of drug packaging. The same applies to the ever expanding range of biopharmaceuticals produced with elaborate process technologies and used in applications such as the fight against cancer. Producers of packaging for pharmaceutical products must also comply with a number of anti-counterfeiting and traceability regulations. Then there are external factors to consider during shipment and storage such as temperature, exposure to light, vibration and contamination hazards. 8832 spontaneous reports of quality deficiencies and undesirable side effects were submitted to the German Pharmacists Association’s Drug Commission (AKM) in 2014. According to information released by the Association, 41.6% of the incidents were the result of packaging faults, 12.5% involved mechanical defects and poor quality was the suspected cause of reduced effectiveness in 3.1% of the incidents. New EU directives mandate additional safety features such as serial numbers, seals and enhanced anti-tamper protection. The intention is to enable users and patients to immediately recognize whether or not the packaging has already been opened.

Challenging: proteins

The risk of quality degradation is a particular concern with medication that contains proteins.  Proteins tend to unfold on surfaces and may interact with glass as well as with plastic, rubber or silicone components. Small amounts of the proteins in the formulation can be absorbed by the packaging material, impairing or altering the effectiveness of the medication. This is a particular concern with low-dose active ingredients. Thermal and mechanical stress during transport, storage and preparation can also significantly degrade the stability of proteins.

Many innovative biotech drugs are packaged as injections in pre-filled syringes which contain the correct concentrations and amounts. Due to their molecular structure, it is essential that protein medicines are administered parenterally. Based on experience, many producers and users know that particularly with pre-filled syringes the medication comes into contact with more materials than is the case with other types of packaging. Not only that, compared to powder or solid ingredients there is a higher probability that liquid medicines will interact with materials in the primary packaging As a general rule, liquid preparations are more likely to leach dubious substances out of the primary packaging than is the case with powder or tablets. Eprex® is a case in point which illustrates the serious consequences of this type of interaction. The medication had to be taken off the market for a time in 2001. Analysis showed that the polysorbate-80 used by the manufacturer as a stabilizer leached organic compounds out of the uncoated rubber stoppers during storage. This resulted in precipitation and formation of micelles which in some cases led to serious immunological reactions in patients.

New dosage forms

Active ingredients in syringes come into contact with all of the parts made of glass, plastic, metal and adhesive as well as the silicon oil lubricant. Schott has introduced a new design which reduces possible interaction between the active ingredient and the primary packaging. The intention is to provide a level of safety for sensitive active ingredients similar to that of pharmaceutical vials. The channel which connects the hub and the needle in the new syringes is made of flexible plastic. A seal keeps the liquid passageway closed during storage. The medication cannot come into contact with the metal needle or the adhesive in the syringe during shipment and storage. For added quality, tamper-proofing makes it immediately obvious whether the syringe is new or has already been used. 

Developers show almost limitless creativity. A subsidiary of Harro Höfliger has developed a straw for children and the elderly which can be used to administer the active ingredient in pellet form. Patients can ingest the medication along with their favorite beverage. Exact dosing and a control filter ensure that the correct dose is taken.

Process integration and flexibility right through to filling

Packaging is by no means excluded from the major trends in the process industry. The strategy is to supply solutions rather than products. Manufacturers must offer a broad range of technologies covering as much of the value-add chain as possible.

A number of acquisitions and partnerships in recent months reveal the tendency to offer one-stop shopping. Romaco acquired Innojet Herbert Hüttlin in order to be able to provide engineering solutions for the entire production and packaging process of pharmaceutical solids. In December 2014, Bosch Packaging announced the formation of a joint venture with Klenzaids to supply complete lines, particularly for the Indian market. Bosch Packaging supplies process water treatment, fermentation, filling, packaging and quality control systems from a single source. Klenzaid specializes in cleanroom and process technology.

Modularization and flexibility are a second major trend. Generics producers and contract manufacturers in particular have to design their lines to handle small batches with minimal changeover time while delivering safe products. Suppliers can provide lines which can be expanded as needed or reconfigured to handle a wide variety of applications. This applies not only to the hardware but to the software as well. Groninger, a producer of specialized machinery, is developing user interfaces which support quality control throughout the process for an average 25 - 100 stored formulations.

In-process and post-process quality control

DIR Technologies has developed a new induction sealing inspection technique for pharmaceutical containers. During the sealing process, the system performs 100% sealing integrity inspection and fill level detection on pharmaceutical containers such as bottles, bags and sachets, taking quality assurance to a new level. Inspection takes place in real time using non-invasive highly sensitive thermal imaging technology through the closed cap. It will be possible in the future to localize defects during induction sealing with greater precision and pinpoint exactly where to take corrective action. The manufacturer claims that the system can handle high throughput rates without slowing down production.

A team of developers in Singapore has designed self-expiring packaging which can automatically draw the user’s attention to the expiry date. The blister pack is made of multi-layer plastic. Warning symbols are printed on the innermost layer. The outer layer contains basic information such as the manufacturer’s logo. Once the expiration date has passed, the diffusible material between the layers disintegrates, exposing the warning symbols. The developers won the Red Dot Design Award for this idea. Among other things, the system could be very useful for older patients who are unable to read the expiry date which appears on the packaging in small print.

Another innovation was on display in 2014 at the Lopec exhibition for printed electronics. The packaging has built-in temperature sensors made of nanomaterials which can remind patients to take their medication.