Christoph Lhota, Engel Medical, outlines the way in which innovative technologies are paving the way for efficient pharmaceutical packaging and drug carriers
Making Advances
Plastic packaging is light, safe in use, easy to functionalise and can be manufactured efficiently. The pharmaceutical industry is therefore also making increasing use of polymers in the production of containers, vials and applicators. Innovative technologies make it possible to combine the positive properties of the material with the strictest demands for product protection. Polymers are also increasingly being used as drug carriers for specific dose delivery directly in the body.
For a long time there was no better material than glass for the packaging and storage of parenteral drugs. It has outstanding barrier properties guaranteeing reliable protection of products. The downside: – glass breaks easily, is heavy and cannot be formed into any shape without problem. Ongoing advances by material manufacturers are however, now accelerating the substitution of glass by plastics. Crystal-clear cyclic polyolefins and copolyolefins (COP and COC) not only also offer high transparency, high drug compatibility and gas tightness but are also break-proof, light and can be worked into very complex shapes. Prefillable syringes are for example, manufactured from COC in high numbers today. The advantages over glass predominate, even though the material is expensive and needs to be processed under inert gas.
Coinjection: Food containers serve as example
Growing pressure in the pharmaceutical industry to keep costs down is moving the focus to an alternative to COC – polypropylene (PP). Large quantities of PP are already being used in the medical industry to manufacture disposable syringes and infusion sets. The material is accepted by the industry and offered with medical-grade specification by many manufacturers. The problem is it has poor barrier properties. Manufacturers of food packaging are exposed to higher cost pressures than pharmaceutical companies, although they often have to meet similarly strict hygiene requirements. They meet both these demands simultaneously by combining inexpensive PP with gas-tight ethylene vinyl alcohol copolymer (EVOH).
Food containers ready for filling are produced by an all-electric Engel e-motion injection moulding machine using Engel coinjection technology. Three layers of material are created in a one-shot process. The EVOH forms the middle layer and is enclosed completely by PP. The shelf life of foods packed in these containers is extended many times over due to reliable exclusion of oxygen and moisture.
Thanks to the sandwich structure, only very little of the barrier material is needed, while the cheap thermoplastic lends the packaging its stability. The middle layer measures just 0.05mm, which corresponds to about a tenth of the total wall thickness.
The integrated injection moulding process also has a positive effect on the overall balance of production. Beginning with the raw materials and a bonding agent, usable, functionalised containers are manufactured in only one step. The all-plastic packaging with a barrier film is therefore well superior to coated glass or metal containers.
Tablets from injection moulding machines
Apart from higher processing efficiency, more safety and lower unit costs, polymer materials open up other opportunities to the pharmaceutical industry, for example as drug carriers.
Around 40% of all drug developments do not dissolve well in water. For an active ingredient to reach its target from a solid form of oral administration and be absorbed there, it must first dissolve. To improve solubility, the latest move is to manufacture solid dispersions. The active ingredient is embedded in these in a matrix of a water-soluble polymer serving as excipient and solubiliser. Solid dispersions are manufactured nowadays by hot-melt extrusion in a multi-step compounding process. The extrudate is first pelletised before the pellets are ground again and passed on in the next step to a tablet pressing line.
Along with partners Engel has been involved in the development of principles for the injection moulding of pharmaceutical dosage forms. For the research work, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer was used as base material and fenofibrate, a lipid reducer classified as having poor solubility in water. Tablets with a diameter of 13mm and a height of 4mm were manufactured from this polymer-active ingredient system. The tablets were shaped in a mould with six cavities and a naturally balanced star-shaped runner system in conjunction with a sprue gate in an all-electric Engel e-mac 50 injection moulding machine.
When plastics are pigmented, the aim is to obtain uniform distribution of the pigments over the surface of the component, for which the complete plastic melt is pigmented during plasticising. In the case of pharmaceutical dosage forms, uniform distribution of the active ingredients over the complete height of the tablets is not only desirable, but essential. Overall the research results clearly show that injection moulding technology harbours interesting potentials for improvements in efficiency and quality in the production of pharmaceutical dosage forms. It is possible, for example, to produce tablets with delayed release of the active ingredient. A further advantage is that, in contrast to tablets pressed from powder, it is possible to shape injection-moulded tablets completely freely in any geometrical form.
Initial mould and injection moulding machine concepts have already been developed to implement these research results in large-scale pharmaceutical production. They are based on a mould with 128 cavities and a target output of 200,000 tablets per hour.
Plastics-based drug carriers reach the market
To supply the body with defined doses of an active ingredient automatically over a longer period of time, implants or other polymer-based dosage forms such as vaginal rings will be used increasingly in the future. A manufacturer in southern Austria plans to start serial production of contraceptive products this year. This is the result of a research project and Engel was involved in the development project from its inception. The rings are manufactured by all-electric Engel e-motion injection moulding machines.
Maximum performance in cleanrooms
Material developers have not alone been instrumental in accelerating the use of plastics in the medical technology and pharmaceutical industries. Machine manufacturers have also played a role by establishing the prerequisites for this. Engel for example, has designed its all-electric Engel e-motion injection moulding machine systematically for high-performance operation and use in cleanrooms. Cleanroom versions of the machines are offered across the complete clamping force range up to 5,000 kN. In this way ENGEL meets the demands for increased use of multi-cavity moulds in GMP environments.
New GAMP 5 fulfilled completely
Engel’s medical business unit works closely together with developers. In this way Engel accounts for the specific requirements of users in the medical technology and pharmaceutical industries from the beginning. One example of this is the control unit generation CC300, which meets the requirements of the new GAMP 5 in full. Whereas GAMP 4 still classified the control system as firmware, GAMP 5 requires validation of all software solutions. The control units for injection moulding machines fall in software category 3, which means that the requirements from the specification book must be evaluated with the help of an FMEA and implemented on the basis of these results. Apart from the risk assessment, GAMP 5-compliant documentation comprises the validation master plan and change management. The complete lifecycle model of the CC300 control unit therefore corresponds to GAMP 5 requirements.