The product development process for pre-filled syringes and injection devices is a little different from that of a ‘traditional’ pharmaceutical. There are essentially five steps (figure 1), and for many, the commencement of clinical testing (stage 4) is regarded as the critical milestone. Hence, in this article we focus on the ways in which analytical testing services can support the process, in stages 1-3.
Stage 1 – Concept and Design
It is sensible to start assessing potential device materials, including lubricants, at the earliest point. Chemical characterisation can be carried out in accordance with pharmacopoeial test methods using a combination of wet chemistry, chromatography, spectroscopy and differential scanning calorimetry.
Stage 2 – Prototyping
Once a lead design has been generated, it is necessary to develop and evaluate a prototype.
The EU Directive on medical devices (93/42/EEC) and its amendments, backed by various guidelines (MEDDEVs), deal with general requirements for marketing medical devices within the EU. Once a prototype has been created there is often a need to develop and validate analytical methods specific to the product. Functional tests on the device alone may be performed by the manufacturer, though the functionality of the device will inevitably require evaluation in conjunction with the Active Pharmaceutical Ingredient (API) or drug product (DP). Once validated, these methods can support the development through the pre-clinical, clinical and commercialisation stages.
There is also scope to commence performance testing during the prototype phase, questioning whether a device might be exposed to impacts and forces during manufacturing, filling, device integration, shipping, and operation by the end user – all of which might result in product defects. The construction can be assessed non-destructively using techniques as simple as visual observation to the more advanced X-ray tomography. The physical characterisation methods outlined by ISO-11040-8 will determine the ease of syringe plunger movement through measurements of break loose and extrusion forces, dead space determination and freedom from air/liquid leakage. Amongst others, a potentially critical performance parameter such as dosage accuracy could also be assessed.
Extractables and Leachables
An extractables profile needs to be determined for all the materials used in the prototype and then the therapeutic drug must be analysed for leachables from the medical device. Techniques used to create the extractables profile include LC-MS, GC-MS, ICP-MS, NMR and ion chromatography (Dionex).
Sub-visible Particle Analysis
Some drugs can be sensitive to hydrophobic syringe surfaces, shear forces and the presence of lubricants. Such unfavourable interactions can lead to increased sub-visible particles which may cause harm to patients. Hence it is useful to determine the numbers of particles shed by a medical device, and this is usually performed according to pharmacopoeial methods such as light obscuration and microscopy. The light obscuration method is preferred by the pharmacopoeias, as it is objective and can be used to count particles down to 2µm. The microscope method is more labour intensive, but is more suitable for coloured, viscous or protein based biological drug products and gives an initial indication of the nature of any particles. In addition, sub-visible particles can be further characterised using a combination of microscopy, FTIR, X-ray microanalysis and NMR techniques.
Host cell DNA determination by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) techniques can be utilised for biopharmaceuticals. It is necessary to validate the removal of both protein and nucleic acid derived from the production host. Host protein detection is mediated through the development of specific antibodies allowing the development of sensitive ELISA’s. The degree of coverage is usually assessed by Western Blotting. The detection and quantitation of host cell DNA can be achieved through nucleotide binding assays such as Picogreen or specific assays based on real-time PCR. The greater sensitivity and specificity of qPCR lends itself to the later stages of pharmaceutical clinical development.
Stage 3 – Pre-clinical
The purpose of pre-clinical studies is to establish medical device safety and to enable a robust design of the full clinical trial. Hence, upon entering the pre-clinical phase, consideration needs to be given to the potential toxicity of medical device materials.
A range of systematic biological based (i.e. biocompatibility) tests need to be done in accordance with ISO 10993.
ISO 13485:2003 requires a medical device developer to establish documented procedures or documented work instructions for preserving the conformity of the medical device product during internal processing and delivery to the intended destination. A combination of real-time and accelerated stability studies will establish stability and it is essential to have robust stability-indicating methods to determine the chemical and physical stability of the pack/device and its contents. It may also be necessary to develop methods for the determination of preservative levels in the product. One aspect that is often overlooked is the need to ensure that enough spare devices are set-down to analyse additional time points during development, and fund out of specification/out of trend (OOS/OOT) investigations.
The medical device product development cycle is necessarily complex to ensure safe and efficacious products. Analytical testing can commence at different stages within the product development cycle and careful planning can contribute to a timely launch. Few medical device developers have all of the analytical resources they require in-house for regulatory submission, which makes outsourcing an attractive proposition, provided they can find a contract laboratory with the latest analytical equipment, knowledge of the standards and experience in problem solving, method development and validation. Reading Scientific Services Ltd (RSSL) offers a range of services to support your product development. For more information please contact Caroline Coupar, email
email@example.com or visit www.rssl.com