Since its introduction a decade ago, portable Raman spectroscopy has become a vital technique for raw materials ID verification in pharma manufacturing. In this article, the benefits and issues surrounding through-container ID verification are examined and whether testing of incoming goods can save more money in raw materials ID testing.
Cobalt Light Systems
The cost savings of Raman compared with traditional techniques are well known1 but can even more money be saved from incoming goods testing?
The largest costs in the incoming goods supply chain arise from the handling steps — quarantine storage of materials before and after testing, the logistics of moving pallets around, sampling the contents for testing, and so on. Sampling requires expensive containment facilities, safety measures and clean-up costs, as well as the difficulties of opening and sealing flexible containers.
One consequence is that cost-constraints may govern a sampling strategy where only a small fraction of incoming containers are verified from a delivery, increasing the potential for bad containers to slip through. Avoiding these errors is one of the cornerstones of the PIC/S scheme,2 which is an internationally-agreed set of guidelines for improving the quality of pharmaceutical products. These guidelines have had a significant impact recently in Asia where several countries, including Japan and Korea, have signed up to them and implemented changes in their national forums.3
The problem with testing containers of incoming goods is that they are often not amenable to conventional Raman spectroscopy. Handheld Raman instruments are generally compatible with thin plastic bags and some glass containers, but are not useful when containers become opaque.
Through the container
The difficulty with measuring through the container is that the containers themselves have very different optical and Raman properties. Some, like brown paper or bottles, are highly fluorescent, whereas plastic containers tend to have strong Raman signals and/or added pigments. As containers vary in their properties, detecting and identifying contents through all of these container-types is difficult and cannot be done using conventional Raman —laser illumination and collection is at the same container location, with either a small or large spot illumination.
Figure 1: Averaged ratio of containers received by number into a manufacturing site warehouse.4
Figure 1
Spatially offset Raman spectroscopy (SORS), a technique using off-axis measurements, has enabled a unique benefit in pharma testing — being able to routinely measure through containers. Raman measurements can be made through most common pharma containers for even relatively weak Raman scatterers. A commercially available unit — RapID, from Cobalt Light Systems — is suitable for routine use for incoming goods testing.
Suppliers of raw materials use a wide variety of containers, which is a key variable in determining the cost benefit; to give some idea of this, a survey of pharma companies4 revealed that 56–81% of containers received are opaque, and therefore impossible for handheld instruments, and 19% are amber glass of various thicknesses, which conventional Raman can find challenging. SORS can measure through most containers — the most notable exception is cardboard/fibre drums, which are optically impenetrable but make up almost 10% of containers on average.
When the container doesn’t need to be opened the testing can be fast, safe and with minimal delay after receipt at the warehouse. An efficiency study, published by Astellas Pharma Tech in 2015,5 examined the cost-savings of through-container analysis versus sampled spectroscopy (in this case, IR spectroscopy). Astellas found that the confirmation test takes the greatest amount of time — though conventional Raman would be quicker than IR — but the additional 13.5 hours of sample-handling time avoided by measuring through the container is the same for any test that requires sampling.
Table 1: Analysis time comparison of IR spectroscopy with SORS for testing 200 sacks of lactose.5
Table 1
The same study confirmed that a wide range of common materials can be measured through paper or plastic sacks, including common sugars such as lactose and mannitol and ‘difficult’ oral solid dosage (OSD) excipients such as magnesium stearate, starches, hypromellose and cross-carmelose sodium.
Other materials and containers
Outside the high volumes of OSD excipients there are other applications that benefit from through-barrier verification. For highly-toxic active ingredients there are obvious benefits to being able to ID compounds with no risk of exposure. Similarly, for materials at risk of externally-derived contamination, avoiding exposure to any peripheral risk is achieved by not breaking the seal of any packaging.
Liquids, such as sterile m-cresol, can work well with Raman, but 2.5 L amber glass can be too thick for conventional Raman, even at longer wavelengths. Polysorbates, which are often packed under nitrogen to avoid degradation by oxygen, are doubly-confounding because their innate Raman efficiency is low. These important liquids, usually supplied in small glass bottles, tend to be used in parenteral formulations where 100% ID is mandatory, which makes the QC burden correspondingly high. ID of m-cresol can be done in <5 seconds per bottle using RapID, whilst polysorbates take around 30 seconds. As batches of these liquid excipients can comprise hundreds of bottles the time saved is considerable.
Summary
Through-container ID verification has significant benefits for incoming goods testing. SORS is an effective technique that works reliably through the most common incoming containers in pharma manufacturing. It is particularly compelling in those environments where there is high throughput testing, parenterals manufacture or safety concerns.
References
- http://www.americanpharmaceuticalreview.com/1504-White-Papers-Application-Notes/129832-Cost-Benefits-of-Handheld-Raman-for-Quality-Control-Testing-of-Incoming-Raw-Materials-in-the-Pharmaceutical-Supply-Chain/
- https://www.picscheme.org/
- https://picscheme.org/useruploads/files/press_release_rome_2014.pdf
- 2016 Global survey of Pharmaceutical QC users. Cobalt Light Systems.
- Kawakubo, S., et al., Pharm. Tech. Japan, 2015;31(12):71–80.