QRM Process

Quality Control with Handheld Raman

Ensuring compliance for raw material identification is easily within reach

By Claire Dentinger, Applications Scientist, Rigaku Analytical Devices

Raw material identification (RMID) is a critical step for ensuring compliance with Good Manufacturing Processes (GMPs) and safeguarding the quality of pharmaceutical products. Increasingly strict regulatory requirements for RMID mean that pharmaceutical manufacturers are under increasing pressure to improve the efficiency of their RMID workflow while also achieving lower costs per analysis.

Traditional lab-based techniques for RMID can be time consuming, costly and do not support the rapid identification of incoming materials. Handheld Raman spectroscopy is increasingly recognized as an effective technique for RMID thanks to its specificity, speed and ease of use. However, devices with traditional excitation wavelength lasers, such as 532nm or 785nm, are affected by fluorescence interference which limits their ability to detect certain materials. The implementation of handheld Raman utilizing a 1064nm excitation wavelength laser removes the barriers to effective RMID while achieving ROI.

THE RMID CHALLENGE
RMID is essential to verifying whether a substance is what it should be to prevent quality issues further down the line. Incorrect formulation, contamination, mislabeled containers and counterfeit materials can result in products being “out of specification,” which can severely damage brand reputation. Ultimately, if these materials are not promptly identified and rejected, this can lead to additional costs due to material waste, re-processed work, time delays or product recalls. Effective and timely RMID helps to improve the quality of pharmaceutical products by identifying these out-of-specification materials before they enter the manufacturing process.

The traditional RMID workflow involves a number of stages before materials can be passed through for manufacturing. In order to perform comprehensive qualitative and quantitative analysis of materials, the majority of techniques used for RMID require containers to be opened to obtain a sample, which introduces the risk of contaminating the material. While the majority of pharmaceutical manufacturers now perform RMID on-site, the analytical techniques commonly used for RMID are not optimized to analyze raw materials on the warehouse floor or in the clean room. HPLC, GC and FTIR are among the commonly used techniques for RMID, and although they deliver powerful analysis, they need to be operated by highly skilled users. This could be considered a waste of a valuable resource when all that is initially required is a simple PASS/FAIL analysis.

The well known saying that “time is money” is certainly applicable to RMID. Raw materials are held in a quarantine area while waiting for verification, which takes up valuable warehouse space as well as causing delays in the manufacturing process. In the drive to achieve lean manufacturing processes it’s clear that there are elements of the traditional RMID workflow that are not optimized to deliver speed, efficiency and cost savings.

Another factor is the wide variety of materials that now require analysis, which are difficult to analyze using existing handheld Raman devices. Materials such as Polysorbate 20, cell culture media, gelatin and Xantum gum are susceptible to fluorescence when being analyzed by handheld Raman analyzers a 532nm or 785nm excitation laser. Fluorescence interference prevents the successful chemical identification and analysis of these materials which is a cause of frustration for QA/QC managers attempting to verify them quickly.

COMPLIANCE CONSIDERATIONS
Pharmaceutical manufacturers are required to comply with the regulations of local pharmacopeia and government agencies such as The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-Operation Scheme. In the majority of countries, 100 percent inspection of incoming raw materials is now required, meaning that every container needs to be analyzed. This makes it more important than ever before for the RMID process to be as efficient as possible to meet these demands without affecting productivity or profit margins.

Manufacturers are also required to pass quality audits to ensure they are compliant with Good Manufacturing Practices (GMPs) for RMID. The PIC/S Guide to Good Manufacturing Practice for Medicinal Products states that “there should be appropriate procedures or measures to assure the identity of the contents of each container of starting material” and recognizes that it is only possible to verify a complete batch of raw materials by sampling all the containers.

STREAMLINING RMID WITH HANDHELD RAMAN
Raman spectroscopy is an accepted technique by the United States Pharmacopeia (USP) and the European Pharmacopeia (EP) for RMID and is widely used as part of the pharmaceutical manufacturing process to ensure the safety and efficacy of pharmaceutical products. Raman spectroscopy is an established vibrational technique that works by first exciting a sample with a laser. This results in a Raman spectrum which contains a series of peaks that relate to features in the sample’s molecular structure. A cartoon schematic of this process is shown in Figure 1.

Handheld Raman is designed to fit seamlessly into any work environment for RMID processes. By providing the ability to analyze and identify materials against a variety of criteria at the point of need, handheld Raman eradicates the delay in waiting for results from external laboratories, improves cycle time and optimizes material movement. Ultimately, pharmaceutical manufacturers are able to easily meet the requirements for 100 percent inspection of incoming materials with handheld Raman, and a comparison between the traditional RMID and handheld Raman RMID workflow is outlined in Figure 2. Utilizing a handheld Raman device enables users to make quick decisions with easy PASS/FAIL results, helping professionals to achieve leaner manufacturing processes without compromising on the quality of the material.

While the popularity of handheld devices for RMID has been increasing in recent years, existing devices have not proven to be as easy to use. The latest generation of handheld Raman devices have been engineered to be quickly and easily implemented into RMID workflows. Large, easily readable angled displays and single-handed operation help to ensure operational excellence and improve the user experience.

When it comes to RMID there is no room for human error and the availability of handheld Raman devices with a 21 CFR Part 11 compliant electronic signature helps to guarantee error-free data entry tracking. It is also now possible to save measurement details with sample images and labels for enhanced sample verification with the integrated digital camera that is unique to the Progeny device. Slow data transfer can cause unnecessary delays in the RMID process, but recent advances in software in the new generation of handheld Raman analyzers (including those from Rigaku Analytical Devices) mean that all data, spectral processing and library searches can now be saved together for future use while data can also be automatically transferred to LIMs with the instrument’s docking station. This capability helps to further improve operational excellence for RMID.

THE POWER OF 1064
Raman spectroscopy has traditionally been done using shorter wavelengths such as 532nm and 785nm, and one of the major limitations of existing handheld Raman devices using shorter wavelengths is fluorescence interference. This increases background intensity and makes colored materials such as cell culture media, xantum gum and gelatin or materials in colored containers impossible to analyze.

With the introduction of handheld Raman analyzers with 1064nm excitation lasers, manufacturers are now able to analyze a wider range of materials than ever before. Handheld Raman analyzers using 1064nm excitation lasers, such as Progeny, enable users to measure colored solids and liquids, which helps to increase inspection rates and improve confidence in results. The power of 1064nm lasers also means that substances can be measured through containers and packaging materials such as polymer bags, glass bottles, flasks and vials. This enables the user to screen materials by non-contact, non-destructive analysis — without needing to open containers — helping to avoid cross contamination and delays on the warehouse floor.

OPTIMIZED RMID FOR SAGE PRODUCTS
Sage Products LLC, a manufacturer and distributor of health and personal care products for the hospital and retail markets was looking for ways to improve the productivity of its manufacturing process. Their key aims were to reduce the time and costs associated with RMID analysis that was being carried out by internal and external laboratories. Sage’s products are manufactured under GMP as required by the FDA and they needed to implement a solution to meet these high performance standards. To overcome these challenges and optimize the RMID process, Sage chose to implement a Rigaku handheld Raman device.

Sage implemented a Standard Operating Procedure (SOP) to address the needs of the QA technicians, enabling a streamlined RMID workflow. The qualification process took just three months to complete. Furthermore, due to the ease of use of the device, the personnel training process took just five days to complete, and within a month the process was completely employed into the RMID workflow. The implementation of handheld Raman utilizing a 1064nm excitation laser enabled Sage to meet industry and internal requirements for RMID quicker and more cost effectively than ever before without compromising on quality. With handheld Raman, QA technicians are able to screen samples at the point of need and can decide whether to release or reject materials within the same day of receipt. This saved valuable time by reducing testing cycles from weeks to just hours. Sage also saw significant reductions in analysis time, meaning that valuable QC resources could be freed up and quarantined material volumes could be reduced.

DRAMATIC IMPROVEMENT AHEAD
Recent developments in Raman spectroscopy have enabled users to dramatically improve their material identification process, and as awareness of the capabilities of handheld Raman grows, we can expect to see an increase in the implementation of handheld Raman for RMID. The rapid ROI delivered by handheld Raman means that pharmaceutical manufacturers can be confident that they are meeting the requirements for material inspection in a way that does not impact their bottom line or productivity and they can focus on continuing to deliver safe and efficacious pharmaceutical products.

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