FPM investigations can be expensive and, on occasion, inconclusive, further complicating decisions regarding product release. Sterile manufacturing has its own unique challenges, and the investigation of foreign particles is very often a concern. The presence of FPM in sterile pharmaceutical products, which as well as affecting efficacy and safety, has recently been one of the reasons for a major increase in the number of product recalls.1
Regulatory requirements are increasing for the characterisation and quantification of visible and subvisible foreign particles in pharmaceutical products. Turnaround times for FPM testing are often critical; companies typically benefit from having dedicated provision for the rapid analysis of samples using a selection of microscopic and spectroscopic techniques. These include:
- Optical microscopy
- Subvisible particulate quantification
- Scanning electron microscopy (SEM) with energy dispersive X-ray spectroscopy (EDX)
- FTIR spectromicroscopy
- Image analysis
The latest instrumentation enables automation for increased throughput and tightly controlled assays. Automated methods have been successfully validated for both residual DNA and residual protein detection, which enhance sensitivity, reduce interanalyst variability and produce the most robust assays possible.
Defining particulate matter
Particulate matter is generally defined as mobile, randomly sourced, extraneous substances (other than gas bubbles) that cannot always be quantified; it is typically classified as the following based on its origin:
- Inherent: particulates derived from the product itself, such as protein agglomerates
- Intrinsic: particulates generated from the production process and primary packaging, such as glass vials
- Extrinsic: particulates originating from outside the process, such as garment fibres
Particulate matter testing forms part of the USP to ensure that unintended and non-therapeutic particulates in solution dosage forms do not exceed established limits. The size of the particulate matter is a critical factor when considering the potential risk to patients. Particulate matter is typically classed as being visible (>100 μm) or subvisible (1–100 μm).
It is important for manufacturers to be able to show a detailed understanding of their process. Not only must the number of particles present be quantified, it is also important to demonstrate knowledge of their identity and origin. This requires the ability to develop bespoke FPM methodology rather than merely do routine test methods such as:
- USP <787> Subvisible Particulate Matter in Therapeutic Protein Injections
- USP <788> Particulate Matter in Injections
- USP <789> Particulate Matter in Ophthalmic Solutions
- USP <790> Visible Particulates in Injection
- USP <1788> Methods for the Determination of Particulate Matter in Injections and Ophthalmic Solutions
FPM investigations can be supported by the following:
- ISO14644 Class 5 standard (FS 209 Class 100) laminar flow cabinets, minimising sample contamination
- Experience of various types of particulate matter isolation, such as the manipulation of small particles, filtration and centrifugation
- Optical microscopy (compound, stereo and inverted microscopes) with image analysis
- light obscuration
- High resolution scanning electron microscopy with EDX for qualitative elemental analysis
- Fourier transform infrared spectroscopy (FTIR) and microscopy
- Near infrared spectroscopy and microscopy
- Image analysis
- X-ray diffraction
- Mass spectrometry
- Inorganic analysis techniques (ICP-OES, ICP-MS and AAS)
- Extensive component/product/contamination libraries
FPM analysis workflow
There is a recognised need for flexibility, speed and attention to detail in all FPM investigations, whether routine counting and/or bespoke characterisation is required. An established, systematic and tiered approach must be applied and carefully managed, ensuring it is fit for the specific product and manufacturing process.
Sample preparation is a key component of FPM analysis and the method employed is determined by the particulate matter encountered and the matrix in which it is present. For example, the handling of fibres and particles present in a clear liquid will require a very different approach to that of collecting particulates following the actuation of an inhaler device. Companies can take advantage of service providers who are experienced and skilled in the analysis of FPM associated with all major drug delivery platforms and formulation types, including pre filled syringes (PFS), vials, ophthalmic solutions, inhalers etc. Typically, service providers will use staff trained in aseptic and sterile handling techniques to minimise contamination and perform all sample preparation prior to analysis in Class 5 laminar flow cabinets.
Particle counting and characterisation
Following sample preparation based on USP guidelines, the particulate count test method applied includes either light obscuration (HIAC) or microscopy, as required by the client (Figure 1).
Light obscuration is fast, automated, reproducible and non-biased. However, it is limited in its ability to identify particles by colour and shape and fails to differentiate between air/gas bubbles or handle high-viscosity samples such as emulsions or colloids. Samples that are viscous, turbid or that contain colloids/surfactants are analysed chiefly by microscopy. Although this technique is more time-consuming, additional information such as size, shape and colour can be obtained. On completion of counting, data are typically reported based on either size range and/or particle category, as shown in Table I.
Further investigation to characterise the foreign matter can be performed as required. Typical foreign matter includes fibres, precipitates, metallic particles, glass shards, polymers and processing aids. Once identified, only then can appropriate control measures be introduced and their presence minimised. A typical investigation is summarised in Figure 2.
To develop a detailed understanding of a particular process or product, particulate matter size and characterisation data can be used to generate a specific library for further routine monitoring and investigations. This approach has proved to be successful in developing bespoke methods for clients that have either been transferred or remained with its provider for subsequent routine testing on an outsourced basis.
FPM in drug products is a common problem in the pharmaceutical industry that can have a major impact on companies from both a financial and a safety aspect. There has been a rise in the number of pharmaceutical product recalls in recent years owing to the presence of FPM, and its effect on product quality, efficacy and safety.
FPM is either inherent from the product itself, intrinsic from the production process or extrinsic from external contaminating particles. Manufacturers are required to thoroughly investigate any incidents involving FPM and quickly determine its origin. Furthermore, the manufacturer needs to demonstrate that they have a thorough understanding of their manufacturing process and control of the composition of their final product. Detection and analysis of FPM is a critical part of product development and quality control and companies need to ensure they do such analysis effectively.