Manufacturing problems

Cleanliness monitoring

We routinely measure plant cleanliness on batch changeover, but we occasionally find cross-contamination between batches. Is cleanliness something that could be monitored by surface analysis?

Many industries, from aerospace to medical devices, conduct cleaning procedures. In general, these industries are concerned with the cleanliness of the component and test methods are based on rinsing residues. These procedures provide no information on the residues remaining on the part that, in the case of a prosthesis, could be a critical factor. In the pharmaceutical industry, the consequences of inadequate clean down can result in cross-contamination and cause significant product loss either through quality control reject levels or, more seriously, product recalls. A cleanliness monitoring procedure based on measurements of the material remaining on surfaces after they have been subject to the cleaning process can minimize the potential for cross-contamination.

Chris Pickles

An analytical protocol for the measurement of surface chemistry, such as CERAM Surface and Materials Analysis's Validata, can be applied throughout a manufacturing activity and can include raw material confirmation, process validation, quality acceptance and packaging specification. Measurements can be made on components directly, on swabs or leachates, or on coupon 'blanks' sent through the process. The procedure analyses the surface of interest for all potential contaminants once the composition of an acceptably clean surface for the application concerned has been established — the specified cleanliness level threshold. The analytical method used is highly sensitive to all elements and the data reduction protocol uses a proprietary combinatorial algorithm to generate a single figure 'cleanliness index' ranging from 0 to 100%. In practice, figures lie between 40–99.5% depending on material, process and potential contaminants.

The benefit of an analytical procedure for manufacturers is that they receive a complete cleanliness validation service based on assessment of the specific application with a 'Go/No Go' decision in the form of a single figure that is directly related to the specification requirement.

In a recent case of inadequate clean down between production cycles, a potential contamination was detected on paracetamol tablets. Surface analysis of a suspect tablet revealed traces of Chloroquin (an antimalarial). There were also traces of production plant lubricating oil, which caused tablet discolouration.¹

Tablets from another batch produced at the same plant were not discoloured, but still contained traces of Chloroquin on their surface. Control tablets manufactured at another plant gave a 'clean' paracetamol spectrum.

In this case study, the company made significant cash savings and created a permanent solution to a manufacturing issue connected with plant clean down between production cycles.

The moral of the story is that all of this could have been prevented if a surface analysis protocol had been implemented during the development and validation of specifications for the original plant clean-down procedures.

Controlled release

We are developing a product where the API is coated with a polymer layer. Is it possible to determine the thickness of the layer using surface analysis?

Many drug formulations are delivered through controlled release mechanisms, one of which is the encapsulation of the API with other formulation components as a bead within a slowly soluble, multilayer polymer coating. As the solubility of the encapsulate determines the rate of drug release, it is critical that the coating is both correctly formulated and applied. The validation of process capability to ensure that a coherent coating is being produced consistently can be achieved by surface analysis of coated bead cross-sections.

Surface mass spectrometry can identify organic species of high molecular weight from which spatial chemical maps can be generated. These spatial chemical maps of different species have exceptional parts per million sensitivity and micron resolution. Surface mass spectrometry is, therefore, ideally suited to providing information on coating thickness and integrity/uniformity. Moreover, it can provide speciated chemical images of the location and distribution of the formulation ingredients within the drug-containing bead.

Surface analysis procedures were recently employed in the development of an encapsulated delayed release pharmaceutical product used in heart medication where the application of the multilayer coating was being developed. By taking mass spectrometric images of each of the characteristic species from the core substance (Si+ signal), the API pellet ([M+H]+ signal) and the ethyl cellulose coating (C₃H₇O+ signal) then overlaying them, a composite chemical map was generated (Figure 1). The manufacturer used this to improve the quality of the multilayer coating and ensure efficacy in vivo.

Figure 1: Overlay chemical map of an encapsulated API bead.

In another analysis of a controlled release product, the surface roughness of implants, as well as cross-sectional distribution of API particles together with their individual shapes, were studied. Surface roughness of delayed release implants is important in that it correlates with surface area and, thereby, with solubility and, hence, dose release profile.

Figure 2: Surface roughness 3D image with root mean square average roughness parameter in microns.

Non-contact white light interferometry was used to generate 3D profiles of the implant surfaces and to generate surface area roughness statistics that allow a direct numerical interpretation of the topography. These can be used to easily compare quite disparate surfaces (Figure 2). Cross-sectional mass spectrometric imaging was conducted to discern API distribution and variation in particle shape and size (1–40 μm) throughout the implant volume. In Figure 3, the API is coded red and the matrix material is coded blue. This image cannot be generated from SEM analysis because there is insufficient contrast between the API and matrix materials.

Figure 3: API distribution chemical map - 50 μm x 50 μm API in red and matrix in blue.

Packaging interactions

We have a retained sample of a liquid formulation in which a faint precipitate is suspended. Is this something that could be characterized by surface analysis?

Indeed it is. The approach here is to filter the material onto a filter paper, dry the filtrate and then analyse the mass spectra 'on' and 'off' the filtrate material. It cannot be analysed by bulk methods because very little suspended material is likely to be present.

A recent study required similar analysis to prove the suspended material was not a component of the liquid formulation itself, but a leachate from the bottle stopper. Packaging interactions are a common concern in the containment of pharmaceutical products.

In this example, mass spectroscopic data were collected over an area of the filter to ensure that the composite signal included both the material of interest and data from the filter paper itself. This total data set was then broken down by pixel selection to generate component mass spectra specific to the two regions of interest: precipitate region and filter region. Using these separate data sets, a composite image was constructed of the material distribution and the respective mass spectra used to identify the materials in each area (Figure 4).

Figure 4: Chemical map of precipitate (orange) and filter (green) regions of interest.

In a separate, but related, packaging interaction investigation, the surface composition of a glass bottle used for drug storage was analysed to determine the potential affinity for adsorption of the API, which could affect dosage and the transfer of impurities into the formulation. Figure 5 shows how different the surface chemistry can be between neck base and side wall.

Figure 5: Surface compositions (atomic wt%) of glass packaging neck, base and side wall.

Quality control

We have a capsule polymer material that shows batch-to-batch variation despite the bulk analysis being equivalent for all batches. Can surface analysis help?

The study of polymeric materials is a vast yet specialized field that includes variations in molecular weight, molecular weight distribution, degree of crystallinity, morphology and molecular structure. Some of these sources of variation regarding the material's mechanical and physical performance properties are inherent in the molecular design (e.g., glass/rubber/plastic) and/or formulation, while others can be affected by their processing experiences (temperature, pressure, rate of cooling, solvent use and mechanical strain).

Surface analysis can be used to investigate the chemical and topographic properties of polymeric materials and items manufactured from them. This can often shed light on the underlying causes of functional variation in practical applications.

One such example is in the distribution of additives that are frequently used in combination but which, because of their potential mobility within the crystalline matrix and thermodynamic affinity for the matrix polymer, can preferentially migrate or form localized concentrations.

Figure 6: Chemical maps for additives 1–4.

The distribution of a mixture of four such additives at the inner surface of polymeric drug containment systems has been investigated as part of a study into their potential influence on physicomechanical properties. The four materials were analysed by surface mass spectrometry and these data were used to map their distribution and relative distribution on the inner surface. The technique used was that of retrospective region of interest analysis, as described earlier. Individual and overlay images of the chemical maps generated are shown in Figures 6 and 7. There is an anticorrelation between three of the additives and the fourth, which is also preferentially present at the surface. This information was used, together with an investigation of structural morphology (which is also process dependent), to define improved process control and quality control procedures for the production and approval of the containment system.

Figure 7: Chemical map overlay of additives 1, 2 and 4.

Summary

There are a number of ways in which surface analyses have helped to resolve key operational issues in pharmaceutical manufacturing. Herein, both process and product features have been considered using chemical and physical investigative techniques. The ability of advanced surface analysis techniques to identify what species are present, in what quantity, in which location and relative to what topography has enabled previously intractable phenomena to be resolved. The insights gained have added value to the business processes either by accelerating time to market or by affecting the rapid recovery of a costly malfunction.

On the go...

Chris Pickles is General Manager of CERAM Surface and Materials Analysis (UK).

Reference

1. S. Bainbridge, Pharm. Technol. Eur., 20(2), 18–20 (2008).