Foreign Bodies in Pharmaceuticals

Despite the best efforts of manufacturers to produce to the highest standards, there are a number of ways in which pharmaceuticals may become contaminated by foreign bodies. Such contamination may at best be unwelcome, or at worst potentially life threatening for users of pharmaceutical products such as injectables.  From a production point of view, the discovery of a contaminant may render the entire batch unusable, resulting in wasted production time and raw materials.

To identify a contaminant and find an explanation for its presence in the product is seldom an easy matter. It can require a significant amount of detective work on behalf of the scientist charged with investigating the problem. Very often, it requires a team effort, involving the skills of microscopists, chemists, and microbiologists working together to reach a satisfactory conclusion. Where this multi-disciplinary expertise is not available in-house, manufacturers must find a Good Manufacturing Practice compliant Contract Research Organisation to assist in the investigation.

Many sources

There are many potential sources of foreign bodies in pharmaceutical products. They can include production equipment, laboratory equipment, raw materials, packaging materials and production errors, as well as deliberate act of malicious tampering. Sometimes the point at which the problem is detected will give a clue as to how the contamination occurred (e.g. glass contamination of product immediately following a known breakage of packaging materials), at other times the possible explanations will be less obvious.

At RSSL Pharma, Microscopy is always the first line of attack in investigating foreign body incidents. There is much that can be learned even from examining the size, shape and surfaces of a foreign body with simple light microscopy. However one of the most powerful analytical tools is X-ray microanalysis linked to scanning electron microscope equipment. An alternative approach is to use X-ray microfluorescence. Both techniques can be used to reveal the elemental composition of a sample and elemental distribution within it and are especially valuable in the analysis and comparison of glass and metallic fragments. FT-IR microspectroscopy is similarly powerful in being able to identify small particles, especially those of an organic nature.

Glass fragments are a potential foreign body hazard in any pharmaceutical product that uses glass packaging. Any breakage on the filling line can easily contaminate other bottles. Metal shards from machinery are another common foreign body contaminant, again arising from wear and tear on factory machinery. In a similar way, plastic fibres can also arise from the use of plastic packaging or from wear and tear on plastic fixtures in the process line. Lubricants are frequently found as co-contaminants with finely divided metal dust on tablet surfaces, but on their own may manifest as droplets within liquid pharmaceuticals.

Whilst glass, metal and plastic fragments from plant and packaging constitute the majority of foreign body cases, they are by no means the only cases. RSSL Pharma has investigated many incidents over the years and identified a wide variety of insects, mammalian hairs, pieces of paper, drops of silicone and 'black bits' (often consisting of thermally degraded product or rubber).

Foreign bodies need not necessarily be of external origin. From the consumer's perspective coagulants and precipitates are also foreign bodies and clearly, their presence is liable to compromise the performance, and possibly safety, of the product. Microscopy is unlikely to be sufficient on its own to identify these foreign bodies. Chemical analysis will also be required.

Chemical contaminants

Where precipitation or coagulation is expected, the chemist at least knows to direct his/her analysis at the actives, excipients and degradation products. A number of analytical techniques may be employed ranging from High Performance Liquid Chromatography with UV or diode array detection, to the more sophisticated liquid chromatography-mass spectrometry, or gas chromatography-mass spectrometry. Thin layer chromatography, Fourier Transform-Infra Red spectrometry and Nuclear Magnetic Resonance spectrometry are also routinely applied to chemical analyses.

To reach any conclusion about the identity and source of the contaminant is no easy matter, and for the investigating team it is always useful to have a full production history of the rogue sample, and a sample of a perfect product (a control sample) against which to compare it. Armed with this information, the experienced chemist can usually target his/her efforts more precisely.

One class of foreign body is worthy of special mention; sub-visible particles in injectable and ophthalmic solutions. The different pharmacopoeias, for example USP<788> and EP 2.9.19, set out limits on the numbers of sub-visible particles (= 10µm and = 25µm) that are acceptable in injectables and routinely, RSSL Pharma tests a variety of different products for the presence of sub-visible particulate matter. It goes without saying that injectables must be tested to ensure that they conform to the requirements of the pharmacopoeia as appropriate, and any sub visible particulates outside the permitted ranges may be investigated using the microscopy techniques described earlier.

Always Investigate

Whilst it may not be possible to prevent every foreign body incident, it is always in the interests of manufacturers to investigate every case.  Continuous improvement is key in any quality systems and the information acquired by a successful investigation will offer an explanation as to how contamination occurred. It should also go a long way to helping the manufacturer to decide what measures need to be introduced to prevent a repeat occurrence and improve the reliability and safety of the manufacturing process.