Quality assurance in the manufacturing process of pharmaceuticals is an essential step in any production line. The inspection is carried out manually, semi-automatically or fully automatically in order to maintain the high standards.
Its application has been expanded to the pharmaceutical industry exploiting the X-ray inspection technology for detecting missing materials and defective goods in opaque containers. It is used for detecting the presence of drug tablets in aluminum foil press-through packaging, the presence of foreign objects in active pharmaceutical ingredients (APIs) as well as the fill level height of fluids inside containers.
Regulatory guidelines for X-ray inspection
The European Medicines Agency (EMA) has issued rules regulating the exposure of drugs to X-rays (3AQ4a). However, the use of X-ray inspection technology is still questioned by many pharmaceutical manufacturers. X-rays have short wavelengths implying a high energy input which could potentially break covalent bonds of the molecules. X-rays also ionize water molecules and generate radicals which can break covalent bonds, a process which is useful in the radiation therapy of some cancer types.
The following article will focus on the available inspection solutions integrating X-ray technology and on the known effects regarding quality changes of the API. We will also highlight the responsibilities of the pharmaceutical manufacturers who integrate X-ray inspection units in their production lines.
Available X-ray technologies
Many pharmaceutical machinery suppliers responded to the market demands and have come up with different technologies integrating X-ray generators. Different constellations are available so far: the high-voltage X-ray emitting generators, the low-voltage X-ray emitting generators and the pulsed X-ray emitting generators.
The high and low-voltage X-ray tubes emit constant uninterrupted X-rays. To minimize the exposure time a shutter can be installed in front of the X-ray source. The shutter consists of metallic lamella which are not translucent to X-rays. Its shutting of X-rays is synchronized with the conveyor or rotator speed so that each inspected product is exposed for a defined period to X-rays.
The pulsed X-ray is rather an interrupted generation of irradiation. Each inspected product is subjected to one pulsed X-ray emission for a certain period of time. The frequency of the pulsed X-rays is adjusted to the conveyor or rotator speed. The inspection task can thus be mastered depending on the intensity and the exposure time of the X-ray irradiation. Any of the mentioned technologies are useless if the resulting images were not processed downstream in an adequate manner. Good image processing software indicating a sensitive and reliable pattern recognition may compensate the gap resulting after exposure to X-rays generated by the low energetic X-ray tubes.
Influence of X-rays on APIs
In a common project between BOSCH GmbH and PHAST GmbH, the influence of X-ray radiation on the model substances was compared to the influence of UV radiation present in the spectrum of daylight. The API Nifedipine is known to be daylight sensitive and it undergoes photodegradation of 10 percent every 30 minutes. Tramadol HCl is a stable product and both were subjected to X-ray irradiation for 2 hours and compared to a photodegradation rate after 30 minutes exposure to artificial daylight. For both APIs, Nifedipine and Tramadol HCl, no degradation was observed when exposed to X-ray irradiation. This in a worst case scenario of two hours X-ray exposure. Tramadol HCl was stable even after exposure to artificial daylight for a period of 30 minutes. Nifedipine showed an increasing photodegradation over time up to 10.06 percent of the total API mass.
According to the SI unit definition, the specific energy “joule per kilogram” [J/kg] is the unit of absorbed radiation dose. The absorbed dose, specific energy (imparted) is “Gray” [Gy], and 1 Gy is equivalent to 1 J/kg.
Uehara et al. conducted similar experiments on Nifedipine tablets, Acetaminophen, Loxoprophen and on Mefenamic acid. Drug content, dissolution, disintegration, hardness and colour were set as test parameters. Each drug in PTP sheets (Push-Through Packaging / blisters) was fractioned in five groups. The fractions were exposed to various X-ray doses of successively 0 Gy, 0.34 mGy, 0.1 Gy, 0.5 Gy and 300 Gy.
No degradation, no quality change
The X-ray exposure did not cause any noticeable degradation of the API. The results also demonstrated that X-ray exposure did not affect the pharmaceutical quality regarding dissolution, disintegration and hardness in this experimental series. Only Nifedipine has shown color change and disintegration after exposure to X-ray radiation under daylight conditions. X-ray exposure in the dark chamber did not cause any changes; this is due to the known daylight and UV instability of Nifedipine.
For the majority of the pharmaceutical products there is no known change in the quality of drug tablets after exposure to X-ray. Aluminum foil sealing is an effective method to protect tablets from moisture and an X-ray inspection is a promising method to ensure the presence of drug tablets within aluminum foil PTP.
Low energy input, low irradiation
The X-ray inspection is also used in the quality assurance of fluids, gels, pastes and lyophilized APIs. No negative impact of the X-ray inspection on APIs is known so far. This is due to the low-energetic X-rays and due to the very short exposure periods. 250 ms exposure duration is the common standard. However, some manufacturers guarantee the maximum exposure duration of 1 ms for each inspected product when generating low-energetic X-rays (pulsed X-ray technology).
The inspection systems of HEUFT subject each product to only 10 μGy energy input, and the measured irradiation inside the glass container (API) was about 2.5 μGy due to the reflection effect of the outer packaging. In comparison, a flight between Paris and San Francisco would cause an exposure to cosmic X-ray radiation of 110 μGy. It is rather hard to imagine that exploiting such an inspection solution would lead to quality reduction.
Manufacturer responsibilities and X-ray physical limits
At the same time, it is the responsibility of the pharmaceutical manufacturers to ensure the quality of the pharmaceutical products when exploiting the X-ray technology. The examples mentioned above cover a wide range of drug formulations but of course do not provide a quality certificate for every inspected product. Pharmaceuticals containing living organisms, proteins or other sensitive biopharmaceuticals must be tested rather for their integrity and quality after an X-ray inspection.
Most inspection machinery suppliers support the downstream analysis but it is still the task and the responsibility of the pharmaceutical manufacturers to initiate these tests. It is also utopic to consider the X-ray inspection as the ultimate solution in the quality management. X-ray detection has its limits. Organic foreign objects such as hair fibers or low density materials like plastic foil, fragments etc. are barely visible in the X-ray image. Glass and metal splinters which have a significantly higher density than the product can be reliably detected.
Most of the pharmaceutical manufacturers express the wish to detect foreign objects of 50 μm diameter. The realistic size of contaminants which can be detected is above 200 μm and the recognition rate for the time being is below 70%. This detection performance is dependent on many limiting factors, mainly on the material of the foreign object (organic, inorganic, metal etc.), the physical features of the container (material, shape, thickness and transparency) and on the position of the particle relative to the container walls.
A promising method
In light of the above information, it can be concluded that the pulsed X-ray inspection is a promising method to ensure the presence and integrity of packaged drugs, to check the correct fill level height of aqueous pharmaceuticals and to detect contaminating foreign objects inside translucent and non-translucent containers. No quality reducing effects are known so far due to the short exposure to X-ray irradiation and the pharmaceutical machinery industry tends to onset low-energetic X-ray irradiation to minimize probable negative effects. It is unscientific to exclude all possible effects on the molecular structure of each drug after an X-ray inspection, which is why in case of uncertainty, it is the responsibility of the pharmaceutical manufacturer to analyze the effects of X-ray exposure on certain APIs.