Significance of Overdose Ratio

A successful gamma radiation processing program encompasses three basic elements. They are Product Qualification, Equipment Qualification and Process Qualification. All three combined form an integral part of the Process Validation..

Product Qualification

A product qualification program demonstrates the effects of ionizing irradiation on the product. The most important outcome of product qualification is the determination of the product’s Maximum Tolerated Dose. In addition, the Maximum Process Dose and the Minimum Process Dose are also set.

The Maximum Tolerated Dose is that dose of radiation which is just below that which induces an unacceptable change in the analytical profile of the pharmaceutical. It may be possible to select a radiation dose at which no radiation-induced changes in the analytical profile can be detected. It is important in the initial product qualification steps to test the product using widely separated radiation doses. This will quickly assess the ability of the product to withstand radiation and to “zero-in” on the most appropriate radiation dose for further testing.

One of the doses chosen should be approximately three times the “expected” dose. This will help to identify the type and nature of the breakdown products to expect at lower doses. Thus, analytical techniques can be adjusted or developed to assess the concentrations of those products produced using the process dose. Control samples should always be included to separate the effects of changes due to transportation or storage from those due to radiation.

It is also important to do “real-time” studies as opposed to accelerated aging studies. Radiation Processing deposits energy into molecules. Some molecules have crystal lattices which can store the energy. This energy will slowly dissipate and may be a source of product failure with time.

Accelerated aging causes a proportionately more rapid loss of this energy which can often give a false indication of the true shelf-life of the product. This can be especially true of certain plastics which may form part of the finished product. Bear in mind that these problems are not new, unique or difficult to solve. The medical device industry has been down this path often. Most, if not all of the problems that the pharmaceutical industry will encounter have been solved. Many good laboratories/consultants are available to avoid “reinventing the wheel”.

The Maximum Process Dose is determined by judgment. It is usually set below the Maximum Tolerated Dose to ensure that the product is not overexposed. It is dependant upon the product loading, and the physical parameters of the irradiator, such as source strength.

A third factor is the Minimum Process Dose. The Minimum Process Dose is determined by the product loading pattern, density, and the operating characteristics of the irradiator. What is sought is that the desired degree of product sanitization/sterilization will occur at this Minimum Process Dose. The ratio of the Maximum Process Dose to the Minimum Process Dose is known as the Dmax/Dmin Ratio or Overdose ratio. This ratio is the key to successful radiation processing. The closer the ratio is to 1, the less risk there is that the product will experience a radiation dose close the Maximum Process Dose. This in turn means that the product will undergo less radiation induced change. In “normal” operating conditions with material densities around 0.2-0.4 g/cc, this ratio is 1.2-1.4. Knowing that there is a need for a tighter ratio (e.g., 1.1), the experienced irradiation operator can position the material to achieve this goal.