Annex 12: Use of Ionising Radiation in the Manufacture of Medicinal Products

Introduction Ionising radiation may be used during the manufacturing process for various purposes including the reduction of bioburden and the sterilisation of starting materials, packaging components or products and the treatment of blood products. There are two types of irradiation process: Gamma Irradiation from a radioactive source and high energy Electron Irradiation (Beta radiation) from an accelerator. Gamma Irradiation: two different processing modes may be employed: (i) Batch mode: the product is arranged at fixed locations around the radiation source and cannot be loaded or unloaded while the radiation source is exposed. (ii) Continuous mode: an automatic system conveys the products into the radiation cell, past the exposed radiation source along a defined path and at an appropriate speed, and out of the cell. Electron Irradiation: the product is conveyed past a continuous or pulsed beam of high energy electrons (Beta radiation) which is scanned back and forth across the product pathway.

Treatment by irradiation may be carried out by the pharmaceutical manufacturer or by an operator of a radiation facility under contract (a “contract manufacturer”), both of whom must hold an appropriate manufacturing authorisation.

The pharmaceutical manufacturer bears responsibility for the quality of the product including the attainment of the objective of irradiation. The contract operator of the radiation facility bears responsibility for ensuring that the dose of radiation required by the manufacturer is delivered to the irradiation container (i.e. the outermost container in which the products are irradiated).

The required dose including justified limits will be stated in the marketing authorisation for the product.

Dosimetry is defined as the measurement of the absorbed dose by the use of dosimeters. Both understanding and correct use of the technique is essential for the validation, commissioning and control of the process.

The calibration of each batch of routine dosimeters should be traceable to a national or international standard. The period of validity of the calibration should be stated, justified and adhered to.

The same instrument should normally be used to establish the calibration curve of the routine dosimeters and to measure the change in their absorbance after irradiation. If a different instrument is used, the absolute absorbance of each instrument should be established.

Depending on the type of dosimeter used, due account should be taken of possible causes of inaccuracy including the change in moisture content, change in temperature, time elapsed between irradiation and measurement, and the dose rate.

The wavelength of the instrument used to measure the change in absorbance of dosimeters and the instrument used to measure their thickness should be subject to regular checks of calibration at intervals established on the basis of stability, purpose and usage.

Validation is the action of proving that the process, i.e. the delivery of the intended absorbed dose to the product, will achieve the expected results. The requirements for validation are given more fully in the note for guidance on “the use of ionising radiation in the manufacture of medicinal products”.

Validation should include dose mapping to establish the distribution of absorbed dose within the irradiation container when packed with product in a defined configuration.

An irradiation process specification should include at least the following: a. details of the packaging of the product; b. the loading pattern(s) of product within the irradiation container. Particular care needs to be taken, when a mixture of products is allowed in the irradiation container, that there is no underdosing of dense product or shadowing of other products by dense product. Each mixed product arrangement must be specified and validated; c. the loading pattern of irradiation containers around the source (batch mode) or the pathway through the cell (continuous mode); d. maximum and minimum limits of absorbed dose to the product [and associated routine dosimetry]; e. maximum and minimum limits of absorbed dose to the irradiation container and associated routine dosimetry to monitor this absorbed dose; f. other process parameters, including dose rate, maximum time of exposure, number of exposures, etc. When irradiation is supplied under contract at least parts (d) and (e) of the irradiation process specification should form part of that contract.

Commissioning is the exercise of obtaining and documenting evidence that the irradiation plant will perform consistently within predetermined limits when operated according to the process specification. In the context of this annex, predetermined limits are the maximum and minimum doses designed to be absorbed by the irradiation container. It must not be possible for variations to occur in the operation of the plant which give a dose to the container outside these limits without the knowledge of the operator.

Commissioning should include the following elements: a) Design; b) Dose mapping; c) Documentation; d) Requirement for re-commissioning.

The absorbed dose received by a particular part of an irradiation container at any specific point in the irradiator depends primarily on the following factors: a) the activity and geometry of the source; b) the distance from source to container; c) The duration of irradiation controlled by the timer setting or conveyor speed; d) The composition and density of material, including other products, between the source and the particular part of the container.

The total absorbed dose will in addition depend on the path of containers through a continuous irradiator or the loading pattern in a batch irradiator, and on the number of exposure cycles.

For a continuous irradiator with a fixed path or a batch irradiator with a fixed loading pattern, and with a given source strength and type of product, the key plant parameter controlled by the operator is conveyor speed or timer setting.

For the dose mapping procedure, the irradiator should be filled with irradiation containers packed with dummy products or a representative product of uniform density. Dosimeters should be placed throughout a minimum of three loaded irradiation containers which are passed through the irradiator, surrounded by similar containers or dummy products. If the product is not uniformly packed, dosimeters should be placed in a larger number of containers.

The positioning of dosimeters will depend on the size of the irradiation container. For example, for containers up to 1 x 1 x 0.5 m, a three-dimensional 20 cm grid throughout the container including the outside surfaces might be suitable. If the expected positions of the minimum and maximum dose are known from a previous irradiator performance characterisation, some dosimeters could be removed from regions of average dose and replaced to form a 10 cm grid in the regions of extreme dose.

The results of this procedure will give minimum and maximum absorbed doses in the product and on the container surface for a given set of plant parameters, product density and loading pattern.

Ideally, reference dosimeters should be used for the dose mapping exercise because of their greater precision. Routine dosimeters are permissible but it is advisable to place reference dosimeters beside them at the expected positions of minimum and maximum dose and at the routine monitoring position in each of the replicate irradiation containers. The observed values of dose will have an associated random uncertainty which can be estimated from the variations in replicate measurements.

The minimum observed dose, as measured by the routine dosimeters, necessary to ensure that all irradiation containers receive the minimum required dose will be set in the knowledge of the random variability of the routine dosimeters used.

Irradiator parameters should be kept constant, monitored and recorded during dose mapping. The records, together with the dosimetry results and all other records generated, should be retained.

The absorbed dose received by a particular portion of an irradiated product depends primarily on the following factors: a) the characteristics of the beam, which are: electron energy, average beam current, scan width and scan uniformity; b) the conveyor speed; c) the product composition and density; d) the composition, density and thickness of material between the output window and the particular portion of product; e) the output window to container distance.

Key parameters controlled by the operator are the characteristics of the beam and the conveyor speed.

For the dose mapping procedure, dosimeters should be placed between layers of homogeneous absorber sheets making up a dummy product, or between layers of representative products of uniform density, such that at least ten measurements can be made within the maximum range of the electrons. Reference should also be made to sections 18 to 21.

Irradiator parameters should be kept constant, monitored and recorded during dose mapping. The records, together with the dosimetry results and all other records generated, should be retained.

Commissioning should be repeated if there is a change to the process or the irradiator which could affect the dose distribution to the irradiation container (e.g. change of source pencils). The extent to re-commissioning depends on the extent of the change in the irradiator or the load that has taken place. If in doubt, re-commission.

Premises should be designed and operated to segregate irradiated from non-irradiated containers to avoid their cross-contamination. Where materials are handled within closed irradiation containers, it may not be necessary to segregate pharmaceutical from nonpharmaceutical materials, provided there is no risk of the former being contaminated by the latter. Any possibility of contamination of the products by radionuclide from the source must be excluded.

Irradiation containers should be packed in accordance with the specified loading pattern(s) established during validation.

During the process, the radiation dose to the irradiation containers should be monitored using validated dosimetry procedures. The relationship between this dose and the dose absorbed by the product inside the container must have been established during process validation and plant commissioning.

Radiation indicators should be used as an aid to differentiating irradiated from nonirradiated containers. They should not be used as the sole means of differentiation or as an indication of satisfactory processing.

Processing of mixed loads of containers within the irradiation cell should only be done when it is known from commissioning trials or other evidence that the radiation dose received by individual containers remains within the limits specified.

When the required radiation dose is by design given during more than one exposure or passage through the plant, this should be with the agreement of the holder of the marketing authorisation and occur within a predetermined time period. Unplanned interruptions during irradiation should be notified to the holder of the marketing authorisation if this extends the irradiation process beyond a previously agreed period.

Non-irradiated products must be segregated from irradiated products at all times. Methods of doing this include the use of radiation indicators (31.) and appropriate design of premises (28.).

For continuous processing modes, dosimeters should be placed so that at least two are exposed in the irradiation at all times.

For batch modes, at least two dosimeters should be exposed in positions related to the minimum dose position.

For continuous process modes, there should be a positive indication of the correct position of the source and an interlock between source position and conveyor movement. Conveyor speed should be monitored continuously and recorded.

For batch process modes source movement and exposure times for each batch should be monitored and recorded.

For a given desired dose, the timer setting or conveyor speed requires adjustment for source decay and source additions. The period of validity of the setting or speed should be recorded and adhered to.

A dosimeter should be placed on every container.

There should be continuous recording of average beam current, electron energy, scan-width and conveyor speed. These variables, other than conveyor speed, need to be controlled within the defined limits established during commissioning since they are liable to instantaneous change.

The numbers of containers received, irradiated and dispatched should be reconciled with each other and with the associated documentation. Any discrepancy should be reported and resolved.

The irradiation plant operator should certify in writing the range of doses received by each irradiated container within a batch or delivery.

Process and control records for each irradiation batch should be checked and signed by a nominated responsible person and retained. The method and place of retention should be agreed between the plant operator and the holder of the marketing authorisation.

The documentation associated with the validation and commissioning of the plant should be retained for one year after the expiry date or at least five years after the release of the last product processed by the plant, whichever is the longer.

Microbiological monitoring is the responsibility of the pharmaceutical manufacturer. It may include environmental monitoring where product is manufactured and pre-irradiation monitoring of the product as specified in the marketing authorisation.