EU-GMP-Part-II-Annexes-12.pdf
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1、115 ANNEX 12 USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL PRODUCTS Note The holder of, or applicant for, a marketing authorisation for a product which includes irradiation as part of its processing should also refer to the note produced by the Committee for Proprietary Medicinal Product
2、s giving guidance on “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
3、 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 arrang
4、ed 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
5、 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. Responsibilities 1.Treatment by irradiation may be carried out by the pharmaceutical manufacturer or by a
6、n operator of a radiation facility under contract (a “contract manufacturer”), both of whom must hold an appropriate manufacturing authorisation. 2.The pharmaceutical manufacturer bears responsibility for the quality of the product including the attainment of the objective of irradiation. The contra
7、ct 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). 3.The required dose including justified limits will be stated
8、 in the marketing authorisation for the product. 116 I Annex 12 Use of ionising radiation in the manufacture of medicinal products _ Dosimetry 4.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
9、 the validation, commissioning and control of the process. 5.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. 6.The same instrument should normally be
10、 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. 7.Depending on the type of dosimeter used, due account should be ta
11、ken of possible causes of inaccuracy including the change in moisture content, change in temperature, time elapsed between irradiation and measurement, and the dose rate. 8.The wavelength of the instrument used to measure the change in absorbance of dosimeters and the instrument used to measure thei
12、r thickness should be subject to regular checks of calibration at intervals established on the basis of stability, purpose and usage. Validation of the process 9.Validation is the action of proving that the process, i.e. the delivery of the intended absorbed dose to the product, will achieve the exp
13、ected 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”. 10.Validation should include dose mapping to establish the distribution of absorbed dose within the irradiation container when pac
14、ked with product in a defined configuration. 11.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 i
15、s 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
16、 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
17、 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. 117 _ Annex 12 Use of ionising radiation in the manufacture of medicinal products I Commi
18、ssioning of the plant General 12.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 maxim
19、um 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. 13.Commissioning should include the following elemen
20、ts: a)Design; b)Dose mapping; c)Documentation; d)Requirement for re-commissioning. Gamma irradiators Design 14.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 o
21、f 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. 15.The total absorbed dose will in
22、 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. 16.For a continuous irradiator with a fixed path or a batch irradiator with a fixed loading pattern, and with a given source strength and typ
23、e of product, the key plant parameter controlled by the operator is conveyor speed or timer setting. Dose Mapping 17.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 shoul
24、d 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. 18.The positioning of dosimeters
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