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Guidelines for sterility testing of therapeutic goods
2. Sampling of lots
200. Relevant sections of the BP/Ph Eur: 'Application of the test to parenteral preparations, ophthalmic and other non-injectable preparations required to comply with the test for sterility'; 'Guidance to manufacturers'; Tables 2.6.1.-2 and 2.6.1.-3.
201. The sampling schedules in Tables 2 and 3 set out the minimum number of items to be sampled from each batch (lot) and the minimum quantity to be tested from each container, unless otherwise justified and authorised. The batch size and conditions of manufacture should be considered when planning a sampling regimen and larger numbers and quantities may be appropriate. It is assumed that the product has been manufactured under conditions designed to exclude contamination.
202. For the purposes of these Guidelines a batch of product is defined as a homogeneous collection of sealed containers prepared in such a manner that the risk of contamination is the same for each of the units of the batch. Where a batch is sterilised as a series of lots or sub- batches, each of which is subjected to a separate sterilising cycle or is subjected in processing to different treatment which may affect its sterility eg different freeze-drying cycles, each lot should be tested for sterility.
203. Any samples used for a sterility retest should reflect the original samples in terms of sampling locations or process times.
204. For aseptically prepared products, the samples should be taken at regular intervals during the filling operations in such a way that every filling point is represented by an approximately equivalent number of samples. Further, the first and last items dispensed at each filling point and the first item filled after any machine break-down or change, any non-validated intervention or interruption, should be included amongst the samples. Items selected as samples need not be discarded if they are under-filled provided they contain sufficient volume of product for the test. In the event of contamination being detected it is useful if the source and place in the filling run of samples can be identified.
205. For terminally sterilised products the samples should be made up from units drawn from various sites throughout the steriliser load. Some of the units should be taken from that place in the load known to be least accessible to the sterilising agent. Samples may be taken representatively from across each load, if the conditions for filling the containers were such as to satisfy the conditions for aseptically filled containers or the design of the equipment, the specification of the sterilising cycles and the validation data for each class of product are acceptable to the competent authority.
206. The minimum number of items or quantity to be tested may be inappropriate for some products and a smaller sample may be tested with the approval of the competent authority.
207. The testing of products which are of high intrinsic value or which are intended for use in clinical trials and which are dispensed in small volumes or produced in small lots of less than 20 containers, may be combined with the filling procedure using the following method:
- a sterile membrane filter is incorporated in the filling line;
- the containers are filled and a number of containers are sampled, the number and manner of selection being as specified in clause 204 and Table 2;
- the sample containers are swirled so as to ensure that the product contacts the entire internal surface of the container, and then, using aseptic procedures, the containers are
- opened and the contents are emptied back into the reservoir for the filling line;
- the product is then refilled into fresh containers;
- the in-line membrane filter is removed and tested for sterility by dividing it into two approximately equal portions and testing one portion in Fluid Thioglycollate Medium (Medium 1) and the other in Soybean-Casein Digest Medium (Medium 2) (see clauses 475-479).
208. Where the goods to be tested are intended for laboratory use only, the test for sterility may be performed on smaller samples than those indicated above, where rational considerations preclude such large-scale tests.
209. When the test method is membrane filtration, whenever possible, the whole contents of the container should be tested, but not less than the quantities indicated in Table 3.
|Type of product||Number of items in the batch||Minimum number of items to be tested for each medium2|
|Injectable pharmaceuticals Injectable medical devices Ophthalmic and other non- injectable pharmaceuticals in single-dose containers Ophthalmic medical devices in single-dose containers||Not more than 100||10% of batch or 4 containers, whichever is the greater|
|More than 500||2% of batch or 20 containers, whichever is the lesser|
|Ophthalmic and other non- injectable pharmaceuticals and medical devices not in single- dose containers||Not more than 200||5% of batch or 2 containers, whichever is the greater|
|More than 200||10 containers|
|Bulk solid products||Not more than 4||Each container|
|5-50||20% of batch or 4 containers, whichever is the greater|
|More than 50||2% of batch or 10 containers, whichever is the greater|
|Pharmacy bulk packages of antibiotics||Less than 5g||20 containers|
|Greater than or equal to 5g||6 containers|
|Solid medical devices||Not more than 100||10% of batch or 4 units, whichever is the greater|
|More than 500||2% of batch or 20 units, whichever is the lesser|
- This Table incorporates Table 2.6.1-3 (BP and Ph Eur) and Table 3 (USP).
- If the contents of one container are sufficient to inoculate the two media, this column gives the number of containers needed for both the media together.
|Type of product||Quantity of product in unit container||Minimum quantity/proportion to be used for each medium from each container2|
|Liquids||Less than 1 mL||The whole contents|
|1 - 40 mL||Half the contents but not less than 1 mL|
|41 - 100 mL||20 mL|
|Greater than 100 mL||10% of the contents but not less than 20 mL|
|Antibiotic liquids||N/A||1 mL|
|Other preparations soluble in water or isopropyl myristate||N/A||The whole contents to provide not less than 200 mg|
|Insoluble preparations, creams and ointments to be suspended or emulsified||N/A||The whole contents to provide not less than 200 mg|
|Solids||Less than 50 mg||The whole contents|
|50 - 299 mg||Half the contents but not less than 50 mg|
|300 mg to 5 g||150 mg|
|Greater than 5 g||500 mg|
|Solid medical devices||One or more dressings||100mg|
|One or more devices||One whole device3, cut/disassembled if necessary|
- This Table incorporates Table 2.6.1-2 (BP and Ph Eur) and Table 2 (USP).
- Unless otherwise justified and authorised
- Refer also to clauses 452 - 455.