EN 12298-1998 en Biotechnology - Equipment - Guidance on Testing Procedures for Leaktightness《生物技术 设备 泄漏安全性检验法指南》.pdf

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1、STD-BSI BS EN L2298-ENGL 1998 m lb24hh9 07285011 h57 BRITISH STANDARD Biotechnology - Equipment - Guidance on testing procedures for leaktightness * * (B The European Standard EN 122981998 has the status of a British Standard ICs 07.080 07.100.01 NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED

2、 BY COPYRIGHT LAW BS EN 12298: 1998 STD-BSI BS EN 12278-ENGL 1978 II lb2Libb9 0728505 595 been prepared under the direction of the Sector Board for hd. No. Da - present to the responsible European committee any enquiries on the - monitor related international and European developments and promulgate

3、 interpretation, or proposals for change, and keep the UK interests informed; them in the UK. A list of organktions represented on this committee can be obtained on request to its secrem. Cross-references The British Stanhds which implement international or European publications referred to in this

4、document may be found in the BSI Standards Catalogue under the section entitled “International Stan: , )peration of the equipment. More operating cycles ando: pxtreme conditions such as highest pressure, highest rotational speed, range of temperature on repeated cycle basis can be required. NOTE 2 i

5、n case of overpressure, the equipment can be regarded as a pressure vessel. Appropriate European and national regulations should be followed. The recommended test method for characterizing and comparing emissions of microorganisms from bioprocess equipment consists of measuring the leak rate. This e

6、nables equipment emissions to be compared independently of the microorganism concentration inside the equipment. As leakage can consist of aerosol andor liquid, the leak rate comprises both liquid leak rates and aerosol leak m. If practicable from a technical and practical viewpoint direct test meth

7、ods of determining leak rates are used since they are representative of the actual operating conditions. Indirect test methods are often more convenient in terms of speed, lack of contamination, economy, and ability for prolonged testing. NOTE 3 Data obtained from indirect methods should be correlat

8、ed with the release of microorganisms. Currently, validated correlations are lacking. Until such validated correlations have been established, results from indirect test methods should be used in accordance with common practice. NOTE 4 Appropriate testing conditions for components of equipment are g

9、iven in the relevant standards. NOTE 5 Additional information on test methods for leak testing can be obtained from annex C 12, 13, i41 and 15). O BSI 1998 STD-BSI BS EN 12298-ENGL 1778 1b24bb9 0728509 130 m Page 4 EN 122981998 3.2 Methodology ?b determine the leaktightness of piant and equipment, c

10、hoose and specify an appropriate test method or combination of test methods (see annexes A and B): a) specify an appropria indicator related to the proposed use of the equipment; b) select the analytical procedure to be used to determine the quantity of this indicator which is present in the equipme

11、nt or plant; c) specify a pressurization protocol including time and pressure. NOTE Potentid hazard to the operator during the pressurization should be assessed. 3.3 Testing procedure Cany out the testing procedures as follows: a) load the equipment or plant with the indicator under conditions repre

12、sentative of conditions during b) using the anaiytical procedure selected in 3.2, determine the quantity of indicator substance present at the time at which pressurization protocol would be applied; c) apply the pressurization protocol specified in 3.2 to the equipment or plant being tested for d) u

13、sing the analytical procedure selected in 3.2, determine the quantity of indicator present in the equipment or piant after application of the Pre- on protocol; e) using the data obtained, express the leaktighness of the equipment or plan$ f) determine the appropriate leaktightness class to the equip

14、ment under test as described in the equipment standards with respect to the chosen indicator and pressurization protocol processing; leaktightness; 3.4 Choice of test methods If the results of the test method should be quickly available and with a limited amount of work involved in leaktightness dem

15、onstration runs, indirect test methods should be used. Indirect test methods may however only be applied if a validated correlation between the measured effect and the desired pexformance has been shown. The required correlations are prepared for each unit of equipment or component. 3.6 Direct test

16、methods 3.6.1 Aerosol An example of a direct test method of measuring the aerosol emission is quantitative bioaerosol monitoring. This can be carried out as described in 3.6.1.1 and 3.6.1.2. 3.6.1.1 Preparation Quantitative bioaerosol monitoring is based on using the following: a) characterized test

17、 microorganism preferably non- pathogenic; b) characterized capture method for aerosolized microorganism; c) characterized detection method d) controlled environment where a representative amount of air should be sampled over the test period e) standardized microorganism concentration in a defined m

18、edium. 3.6.1.2 Procedure Determine the leak rates for biotechnological equipment as follows: a) ensure that the equipment under test is located in a controlled environment where emissions can be captured in a bioaerosol monitor; b) collect and assay a measurable quantim of microorganisms over a know

19、n sampi.ig time in the bioaerosol monitor; c) calculate the airborne microorganism concenation within the controlled environment with the known volumetric sampiing rate; d) calculate the emission rate from the airborne microorganism concentration multiplied by the total rate of removal of air from t

20、he controlled environment; e) calculate the leak rate by ividing the emission rate by the known microorganism concentration inside the equipment under test. NOTE Details of methods and attributes are described by Behiza et al. (see annex C 3) and Griffiths and Decosemo (see annex C 141). 3.6.2 Liqui

21、d Direct measurement of smal flows of liquid leakage can be achieved semiquantitatively by surface contact test methods such as swabbing and contact plates. In this case, estimates of the volume of carrier fluid are made. For larger leakage, liquid can be collected and the microorganism concentsatio

22、n determined. In this case estimates of the volume of carrier fluid are also mae. O BSI 1998 STDmSSI BS EN L229A-ENGL 1998 W Lb2Libb7 0728530 752 Page 6 EN 12298:1998 3.6 Indirect test methods indirect test methods can be used to determine the leak rate in aerosol or liquid form. if there are valida

23、ted correlations to the release of microorganisms, these should be used and reportea In the absence of such correlations, the result of the indirect test , :hod should be reported as a leak rate based on the : fluid or baca used. The following indirect test methods (see annex B) can be used for quan

24、titative leaktightnes measurement a) pressure stability test method with gas such as air, helium, sulfur hexafluoride (SF6) tracer gas, b) pressure stability test method with liquid; c) transmembrane gas diffusion and bubble point test method (lters only); d) particle counting; e) tracer fluis; f) v

25、acuum test method. 4 Documentation The equipment manufacturer/suppiier andor the user should establish and document the procedure(s) used for the assessment of the leaktightness of the component or unit of equipment. This documentation should include the applied test conditions (test method, indicat

26、or, anaytical procedure) and the resuits of the test. O BSI 1998 Page 6 EN 1229 severai of the test methods require the equipment to be pressurized above its normal working pressure with test pressures which are austed to the equation methods and the coefficients. The maximum permissible working pre

27、ssure should not be exceeded. I Pressure loss - gadair Pressure loss - liquid A.6 Access to the equipment If a piece of equipment fails a test, the location of a leak can be required so that it can be corrected and retested. Reasonable access to the potential leakage points becomes necem. Access can

28、 be as simple as being able to observe a leak by a bubble emission or it can be necessary to approach the equipment with probes. Access can also be a requirement of other test methods for leaktightness, e.g. access to a pressure gauge can be required when pressure stabiity testing equipment. A.7 Int

29、rusive test method An inmsive test method requires fluids other than the process fluid to be introduced into the equipment. This can be a tracer gas or fluid and is an important consideration if, for example, GMP (good manufacturing practice) could be compromised. 3 4 Table A.l- Test methods for lea

30、ktightness Helium probe SFOeon probe I I Number I Test method 5 6 Thermal conductivity ultrasonics 8 9 Mer liquid dyes Bubble point (filters only) 17 I snics (monitorjng only) I 10 11 Bubble formation (only qualitative) 1 Electronic wuticle counting 13 14 112 I Mer aerosol (NaC1) I Product aerosol (

31、non-microbial) Qualitative bioaerosol monitoring 15 16 Quantitative bioaerosol monitoring Surface swabbing Suface conductivity Visual mction (only qualitative) 17 18 I . - 19 I teria tightness * Use of BATNEEC does not mean that financial issues moderate the degree of safety. Where several methods a

32、re available, the user can choose the most convenient, provided that it gives results of the necessary quality. O BSI 1998 Page 7 EN 122981998 O BSI 1998 STD-BSI BS EN 32298-ENGL 1998 3b24bb7 0728533 bb3 Page 8 EN 12298:1998 O BSI 1998 STD.BSI BS EN 12298-ENGL 1998 lb24bb9 0728514 5T8 Page 9 EN 1229

33、 is the microorganism leak rate in numbers per second or in grams per second; is the concentration of microorganisms inside the equipment in numbers per milliltre or in grams per miliiiitre. The correlation is based on the assumption of homogenicity, which means first uniform distribution of the mic

34、roorganism inside the equipment and secondly the same concentration inside the equipment and in the released gas or liquid. It is well known that in some cases this assumption is not correct and can result in leak rates of microorganisms that are too high if determined by indirect test methods - in

35、case of pressure stability testing (gas or air) diffusion of gas through elastomer material will lead to a measured gas leak rate not contributing to leakage of microorganism; - in case of pressure stability testing (liquid) one can nd higher liquid aerosol release than estimated from measured leaka

36、ge of microorganism (see annex C 6). Therefore interpretation of test results always should take into account the specific aspects of the used testing procedures and experimental Set-ups. Considering this, the formula give above can be useful to: - calculate leakage of gas or liquid from counting re

37、leased microorganism; - calculate leakage of microorganism from measured leakage of gas or liquid - recalculate leak rates determined under specified test conditions to the conditions of equipment in use. Page 11 EN 122981998 B.2 Pressure stability testing (gas or air) B.2.1 General Pressure stabili

38、ty testing is a simple and straightforwxd means of determjnjng leak rates. The method consists of filling the system or equipment under test with gas, pressurizing the system, and recording pressure decrease over a period of time. The sophistication can range from noting the pressure hm a pressure g

39、auge to accurate and sensitive pressure transducers linked to automated data recording with microprocessor control. Pressure stability testing can be carried out during a long period of time (severai hours, or even a day). It is essential that equipment is capable of being pressurized. The test is m

40、ore suited to small equipment volumes for greater accuracy The test gas should be in thermal equilibrium with the equipment wail otherwise there will be changes of pressure not attributable to leakage. Variations of outside temperature should be followed. B.2.2 Example of procedure This clause gives

41、 an example of a pressure stability testing procedure. It should be as follows: a) check the caiibration of the pressure indicator and adjust if necessary; b) ensure equipment is clean, free from dust, fibres, etc; c) measure the absolute pressure and temperature of the surroundings; d) pressurize t

42、he equipment to a chosen pressure and isolate pressure line; e) ailow time for gas to come to the NOTE 1 During this waiting period, the pressure can fall. f) commence the test and note the initial pressure pi when the gas temperature and ambient temperature are the same; g) note the na pressure pf

43、at the end of the test time period t; NOTE 2 The ambient temperature should not change by more than a specified amount, typically 1 “C, over the test period. if temperature changes by more than 1 “C, appropriate austments of pressure should be carried out NOTE 3 The minimum data required are the tes

44、t volume, ambient temperature, time period, and the initial and the final pressures. With more pressure/time data, a plot of pressure against time will be approximately a straight line for laminar flow leaks. O BSI 1998 STD-BSI BS EN 32278-ENGL 1778 D Lb29bbS 0728537 207 Page 12 EN lz298:1998 The ga

45、s leak rate for the testing conditions is calculated from: where: is the test volume, in metres to the third power; is the ambient temperature of gas, in kelvins, is the testing time, in seconds, is the initial pressure, in pascals; is the final pressure, in pascals. Ps(1Ol0) Ls = fibin - Pou?) wher

46、e: L, is the standardized leak rate, in metre to the third power pascals per second; p is the gas viscosity, in pascal seconds at the temperature of assax p, is the gas viscosity at 298 K, in pascal seconds; pi, is the inside gas pressure, in pascals; pout is the outside gas pressure or ambient pres

47、sure, in pascals. The standardized leak rate is the leak rate that one would have if the pressure inside the equipment was atmospheric and the pressure outside was vacuum. It ailows comparison of data from tests carried out at different conditions. The formula for L, is only valid using absolute pre

48、ssure values. Equivaent liquid leak rates at operating conditions can be estimated from gas leak rates at test conditions by: where: Q istheestimated volumetric flow rate at operahg conditions, in metres to the third power per second; is the liquid viscosity at operating conditions, in pascal second

49、s, is the difference between inside pressure and outside pressure for liquid flow at operating conditions, in P-. Pliq i, - An estimate of potentid release of microorganisms is obtained by muitiplying Q by the microorganism concenti-ation in the feed. This concentration could be defined as a standard concenimiion for purposes of reporting the test The fomula for Q is only valid using absolute pressure values. B.3 Pressure stability testing (iiquid) Pressure stability testing with liquid is an altemative to gas pressurization. The systedequipment