Validation Guide for Microsart @filter and Microsart @media
Table of Contents 1. Introduction 4 2 Quality and Its Assurance 5 2.1 Quality Assurance 5 2.2 Complete Traceability 5 2.3 DIN EN ISO Certificates 5 2.4 Product Quality Certificates 5 2.5 Requirements to Be Fulfilled 6 2.5.1 General Requirements 6 2.5.2 Requirements for Microbiological Examination of Non-sterile Products and of Pharmaceutical Water (EP 2.6.12, 2.6.13, 5.1.4, Chapter on Water for Injection; USP 61, 62, 2021, 2022) 6 5. Test Parameters for Quality Assurance 31 5.1 Test Parameters for Microsart @filter 31 5.1.1 Test Scheme 31 5.1.2 Quality Control Tests 32 5.2 Test Parameters for Microsart @media 33 5.2.1 Test Scheme 33 5.2.2 In-Process Quality Control Tests 34 5.2.3 Final Product Quality Control Tests 34 6. Conclusion 35 3. Technical Specifications 7 3.1 Product Description 7 3.2 Ordering Information 7 3.2.1 Microsart @filter 7 3.2.2 Microsart @media 8 3.3 Technical Specifications 9 3.3.1 Microsart @filter 9 3.3.2 Microsart @media 10 4. Validation Tests 13 4.1 Visual Tests 13 4.1.1 Microsart @filter 13 4.1.2 Microsart @media 15 4.1.3 Microsart @filter in Combination with Microsart @media 16 4.2 Analytical Tests 17 4.2.1 ph Measurement of Microsart @media 17 4.2.2 Fill Weight and Media Shrinkage of Microsart @media 17 4.3 Microbiological Tests 18 4.3.1 Growth Promotion Tests of Microsart @media 18 4.3.2 Microbial Recovery from Microsart @filter and Microsart @media 18 4.4 Sterilization Validation 24 4.4.1 Presterilization Bioburden of Microsart @filter 24 4.4.2 Examination of the Gamma Irradiation of Microsart @filter 25 4.4.3 Dose Mapping of Microsart @filter 26 4.4.4 Performance Test after Irradiation with 15 kgy 30 kgy 27 4.5 Shelf Life Tests Performed on Microsart @filter 28 4.6 Sterilization Validation Microsart @media 30 4.7 Shelf Life Tests Performed on Microsart @media 30
1. Introduction Pharmaceutical products, as well as water for injections (WFI) and raw materials (especially water), must conform to defined quality standards and regulations. The desired quality of the final product can be ensured only if the entire production process is adequately monitored and controlled. Microbiological in-process and final product quality control tests of non-sterile pharmaceuticals are performed according to the following pharmacopeia regulations. EP 2.6.12, EP 2.6.13 and USP <61> and <62> on Microbiological Examination of Non-sterile Products EP 5.1.4 and USP 2021 on Microbiological Quality of Non-sterile Pharmaceutical Preparations and Substances for Pharmaceutical Use EP and USP chapters concerning water (USP 1231, EP and USP Purified Water, Highly Purified Water and Water for Injection) Even more important than testing is the mitigation of any risks of secondary contamination, particularly at critical manufacturing points where the product is exposed to the environment. The lower the bioburden of raw materials used and the better the analysis of critical control points, the easier a final product can be released following final quality control testing. The process and the methods used for quality control must be validated and need to take all aspects of the product characteristics and of the production process into account. Validation is indispensable for confirming the safety of any pharmaceutical product. Therefore, it is a logical supplement to and a significant part of the cgmp regulations. Guidelines for validation are given in the U.S. Code of Federal Regulations Title 21 and in various pharmacopeias, such as the USP and EP. In addition, guidelines have been jointly established by the Committee for Laboratories and Official Drug Product Inspection Services as well as the Department of Industrial Pharmacists of the Fédération Internationale Pharmaceutique (F.I.P.). These guidelines define validation as follows: Validation, as used in these guidelines, comprises the systematic testing of essential production steps and equipment in R & D and production departments, including testing and inspection of pharmaceutical products, with the goal of ensuring that the finished products can be manufactured reliably and reproducibly and in the desired quality in keeping with the established production and quality control procedures. Sartorius follows the EEC guide to good manufacturing practice published by the Commission of the European Communities. This Validation Guide is a compilation of the qualification and validation procedures performed at Sartorius for the combined use of Microsart @filter and Microsart @media. The detailed information provided is intended to give you guidance on planning, implementing and documenting your own validation procedures for bioburden testing and or microbial limit testing. Such information covers the test methods used by Sartorius during product development and quality assurance (QA) and or quality control (QC), ranging from inspection of raw materials to the final release of Microsart products. In addition, Sartorius can design and perform such validation procedures according to your specific requirements. Because the Microsart system constituted by the combination of Microsart @filter and Microsart @media is designed for touch-free membrane transfer, it reduces the risk of secondary contamination to an absolute minimum. This convenient Quality by Design product will not only save you work, but will also give you confidence in the reliability of the results of your validation testing procedures. 4
2. Quality and Its Assurance 2.1 Quality Assurance The consistently high quality of Sartorius products is assured by careful selection of all raw materials in accordance with current regulations, such as FDA, CFRs and cgmp in-house standards; well-planned and validated production technologies; and an exceptionally efficient Quality Assurance Department. All of these measures together result in excellent batch-to-batch reproducibility. Documentation begins with the inspection of incoming raw materials, including in-process materials, molded parts, glue, etc., for the manufacturing process. Suppliers of these materials and parts are audited regularly. At Sartorius, compliance with cgmp requirements for example, on cleanroom conditions, gowning and personnel hygiene standards is monitored by documented in-process quality control tests, ensuring optimal quality control in standard operating procedures for manufacture. Final Microsart @filter and Microsart @media products undergo strict final quality control testing, which entails individual tests that are carried out on a representative number of samples. A lot is released only if all in-process and final quality control data are available and confirmed to be within the specifications. 2.2 Complete Traceability The type, lot number, sterilization and expiration date are printed on each Microsart @media dish as well as on the label on each bag and on each box of the product. For Microsart @filter this information is given on each bag tray of Microsart @filter (depending on which packaging type is being used) as well as on the outer box of the products. The traceable lot numbers allow convenient retrieval of all data compiled on the materials, production steps and QC tests used. 2.3 DIN EN ISO Certificates The quality management system of Sartorius AG has been certified for compliance by SQS International Certification Service GmbH with the following standards: the DIN EN ISO 9001 series on quality management systems; DIN EN ISO 14001 on environmental management systems; and DIN EN ISO 50001 on energy management systems. These International Standards have been adopted by the European Standards EN and transposed into national law by German Industrial Standards, DIN. All certificates can be downloaded from our website at: http://www.sartorius.com/en/ company/legal-documents/ 2.4 Product Quality Certificates The certificates of Microsart @filter are enclosed in each package of this product. The certificates of Microsart @media can be downloaded from the BD website at: http://regdocs.bd.com/regdocs/ regdocshomepage.do 5
2.5 Requirements to Be Fulfilled 2.5.1 General Requirements Requirements Steps Needed for Compliance Tests Completed A reliable and significant product quality needs to be assured. The products may not deteriorate during transport and storage. The system must allow the shortest possible test time. The system must be practical. User environmental safety must be ensured. Effective quality control procedures must be determined and performed. The integrity of the packaging must be maintained up to the time of use. No aging that could affect the function may occur, at least up to the indicated expiration date. Quick filtration of the sample has to be ensured. Graduated marks to simplify filling. Easy and contamination-free transfer of Microsart @filter to Microsart @media. The membrane may not burst. Touch-free contamination to prevent bacterial contamination. QC lot release tests (see Sections 5.1, 5.2) QC lot release tests (see Sections 5.1, 5.2) Shelf life tests (see Sections 4.5, 4.6) Flow rate for water Wetting time Drop adsorption test (see Section 5.1) Validation tests (see Section 4.1) Burst pressure test (see Section 5.1) Validation tests (see Section 4.3.2) 2.5.2 Requirements for Microbiological Examination of Non-sterile Products and of Pharmaceutical Water (EP 2.6.12, 2.6.13, 5.1.4, Chapter on Water for Injection; USP 61, 62, 2021, 2022) Requirements Steps Needed for Compliance Tests Completed Testing has to be carried out under The product must be sterile and fully functional. Sterilization validation conditions designed to avoid extrinsic The product design and handling enable (see Section 4.4) microbial contamination of the customers to avoid extrinsic contamination. Validation tests (see Section 4.3) product to be examined. Membrane filtration method: The method chosen must allow testing of a sufficient sample size. The suitability of the method selected must be verified. The ability of the test system to detect microorganisms must be demonstrated. The media must pass growth promotion tests. The enumeration method must be suitable for testing the product. The product design and handling enable customer to use different filtration volumes. Products used for membrane filtration are suitable for this application. Perform growth promotion tests with using a sterility test system. Test each batch of medium for growth-promoting ability. Perform growth promotion tests using the product. Validation tests (see Sections 4.1.3, 4.3.1, 4.3.2) QC lot release tests (see Section 5) Validation tests (see Sections 143.2.1, 143.2.2) QC lot release tests (see Section 305) Validation tests (see Section 143.2.1) QC lot release tests (see Section 305) To be done by the customer. 6
3. Technical Specifications 3.1 Product Description Microsart @filter units are used for microbial enumeration. They enable reliable detection and enumeration of microorganisms in pharmaceuticals, cosmetics, foods, beverages, water and other liquids. The devices are sterile, ready to use and combine a funnel and a gridded membrane filter all into one unit. The optimized design of Microsart @filter permits thorough rinsing of the system after filtration to remove inhibitors; no liquid is retained in the filter funnel. Microsart @media are dishes prefilled with different types of agar medium, sterile-packaged and ready to use. Together with the Microsart @filter units, they introduce a brand-new membrane transfer and agar media concept for microbial limit testing. The active lid of Microsart @media allows touch-free membrane transfer from the Microsart @filter base, thus reducing the risk of secondary contamination to an absolute minimum. Both products have been specifically developed for microbial limit testing according to the USP (Chapter <61>) and EP (Chapter 2.6.12). 3.2 Ordering Information 3.2.1 Microsart @filter Microsart @filter 100, sterile single-use filter units with lid, 47 mm, 100 ml, packaged on trays, ideal for use in clean benches, 24 units. Pore Size [µm] Membrane Filter* Color Grid Color Order No. 0.2 White Black 16D01--10-07--TG 0.45 White Black 16D01--10-06--TG 0.45, High Flow White Black 16D01--10-H6--TG 0.45, High Flow Gray White* 16D03--10-H6--TG 0.45 Green Dark green 16D02--10-06--TG Microsart @filter 250, sterile single-use filter units with lid, 47 mm, 250 ml, packaged on trays, ideal for use in clean benches, 16 units Pore Size [µm] Membrane Filter* Color Grid Color Order No. 0.2 White Black 16D01--25-07--TF 0.45 White Black 16D01--25-06--TF 0.45, High Flow White Black 16D01--25-H6--TF 0.45, High Flow Gray White* 16D03--25-H6--TF 0.45 Green Dark green 16D02--25-06--TF 0.65 Gray White* 16D03--25-05--TF Microsart @filter 100, sterile single-use filter units, 47 mm, 100 ml, stacked and packaged in bags, ideal for use with Microsart Funnel Dispenser, 60 units Pore Size [µm] Membrane Filter* Color Grid Color Order No. 0.2 White Black 16D01--10-07--BL 0.45 White Black 16D01--10-06--BL 0.45, High Flow White Black 0.45, High Flow Gray White* 16D03--10-H6--BL 0.45 Green Dark green 16D02--10-06--BL Microsart @filter 250, sterile single-use filter units, 47 mm, 250 ml, stacked and packaged in bags, ideal for use with Microsart Funnel Dispenser, 48 units Pore Size [µm] Membrane Filter* Color Grid Color Order No. 0.2 White Black 16D01--25-07--BK 0.45 White Black 16D01--25-06--BK 0.45, High Flow White Black 0.45, High Flow Gray White* 16D03--25-H6--BK 0.45 Green Dark green 16D02--25-06--BK 0.65 Gray White* 16D03--25-05--BK * Gray membranes; black after wetting 7
Microsart @filter 100, individually sterile-packaged, 100 ml capacity, with covers, 27 units Pore Size [µm] Membrane Filter* Color Grid Color Order No. 0.45, High Flow White Black 16D01--10-H6--ACG 0.45, High Flow Gray White* 16D03--10-H6--ACG 0.2 White Black 16D01--10-07--ACG Microsart @filter 250, individually sterile-packaged, 250 ml capacity, with covers, 18 units Pore Size [µm] Membrane Filter* Color Grid Color Order No. 0.45, High Flow White Black 16D01--25-H6--ACF 0.45, High Flow Gray White* 16D03--25-H6--ACF 0.2 White Black 16D01--25-07--ACF * Gray membranes; black after wetting 3.2.2 Microsart @media Microsart @media prefilled agar media dishes, sterile-doublepackaged and ready-to-use, quantity of 100 per box, 10 bags, each containing 10 media dishes. Media Type Microsart @media TSA (Tryptic Soy Agar) Microsart @media SDA (Sabouraud Dextrose Agar) Microsart @media R2A Target Microorganism Order No. Typical Incubation Time and Temperature Total count 14313--47----ACN 1 to 5 days (EP) or 48 to 72 hrs (USP) at 30 C to 35 C Yeasts and molds 14314--47----ACN 5 to 7 days at 20 C to 25 C Total count 14322--47----ACN 5 to 7 days at 20 C to 28 C 8
3.3 Technical Specifications 3.3.1 Microsart @filter Materials Funnel: polypropylene Base: ABS (acrylonitrile butadiene styrene) Membrane filter: cellulose nitrate (cellulose mixed ester); choice of various colors and grids Bacterial recovery testing has shown that the grid lines do not enhance or inhibit the growth of microorganisms. Capacity 100 ml; graduated marks at 20, 50 and 100 ml 250 ml; graduated marks at 50, 100, 200 and 250 ml Filter diameter 47 mm Filtration area 13.2 cm 2 Pore size 0.2, 0.45, 0.45 High Flow or 0.65 µm The pore size of the 0.2 µm membrane filters is determined by quantitative retention of Brevundimonas diminuta in accordance with the ASTM document F838-05 (2005) standard test method for determining the bacterial retention of membrane filters utilized for liquid filtration. The pore size of the 0.45 µm and 0.45 µm High Flow membrane filters is determined by retention of Serratia marcescens in accordance with the standard methods of water and wastewater. All membrane filters with a pore size of 0.45 µm meet the requirements of international standards, such as the European Drinking Water Directive 98 83 EC, the European Pharmacopoeia (EP), the U.S. Pharmacopeia and the American Standard Methods for Water and Wastewater. Max. operating pressure Vacuum only Sterilization Gamma irradiation; units have been irradiated to a safety assurance level (SAL) of 10-5 The sterilization process does not enhance or inhibit subsequent growth of microorganisms. ph of filter extract < 8.3 Thermal resistance 130 C max. Thickness acc. to DIN 53105 > 110 µm Chemical compatibility Aqueous solutions (ph 4 8), hydrocarbons and several other organic solvents Extractable content in water < 1% Wetting time < 5 s Area weight 47.5 g/m 2 Growth promotion test All the membrane filters tested exhibited excellent growth properties and typical colony morphology when challenged with a solution of approx. 100 colony-forming units (cfu). Recovery rates of total and coliform bacteria show that there is no influence on bacterial growth or development due to chemical extractables. Escherichia coli ATCC 8739: recovery > 90% vs. control lot filter tested according to ISO 7704. Pseudomonas aeruginosa ATCC 9027: recovery > 90% vs. control lot filter tested according to ISO 7704. Bubble Point with Water (Visual Method acc. to DIN 58355) Pore Size 0.2 µm 0.45 µm 0.45 µm High Flow 0.65 µm Bubble point > 3.5 > 2.0 > 2.0 > 1.8 Burst pressure 0.5 0.6 bar Typical flow rate for water [ml/(min + cm 2 + bar)] 20 70 100 130 9
3.3.2 Microsart @media Dimensions Materials Lid and base Membrane ring Adhesive Sterilization Plate appearance Fill Gel strength ph at 25 C Animal source Dish diameter Dish height Agar area Polystyrene Polypropylene Acrylate Agar media: R2A, TSA, SDA Inhibitor-free glue Gamma irradiation within a range of 11.8 kgy to 25.0 kgy R2A TSA SDA 8.0 9.5 ml Firm R2A TSA SDA See lot-specific certificates of analysis 68.8 mm 14.9 mm 13.2 cm 2 Pale to light tan and clear to trace hazy Light to medium tan yellow and clear to trace hazy Light tan cream to tan yellow and trace hazy 7.0 7.4 7.1 7.5 5.4 5.8 10
3.3.2.1 Biological Performance of Microsart @media The tests for biological performance were performed with spread plates and membrane filtration versus a reference agar. The inoculum was 10 cfu to 100 cfu for all test strains. TSA with 5% sheep blood was used as control for all tests. Specification: The recovery rate of the test strains must be satisfactory (= 50 % 200 % compared to the control) and must be comparable to a previously released batch. If the recovery rate cannot be quantified, there must be fair to heavy growth that has to be comparable to the control and to a previously released batch. Biological Performance for R2A Strain ATCC No. Incubation Temperature Incubation Time Result Bacillus subtilis 6633 30 35 C 3 days Satisfactory Candida albicans 10231 35 37 C 18 48 hrs Satisfactory Escherichia coli 8739 35 37 C 18 48 hrs Satisfactory Kocuria rhizophila 9341 35 37 C 18 48 hrs Satisfactory Pseudomonas aeruginosa* 9027 30 35 C 3 days Satisfactory Staphylococcus aureus 6538 35 37 C 18 48 hrs Satisfactory Staphylococcus epidermidis 12228 35 37 C 18 48 hrs Satisfactory * This strain has also been tested using the membrane filtration method. Biological Performance for TSA Strain ATCC No. Incubation Temperature Incubation Time Result Aspergillus brasiliensis 16404 30 35 C Up to 5 days Satisfactory Aspergillus brasiliensis 16404 20 25 C Up to 5 days Satisfactory Bacillus subtilis 6633 30 35 C Up to 3 days Satisfactory Bacillus subtilis 6633 20 25 C Up to 3 days Satisfactory Candida albicans 10231 30 35 C Up to 5 days Satisfactory Candida albicans 10231 20 25 C Up to 5 days Satisfactory Escherichia coli 8739 30 35 C Up to 3 days Satisfactory Kocuria rhizophila 9341 30 35 C Up to 3 days Satisfactory Pseudomonas aeruginosa* 9027 30 35 C Up to 3 days Satisfactory Staphylococcus aureus 6538 30 35 C Up to 3 days Satisfactory Staphylococcus epidermidis 12228 30 35 C Up to 3 days Satisfactory * This strain has also been tested using the membrane filtration method. 11
Biological Performance SDA Strain ATCC No. Incubation Temperature Incubation Time Result Aspergillus brasiliensis 16404 20 25 C 5 days Satisfactory Aspergillus fumigatus 26934 20 25 C 5 days Fair to heavy growth Candida albicans* 10231 20 25 C 5 days Satisfactory Candida albicans 10231 30 35 C 5 days Satisfactory Candida albicans 60193 20 25 C 5 days Fair to heavy growth Escherichia coli 8739 30 35 C 18 48 hrs Satisfactory Trichophyton mentagrophytes 8739 20 25 C 5 days Fair to heavy growth * This strain has also been tested using the membrane filtration method. The inoculum of the tests strains that are not counted is taken directly from plates and, therefore, not quantified. 12
4. Validation Tests 4.1 Visual Tests Background Microsart @filter and Microsart @media are manufactured under controlled conditions. All parts are treated with care so there are no scratches or any other visible damage. The agar has to be smooth and homogeneous and does not contain any particles or air bubbles. The methods and results are described in the following sections. For testing the Microsart @filter product group, Microsart @filter was chosen as representative of this group. The packaging in bags was selected as the type of packaging to provide the worst-case scenario in comparison with the tray version. 4.1.1 Microsart @filter Method The Microsart @filter products were inspected visually for the following: Dimensions of the base and funnel match tolerances specified on the drawing Volumetric accuracy: graduated marks within a tolerance range of ± 10 % Base-to-manifold fit (using manual force for attachment): bases must engage in disengage from manifold using the appropriate manual force. Base-to-manifold fit (vacuum automatically created): bases should fit on the manifold so that a sufficient vacuum can be created to enable rapid filtration. Funnel-to-base fit (using manual force for attachment): appropriate manual force required for device assembly Membrane flatness after assembly: membrane must lie flat within a tolerance of 2 mm Leak-tightness with 114H6 CN (cellulose nitrate = cellulose mixed ester) membrane: units leak-tight after 1 min. Hold-up volume: < 1 ml residual volume after filtration The labels of the products and their packaging have to be accurate, complete and identical to the reference photographs of labels. There may be no visible scratches or any other damage > 1 cm. 13
Results Test Product Order No. Lot No. No. of Samples Tested (per Product Lot) Dimensions match tolerances V2-00764 1000005669 1000005116 Volumetric accuracy 100 ml funnel 250 ml funnel Base-to-manifold fit (man. force) Base-to-manifold fit (auto. vacuum) Funnel-to-base fit (man. force) Membrane flatness after assembly Leak-tightness Hold-up volume Labeling is accurate, complete and identical to reference photographs. 1303005M T15.3.13 T52 151033M 1501021M 1305002RD 1305003RD No visible damage or scratches > 1 cm 1305002RD 1305003RD * All samples have to be within the specifications to pass. 8 Yes 24 Yes 180 Yes 96 Yes 96 Yes 180 Yes 180 Yes 180 Yes 20 Yes 20 Yes Passed* Yes No 14
4.1.2 Microsart @media Method The Microsart @media products were inspected visually for the following: Correct labeling of the outer and inner package (tested against reference photographs of labels) Visible damage to the packaging: The packaging must be intact; in particular, the inner packaging (bag) must be intact to ensure the sterility of the product. Visible damage to Microsart @media: There may be no visible scratches or any other damage > 1 cm. No plastic dishes may be broken. The agar must be homogeneous and of uniform color, and not contain any particles. The visual inspections further included testing of the color and consistency of the agar for a period of 38 weeks, with inspections after 8, 12, 18, 20, 26, 28, 32 and 38 weeks. The samples were stored at 2 C 8 C before testing. The consistency was tested by running a finger over the agar surface by applying slight pressure. Results Test Product Order No. Lot No. No. of Samples Tested (per Product Lot) Inspection of labeling of outer and inner packaging The packaging is intact and free of visible damage No visible scratches or any other damage ratches or and free of visible damage agar is homogeneous and of uniform color and does not contain any particles. The agar is firm to the touch, pale to light tan and clear to trace hazy. The agar is firm to the touch, light to medium tan yellow and clear to trace hazy The agar is firm to the touch, light tan cream to tan yellow and trace hazy TSA: 14313--47----ACN SDA: 14314--47----ACN R2A: 14322--47----ACN TSA: 14313--47----ACN SDA: 14314--47----ACN R2A: 14322--47----ACN TSA: 14313--47----ACN SDA: 14314--47----ACN R2A: 14322--47----ACN R2A: 14322--47----ACN TSA: 14313--47----ACN SDA: 14314--47----ACN 3070098 3112270 3170348 20 Yes 3070100 20 Yes 3112269 3070103 20 Yes 3070098 3112270 3170348 20 Yes 3070100 20 Yes 3112269 3070103 20 Yes 3070098 3112270 3170348 20 Yes 3070100 20 Yes 3112269 3070103 20 Yes 3283226 3283228 3283236 3281360 3281364 3282242 3282239 3282240 3282241 1 per lot and point in time 1 per lot and point in time 1 per lot and point in time Passed* Yes No Yes Yes Yes * All samples have to be within the specifications to pass. 15
4.1.3 Microsart @filter in Combination with Microsart @media For testing of the Microsart @filter product group, Microsart @filter was chosen as representative of this group. The packaging in bags was selected as the type of packaging to provide the worst-case scenario in comparison with the tray version. Membrane transfer from Microsart @filter base to Microsart @media: The membrane must be easily transferred to Microsart @media. There may be no visible bubbles, pleats or waviness of the membrane on the agar. There may be no glue sticking to the underside of the membrane. The membrane is glued correctly and uniformly to fit concentrically over the ring of medium in Microsart @media. Results Test Product Order No. Lot No. No. of Samples Tested (per Product Lot) The membrane can be easily transferred to Microsart @media. No visible bubbles, no pleats or waviness of the membrane on the agar. No glue sticks to the underside of the membrane. The membrane is glued correctly and uniformly to fit concentrically over the ring of medium in Microsart @media * All samples have to be within the specifications to pass. 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 20 Yes 20 Yes 20 Yes Passed* Yes No 16
4.2 Analytical Tests 4.2.1 ph Measurement of Microsart @media Background The Microsart @media products have a specified ph (see Section 3.3.2). The ph must remain stable throughout the shelf life of the products. The ph of the media was measured by BD in its validation study and is required to be within the specified range (see Section 3.3.2). Method The method used is described in the validation report issued by BD. Results The results of the ph measurement are documented in the validation report issued by BD. All products passed the test. For further information, please contact BD. 4.2.2 Fill Weight and Media Shrinkage of Microsart @media Background The Microsart @media products have a specified fill volume (see Section 3.3.2) that has to remain stable throughout the shelf life of the products. Measurements of the fill weight and media shrinkage were performed by BD in their validation study. The fill weight and media shrinkage must be within the specified range (see Section 3.3.2). Method The method used is described in the validation report issued by BD. Results The results of the fill weight and media shrinkage measurements are documented in the validation report issued by BD. All products passed the test. For further information, please contact BD. 17
4.3 Microbiological Tests 4.3.1 Growth Promotion Tests of Microsart @media Background For the method according to EP 2.6.12 and USP 61, each lot of growth media must be tested for its growth-promoting ability throughout its shelf life. Therefore, growth promotion of Microsart @media has been validated by BD. The products have to be within the specified range (3.3.2.1). Method The method used is described in the validation report issued by BD. Results The results of growth promotion tests are documented in the validation report issued by BD. All products passed the test. For further information, please contact BD. 4.3.2 Microbial Recovery from Microsart @filter and Microsart @media Background Microsart @filter and Microsart @media were tested in their intended use to demonstrate their ability to promote the growth of microorganisms. The strains specified by the EP 2.6.12 and USP 61 for the growth promotion tests based on membrane filtration were used in the present validation study. For testing the Microsart @filter product group, Microsart @filter was chosen as representative of this product group. The packaging in bags was selected as the type of packaging to provide the worst-case scenario in comparison with the tray version. For the validation tests, 3 lots of Microsart @filter were tested in combination with at least one lot of Microsart @media with the microorganisms shown below. Strain ATCC No. Manufacturer Lot Number Aspergillus brasiliensis 16404 Microbiologics 392-152-1 Bacillus subtilis 6633 LGC Promochem 59138416 Candida albicans 10231 LGC Promochem Q A 6904 Escherichia coli 8739 LGC Promochem 59740475 Pseudomonas aeruginosa 9027 Microbiologics 484-232-7 Salmonella enterica subsp. enterica 14028 Microbiologics 363-123-13 serovar typhimurium Staphylococcus aureus 6538 LGC Promochem 58834359 18
Tests were performed per Microsart @filter lot according to the validation matrix below. Test Organism TSA Merck Samples to be Plated on Agar Filters of Reference Lot (conventional filtration in stainless steel devices) TSA Microsart @media Sabouraud Dextrose Merck Sabouraud Dextrose Microsart @media R2A Oxoid R2A Microsart @media TSA Merck TSA Microsart @media Sabouraud Dextrose Merck Sabouraud Dextrose Microsart @media R2A Oxoid R2A Microsart @media TSA Merck TSA Microsart @media Filters per Product Lot Sabouraud Dextrose Merck Sabouraud Dextrose Microsart @media R2A Oxoid R2A Microsart @media Bacillus subtilis 20 20 20 20 20 20 20 20 20 20 20 20 Escherichia coli 20 20 20 20 20 20 Pseudomonas aeruginosa 20 20 20 20 20 20 20 20 20 20 20 20 Salmonella enterica subsp. Enterica serovar typhimurium 20 20 20 20 20 20 Staphylococcus aureus 20 20 20 20 20 20 Aspergillus brasiliensis 20 20 20 20 20 20 20 20 20 20 20 20 Candida albicans 20 20 20 20 20 20 20 20 20 20 20 20 A total of 60 filters per test organism and growth medium were tested, resulting in 440 filters per Microsart @filter lot and an overall sample size of 1,320 filters. For robustness testing, P. aeruginosa was tested on all three Microsart @filter lots with R2A in Goettingen, Germany, and with TSA in India. Acceptance criteria: the mean recovery of all test organisms by the filters and by Microsart @media must be >70 % compared plates (spread plates) and > 80% compared to the reference membrane on reference agar, with confidence intervals of 95%. 19
Method Preparation of the Test Microorganisms (Working Cultures) For filtration, cells from the cryo-cultures were transferred into 10 ml of liquid TSA medium. Bacteria were incubated at 30 C 35 C for 24 hours. Candida albicans was incubated at 20 C 24 C for 3 5 days. These precultures were stored for 1 7 days at 4 C 8 C for use in filtration trials. Aspergillus brasiliensis was purchased in predetermined titers and was suspended according to the suppliers instructions directly before filtration. Test Protocol 1. Prepare a serial dilution of the culture to a final concentration of 100 cfu/50 µl. 2. Prepare a spread plate with 50 µl of the cell suspension (100 cfu/50 µl) onto 1 plate of reference agar. 3. Prepare a spread plate with 50 µl of the cell suspension (100 cfu/50 µll) onto 1 plate of Microsart @media. 4. Place 2 reference filters and 2 Microsart @filter units into the corresponding filtration units (if all 3 validation lots of Microsart @filter are tested, use 2 Microsart @filter units of each validation lot => 6 filters total). 5. Prefill all 4 funnels with 10 ml of phosphate buffer (all organisms except B. subtilis) or peptone buffer (B. subtilis) each (with the vacuum tap closed). 6. Add 50 µl of the cell suspension (100 cfu/50 µl) to each funnel, mix gently and filter. 7. Place reference filters onto 1 reference agar plate and 1 Microsart @media plate. 8. Place Microsart @filter onto 1 reference agar plate and 1 Microsart @media plate. 9. Repeat steps 1 7 nineteen times (to have 20 samples each). 10. Incubate all agar plates upside down for 24 48 h at 30 C 35 C (bacteria) or 1 5 days at 20 C 24 C (molds). 11. Check colony morphology and record the cell count; take photos of each plate. 12. Document results and photos. Only plate counts of 30 to 250 cfu/plate (bacteria) or 15 to 150 cfu/plate (yeasts/molds) were used in this validation. If the titer of more than 3 plates per sample (of 20 samples) was out of this range, the entire test was repeated. 20
Results Test Strain Media Type Bacillus subtilis with TSA Bacillus subtilis with R2A Escherichia coli with TSA Pseudomonas aeruginosa with TSA Pseudomonas aeruginosa with R2A Salmonella enterica with TSA Staphylococcus aureus with TSA Aspergillus brasiliensis with TSA Aspergillus brasiliensis with SDA Candida albicans with TSA Candida albicans with SDA Acceptance Criteria > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared > 70 % recovery compared > 80 % recovery compared Lot No. Microsart @filter 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD 1305002RD 1305003RD Lot No. Microsart @media No. of Samples Tested (per Product Lot) 3112270 20 Yes 20 Yes 3070103 20 Yes 20 Yes 3070098 20 Yes 20 Yes 3112270 20 Yes 20 Yes 3070103 20 Yes 20 Yes 3070098 20 Yes 20 Yes 3070098 20 Yes 20 Yes 3170348 20 Yes 20 Yes 3112269 20 Yes 20 Yes 3112270 20 Yes 20 Yes 3070100 20 Yes 20 Yes Passed* Yes No * All samples have to be within the specifications to pass. Microsart @filter validation lots were labeled as: Lot 1302024RD = validation lot 1; lot 1305002RD = validation lot 2; lot 1305003 RD = validation lot 3 21
In the following graphs (Figs. 1 3), exemplary validation results are shown for all three validation lots of Microsart @filter with each Microsart @media type and three different microorganisms. Fig. 1: Validation Results for Pseudomonas aeruginosa on R2A Recovery [cfu/plate] Recovery of Pseudomonas aeruginosa on Microsart @filter 16D01 on Microsart @media R2A in comparison to reference agar and reference membrane 90 80 70 60 50 40 30 20 10 0 Reference agar 100% 81% 81% 78% 103% 108% 99% 103% 102% 96% Microsart @media ref. filter on reference agar ref. filter on Microsart @media Microsart @filter lot 1 on ref. agar Microsart @filter lot 2 on reference agar Microsart @filter lot 1 on Microsart @media Filter and or Growth Medium Microsart @filter lot 3 on reference agar Microsart @filter lot 2 on Microsart @media Microsart @filter lot 3 on Microsart @media The recovery is shown in cfu/plate and in percent (with the reference agar as 100%). 22
Fig. 2: Validation Results for Escherichia coli on TSA with Validation Lot Recovery of E. coli on Microsart @filter 16D01 and Microsart @media TSA in comparison and membrane Recovery [cfu/plate] 90 80 70 60 50 40 30 20 10 0 Reference agar 100% 98% 103% 105% 110% 109% Microsart @media reference filter on reference agar reference filter on Microsart @media Microsart @filter on reference agar Microsart @filter on Microsart @media Filter and or Growth Medium The recovery is shown in cfu/plate and in percent (with the reference agar as 100%). Fig. 3: Validation Results for Aspergillus brasiliensis on SDA Recovery [cfu/plate] Recovery of Aspergillus brasiliensis on Microsart @filter 16D01 and Microsart @media Sabouraud dextrose agar in comparison and reference membrane 90 80 70 60 50 40 30 20 10 0 Reference agar 100% 73% 110% 105% 103% 122% 103% 115% 106% 116% Microsart @media ref. filter on reference agar ref. filter on Microsart @media Microsart @filter lot 1 on ref. agar Microsart @filter lot 2 on reference agar Microsart @filter lot 1 on Microsart @media Filter and or Growth Medium The recovery is shown in cfu/plate and in percent (with the reference agar as 100%). Microsart @filter lot 3 on reference agar Microsart @filter lot 2 on Microsart @media Microsart @filter lot 3 on Microsart @media 23
4.4 Sterilization Validation Background A series of tests is needed to confirm that a sterilization procedure has been carried out successfully. Sterility testing of a system is used to prove that the entire contents of the inner packaging are sterile. The growth promotion test ensures that no sterilization process residue that could promote or inhibit the subsequent growth of microorganisms remains inside the packaging. Sartorius uses gamma irradiation to sterilize Microsart @filter products. This procedure is carried out as required by DIN EN 552 ( Sterilization of medical devices) and ISO 11137 (Sterilization of health care products). The Microsart @media products are sterilized at BD by gamma irradiation as required by ISO 11137. 4.4.1 Presterilization Bioburden of Microsart @filter Background The European Pharmacopoeia describes how the safety assurance level (SAL) of sterilization processes is calculated. The microbial load of a system is determined before sterilization to ensure that the burden is not too high for the sterilization process in order for this process to be reliable. For every type of packaging, one product was tested as representative of each type. Acceptance Criteria: The average of 10 units must be < 100 cfu per unit. Method The bioburden for all inner surfaces of Microsart @filter was determined by filling, shaking and rinsing the units in succession. The rinsing solution collected was filtered through a 0.45 µm gridded membrane filter made of cellulose nitrate (cellulose mixed ester). The filter was transferred to TSA and incubated for 5 7 days at 30 C 35 C. The resulting colonies were counted. Results Product Order No. Lot No. No. of Units Tested Average Bioburden Inner Surface (cfu) 16D01--25-06--TF 1403023RD 10 3.6 Yes 16D01--10-06--TG 1403024RD 10 2.1 Yes 16D01--25-06--BK 1403025RD 10 1.9 Yes 16D01--10-06--BL 1403026RD 10 2.6 Yes Conclusion The bioburden of the Microsart @filter products is low enough to ensure that any standard sterilization procedure using gamma irradiation will reduce the bioburden to zero. Passed Yes No 24
4.4.2 Examination of the Gamma Irradiation of Microsart @filter Background The validation of gamma irradiation was carried out according to ISO 11137-2 and with a safety assurance level (SAL) level 10-2. This corresponds to a minimum dose of 3.6 kgy. Of each funnel size of Microsart @filter, one representative type was selected and sterilized. Afterwards, a sterility test according to EP USP was performed. Acceptance Criteria: 8 of 8 units must be sterile. Method After sterilization of the Microsart @filter products in their original packaging, the individual packaging was opened under sterile conditions. Four Microsart @filter units were then placed in 600 ml of TSB broth (tryptone soy broth) and incubated under aerobic conditions for 14 days at 30 C 35 C. Four units were placed in thioglycollate medium and incubated under anaerobic conditions for 14 days at 20 C 25 C. The sterility of the samples was checked regularly during the incubation period. Results Product Order No. Lot No. No. of Sterile Units in TSB No. of Sterile Units in Thioglycollate Medium 16D01--10-06--TG 1403024RD 4 4 Yes 16D01--25-06--BK 1403025RD 4 4 Yes Conclusion The results demonstrate that even a minimum dose of 3.6 kgy sterilizes all Microsart @filter units tested. Therefore, it can be assumed that sterilization with 15 kgy 30 kgy will always produce a sterile product. In addition, the results of the bioburden test and the sterility test at the minimum dose demonstrate compliance with ISO 11137 by a safety assurance level (SAL) of 10-5. Passed Yes No 25
4.4.3 Dose Mapping of Microsart @filter Background The purpose of the dose mapping study was to evaluate the minimum and maximum dose locations and determine adjustment factors for the calculation of the minimum and maximum dose in the dose reference point for the routine gamma processing. Acceptance Criteria: The dose in the product must be 15 kgy 30 kgy at all control points. Method During dose mapping according to DIN EN ISO 11137 1, the dosimeters are placed on the packed pallet at various depths on two parallel levels according to a predefined pattern, one on the surface and one in the middle of the pallet. The density and the specific weight of the load were determined to establish a dose mapping guide value for the sterilizer. After sterilization, all dosimeters were subjected to photometric analysis. Dosimeter manufacturer: FWT Far West Technology, USA Dosimeter type: Nylon dosimeter FWT60-00 Photometer manufacturer: Spectronic Genesys Photometer type: Spectronic Genesys-5 Calibrated with: NPL (National Physical Laboratory, England) - Aérial dosimeter Results Product Family: Microsart @filter, 100 ml Bag Version Representative Product of this Product Family:, lot 1401013VS Level I (Measuring Depth 0 cm) Width [cm] 5 28.5 52 Passed Yes No Dosimeter on the surface 160 26.32 27.20 26.18 Yes Reference dosimeter 70 25.89 26.47 26.62 Yes Dosimeter in the geometric middle 55 25.60 25.46 24.75 Yes Dosimeter on the surface 15 24.04 23.34 23.90 Yes Level II (Measuring Depth 37 cm) Width [cm] 5 28.5 52 Passed Yes No Dosimeter on the surface 160 22.51 21.83 21.29 Yes Dosimeter in the geometric middle 55 22.10 22.65 21.69 Yes Dosimeter on the surface 15 20.08 20.48 20.35 Yes Product Family: Microsart @filter, 100 ml Tray Version Representative Product of this Product Family: 16D01--10-H6--TG, lot 1401015VS Level I (Measuring Depth 0 cm) Width [cm] 5 26.5 48 Passed Yes No Dosimeter on the surface 172 25.46 26.31 26.32 Yes Reference dosimeter 70 25.17 25.89 25.89 Yes Dosimeter in the geometric center 55 25.89 25.32 26.12 Yes Dosimeter on the surface 15 24.32 24.04 24.32 Yes Level II (Measuring Depth 39.5 cm) 1 International Standard ISO 11137 fully adopted by the European Standard EN and transposed into German national law DIN (German Industrial Standard); the German version is identical to ISO 11137 Width [cm] 5 26.5 48 Passed Yes No Dosimeter on the surface 172 21.83 22.24 21.69 Yes Dosimeter in the geometric center 55 22.24 21.15 22.10 Yes Dosimeter on the surface 15 20.35 22.24 21.15 Yes 26
Product Family: Microsart @filter, 250 ml Bag Version 4.4.4 Performance Test after Irradiation with 15 kgy 30 kgy All physical testing detailed in 4.1.1 was carried out on final irradiated product. Representative Product of this Product Family:: 16D03--25-H6--BK, lot 1401018VS Level I (Measuring Depth 0 cm) Width [cm] 5 28.5 52 Passed Yes No Dosimeter on the surface 172 27.79 28.53 27.94 Yes Reference dosimeter 70 27.79 26.47 27.05 Yes Dosimeter in the geometric center 55 27.35 28.53 27.94 Yes Dosimeter on the surface 15 25.60 25.60 27.20 Yes Level II (Measuring Depth 37 cm) Width [cm] 5 28.5 52 Passed Yes No Dosimeter on the surface 172 23.48 22.92 22.92 Yes Dosimeter in the geometric center 55 22.92 22.92 22.51 Yes Dosimeter on the surface 15 20.21 21.02 20.35 Yes Product Family: Microsart @filter, 250 ml Tray Version Representative product of this product family: 16D01--25-06--TF, lot 1402007VS Level I (Measuring Depth 0 cm) Width [cm] 5 26.5 48 Passed Yes No Dosimeter on the surface 172 27.94 28.39 28.39 Yes Reference dosimeter 70 28.53 28.83 28.83 Yes Dosimeter in the geometric center 55 28.53 27.79 28.24 Yes Dosimeter on the surface 15 27.20 26.32 26.76 Yes Level II (Measuring Depth 39.5 cm) Width [cm] 5 26.5 48 Passed Yes No Dosimeter on the surface 172 23.76 23.48 23.90 Yes Dosimeter in the geometric center 55 23.62 23.48 24.18 Yes Dosimeter on the surface 15 23.90 24.04 23.06 Yes Conclusion When the validation procedure is followed, Microsart @filter units are gamma-irradiated, as required, with a dose of 15 kgy 30 kgy reaching all areas. 27
4.5 Shelf Life Tests Performed on Microsart @filter The shelf life of Microsart @filter was tested after 1 month as well as after 3, 12 and 24 months. Devices tested after 1 month Test Product Order No. Lot No. No. of Samples Tested Passed* Yes No (per Product Lot) Visual inspection Base-to-manifold fit (manual force) Base-to-manifold fit (automatic vacuum) Funnel-to-base fit (manual force) Leak-tightness Membrane flatness after assembly Devices tested after 3 months Test Product Order No. Lot No. No. of Samples Tested Passed* Yes No (per Product Lot) Visual inspection Base-to-manifold fit (manual force) Base-to-manifold fit (automatic vacuum) Funnel-to-base fit (manual force) Leak-tightness Membrane flatness after assembly Devices tested after 12 months Test Product Order No. Lot No. No. of Samples Tested Passed* Yes No (per Product Lot) Visual inspection Base-to-manifold fit (manual force) Base-to-manifold fit (automatic vacuum) Funnel-to-base fit (manual force) Leak-tightness Membrane flatness after assembly 16D01--25-H6--B * All samples have to be within the specifications to pass. 28
Devices tested after 24 months Test Product Order No. Lot No. No. of Samples Tested Passed* Yes No (per Product Lot) Visual inspection Base-to-manifold fit (manual force) Base-to-manifold fit (automatic vacuum) Funnel-to-base fit (manual force) Leak-tightness Membrane flatness after assembly * All samples have to be within the specifications to pass. 16D01--25-H6--B 29
4.6 Sterilization Validation of Microsart @media Background The purpose was to establish the level of sterility assurance for the Microsart @media products at 10-6. The validation was conducted in compliance with the BD Corporate Process Validation Procedure (CPR-069). As a guideline for this validation, BD used American National Standard ANSI/AAMI/ISO 11137-2:2012 - Sterilization of health care products - Radiation - Part 2 Establishing the sterilization dose (Method 2A). This standard is referred to as the AAMI guideline. Method A Sterility Assurance Level (SAL) 10-6 was selected. Incremental dosing was conducted on three lots of a representative medium with subsequent dose verification on a fourth lot. Biological performance at the high end of the gamma irradiation range was evaluated. A minimum of three lots of each Microsart @media type was evaluated for growth promotion and recovery of microorganisms, according to product specifications. Physical parameters including ph, appearance and consistency were also evaluated. Release Criteria As part of the validation of the SAL claim, the identified processes and monitoring results are reviewed for conformance to predetermined validation criteria and product specifications. All specifications need to be met for release. Procedure and Testing The validation was conducted according to BD Corporate Process Validation Procedure (CPR-069), using the AAMI guideline. For this study, a unit was defined as one dish of prepared medium. Samples were taken from three production lots from an aseptic filling line used for manufacturing Microsart @media. The samples were used to perform an incremental dose experiment according to method 2A of the AAMI guideline. In this experiment, samples were exposed to a series of irradiation doses, ranging from 2 to 20 kgy. After exposure, these samples were tested for sterility. Samples of a fourth lot were irradiated at a verification dose, calculated from results of the incremental dose series. These calculations were made following the AAMI guideline. In addition, sterility testing was conducted on this lot after irradiation. Results of the testing of the verification dose lot were used to establish the sterilization dose of the Microsart @media agar dishes. The acceptance criteria were met and the gamma irradiation processing range was established at 11.8 to 25.0 kgy for an SAL of 10-6. Performance at High-End Dose The Microsart @media product line was subjected to a high-end gamma irradiation dose of 25.0 kgy to 27.0 kgy and evaluated for performance. Three lots were tested for growth promotion using a quantitative method in which samples were inoculated with 10 to 100 colony forming units of appropriate microorganisms and compared to an approved control lot for verification of recovery and growth capabilities of the medium. Recovery of the test organisms was greater than or equal to 50 % of the recovery on the control lot. In some cases, a qualitative method was used for evaluation of fungal organisms. Recovery of these organisms on the test lots was comparable to recovery on the control lot. Physical parameters including ph, appearance and consistency were also verfied for each lot. Real time stability testing was done. These studies were conducted on plates stored at 2 8 C with a 10-day room temperature storage interval at the end of the stability period. The Microsart @media products fulfilled the stability testing. Stability data are on file for all product types. 4.7 Shelf Life Tests Performed on Microsart @media BD tested the shelf life of Microsart @media in its validation study (see Sections 4.1, 1.1, 4.3). Please contact BD for more information. 30
5. Test Parameters for Quality Assurance 5.1 Test Parameters for Microsart @filter 5.1.1 Test Scheme Funnel and base Injection molding flaws and residues No particles > 1 mm Damage Water leak test of base and funnel Membrane filter Bacteria challenge test with 10-7 cfu/cm 2 Brevundimonas diminuta (0.2 µm pore size) or Serratia marcescens (0.45 µm pore size) Growth promotion test with Escherichia coli and Pseudomonas aeruginosa Bubble point Burst pressure Flow rate for water Thickness Mass per unit area Extractables for water Wetting time for water Drop adsorption time with NaCl Filtration device Visual inspection of packaging 31
5.1.2 Quality Control Tests Test Type Membrane Filter Bacteria challenge test with Brevundimonas diminuta Bacteria challenge test with Serratia marcescens Growth promotion test Reference and Test Method Equipment Acc. to DIN 58355; suspension of B. diminuta (filters with 0.2 µm pore size) Acc. to standard methods of water and wastewater; suspension of S. marcescens (filters with 0.45 µm pore size) Acc. to DIN EN ISO 7704; suspensions of Escherichia coli and Pseudomonas aeruginosa Reference to Method Description Internal SOP Internal SOP Internal SOP Measuring Unit Number of filtrates, sterile non-sterile Number of filtrates, sterile non-sterile In % recovery compared to reference filter Bubble point test Visual test acc. to DIN 58355, Internal SOP In bar (~ 14.5 psi) compressed air, calibrated measuring device Burst pressure test Compressed air, calibrated measuring Internal SOP In bar device Flow rate for water Acc. to DIN 58355; water, pressure Internal SOP In ml/(min + cm 2 + bar) gauge, stop watch, balance Thickness Acc. to DIN 53105; thickness gauge Internal SOP In µm Mass per unit area Balance Internal SOP In g/m 2 Extractables for water Boiled water, moisture analyzer, Internal SOP In % balance Wetting time for water Water, stopwatch Internal SOP Seconds (sec.) Drop adsorption time with NaCl Pipet, stopwatch, NaCl solution Internal SOP Seconds (sec.) Base Funnel Visual inspections Task lighting, inspection lamp with magnifier Internal SOP Number of rejected devices Water leak tests Device Assembly Packaging Visual inspections Vacuum pump, filtration equipment, water Task lighting, inspection lamp with magnifier Internal SOP Internal SOP Percentage of rejected devices Percentage of rejected devices 32
5.2 Test Parameters for Microsart @media 5.2.1 Test Scheme Plastic parts Visual inspections: Absence of damage No flash No sink holes Clarity of base and lid Ring correctly glued Fit and function: All parts fit Agar media Agar fill volume ph Biological performance 33
5.2.2 In-Process Quality Control Tests Test Type Reference and Test Method Equipment Plastic Parts Visual inspections No flash No sink holes Clarity of base and lid Gluing of ring Fit and function Ring must fit base and lid Lid must fit ring Base must fit ring Reference to Method Description Measuring Unit Inspection lamp with magnifier Internal SOP Percentage of rejected devices None Internal SOP Percentage of rejected devices 5.2.3 Final Product Quality Control Tests Test Type Agar fill volume Correct ph Reference and Test Method Equipment Please refer to BD site for further information Please refer to BD site for further information Reference to Method Description BD s internal SOP BD s internal SOP Measuring Unit Biological performance 8 microbial strains (3.3.2.1) BD s internal SOP Growth percentage of recovery In ml ph 34
6. Conclusion Using the validation and quality assurance measures presented in this Validation Guide (Sections 4 to 5), the independent testing laboratory of BD verified that the Microsart @filter and Microsart @media products comply with the applicable national and international standards (e.g., DIN EN ISO 7704 2 ) and with the European and U.S. pharmacopeias. All relevant standards are specified in the individual sections of this document. This Validation Guide is provided as guidance to help Sartorius customers perform their own specific validation procedures on these products and reduce their validation time and effort. 2 Water quality Evaluation of membrane filters used for microbiological analyses 35
Sales and Service Contacts For further contacts, visit www.sartorius.com Europe Americas Asia Pacific Germany Sartorius Lab Instruments GmbH & Co. KG Otto-Brenner-Strasse 20 37079 Goettingen Phone +49.551.308.0 Fax +49.551.308.3289 France & Suisse Romande Sartorius France 2, rue Antoine Laurent de Lavoisier ZA de la Gaudrée 91410 Dourdan Phone +33.1.70.62.50.00 Fax +33.1.64.59.76.39 Austria Sartorius Austria GmbH Modecenterstrasse 22 1030 Vienna Phone +43.1.7965760.0 Fax +43.1.7965760.24 Belgium Sartorius Belgium N.V. Rue Colonel Bourg 105 1030 Bruxelles Phone +32.2.756.06.90 Fax +32.2.481.84.11 Finland & Baltics Sartorius Biohit Liquid Handling Oy Laippatie 1 00880 Helsinki Phone +358.9.755.951 Fax +358.9.755.95.200 Hungary Sartorius Hungária Kft. Kagyló u. 5. 2092 Budakeszi Phone +3623.457.227 Fax +3623.457.147 Ireland Sartorius Ireland Ltd. Unit 41, The Business Centre Stadium Business Park Ballycoolin Road Dublin 11 Phone +353.1.8089050 Fax +353.1.8089388 Italy Sartorius Italy S.r.l. Viale A. Casati, 4 20835 Muggiò (MB) Phone +39.039.4659.1 Fax +39.039.4659.88 www.sartorius.com Netherlands Sartorius Netherlands B.V. Phone +31.30.60.53.001 Fax +31.30.60.52.917 info.netherlands@sartorius.com Poland Sartorius Poland sp.z o.o. ul. Wrzesinska 70 62-025 Kostrzyn Phone +48.61.6473830 Fax +48.61.6473839 Russian Federation LLC Sartorius RUS Uralskaya str. 4, Lit. B 199155, St. Petersburg Phone +7.812.327.53.27 Fax +7.812.327.53.23 Spain & Portugal Sartorius Spain, S.A. Avda. de la Industria, 32 Edificio PAYMA 28108 Alcobendas (Madrid) Phone Spain +34.913.586.095 Phone Portugal +351.800.855.800 Fax Spain +34.913.589.623 Fax Portugal +351.800.855.799 Switzerland Sartorius Mechatronics Switzerland AG Ringstrasse 24a 8317 Tagelswangen (ZH) Phone +41.44.746.50.00 Fax +41.44.746.50.50 U.K. Sartorius UK Ltd. Longmead Business Centre Blenheim Road, Epsom Surrey KT19 9QQ Phone +44.1372.737159 Fax +44.1372.726171 Ukraine LLS Sartorius RUS Post Box 440 B 01001 Kiev, Ukraine Phone +380.44.411.4918 Fax +380.50.623.3162 USA Sartorius Corporation 5 Orville Drive, Suite 200 Bohemia, NY 11716 Phone +1.631.254.4249 Toll-free +1.800.635.2906 Fax +1.631.254.4253 Argentina Sartorius Argentina S.A. Int. A. Ávalos 4251 B1605ECS Munro Buenos Aires Phone +54.11.4721.0505 Fax +54.11.4762.2333 Brazil Sartorius do Brasil Ltda Avenida Senador Vergueiro 2962 São Bernardo do Campo CEP 09600-000 - SP - Brasil Phone +55.11.4362.8900 Fax +55.11.4362.8901 Canada Sartorius Canada Inc. 2179 Dunwin Drive #4 Mississauga, ON L5L 1X2 Phone +1.905.569.7977 Toll-Free +1.800.668.4234 Fax +1.905.569.7021 Mexico Sartorius de México, S.A. de C.V. Libramiento Norte de Tepotzotlan s/n, Colonia Barrio Tlacateco, Municipio de Tepotzotlan, Estado de México, C.P. 54605 Phone +52.55.5562.1102 Fax +52.55.5562.2942 leadsmex@sartorius.com Peru Sartorius Peru S.A.C. Av. Emilio Cavenecia 264 San Isidro 15073 Lima, Perú Phone +51.1.441 0158 Fax +51.1.422 6100 Australia Sartorius Australia Pty. Ltd. Unit 5, 7-11 Rodeo Drive Dandenong South Vic 3175 Phone +61.3.8762.1800 Fax +61.3.8762.1828 China Sartorius (Shanghai) Trading Co., Ltd. 3 rd Floor, North Wing, Tower 1 No. 4560 Jinke Road Zhangjiang Hi-Tech Park Pudong District Shanghai 201210, P.R. China Phone +86.21.6878.2300 Fax +86.21.6878.2882 Hong Kong Sartorius Hong Kong Ltd. Unit 1012, Lu Plaza 2 Wing Yip Street Kwun Tong Kowloon, Hong Kong Phone +852.2774.2678 Fax +852.2766.3526 India Sartorius Weighing India Pvt. Ltd. #69/2-69/3, NH 48, Jakkasandra, Nelamangala Tq 562 123 Bangalore, India Phone +91.80.4350.5250 Fax +91.80.4350.5253 Japan Sartorius Japan K.K. 4 th Fl., Daiwa Shinagawa North Bldg. 8-11, Kita-Shinagawa 1-chome Shinagawa-ku, Tokyo, 140-0001 Japan Phone +81.3.3740.5408 Fax +81.3.3740.5406 Malaysia Sartorius Malaysia Sdn. Bhd Lot L3-E-3B, Enterprise 4 Technology Park Malaysia Bukit Jalil 57000 Kuala Lumpur, Malaysia Phone +60.3.8996.0622 Fax +60.3.8996.0755 Singapore Sartorius Singapore Pte. Ltd 1 Science Park Road, The Capricorn, #05-08A, Singapore Science Park II Singapore 117528 Phone +65.6872.3966 Fax +65.6778.2494 South Korea Sartorius Korea Ltd. 8 th Floor, Solid Space B/D, PanGyoYeok-Ro 220, BunDang-Gu SeongNam-Si, GyeongGi-Do, 463-400 Phone +82.31.622.5700 Fax +82.31.622.5799 Thailand Sartorius (Thailand) Co. Ltd. 129 Rama 9 Road, Huaykwang Bangkok 10310 Phone +66.2643.8361-6 Fax +66.2643.8367 Specifications subject to change without notice. Printed in Germany on paper that has been bleached without any use of chlorine.. Publication No.: SL-5713-e160501 Order No.: 85037-554-92 Ver. 06/2016