28909472

GE Healthcare

Validation guideULTA Prime GFcapsule and cartridge filters

28-9094-72 AA

Table of contentsIntroduction 3

Quality policy 3Quality assurance 3

Product traceability 4

Summary of test methods 5

Preparation of pharmaceutical grade filters 6Pharmaceutical grade standard 6Quality of purified water used in the preparation of pharmaceutical grade filters 6

Certificate of Quality 7

Product coding and range for ULTA Prime GF cartridges 8

Product coding and range for ULTA Prime GF capsule filters 8

Capsule dimensions 9

Product specifications 9Application 9Materials of construction for ULTA Prime GF cartridges and capsules 9Filter media 9Flow Characteristics 10Operating temperatures and pressures 11Steam sterilization 11Autoclave 11Steam in Place (SIP) 11Tests for BioCompatibility 11

Determination of micron ratings 12

Chemical compatibility 13Chemical compatibility summary chart for pharmaceutical products 13Chemical compatibility user instructions and notes 15

2 Validation Guide 28-9094-72 AA

IntroductionClarification or pre-filters that come into contact with pharmaceu-tical products, such as injectable or infusion liquids, must conformto strictly defined quality standards.

By using filter technology that conforms to the standards laiddown by the various certifying bodies, the quality of the finalproduct can be assured. Contamination can also be preventedfrom entering the final product by its comprehensive removal ateach stage of the primary and secondary process.

When pharmaceutical grade filters are used in the manufactureof products, the interactions between product, filter and processmust be fully investigated and validated.

Guidelines for validation can be sourced from publications issuedby the FDA, EMEA, USP, EP, BP, PDA1 etc. This Validation Document has been produced with these guidelines in mind toenable the end user to incorporate this information within theirown validation documentation or standard operating instructionsfor the process.

This Validation Document shows that ULTA™ Prime GF surpassesthe product specification requirements that have to be imposedon pharmaceutical grade filters.

1 FDA, EMEA, USP, EP, BP, PDA – Food and Drug Administration, European Medicines Evaluation Agency, United States, European, and BritishPharmacopoeia, Parenteral Drug Association.

Validation Guide 28-9094-72 AA 3

Quality policyQuality assuranceQuality is of paramount importance to GE Healthcare. The filtrationproducts are manufactured under controlled environmental conditions to the highest quality regimes and are subjected to a demanding program of Quality Assurance. Inspection and testprotocols are implemented from vendor assessment, specificationand receipt of raw materials, through every stage of the manu-facturing process culminating in a nondestructive integrity test of the filter prior to packing and release.

Every stage of the manufacturing process has well defined assemblyprotocols laid down, thus ensuring operational repeatability.

GE Healthcare’s responsibility as a manufacturer of qualityextends beyond the manufacturing site, through a world-widenetwork of filter and separation specialists.

The Quality Assurance Department operates with a well-equippedLaboratory Services Department, in which specialized personnelare employed to perform the essential quality inspections. Themanufacturing site has been assessed by the British StandardsInstitution and is registered to BS EN ISO 9001:2000, which definesthe standards for quality systems, model for quality assurance indesign, development, production, installation and servicing.

As a concerned environmentally aware manufacturer, the site is also audited and certified to BS EN ISO 14001:1996 for itsEnvironmental Management System.

Product traceabilityTo enable full traceability of all pharmaceutical grade filter prod-ucts, each filter module is marked with an individual serial num-ber. In addition, each filter product is marked with a lot number,product code and general description which is also shown onboth the protective polyethylene bag in which the filter is sealedand on the outer surface of the final product packaging.



Summary of test methodsA number of the critical procedures used within this validationdocument are based on external methods sourced from publica-tions issued by the USP, EP, FDA, ISO2 and ASTM3. The remainingprocedures are in-house methods prepared using GE Healthcare’srelevant experience and industry accepted standards in the finefiltration field. The comprehensive nature of these proceduresensures high batch to batch compliance to the specification.

2 ISO – International Organisation for Standardisation3 ASTM – American Society for Testing and Materials4 ACFTD – AC Fine Test Dust

4


Preparation of pharmaceutical grade filtersPharmaceutical grade standardULTA Prime GF filters must meet stringent standards to be certified P-grade product by GE Healthcare. The standards thatmust be met are:

• Effluent quality following a purified water flush must also bemet as determined by the following tests:

– Test for oxidizable material per USP 23 Purified Water.

– Test for bacterial endotoxins using a gel clot LAL (Limulus Amoebocyte Lysate).

– Test for particulates.

– Test for TOC (Total Organic Carbon).

– Test for Conductivity.

• All components conform to the Biological Safety Standardsidentified in USP <88> to Class VI-121°C levels.

• All P-grade filters are flushed with a high flux of purified waterprior to despatch, as a guarantee of product cleanliness.

Quality of purified water used in the preparation ofpharmaceutical grade filtersThe current USP and EP standards for Purified Water and HighlyPurified Water specify a maximum conductivity of 1.1 ÌS/cm @20°C (68°F) and a maximum TOC (Total Organic Carbon) content of 0.5 mg (500ppb) of carbon per liter.

The water used in the flushing stages of pharmaceutical grade filters exceeds these Pharmacopoeial requirements.

In addition, two other tests are carried out on samples taken frompoint of use and from a number of points in the supply pipework:

• A Membrane Filtration Method Standard Plate Count Technique,to establish the microbial content.

• A gel clot LAL (Limulus Amoebocyte Lysate) test, for detection of bacterial endotoxins at 0.125 EU/ml sensitivity.


Certificate of QualityTo certify that GE Healthcare’s ULTA Prime GF filter products meet the highest pharmaceutical quality and performancerequirements, a Certificate of Quality is issued.

A specific Certificate of Quality is issued for ULTA Prime GF capsules.


Product coding and range for ULTA Prime GF cartridgesRepresented below are details of the product code structure forULTA Prime GF cartridges. This product code structure indicatescartridge sizes, micron ratings, end-cap configurations and ‘O’ ringmaterials that are available within the product range.

Product coding and range for ULTA Prime GF capsule filtersRepresented below are details of the product code structure forULTA Prime GF capsules. This product code structure indicates capsule sizes, micron ratings, connection configurations, sterility andmaterial options that are available within the product range.

Digit

Device Type Media Type Special Detail Special Micron Rating Size Code Cartridge O-ring

1 2 3 4 5 6 7 8 9 10 11 12

C = CartridgeD = Disc

0 = Code 0, 222 Double O-ring7 = Code 7, 226 Locking Tab,Double O-ring/ Fin* (Flat Top5” Only)

Hyphen - HyphenA H = 5” 0 E = EPDMS = Silicone

900001

612570

1 = 10”2 = 20”3 = 30”

FG

Hyphen 4 7 Disc0Example: ULTA™ Prime GF, 0.6 µm, 10” 226, Silicone O-ring CGF-A-96170S

Digit

Device Type Media Type Special Detail Special Micron Rating Size End Fittings

1 2 3 4 5 6 7 8 9 10 11 12

K = Capsule Hyphen - 900001

612570

Size

02 = 2”04 = 4”06 = 6”

T = 1.5” TCG = SHB*H = 1/2” HB

* Stepped Hose Barb 1/4”

T = 1.5” TCG = SHB*H = 1/2” HB

FG HyphenA

Inlet Outlet

Example: ULTA™ Cap PP, 1.0 µm, 4”, 1/2 Hosebarb inlet, 1.5 inch TC outlet KGF-A-0104HT


Product specificationApplicationAll products within the ULTA Prime GF range, cartridge, capsuleand disc have been designed for use in pharmaceutical applica-tions for prefiltration and clarification duties. Whilst these prod-ucts present minimal fiber shedding potential as required bycGMP guidelines, when they are used with 0.20um or 0.45ummembrane based products downstream in the process, the ULTAPrime GF products are seen to meet the FDA guideline21CFR211.72 for non fiber-shedding filters.

Materials of construction for ULTA Prime GF cartridges and capsulesAll materials used in the construction of ULTA Prime GF productsthat have product contact have met the requirements of the cur-rent USP Biological Reactivity Tests, In Vivo to Plastics Class VI-121°C.

All jointed surfaces are assembled by the use of heat sealing tech-nology. No resins or binders are used in the manufacture of the fil-ter and no surfactants are added to aid wetting.

Component Material of construction

Filtration Media Borosilicate Glass Microfiberwith Acrylic Binder5

Upstream Support Polypropylene

Downstream Support Polypropylene

Inner Support Core Polypropylene

Outer Protection Cage Polypropylene

Endcaps Polypropylene

Endcap Insert 316 Stainless Steel

Standard O’rings Silicone

Capsule Body Polypropylene

Capsule Vent Seals Silicone

Filling Bell Polycarbonate

Capsule dimensions

50.6μm Grade includes a dioctyl sodium sulfosuccinate surfactant.

Filter MediaThe high efficiency of each ULTA Prime GF filter cartridge and cap-sule is achieved using a composite structure offering high voidsvolume. High dirt holding capacity results from the depth of filtra-tion within each composite layer giving the extended life of ULTAPrime GF from coarse particulate prefiltration to very fine ultimateretention at the filters quoted micron rating.


Flow characteristicsThe effective filtration area of a standard 250mm (10”) module isup to 0.57 m2 (6.4 ft2), dependent on the grade selected.


Operating temperatures and pressuresBelow are the recommended maximum differential operatingpressures at various temperatures:

Steam sterilization

Tests for biocompatibilityAn independent research establishment has assessed the biologicalsafety associated with the use of ULTA Prime GF filters designed for processing pharmaceutical products. The materials used in theconstruction of ULTA Prime CG products meet the requirements ofthe current USP <88> Biological Reactivity tests at Plastics Class VI – 121°C.

Differential pressure Operating pressure capsulesTemperature Cartridges Liquids (gases)°C °F bar psi barg psig

20 68 5.00 72.5 5.00 (4.00) 72.5 (58.0)

40 104 4.00 58.0 5.00 (4.00) 72.5 (58.0)

50 122 3.00 43.5 3.00 (3.00) 43.5 (43.5)

70 158 2.00 29.0 Not Recommended

AutoclaveAutoclave temperature Number of Cycle time

Product format °C °F cycles Minutes at temp.

Cartridges 121 250 10 30

Capsules 121 250 10 30

To maximize cartridge and capsule life, a slow exhaust cycle is recommended.

Steam in Place (SIP)SIP temperature Number of Cycle time

Product format °C °F cycles Minutes at temp.

Cartridges 121 250 10 30

Capsules Do not Steam in Place

To maximize the life of the cartridge, the differential pressure across the cartridge shouldnot exceed 0.30 bar (4.4 psi) at 121°C (250°F). For new applications it is recommendedthat GE Healthcare guidance for the method of steam sterilization be followed.


Determination of micron ratingsParticle removal efficiencies of ULTA Prime GF filter cartridgeshave been determined by challenging with a standard aqueoussuspension of ACFTD (AC Fine Test Dust) with particle size asdefined in table 1, using in-line laser particle counters.

Ratings are based on Beta ratio of 5000 or >99.98% efficiency atthe micron size specified.

Testing is carried out in accordance with ASTM F795-88 StandardPractice for Determining the Performance of the Filter MediumEmploying a Single-Pass, Constant-Rate, Liquid Test.

Particle size Volume % smaller than Approximate number of particles per gram in band

1 2.5 - 3.5 5 x 1010

2 10.5 - 12.5 3 x 1010

3 18.5 - 22.0 1 x 1010

4 25.5 - 29.5 4 x 109

5 31.0 - 36.0 1 x 109

7 41.0 - 46.0 8 x 108

10 50.0 - 54.0 1 x 108

20 70.0 - 74.0 4 x 107

40 88.0 - 91.0 4 x 106

80 95.5 - 100 7 x 106

Table 1. ACFTD Specification (SAE J 726 Fine ISO 12103 Pt 1 A2 Fine) s.g. 2.6 – 2.7 g/cm3


Chemical compatibilityTesting has been carried out that shows ULTA Prime GF filters andcapsules have a broad range of chemical compatibility withchemicals commonly used in the pharmaceutical industry.

Chemical compatibility summary chart for pharmaceutical products

ULTA Pure SG ULTA Pure HC ULTA Prime CG ULTA Prime PP ULTA Prime GF

Acetic Acid 3.5N C C C C CAcetic Acid 8.75N - - - C CAcetic Acid Conc. 17.5N - - - C CAcetone NC NC NC C CAcetonitrile - - - C LCAcidbrite 4 (Diversey) 3.0% v/v - - - C CAmmonium Hydroxide 8N LC LC LC C CAmmonium Oxalate 0.07N - - - C CAmyl Acetate LC LC LC C LCAqueous Ammonia 15.5N LC LC LC C LCBenzyl Alcohol - - - NC NCBenzyalkonium Chloride 0.1% - - - C CBoric Acid, Saturated - - - C CButan-1-ol C C C C CButan-2-ol C C C C CCarbon Tetrachloride - - - NC NCChloroform NC NC NC NC NCCyclohexane - - - NC NC1,4 - Dioxane - - - C LCDiverflow (Diversey) 3% v/v C C C C NCDiversey 212G 0.6% v/v - - - CDivosan Forte 0.5% v/v C C C C CDivosan XT 1% v/v - - - C CEthanol C C C C CEthanol 45% C C C C CEthyl Acetate NC NC NC LC LCFormaldehyde 0.3% C C C C CFormaldehyde 37% - - - C CFormic Acid Conc. - - - C NCGlycerol C C C C CHexane - - - NC -Hydrochloric Acid 1N C C C CHydrochloric Acid Conc. - - - C NCHydrochloric Acid Conc. 13% - - - - -Hydrogen Peroxide - - - C -Hydrogen Peroxide 10 Vol C C C C CHydrogen Peroxide 100 Vol - - - C C

C= Compatible LC= Limited Compatibility NC=Not Compatible


ULTA Pure SG ULTA Pure HC ULTA Prime CG ULTA Prime PP ULTA Prime GF

Methanol C C C C CMethyl-iso-Butylketone NC NC NC C CMethylene Chloride @ 40C - - - LC LNitric Acid 2N 14.4% C C C C CNitric Acid 15.8N - - - C NCOzone NC NC NC - -Paraffin Yellow - - - C LCPentane - - - LC LCPeracetic Acid 0.5% - - - - -Peracetic Acid 4% C C C C CPerchloroethylene NC NC NC - -Petroleum Spirits - - - NC NCPhenol (aq) 0.5N - - - - -Phenol 5% - - - CPhenol 0.25% - - - CPolyethylene Glycol 600 NC NC NC LC NCPolyglycol 2000-E - - - - -Potassium Dichromate 0.1N - - - C CPotassium Iodine 0.6N - - - C CPotassium Hydroxide 10N LC LC LC C NCPotassium Permanganate 0.1N C C C C NCPropan-1-ol C C C C NCPropan-2-ol C C C C NPropan-2-ol, 60:40 H2O C C C C NPyridine NC NC NC C NCSodium Chloride 0.5N C C C C CSaline Lactose Broth C C C C CSodium Hydroxide 2N 8% C C C C CSodium Hydroxide 7N 28% NC NC NC C NSodium Hypochlorite (14% Free Cl2) C C C C CSodium Thiosulphate 0.1N - - - C CSulphuric Acid 1N C C C C LCSulphuric Acid Conc. NC NC NC LC LCSulphurous Acid NC NC NC - -Toluene NC NC NC NC -1,1,1 Trichloroethane - - - - -1,1,2 Trichloroethane NC NC NC LC LCTrichloracetic Acid 80% - - - C LCTrichloracetic Acid 5N - - - - -Xylene LC LC LC NC NC

This chemical compatibility chart is intended for use as a guide only. Factors such as temperature, pH, concentration, system pressures and exposure times can all have an effect onthe chemical compatibility of our filter products. Though we believe this information to be current and of value in screening the filter media against liquid solutions for general com-patibility, no warranty is given or implied with respect to this information.

Note that the temperature at which these recommendations were given is 25C. For compatibilities at higher temperatures please contact GE Healthcare technical services.

Note that compatibility recommendations for each cartridge apply only to the filter media of that cartridge. Liquid compatibility for core and o-ring materials must be determined byfollowing the compatibility for those core and o-ring materials.

C= Compatible

LC= Limited Compatibility

NC=Not Compatible

28-9094-72 AA 06/2007

GE, imagination at work and GE monogram aretrademarks of General Electric Company.

ULTA™ is a trademark of GE Healthcare companies.

© 2007 General Electric Company–All rights reserved.First published Feb. 2007

All goods and services are sold subject to the terms andconditions of sale of the company within GE Healthcarewhich supplies them. A copy of these terms andconditions is available on request.

Contact your local GE Healthcare representative for themost current information.

GE Healthcare Bio-Sciences ABBjörkgatan 30, 751 84 UppsalaSweden

GE Healthcare Europe, GmbHMunzinger Strasse 5, D-79111 FreiburgGermany

GE Healthcare Bio-Sciences Corp.800 Centennial Avenue, P.O. Box 1327Piscataway, NJ 08855-1327

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For contact information for your local offi ce,please visit: www.gelifesciences.com/contact

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www.gelifesciences.com

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