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Certificates of Conformance: »» Document individually measured dimensions and verify conformance to USP specifications and tolerances »» Reference the unique, traceable serial number for each measured component »» Provide traceability of NIST standards used to calibrate measuring devices

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Component Verification: Understanding the Certificate of Conformance (COC) Required for Mechanical Qualification Draft regulatory guidance states that a COC for components used in USP dissolution Apparatus 1 or 2 is critical to Mechanical Qualification (MQ).1 Apparatus components must be individually measured and certified to ensure that the dimensions are within stated tolerances and adhere to USP guidelines. Laboratories must make the determination as to the preferred method of verifying these components, either by purchasing components with a COC or by measuring each component internally. By selecting accessory components with a COC, laboratories can avoid tedious and time-consuming measurements with expensive instruments. Varian understands that there may be many questions surrounding component verification; so to simplify the guidelines, we’ve put together this Q&A to assist with MQ implementation. Q: Why do I need to certify that a component conforms to USP specifications and tolerances? A: By replacing the Performance Qualification (PQ) procedure with a MQ procedure, the detection of problems with vessel symmetry, basket condition, Practical Solutions

condition of coated paddles, vibration, etc., may no longer be possible. The implementation of an MQ procedure relies upon a solid foundation of certified critical components, used in the dissolution apparatus, which conform to USP <711> Dissolution Physical Test Chapter. Although Varian components are manufactured to USP specifications, not all dissolution equipment and components manufactured around the world meet the same quality and reliability standards. Without the use of a performance challenge with actual tablets, critical components including paddles, baskets/shafts, and vessels will need to be individually measured and documented in a COC to certify that they are free of defects. Q: Is a statement by an equipment manufacturer guaranteeing that its paddles are manufactured according to USP specifications good enough?

Visit our Web site for more information on Varian’s dissolution systems: www.varianinc.com/dissolution/

A: No, a generic statement is not enough to meet the MQ requirements. Reputable manufacturers produce components that are manufactured to USP specifications just as thermometer manufacturers manufacture a thermometer to specifications. continues p2

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Varian, Inc. Dissolution Systems 13000 Weston Parkway Cary, NC 27513 Phone: +1 919.677.1108 Fax: +1 919.677.1138

Certificate of Conformance 12-1000V, VK Verified Pddl,15"Tef Coat Part Number - Part Description Sample Serial Number

Teflon Coated Stainless Steel Material

The accuracy of these parts was determined by reference comparison to working standards traceable to the National Institute of Standards and Technology (NIST). Any limitations or remarks pertaining to this instrument or calibration are shown below.

Ref No. 1 2 3 4 5 6 7 8 9

Certified By

Sample

Model Number V12X12X6 CD-6 CS CD-6 CS CS-12” .061 - .250 Ser #1090 No.293-344

Signature

Serial Number VAR002 VAR026 VAR035 VAR025 VAR018 VAR024 VAR034

Actual 9.7 19.0 4.0 74.5 42 1.2 41.5 0.5 0.5

Accuracy .01 mm .01 mm .01 mm .01 mm + .0002 / - .0000 in. .01 mm .01mm

Due Date 15-Apr-2009 24-Oct-2008 7-May-2009 7-May-2009 24-Oct-2010 7-May-2009 16-Apr-2009

Sample

Date

Each component in the dissolution apparatus, including paddles, baskets/shafts, and vessels requires certification that its critical dimensions conform to USP specifications and tolerances. Each certificate must be traceable to the component by its serial number and every certificate must carry a detailed description of the component including the material from which it’s constructed.

Measurement

USP Spec Inspection (mm) Range 9.4 – 10.1 9.4 – 10.1 19.0 ± 0.5 18.5 – 19.5 4.0 ± 1.0 3.0 – 5.0 74.0 – 75.0 74.0 – 75.0 42.0 ± 1.0 41.0 – 43.0 1.2 ± 0.2 1.0 – 1.4 41.5 ± 1.0 40.5 – 42.5 0.5 See Note 0.5 See Note All readings are in mm

Note: Not to vary more than 0.5 mm when part is rotated on center line axis.

Equipment Used: Instrument MicroVu Video Comparator Mitutoyo 6” Caliper Mitutoyo 6” Caliper (Opt.) ST Ind. 12” Caliper (Opt.) Vermont Gage Pins Trimos Height Gauge Mitutoyo 1” Micrometer

Individual Certification

Critical dimensions for each component must be listed as stated in the USP Physical Test Chapter <711> Dissolution. Actual measurements should be performed and documented to certify that the component meets each critical dimension.

Conformance

The critical dimensions for each component must be illustrated in a drawing showing the reference points for the measurements taken. Some components, such as the vessel, require additional dimensions to ensure that the vessel is circular and hemispherical.

Traceability

Only NIST traceable devices may be used to verify each critical dimension. Each of the measuring devices is maintained in a calibration program and identified by the instrument name, model number, serial number, its accuracy and its calibration due date.

This certificate shall not be reproduced without written approval of Varian, Inc. 4650-0070B, COC, Paddle, USP.doc

Component Verification continued from cover. However, just as thermometer manufacturers are required to certify that their thermometers used in the pharmaceutical environment meet compendial specifications and tolerances with actual measurements documented on a certificate, dissolution components must be similarly documented with actual measurements. The easiest way to remember what to do: if it has a serial number, it needs to be certified with a measurement. Even lot verification, where a representative number of components are measured, is not considered to be an acceptable practice for a component requiring an individual COC. Q: What is an acceptable component certification? A: In the spirit of MQ guidance, individual certificates are to be created for each individual

Practical Solutions

paddle, basket/shaft, and vessel used in the dissolution test. The wording in ASTM E 2503-07 states “In the absence of a COA or COC, an appropriate measuring device is used to measure the relevant dimensions of the paddle.” Quite simply, this implies that a COC or a Certificate of Analysis (COA) must contain individual measurements taken with traceable and calibrated devices to measure the specifications and tolerances of the component. Each certificate will be traceable to an individual component. Q: Once I certify a component, will it be valid until the component is lost, broken or removed from service? A: We usually look at the certification of a “Class A” 100 mL volumetric flask as being a onceand-done process since the risk of a change in its critical dimension, volume, will be negligible

until it is broken. The critical dimensions for dissolution components should be fairly robust but they are subject to change before they may be considered broken. For instance, a basket could be mishandled resulting in a severe deformation in the dimensions of the basket. This should prompt a periodic recertification of components or should require such a basket to be removed from the laboratory and placed out of conformance until certified that it is within its proper dimensions and tolerances. Other components, such as basket and paddle shafts, could also be damaged by dropping or mishandling, and should be recertified to verify that they do not contribute to erroneous dissolution test results. Q: Are parameters in addition to the USP specifications and tolerances needed to certify the conformance of a vessel? A: The USP specifies only two dimensions for the 2

VK Verified Components with Certificates of Conformance Varian offers a variety of VK Verified Components, including paddles, baskets/shafts, and vessels to meet your needs for Mechanical Qualification. These verified components include a COC that documents individually measured dimensions to verify conformance to USP specifications and tolerances.

VK Verified, Interchangeable Paddle/Basket Accessories The Interchangeable Paddle/Basket Shaft System is a two-piece assembly designed for efficient switching between paddles and baskets without height readjustment. Universal upper shaft, 15 in. 12-1400V Universal upper shaft, 19 in. 12-1401V Universal upper shaft, 21 in. 12-1433V Universal upper shaft, 24 in. 12-1402V Interchangeable lower shaft with 12-1420V Teflon-coated paddle blade Interchangeable lower shaft with 12-1421V electropolished paddle blade Interchangeable lower basket shaft 12-1430V with clips

VK Verified, Basket Assemblies

VK Verified, One-piece, Teflon-coated Paddles Paddle, 14.5 in. for use with V-Series

12-1005V

Paddle, 15 in.

12-1000V

Paddle, 19 in.

12-1010V

Paddle, 24 in.

12-1015V

VK Verified, One-piece Electropolished Paddles Paddle, for V-Series, 14.5 in.

12-1035V

Paddle, 15 in.

12-1030V

Paddle, 19 in.

12-1040V

Paddle, 24 in.

12-1045V

VK Verified, One-piece, PEEK Paddles

Rotating basket assembly, 15 in. shaft 12-2000V with 40-Mesh basket Rotating basket assembly, 19 in. shaft 12-2020V with 40-Mesh basket Rotating basket assembly, 24 in. shaft 12-2025V with 40-Mesh basket Basket shaft, Teflon-coated, USP, 14.5 in. for use with V-Series

12-2041V

Basket shaft with clips, 14.5 in., for V-Series

12-2073V

Basket shaft with clips, 15 in.

12-2070V

Basket shaft with clips, 19 in.

12-2080V

Basket shaft with clips, 24 in.

12-2095V

Basket, 40-Mesh, 381-µm

12-2100V

Basket, 20-Mesh, 864-µm

12-2120V

VK Verified, USP Vessels Vessel, clear glass, 1000 mL

12-5000V

Vessel, amber glass, 1000 mL

12-5010V

Vessel, TruCenter, ground centering groove with collar, 1000 mL

12-5035V

Vessel, DVH, ground centering groove, 12-5039V 1000 mL Vessel, TruCenter™, amber glass, 1000 mL

12-5120V

Vessel, clear plastic, 1000 mL

12-5200V

Paddle, 15 in.

12-1201V

Vessel, clear glass, 2 L

12-5070V

Paddle, 19 in.

12-1211V

Vessel, clear glass, 4 L

12-5080V

Paddle, 24 in.

12-1216V

VK Verified, One-piece, Dura-Tef Shaft Shaft only, 15 in.

12-1221V

For VK Verified Component pricing and orders: call Varian Customer Service at 800.926.3000, visit www.varianinc.com, or contact your local sales representative.

vessels; height and inner diameter, which may be easily measured. Two other qualifications require the vessel to be cylindrical and hemispherical.2 While we understand what these mean, how do we ensure that the vessel is cylindrical and hemispherical? Most facilities lack the instrumentation to measure inner surfaces, which is usually accomplished with a coordinate measuring machine (CMM). Traditional glass vessels are produced from a variety of techniques around the world. Some manufacturers produce vessels with deformities in the bottom of the vessels, which cause additional turbulence and variability in the dissolution test. Without proper certification of circular and hemispherical surfaces, the integrity of dissolution results may be jeopardized. Q: If I drop a paddle on the floor, should I recertify that it meets compendial requirements? Practical Solutions

A: For reasons mentioned above with a basket, the perpendicularity of the blade with the shaft could be affected if dropped. A recertification of the paddle shaft should occur to document that the paddle is within its proper specification and tolerance, and will not contribute to higher test results due to greater turbulence.

Unfortunately, the verification of wire diameter requires sophisticated equipment such as an optical comparator or videographic measuring system. Again, without a PQ test, changes in the performance of the dissolution basket will need to be captured in other ways to ensure the integrity of the dissolution test.

Q: If I have components that are several years old and they have passed USP calibration in the past, should they be mechanically verified?

1 FDA Draft Guidance for Industry: The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 - Current Good Manufacturing Practice (cGMP). http://www.fda.gov/CDER/ GUIDANCE/7232dft.pdf

A: Baskets have failed PQ as they have aged. When stainless steel baskets age, the wire becomes more thin which means that the aperture size becomes larger. Particles may leave the basket earlier, thus changing the performance of the dissolution basket. A recertification of the basket wire cloth dimensions may be needed periodically to ensure that the baskets still conform to specifications for the rotating basket found in USP <711> Dissolution.

CDER’s Division of Pharmaceutical Analysis Document #DPA-LOP.002, “Mechanical Qualification of Dissolution Apparatus 1 and 2”. http://www.fda.gov/cder/Offices/OTR/ dissolution.pdf ASTM E 2503-07 Standard, “Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus”. 2 USP 31 NF 26 United States Pharmacopeial Convention <711> Dissolution Physical Test Chapter, official May 1, 2009.

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Verifying Physical Dimensions There are many tools on the market designed to obtain and verify physical dimensions. The Varian QAII C Dissolution Systems Suitability Station was developed specifically to measure critical physical parameters associated with the proper operation of dissolution apparatus.

These parameters conform with pharmacopoeial standards around the world. The QAII C is fully compliant with guidelines for measurement contained in the official FDA DPA-LOP.002 and the ASTM E2503-07 Mechanical Qualification procedures noted in this publication. In fact, the QAII C Stations

manufactured by Varian were instrumental in providing critical data used in the development of the MQ procedures and are used in the MQ service available through the Varian Care Program.

Varian QAII C Dissolution Systems Suitability Station

For more information on Varian’s Analytical Instrument Qualification services, including Mechanical Qualification, visit www.varianinc.com/dissolutionaiq/

DISSOLUTION DISSCUSSION GROUP www.dissolution.com Sponsored by Varian, Inc.

The Dissolution Discussion Group (DDG) Web site is an invaluable resource for you to research best practices and get direct, timely feedback from industry peers. Although sponsored by Varian, DDG is a vendor-neutral forum for open scientific discussion in an environment that is free from regulatory oversight. Register on www.dissolution.com to participate in interactive scientific discussions on the latest regulatory issues in quality control, R&D challenges, and more.

Varian, Inc. 13000 Weston Parkway Cary, NC 27513

Practical Solutions

Toll-free: 800.926.3000 www.varianinc.com

SI-1986 03/09 Printed in USA

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