Revision of USP General Chapters 41 and 1251Switzerland, May 2013Dr. Klaus FritschManager Compliance Global Business Area LabTec

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HistoryRevision of USP General Chapter 41Revision of USP General Chapter 1251Summary of Technical Changes*Agenda

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*US PharmacopeiaFounded 1820 by 11 physiciansThe United States Pharmacopeia and The National Formulary (USPNF) is a book of public pharmacopeial standards. It contains standards for chemical & biological drug substances, dosage forms, compounded preparations, excipients, medical devices, and dietary supplements.A drug product in the U.S. market or imported in the U.S. must conform to the standards in USPNF1938 Federal Food, Drug & Cosmetics Act: USP standards recognized, enforced by FDAScientific non-profit and non-governmental organization

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*Excerpt of USP General Chapter 41

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*New USP General Chapters 41 & 1251Publication of the ProposalsPharmacopeial Forum PF38(5), September 4th, 2012

THE PROPOSALS HAVE BEEN APPROVED!

Official Publication: Second Supplement to USP36-NF31Release / Posting date: June 3rd, 2013Official date: December 1st, 2013

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*In memoriam Arthur (Thuri) Reichmuth

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*USP Expert PanelConvenor: Gregory Martin, Complectors ConsultingScientific Liaison: Horacio Pappa, USPIndustry representatives:MerckPfizerAbbottGenzyme (Sanofi)Representative from NISTSupplier representatives:Mettler-Toledo AG (Arthur Reichmuth, Klaus Fritsch)Sartorius (Dirk Ahlbrecht)

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HistoryRevision of USP General Chapter 41Revision of USP General Chapter 1251Summary of Technical Changes

*Agenda

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New General Chapter 41 "Balances"*Scope"States the requirements for balances used for materials that must be accurately weighed (see General Notices, 8.20)." Weighing of analytes for quantitative measures Scope unchanged but better defined/explainedRequirements"Weighing shall be performed using a balance that is calibrated []""[] and meets the requirements defined for repeatability and accuracy.""For balances used for other applications the balance repeatability and accuracy should be commensurate with the requirements of its use."

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*USP 41 - Requirement for RepeatabilityRequirement"Repeatability is assessed by weighing one test weight not less than 10 times." "Repeatability is satisfactory if two times the standard deviation of the weighed value, divided by the nominal value of the weight used, does not exceed 0.10%." "If the repeatability obtained is smaller than 0.41 d, where d is the scale interval, replace this standard deviation with 0.41 d."Additional Statement"Because repeatability is virtually independent of sample mass within the balances capacity, use of a small test weight, which may be difficult to handle, is not required."

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*Requirement for RepeatabilityExample: Repeatability test with a semi-micro balance using a weight with a nominal mass of 20 mg

Standard deviation sExisting USP criterion 3*s/m 0.1%Pass / FailProposed new USP criterion 2*s/m 0.10% Pass / Fail0.005 mg0.08% (0.1%)Pass0.05%Pass0.007 mg0.11% (0.1%)Pass0.07%Pass0.009 mg0.14% (0.1%)Pass0.09%Pass0.010 mg0.15% (0.2%)Failed0.10%Pass0.011 mg0.17% (0.2%)Failed0.11%Failed

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USP 41 - Requirement for Accuracy"The accuracy of a balance is satisfactory if its weighing value, when tested with a suitable weight(s) is within 0.10% of the test weight value.""A test weight is suitable if it has a mass between 5% and 100% of the balance's capacity."Characteristic curve withsensitivity deviationCorrect sensitivity

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*Trueness (ISO/VIM) = Accuracy (USP/ICH)imprecise:values are dispersed(random deviations)precise (precision):values are close within each other(good repeatability)biased (bias):average value is NOT on target(systematic deviation)true (trueness):average value is on target (no systematic deviation)

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*USP Requirement for Repeatability and AccuracyRequirement on repeatability / standard deviation (0.10%)Requirement on accuracy / systematic deviations (0.10%)

repeatability & accuracy

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*New Certificate USP 41Consists of Requirements for Repeatability and Accuracy

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HistoryRevision of USP General Chapter 41Revision of USP General Chapter 1251Summary of Technical ChangesProject "Robin Hood" Go to Market Strategy

*Agenda

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*Scope of USP General Chapter 1251All USP Generel Chapters with a number equal or larger than 1000 are for information only and not legally binding.

Provides information on Installation and Operational QualificationPerformance Qualification and Balance ChecksMinimum WeightBalance Operation

Important Statement at the beginning of the chapter: "The information given in this chapter is applicable not only to balances used for materials that must be accurately weighed (see Balances 41) but also to balances used in all analytical procedures."

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USP 1251 - Frequency of PQ and of Balance Checks*"The balance check is performed at appropriate intervals based on applicable standard operating procedures. The frequency of the balance check depends on the risk of the application and the required weighing tolerance.""Checks with external weights can be replaced partially using (automatic or manually triggered) adjustment by means of built-in weights."

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Performance Qualification as per GC 1251*"Table 1 provides a list of the most important balance properties that should be assessed during performance qualification. Depending on the risk of the application and the required weighing process tolerance, some of these tests may be omitted. Tests also can be omitted if there is evidence that the property in question has only minimal effect on the weighing performance."

PropertyExamplesSensitivityThe test load at or sufficiently close to the capacity of the balance.LinearityFrom 3 to 6 points over the range of the balance.EccentricityPerformed in the center of gravity and the four quadrants []. Test load usually should be 30% of the capacity of the balance or higher.Repeatability10 replicate weighings (using a test weight that is a few percent of the nominal capacity of the balance).

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*USP 1251 - The Concept of Minimum Weight"The minimum net sample weight, mmin, of a balance can be expressed by the equation:mmin = k*s/required weighing toleranceFor materials that must be accurately weighed, Balances 41 stipulates that repeatability is satisfactory if two times the standard deviation of the weighed value, divided by the nominal value of the weight used, does not exceed 0.10%. For this criterion the equation above simplifies to:mmin = 2000*sIf not subject to the requirements of Balances 41, the minimum weight value may vary depending on the required weighing tolerance and the specific use of the balance."

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IndicationLoadWhich Test Weight for Repeatability? 5%"To facilitate handling, the test weight that is used for the repeatability test does not need to be at the minimum weight value but can be larger because the standard deviation of repeatability is only a weak function of the test weight value."

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Routine Test of Balances

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USP 1251 - The Concept of Minimum Weight*"In order to satisfy the required weighing tolerance, when samples are weighed the amount of sample mass (i.e., the net weight) must be equal to or larger than the minimum weight. The minimum weight applies to the sample weight, not to the tare or gross weight."

The net sample weight has to fulfill the minimum weight requirement.

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*The Concept of Minimum Weight"Factors that can influence repeatability while the balance is in use include: The performance of the balance and thus the minimum weight can vary over time because of changing environmental conditionsDifferent operators may weigh differently on the balancei.e., the minimum weight determined by different operators may be different The standard deviation of a finite number of replicate weighings is only an estimation of the true standard deviation, which is unknownThe determination of the minimum weight with a test weight may not be completely representative for the weighing application. The tare vessel also may influence minimum weight because of the interaction of the environment with the surface of the tare vessel.""For these reasons, when possible, weighings should be made at larger values than the minimum weight."

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Variability of Minimum Weight Safety FactorSmallest net weight*

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*Environmental Influences Installation Problem Samples"Potential facility issues:"Air currentsTemperature changesLow or high humidity; electrostaticsVibrationCorrosive materialsFume hoodMagnetic influencesDirect sunlight"In situations when the balance is located near equipment or systems that induce vibration, drafts, electromagnetic radiation, magnetic fields, or changes in temperature or humidity, the assessment should be conducted with those systems operating in order to duplicate a worst-case scenario."

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*Types of Weighing Selected Example"Gravimetric DosingGravimetric dosing typically is used for sample and standard preparations or capsule filling. For such weighing the analyst places the volumetric flask, vial, or capsule shell on the balance; tares the balance after the balance display stabilizes; adds the solid or liquid components into the receiver by means of dosing units; and records the respective weights."

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HistoryRevision of USP General Chapter 41Revision of USP General Chapter 1251Summary of Technical ChangesProject "Robin Hood" Go to Market Strategy

*Agenda

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GMP: All balances & scales2 USP41 Statement1*Scope of USP and GMPUSP1251"All analytical procedures"1) "For balances used for other applications the balance repeatability and accuracy should be commensurate with the requirements of its use."USP41 "Quantitative Analysis"Scope of USP: Quality Control of Drugs Lab Balances onlyEnsure quality & safety of drugsScope of GMP: Consistent Production and Quality Control All Scales and BalancesBuild quality into the process to ensure quality & safety of drugs2) "Measuring equipment of an appropriate range and precision should be available for production and control operations. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. EC Guide to GMP, Chapter 3.40/3.41

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*Impact of the proposed new GC 41 and 1251 The applicability of GC 41 ("used for materials that must be accurately weighed") is now clearly defined.Two independent tests with their respective test limits are described (repeatability and accuracy).Change of the coverage factor k from three to two reflects current metrology practice (as e.g. in calibration certificates).The change of the repeatability test limit from 0.1% to 0.10% affects the rounding of the test result.The effective requirement for the repeatability essentially remains unchanged from a practical perspective (changed coverage factor and rounding essentially compensate each other).The use of 0.41d as the minimum repeatability value accounts for the rounding error of digital indications as already incorporated in international guidance documents for calibration of non-automatic weighing systems.

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*Impact of the proposed new GC 41 and 1251 An alternative method is described to determine the minimum weight of balances, using a larger test weight than the minimum weight. It is clearly stated that the minimum weight applies to the sample weight, not to the tare or gross weight.As repeatability fluctuates over time, when possible, weighings should be made at larger values than the minimum weight (safety factor). It is not permitted to carry out an accuracy test using a test weight with a mass of smaller than 5% of the balance's capacity.A daily balance assessment or check is not described anymore. Risk analysis determines the frequency of any test.Checks with external weights can be replaced partially using (automatic or manually triggered) adjustment by means of built-in weights.

Revision of USP General Chapters 41 and 1251Switzerland, May 2013Dr. Klaus FritschManager Compliance Global Business Area LabTec

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