Monday, October 7, 2013

Have you heard about the New USP Chapter 41 changes?



Sartorius AG (USA) - How to use new balance standards to perform accurate measurements in the pharmaceutical industry, by Dirk Ahlbrecht, Sartorius Group and a member of the expert panel of US Pharmacopeia for chapters 41 and 1251.

Pharmaceutical manufacturing companies have been nervously awaiting the fallout from major modifications in the U.S. Pharmacopeial Convention’s (USP’s) Chapter 41 minimum quality standards for weights and balances. The Chapter 41 standard, previously used in assays to determine drug content and potency, was last updated more than twenty years ago. A global team of experts drafted the new version, which was recently approved for release by the USP, and officially goes into effect in December 2013.

The actual results will likely be similar to those in the previous standard, but the techniques required and the wording of the standards is a bit more complex. While some have suggested that the modifications require the purchase of expensive new high resolution measuring equipment or services from outside parties, in fact many laboratories can easily and efficiently comply themselves, using their existing equipment – if they understand the nuances of Chapter 41 and follow a few simple guidelines.

USP standard basics:
The Food and Drug Administration (FDA) is responsible for enforcing the new USP Chapter 41 standards, which are used during inspections of US pharmaceutical companies and companies that wants to export products to the US. This is causing some concern, since USP standards usually require a fair amount of interpretation. Larger manufacturers may have in-house metrology departments to help develop interpretations, but most rely on interpretation by manufacturers of weighing equipment.

In most cases, individual pharmaceutical manufacturers decide for themselves what needs to be weighed accurately within their own manufacturing environment. The most appropriate method is to use FDA’s risk-based approach, which evaluates each measurement according to such established risk analysis standards as those used in the failure modes and effects analysis (FMEA) approach, ensuring that the user will arrive at a proper and practical definition.

As a manufacturer of premium lab balances, Sartorius has been thoroughly reviewing the challenges posed by the new Chapter 41 changes and has been assisting with interpretations to make compliance as easy as possible. For example, the Sartorius Cubis® individual premium lab balance, widely used in regulated sectors like global pharmaceutical labs with the most stringent requirements, can be equipped retrospectively with workflow software that enables users to perform the required USP Chapter 41 compliance tests by themselves. Once installed, the software guides users step by step through the determination process.

New standards strive for accuracy and repeatability:
The Chapter 41 minimum quality standard for accurate weighing is of great importance, because any mistakes in weighing will be multiplied during all other analytic tests conducted afterwards. Table 1 provides a summary of the changes, which fall under the two main headings of repeatability and accuracy.

Repeatability:
In the past the USP defined the minimal sample weight – the smallest sample the customer is allowed to weigh on a balance. In the revised Chapter 41, minimum weight has been replaced by the requirement to determine the balance’s “operating range,” which is limited above and below by the maximum capacity of the balance and begins at the point at which the balance’s repeatability is less than or equal to 0.10 percent. The start point (comparable to what was formerly known as minimum weight) must be calculated according to a newly modified algorithm.

The repeatability of a balance must be determined based on at least 10 comparable weighed values. For this test, Sartorius recommends using one weight that is approximately half the maximum capacity of the particular balance. For example, for a 200 gram (g) analytical balance, use a 100 g weight. It is important to perform the test with a single piece weight. It is not necessary to use a small test weight to assess repeatability. Performing a repeatability test at approximately half a balance’s maximum capacity combines the repeatability test and the accuracy test, which ensures maximum efficiency in determining the required specifications. Besides, it is much easier to handle a weight of a larger value compared to a small weight.

Determine the standard deviation from 10 comparable weighed values and multiply these by an expansion factor of 2 (2 times the standard deviation). Multiply this value by 1,000 to get a balance’s operating range starting point.

If the standard deviation is less than 0.41 digit (0.041 milligram (mg) for an analytical balance with a readability of 0.1 mg), replace it with 0.41 d so you can achieve the smallest possible starting point of an operating range of up to 820 d (2 * 0.41*1,000). For an analytical balance with a readability of 0.1 mg, this means the starting point is 82 mg. This approach specifies an absolute minimum, which is a positive addition; previous USP versions did not specify a minimum, leading to different interpretations.

Accuracy:
The USP now requires a simple test to assess a balance’s accuracy – a balance/ test weight must not differ by more than 0.10 percent of the conventional mass of the weight placed on the balance. The conventional mass consists of the nominal value of the weight used and the actual difference given on its respective calibration certificate. For example, when using a test weight with a nominal weight of 100 g the permissible readout on a balance is between 99.90000 g and 100.10000 g. This is not usually a challenge for a modern lab balance or a traceable weight of a proper weight class.

Weights used for this test must have a maximum permissible error (mpe) of no more than 1/3 of 0.10 percent (=0.03 percent), which means that it is not always mandatory to use a high-class E2 weight; class F weights can be used. (Weight classes are according to International Organization of Legal Metrology). The weight must have a mass value between 5 and 100 percent of the capacity of the particular balance. For example, for a 200 g analytical balance, use a weight with a mass of between 10 g and 200 g.

As noted, you can combine repeatability and accuracy tests if a weight corresponding to half of the maximum capacity of a balance is used to determine the repeatability. One of the 10 weighed values of this repeatability test can be used to determine the balance’s accuracy.



To meet the new requirement to calibrate the balance over the operating range, Sartorius strongly recommends using the globally established ISO17025 standard, General requirements for the competence of testing and calibration laboratories. If using a service for balance calibration, be sure to select a provider with ISO17025 accreditation.

The revised Chapter 41 can be accessed on the online forum USP PF. The updated Chapter 41 will be binding as soon as the printed version is available. During the current transitional period, users may proceed according to either the old or new USP.

Note: This article was previously published in Advantage Business Media’s Laboratory Equipment magazine.

For more information about the Sartorius Cubis® Laboratory Balance click here.


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