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 20 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 from the methods detailed in the new standard will likely be in a similar range as those in the previous standard, but the techniques required and the wording of the standards are 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
With the help of panels of experts, USP regularly and frequently updates and modifies the more than 1700 chapters it sets for the identity, strength, quality and purity of medicines, food ingredients and dietary supplements manufactured, distributed and consumed worldwide.1 Chapter 41, which covers the minimum accuracy of weights and balances used to perform assays, was one of a few that had remained unchanged for 20 years.
While USP's main goal is to describe mandatory standards that lead to a common production quality within the US, in fact their reach is far greater, as USP standards and regulations are used globally by any pharmaceutical company that wants to export products to the US. The FDA inspects facilities in more than 140 countries on the basis of American standards and regulations, and is responsible for enforcing the new USP Chapter 41 standards.
This has some pharmaceutical and nutraceutical manufacturers somewhat nervous, as USP standards are rarely self-explanatory, and usually require a fair amount of interpretation. Larger manufacturers may have in-house metrology departments, and come up with their own interpretations, which they are prepared to argue with FDA. However, the vast majority relies 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. When conducting assays, accuracy is always required, whereas preparing buffers is not normally covered by Chapter 41. With the many methods and applications in the marketplace, it is not possible to outline exactly when Chapter 41 is required; there must be space for individual pharmaceutical or nutraceutical manufacturers to make their own interpretations. The most appropriate method of defining which substances are covered by Chapter 41 is the risk-based approach described by the FDA. This approach evaluates each measurement according to established risk analysis standards, like 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 lab balances, Sartorius has been thoroughly reviewing solutions for the challenges posed by the new Chapter 41 changes and has been assisting with interpretations where necessary to make it as easy as possible for compliance with the new standard. 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 tests to meet compliance with the new USP Chapter 41 by themselves. Once installed, the software guides users step by step through the determination process.
Accuracy and Repeatability
Chapter 41 defines the minimum quality standard for accurate weighing, which is of great importance, because any mistakes in weighing will be multiplied during all other analytic tests conducted afterwards.
So just exactly what are the changes and how do they differ from past? Let's take a closer look -- the Table provides a summary of the changes discussed, which fall under the two main headings of repeatability and accuracy.
The modified USP Chapter 41 standard states, "Repeatability is assessed by weighing one test weight NLT 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 standard deviation obtained is less than 0.41d, where d is the scale interval, replace this standard deviation with 0.41d. In this case, repeatability is satisfactory if two times 0.41d, divided by the nominal value of the weight used, does not exceed 0.10%.
Regarding accuracy, "The accuracy of a balance is satisfactory if its weighing value, when tested with suitable weights, 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. Its maximum permissible error (mpe), or alternatively its calibration uncertainty, shall be NMT one-third of the applied test limit of the accuracy test.
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, the USP does not refer to a minimum weight; this 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%. The start point (which can be compared with what was formerly known as minimum weight) must be calculated according to a newly modified algorithm.
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