Pharmaceutical manufacturing companies have been nervously awaiting the fallout from major modifications in the US Pharmacopeial (USP) Convention’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 which officially comes into effect in December 2013.
The actual results from the methods detailed in the new standard will probably be in a range similar to those in the previous standard, but the techniques required and the wording of the standards are 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 using their existing equipment – if they understand the nuances of Chapter 41 and follow a few simple guidelines.
With the help of panels of experts, USP regularly updates and modifies the standards 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 the USP’s main goal is to describe mandatory standards that lead to a common production quality within the US, its reach is far greater, since USP standards and regulations are used globally by any pharmaceutical company that wants to export products to the US. The US Food and Drug Administration (FDA) inspects facilities in more than 140 countries on the basis of US standards and regulations, and is responsible for enforcing the new USP Chapter 41 standards.
USP standards are rarely self-explanatory, and usually require a fair amount of interpretation
This has made some pharmaceutical and nutraceutical manufacturers somewhat nervous, since 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 the FDA. However, the vast majority rely on interpretation by manufacturers of weighing equipment.
In most cases, individual pharmaceutical manufacturers make their own decisions on what needs to be weighed accurately within their manufacturing environment. When conducting assays, accuracy is always required, whereas buffer preparation 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 premium lab balances, Sartorius has reviewed thoroughly solutions for the challenges posed by the new Chapter 41 changes and has assisted 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 such as 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 themselves. Once installed, the software guides users step by step through the determination process.
The Sartorius Cubis, widely used in regulated sectors such as 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 themselves
The new standards strive for accuracy and repeatability. Chapter 41 defines the minimum quality standard for accurate weighing; this is of great importance, because any mistakes in weighing will be multiplied during all other analytic tests conducted afterwards. The changes discussed in this article are summarised in Table 1, under the two main headings of repeatability and accuracy.
| Table 1: Overview of Chapter 41 changes | ||
| Feature | ||
| Scope | ||
| Repeatability tolerance | | |
| Expansion factor K | | |
| Number of weighing values for the repeatability test | | |
| Acceptance criterion | | |
| Smallest possible sample weight/lowest starting point | | |
| Tolerance | | |
| Test weight | ||
Repeatability
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 it says: ‘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 not more than 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 to what was formerly known as minimum weight) must be calculated according to a newly modified algorithm.
In the revised Chapter 41, the minimum weight has been replaced by the requirement to determine the balance’s ‘operating range’
The new USP requires that the repeatability of a balance 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 200g analytical balance, use a 100g weight. It is important to perform the test with a single piece weight. The USP states that 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 with a small weight.
Determine the standard deviation from 10 comparable weighed values and multiply these by an expansion factor of 2 (twice the standard deviation). Multiply this value by 1,000 to get the operating range starting point for a particular balance.
If a standard deviation of less than 0.41 digit (0.041mg is obtained for an analytical balance with a readability of 0.1mg), replace it with 0.41 d so that the smallest possible starting point of an operating range of up to 820 d (2 * 0.41* 1,000) can be achieved. For an analytical balance with a readability of 0.1mg, this means the starting point yielded is 82mg. This approach specifies an absolute minimum, which is a positive addition; in previous USP versions, the minimum was not specified, so different interpretations were established.
Determining accuracy
In addition to repeatability, the accuracy of a balance and the test weight must now also be determined. The USP requires a simple test – ‘a balance/the test weight’ is sufficiently accurate if the weighed value displayed does not differ by more than 0.10% 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 100g the permissible readout on a balance is between 99.90000g and 100.10000g. Generally this is not a challenge for a modern lab balance or a traceable weight of a proper weight class.
For this test, weights used must have a maximum permissible error (mpe) of no more than 1/3 of 0.10% (0.03%). This requirement merely signifies that it is not always mandatory to use a high-class E2 weight. In most cases, it is sufficient to use class F weights (weight classes according to International Organization of Legal Metrology (OIML)). A further requirement is that the accuracy must be determined using a weight with a mass value between 5% and 100% of the capacity of the particular balance. For example, for a 200g analytical balance, use a weight with a mass of between 10g and 200g.
As explained above, repeatability and accuracy tests can be combined 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.
One other important revision to the USP 41 is a new requirement that, ‘...Unless otherwise specified, when substances must be ‘accurately weighed,’ the weighing shall be performed using a balance that is calibrated over the operating range and meets the requirements defined for repeatability and accuracy.’
The requirement to calibrate the balance over the operating range raises interesting questions
The requirement to calibrate the balance over the operating range is subject to a great deal of interpretation and raises interesting questions. The fact is that there are many different ways to calibrate a balance. As a leading balance manufacturer, Sartorius strongly recommends using the globally established ISO17025 standard, General requirements for the competence of testing and calibration laboratories, which incorporates a variety of influencing factors and parameters. The USP minimums incorporate only the repeatability and some of the test weight information. The ISO17025 standard also supplies detailed information on the measuring uncertainty of a balance.
Various service providers offer balance calibrations in accordance with ISO17025. It is extremely important to select a service provider with ISO17025 accreditation, because only those with such accreditation have proven that their procedures really follow the standard and that they are authorised to issue valuable certificates on the measuring uncertainty of a particular balance.
Currently the revised Chapter 41 can be accessed in the USP’s online forum, the USP PF. As soon as the printed version is available, the updated Chapter 41 will also be binding. At the time of going to press, the transitional period was in effect, during which users may proceed according to either the old or the new USP.
References
1. http://www.usp.org/about-usp
2. http://www.pharmacopeia.cn/v29240/usp29nf24s0_c41.html
Dirk Ahlbrecht is a Member of the USP experts panel for general chapters 41 and 1251
