Introduction
Weighing of raw materials, products, reagents, excipients and other product related materials is an area which has risks in the biotechnology and pharmaceutical industries. Any weighing mistake which is not detected immediately and rectified may affect the final drug substance/drug product purity, strength, quality and safety, and may lead to recall or harm to the patient or end user.
As part of GMP audits, many FDA 483 observations and warning letters have included comments regarding inappropriate balance and weighing processes in production departments and quality control laboratories.
We are aware that, quite often, pharmaceutical and biotechnology companies use a balance which does not comply with the required characteristics, such as minimum weight, certainty and accuracy. The importance and risks of weighing considerations is well defined in several authorities’ official documents and guidelines, such as:
- FDA 21 CFR part 211.68 (USP GMP guide for pharmaceutical products) states that automatic mechanical or electronic equipment for pharmaceutical production “will be routinely calibrated, inspected or checked according to written program designed to assure proper performance”.
- OECD principles of GLP (good laboratory practice) state that laboratory apparatus “used in a study should be periodically inspected, maintained and calibrated according to standard operation procedures”. As all the good practice issues related to the biotechnology, medical device and pharmaceutical industries are defined as GxP, good weighing practice (GWP) was also adopted. GWP is an integral part of the Good Manufacturing Practice (GMP) requirements for production purposes and of GLP for laboratories. GWP principles were defined to improve the measuring process of weight in production as well as in pharmaceutical and biotechnology company laboratories.
Good Weighing Practice
Good weighing practice is a risk based approach considering all the requirements related to quality management system. GWP can improve the control on the weighing process by implementing the principles detailed below:
- Clear definition of weighing related factors such as risks, process requirements, quality standards, required accuracy, weighing capacity, environmental factors, weighing area size and shape, documentation etc.
- Selection of the suitable balance based on the definition as well as considering other balance characteristics such as balance readability, minimum weight, capacity, accuracy, built-in calibration and uncertainty values.
- Installation and qualification of the balance on site. The initial installation of the balance and training is recommended to be performed by the balance manufacturer/supplier. Moreover, a validation procedure should be performed in order to cover the installation and operation of the balance using a detailed and controlled validation protocols:
- IQ- Installation Qualification
- OQ- Operational Qualification
- Calibration of the balance will be verified as part of the Installation Qualification. Balance calibration examines its performance on site in order to assure that the weighing instrument performance meets the user requirements and balance manufacturer declaration. As part of balance calibration, minimum weight and balance uncertainty values are tested. Calibration should be performed after balances are installed and placed in the specific location. Balance performance on site may differ from balance performance on the manufacturer’s site.
- Balance testing in routine operation and usage will be based on risk analysis issues and will included accuracy testing in addition to balance maintenance procedures and other operation and verification activities implementation.
- Weighing safety factor should be established as part of the GWP methodology. Safety factors will be determined according based on risk analysis that should be completed before balance purchasing.
Definitions
- Balance readability is the electronic weighing instruments’ reading ability (and accuracy) by the balance user. The Balance readability value is often mistakenly confused with balance accuracy value. Balance accuracy value is not necessarily similar to the balance readability value because these are two different values. Balance readability value is not related to balance accuracy value. Weighting instruments should not be selected based on the readability value only. New balance should be selected based on other characteristics such as accuracy, uncertainty, minimum weight and others.
- Balance linearity Any electronic weighing instrument should represent linearity through the entire weight range.
- Balance uncertainly There are two uncertainly types related to weighing instruments:
- Absolute uncertainly- Increases as the weight value is higher vice versa.
- Relative uncertainly- Measured in % units. Calculated as absolute uncertainly value divided by weight value. Relative uncertainly increases as the weight value is lower vice versa. For small mass samples, the relative uncertainly value will be very high and will represent low integrity of weighting results.
- Balance minimum weight value is defined as the lowest mass which can be weighed using the balance, which enables high integrity weight results and in the required accuracy level. Balance minimum weight values should be based on the required accuracy value of the user. Several balance manufacturer offer minimum weight alert values that can be programmed into the balance software in order to avoid inaccuracies, to minimize human errors and to support Good Practice in cases of lower mass than the minimum weight value of the balance.
- Balance eccentricity Weighting results may be affected by the object/material location on the balance surface.
- Balance repeat ability The ability of the balance to deliver the same result, in case the same mass is being placed on the balance several times and under the same conditions.
Balance Validation
Installation issues as well as calibration, manufacturer documentation and balance specification verification will be covered under Installation Qualification protocol. In case the IQ was completed successfully and the IQ report was approved, the Operational Qualification can begin based on Operational Qualification protocol.
Routine testing, weighing tolerance, SOP’s and other balance operation related issues will be covered as part of the Operational Qualification. The balance should not be in usage before Validation stage was completed successfully, documented and summarized.
Balance Routine Testing
Routine testing for balance should be defined, documented and performed in order to keep balance data integrity, product safety and product quality. Under ISO 9001 part 7.6 (Control of monitoring and measuring devices) which is a very basic standard for the Biotechnology, Pharmaceutical and Medical Device industries, it was mentioned that measuring equipment shall be calibrated or verified at specific intervals against measuring standards traceable to international or national measurement standards.
After balance installation, calibration and qualifications stages, as part of balance routine operation, routine testing should performed by the user to assure high integrity, reliable, traceable and accurate weighing results in order to minimize weighing errors and to increase product quality and safety.
Balance calibration is usually performed once a year, therefore the balance status between calibrations is unknown. Balance routine tests should be defined based on Risk Assessment. Routine tests should be established by the user, controlled and documented under relevant policies and SOP’s.
Modern balance models offer built-in calibration system which may minimize environmental effect on balance accuracy level as well as reduce routine testing frequency. The reference weight that installed on the balance should be in calibrated state (by external qualified laboratory).
There are several additional balance measurements parameters such as balance sensitivity, eccentricity, non linearity and repeat ability. Balance repeat ability may be affected from several factors such as balance type/model, balance configuration, gross load, operator weighing skills, ambient conditions, size and shape of the weighted object/material and others.
Routine tests’ frequency should be determined based on Risk Analysis and balance usage frequency. The higher the impact of the weighing results, the higher the balance accuracy and routine testing frequency. Routine balance testing results should be compared to control and action limits that will be established by the user.
In case control limits were triggered, usually no immediate action is required but the following balance performance should be inspected and investigated. In cases action limits were triggered, the user should not use the balance till the root cause investigation was performed and the balance malfunction was detected and fixed.
Choosing the Right Balance
For laboratory applications in which small amount of material is being weighted, balance repeat ability is a major factor that should be considered. Therefore, in order to reduce balance uncertainty value, the minimum weight will be determined based on the repeat ability characteristics of the balance.
Balance non-linearity is a less dominant factor for small mass weighing. For mass production balance, balance sensitivity and eccentricity are major factors for consideration.
Balance Calibration by the User
In cases where calibration is being performed by the balance user, two test weights with a defined mass will be required. Test weight should be calibrated by qualified external laboratory.
As part of the calibration procedure, eccentricity test should be performed especially in cases the balance tare function is in usage and the container is being removed and placed back on the balance plate (may be not to the same location).
