What Is Difference Between Working Standards and Reference Standards?

In drug development, manufacturing, and the quality control procedure, reference standard and working standard are the most common standard substances used to make sure the analytical method and statistics accurate and reliable. They are significantly different in the application, source and potency, but are also related each other and play different roles in the drug quality control system.

Reference standard is commonly certified by the authorities (Pharmacopoeia Committee, WHO, etc.), applicable in verifying critical analysis method and regulatory declaration, while working standard is prepared from the inner lab of the pharmaceutical company, mainly used for the test in the daily work in order to reduce the analysis cost and increase the efficiency. Although they have differences from the source, application and management method, they jointly constitute an integral drug quality control system to assure of the statistics accuracy and consistency throughout the entire process from R&D to production.

On this blog, we will introduce the definition, feature, application, importance of the reference standard and working standard, and analyze their connection and differentiation in detail, in order to help the practitioners in pharmaceutical industry to better understand them.

Reference Standard

Definition

Reference standard, also called official standard, is the standard substance certified by the authorities (such as USP, EP, ChP, WHO etc), used for the establishment, verification and testing of drug quality analysis methods. They are the key standard of drug development, production and quality control to assure the accuracy of the test result, comparability and traceability.

Feature

Legality: Certified by official authorities, has legal validity, and is applicable to pharmacopoeial methods and regulatory requirements.
High purity: commonly has very strict quality standard, for example, purity is commonly ≥99.5%, as with certificate of analysis
Traceability: CoA (Certificate of Analysis) is available, with the information of source, batch number and validity etc.
Stability: Require strict storage conditions (such as low temperature, avoid direct sunlight), to make sure the long-term stability.

Application

Method validation: Used to found and validate the key analysis method such as HPLC, GC
Assay Test: Can be used as the reference standard for the statutory testing, such as the assay test of main components of active pharmaceutical ingredients.
Impurity Analysis: Used for the qualitative and quantitative analysis of the known impurity.
Regulatory Declaration: Reference standard must be needed to provide the key data support in drug registration application

Importance

Reference standard is the official standard for the drug quality control, its quality data will directly affect the safety, efficacy and regulatory compliance of the drugs. Upon the GMP management, the uncertified reference standard may cause the data not accepted by the regulatory agency, even affect the drugs marketing approval.

Working Standard

Definition

Working standard is prepared and calibrated by the inner lab of the pharmaceutical companies, and used for daily test to ensure the drug quality, it is commonly calibrated with the reference standard, but does not have the official certification effects. It is a detailed guideline developed within a pharmaceutical company or organization to unify processes, reduce deviations, and meet regulatory requirements (such as GMP, GLP, etc).

Feature

Prepared by inner lab of pharmaceutical company: Selected and calibrated from the high purity of products by the pharmaceutical company, or provided by the 3rd pharmaceutical firms ( non-official authority agencies).

Lower cost: Compared with the reference standard, working standard can greatly reduce the testing costs.
Needs regular calibration: Needs regular calibration with the reference standard to ensure the accuracy.
Limited Application: Mainly used for the internal quality control, not suitable for regulatory declaration.

Application

Daily Testing: such as API assay test, pharmaceutical intermediate tests.
Method Optimization: Used for analyzing the method development and optimization, to reduce the consumption of reference standards.
Stability Studies: Used for monitoring samples in long-term stability studies.

Importance

Working standard can increase the test efficiency and reduce the testing costs, especially applicable for high-frequency testing in large-scale production, but it is just applicable for the internal quality control purpose, can’t replace reference standard for critical decision making or regulatory declaration.

The Relation of Reference Standard and Working Standard

Although they have differences in the source and application, they are related each other in drug quality control system.

Calibration Dependency

Working standards must be calibrated with reference standards to ensure the accuracy of their data.
For example, in HPLC analysis, the correction factor (such as relative response factor) of the working standard needs to be compared with the reference standard.

Jointly Support for Quality Control System

Reference standards are used for key analysis (such as method validation, regulatory testing), while working standards are used for daily monitoring, forming a complete quality control chain. They work together to ensure data consistency throughout the entire process from R&D to production.

Method Transfer and Comparison

When analytical methods transfer (such as from R&D to production), reference standards are used to confirm the applicability of the method, while working standards are used for daily execution.

Main Differences between Reference Standard and Working Standard

Conclusion

Reference standard and working standard have different focuses in the quality control of pharmaceutical APIs and intermediates.
Reference standards are legal benchmarks, used for key analysis and regulatory compliance, while working standards are cost-effective alternatives used for routine testing.

The main difference between reference standard and working standard lies in their source and legal effect, but through reasonable calibration and management, they can work together to ensure drug quality. Pharmaceutical enterprises should establish a scientific standard management system to meet regulatory requirements and optimize the testing process. In the future, with the development of analytical technology, the management of standards may tend to be intelligent, but the core roles of the reference standard and working standard are still irreplaceable.