Reference-Standard and Working Standards
The US Food and Drug Administration defines a reference-standard material as a “highly purified compound that is well characterized”
(1). The US Pharmacopeia (USP) defines reference-standard materials as “highly characterized specimens of drug substances, excipients, reportable impurities, degradation products, compendial reagents, and performance calibrators”
(2). Scientists performing analytical testing use reference standards to determine quantitative (e.g., assay and impurity) as well as qualitative (e.g., identification tests) data, performance standards, and calibrators (e.g., melting point standards). The quality and purity of reference standards, therefore, are critical for reaching scientifically valid results.
Reference standards can be segregated into two groups: chemical and nuclidic.
Chemical purity must be determined for both groups.
Nuclidic reference standards, however, also need to be evaluated for radionuclidic and radiochemical purity.
Reference standards are authentic substances approved by the reference standard approving authority as a preferred method for use. Comparison Standards are described as individual monographs and methods of analysis. The purpose of this is to define the procedure for the preparation, standardization, and usage of a working standard.
The precautions that have to be taken like using a clean and dry amber-colored vial for storage of working standards. All reference standards or impurity standards have to be stored as per the storage condition mentioned in MSDS from the supplier. Remember before usage, the temperature of the vials must reach room temperature. In the case that the potency of the working standard is found more than 100.0% during the standardization, as a policy cut off the potency of the working standard will be considered as 100.0%.
Maintenance of Reference Standard
According to pharmaceutical standards, reference substances or standards are authentic purified chemicals supplied by the official pharmacopeia commission. These are generally used for comparison to determine the purity of the test specimen. In case the reference standard isn’t available in the pharmacopeial catalog, the manufacturer shall be asked for their reference standard or working standard with a certificate of analysis. As reference standards are usually available only in small quantities, working standards can be prepared to act as a substitute, these are prepared from approved raw materials and validated against authentic reference standards or substances.
All standardized records of working standards shall be maintained in a QC laboratory. The Inventory and consumption of reference standards shall be maintained, and the validity of reference standards shall be verified on a quarterly basis, and before preparing for a working standard.
Now, in case the reference standard is found to be consumed or expired during verification, then the indent for procurement of a fresh lot shall be initiated by the Manager Q.C.
Storage and Expiry Working Standards
All working standards are to be stored under refrigeration, in case a specific storage condition is mentioned then the material should be stored according to that. All working standards shall be brought to ambient temperature before use and the details are to be recorded in the usage log book. The expiry period for the working standard is one year from the day of preparation, and for a vial is one month, the expiry period should not exceed the retest period of the selected API batch.
Types of reference-standard materials
Reference-standard materials can be broadly categorized as such:
- Assays—used to determine the potency of active pharmaceutical ingredients (APIs) and salts.
- Degradation products—used to identify and possibly quantitate degradation products.
- Process impurities—used to identify and possibly quantitate process-related compounds.
- Resolution—used to determine assay performance or impurity method.
- Metabolites—used to identify and possibly quantitate substances generated through a metabolic process.
Sources of reference-standard materials
Reference standards can be compendial or non-compendial and are typically obtained from the following sources.
- Pharmacopeias such as the United States Pharmacopeia (USP), European Pharmacopoeia (EP), or Japanese Pharmacopoeia (JP).
- Nationally recognized standard institutions such as the National Institute for Standards and Testing (NIST).
- The user (custom manufactures or synthesizes the reference standard)
- Contract manufacturer
- Companies such as chemical suppliers.
Pharmaceutical Secondary Standards
Our secondary standards have multi-traceability to the USP, EP, and BP primary standards; in addition, they are manufactured according to ISO/IEC 17025 and ISO Guide 17034.
The FDA and EP all recognize the use of secondary standards or working standards that are established with reference to the corresponding primary standard.
FEATURES & BENEFITS
The important product features are:
- Traceability to United States Pharmacopeia (USP); also to European Pharmacopoeia (EP) and British Pharmacopoeia (BP), if available
- Analysis performed on instruments validated according to GMP using pharmacopeia monograph methods
- Certified value according to ISO Guide 17034 and ISO 17025 using mass balance approach
The main benefit is:
- Eliminate the time and effort involved with preparing and validating your own working standards.
The values on the certificate are always traceable to the current pharmacopeia lots.
Note: If a valid pharmacopeia lot changes, then the corresponding secondary standard will be recertified with traceability to the new lot and a new certificate will be made available online.
For this reason, the certificate always needs to be downloaded from the website prior to the use of the material!
The certificate contains the following data:
- Traceability assay results versus pharmacopeia primary standards
- Value by mass balance
- Handling and storage instructions
- Analytical data
An excerpt of the certificate is shown in the image below, highlighting some of the key information that is displayed.