Profiling Reference Standard Management

by Harley Wilcox, Senior Scientific Advisor (CMC Small Molecule), Eurofins BioPharma Product Testing-Columbia

Reference standards play a critical analytical support role in the pharmaceutical drug life cycle, from preclinical to commercial. Standards used in cGMP testing are typically introduced during clinical trial manufacturing of a drug substance and drug product. The management of CoAs, inventory, and supply chain to external users, are critical in avoiding delays.

Below we profile reference standard management for small molecule compounds and will discuss types of standards, synthesis based standards, officially sourced  standards, suppliers, characterization, and impurity assessment. Additionally we provide an overview of standards storage, retesting, and material administration.

Types of Standards

Officially sourced standards are often procured from pharmacopeia (USP/ EP), NIST or other industry recognized sources. CoAs are provided. Bottle label information and certificates provide purity information. USP standards do not have a “use by” or “retest” date; they list a current lot or previous lot, and the end user must monitor what is considered “current” lots from the compendia. A “previous lot” designation implies a use period will be assigned. If a test article has a current issued monograph, it is expected that the corresponding compendia has reference standard material available for purchase and use.

In-house standards can be obtained from synthesis or in some cases isolation, but must then have characterization performed to establish purity values.

Primary Standards

Primary reference standards typically should have a purity of 99.5 percent or higher. Reference standards are typically sourced from APIs with additional purification. Lower purity is acceptable if further purification steps are ineffective.

For impurities of interest used for analytical identification purposes, they are often isolated and collected initially from API chromatography. After the impurity structures are determined, a unique synthesis scheme is typically required to prepare adequate quantities for further characterization and purity assessment.

Secondary standards

Secondary standards, typically from vendor based sources, are analyzed using a primary standard calibration scheme to establish their purity value.

Reference Material

Reference materials are used for nonquantitative purposes such as retention time markers.

Storage

Standard inventory may be subdivided or fractionated into similar type containers for ready shipping to other labs or vendors. Both primary (bulk) standard container and fractionated containers are stored together (same chamber/condition) to allow for equalification options. When a new CoA is generated for the reference standard lot, the primary container and fractionated sample containers are relabeled in accordance with the new CoA. Fractionated containers often contain smaller amounts of standard i.e. 100-500 mg, and depending on the extent of testing required for re-certification testing, the smaller containers may not be individually re-tested, and only the bulk material used for new CoA generation. Depending on risk assessment this could also mean any fractionating of bulk material should only be done at the time a distribution is needed.

The storage condition for an individual standard should be based on the already established stability profile. Storage conditions often range from (-80C to RT), and could include requirements for protection from light and ambient humidity.

Retesting and Retest Dating

A common topic for new reference standard management is how to establish a retest date. When limited stability information is available for the API, one may consider a 6M or earlier retest date interval. An API with more established stability data, typically have longer retest periods, i.e. 12M.

A retesting notification system, electronic or other, is essential to avoid lapse in new CoA establishment. A 60-day notification of retest due date is recommended to allow adequate laboratory time for protocols, testing and documentation.

Structural characterization techniques utilized include

• Infrared Spectroscopy
• Mass Spectrometry
• NMR Spectroscopy (QNMR, correlation and two-dimensional)
• UV Spectroscopy
• XRD
• CHN

Purity determination includes assessment of volatile impurities, organic impurities, and inorganic impurities.

• Organic Impurities-HPLC
• Inorganic Impurities—ROI, and ICP
• Volatile Impurities—KF Water, GC, TGA, and LOD
• Qualitative Testing—DSC, XRPD, melting point, specific rotation
• Stoichiometry Testing-quantitation of counter ion, salts of active moiety

Standards used for non-quantitative analysis may require less testing.

Note: Moisture is often assessed in reference standard CoA establishment, and purity values can often be listed both “as is” and “dried” basis. Many reference standards will have drying requirements listed prior to utilization.

Managed reference standard program overview through Eurofins

• Utilize LIMS for software management
• Extensive experience in material shipments, controls, etc.
• Each program may be designed to fit the individual client’s systems and needs

Reference standard receipt from clients

• Processed by established SOPs which detail time of sample log-in and subsequent shipment processing for entry into LIMS
• Materials received need to have clear identification as a reference standard, lot, storage conditions, retest date, product, etc.
• Shipping information retained for future reference

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