Reference Standard Characterization and Management
Reference standards are highly purified and well-characterized compounds that are essential for validating the quantitative and qualitative accuracy of analytical testing methods. Thus, their development, characterization and management is critical for companies working to deliver safe and efficacious therapeutics that can withstand regulatory scrutiny.
In some cases, well-characterized, high-purity (>99.5%) compendial reference standards – often called primary reference standards – are available for purchase from pharmacopoeias, such as the USP or other national formularies. In other instances, there may be no established reference standards on record. Fortunately, the FDA provides a roadmap for establishing a chemical as a reference standard in the absence of a readily available official source. Despite this regulatory guidance, there are a variety of challenges and considerations, including reliability and operational efficiency, that need to be considered when developing and characterizing new reference standards.
Non-Compendial Reference Standard Development
The purchase of compendial reference standards is a safe and easy way to get high-quality, well-characterized standards. However, there are many common instances throughout pre-clinical and clinical development, including phase 1 lot release and phase 2 and/or 3 impurities testing, when compendial reference standards may not exist.
Here are a few examples of the types of situations when compendial standards may not be available:
- Proprietary compounds: many cutting-edge pharmaceutical companies are investigating novel small molecules or biopharmaceuticals which have never been characterized outside of the company
- Generic drug applications: due to the regulatory requirements for impurity testing methods, even for older compendial medications, impurity reference standards may not exist
- Extractables and leachables: the expansion in this type of work has required control methods for potential leachants from packaging
Synthesis, characterization, qualification and management of new non-compendial reference standards may be challenging for an in-house pharmaceutical team.
Avomeen’s Reference Standard Management Program
Avomeen offers a complete reference standard management program with three services that are designed to meet the needs of small-, mid-, and large-sized companies, as well as those with a virtual or semi-virtual business model:
- Reference standard characterization for both structure and purity
- Periodic requalification
- Reference standard storage and distribution
These capabilities apply to the development of both small molecule drugs and some biologics and are described in more detail below.
Reference Standard Characterization
Our characterization process focuses on the accurate chemical and structural identification of your reference material, as well as an assessment of purity.
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Avomeen can validate, from first principles, the chemical identity and structure of your reference standard using multiple orthogonal techniques including:
- 1- and 2-D NMR: proof-of-structure in which the 1H and 13C NMR resonances are assigned and the connectivities along all the rings and chains are demonstrated
- LC-MS: identifies the molecular mass of a standard
- FT-IR and UV Spectroscopy: demonstrates consistency with putative structure
- DSC: demonstrate consistency with reported melting point and known thermal characteristics
- Elemental analysis (CHON): performed to verify consistency with putative structure
Purity can also be assigned from first principles, without an external reference standard. Avomeen uses the following methods when assessing purity of a reference standard:
- HPLC: used to calculate an area-under-the-curve purity which is corrected for water by Karl Fischer titration
- ICP-MS: detects the presence of heavy metals
- TGA: detects residual solvents
How Much Does Reference Standard Characterization Cost?
Reference standard characterization is just one of many tests that need to be done throughout the drug development journey. Over time, these costs and timelines inevitably add up, so it’s important to be strategic when contracting these and other analytical services.
As you might expect, the turnaround time for full reference standard characterization will vary depending on your project specifics. At Avomeen, we can execute on novel chemical characterization in as little as 20 business days.
Along with timelines, we provide value and cost-efficiency to our clients in a number of ways. Chief among them is our commitment to customization and customer choice. For example, we offer structure and purity determination testing as a standalone service, so you’re not forced into a package with services you don’t need. As a rough guide, a proof of structure will cost approximately $15,000 – $20,000.
Reference Standards Requalification
Annual requalification is generally recommended for reference standards. Avomeen’s initial qualification expires 12 months following report issuance. Depending on what your reference standard is being used for, the analytical procedure for requalification can be less involved than the initial qualification process. If you undertook your initial testing with Avomeen, let us know and we can delve back into the data.
Requalification Based on Application
If your reference is being used for chemical identification, the requalification process may be significantly easier. Typically, it requires two components: identification testing using NMR or FT-IR and a comparison of the new data to that data collected during the initial characterization.
Likewise, if the standard is being used for purity testing, then purity must be reassigned as well. Full purity testing is necessary for requalification as degradation as well as moisture absorption may have occurred.
How Much Does Reference Standard Requalification Cost?
Full requalification can take as little as 20 days and cost can depend on the scope of your project and if it includes requalification for chemical identification, requalification for purity, or both. If you would like a detailed estimate, click here for a quote.
Reference Standard Storage and Distribution
Our storage and distribution services are particularly useful for virtual pharmaceutical companies who don’t have the capacity or desire to store the associated materials.
Avomeen can qualify your reference standards, store them, and ship them to other laboratories as needed to support your clinical needs. We follow GMP procedures for all reference standard management, including storage under the proper conditions, requalification according to schedule, and shipment to location of your need.
How Much Does Reference Standard Storage and Distribution Cost?
There is a regular monthly fee for the storage of reference standards and a one-time fee for each shipment.
Tell us more about your projects and challenges. For pricing and timeline information for any of our reference standard characterization or management services, contact us below and we’ll make time to chat.