Reference Standard – An Essential Investment to Expedite Development Milestones

There seems no end to the needs and activities competing for precious start-up funds throughout drug development. One need that is often overlooked is for the provision of a certified reference standard. This item can be viewed as a ticket to meet many Development milestones, and facilitates the R&D supply chain.

A Developer does not have a compendial catalogue of standards available for their novel small molecule candidate drug for purchase, so they must source and ensure certification of their reference standard to support the most critical activities, such as:

• GMP Release and Stability testing of API and drug product clinical trial materials
• Execution of GLP toxicology studies
• Analyses of all clinical samples through Development to Registration

Attributes of the Reference Standard:

1. Consists of only a few 10s of grams of the API drug candidate active substance
2. The standard must be:
   • Well characterized (quality, identity, strength, purity) using both QC control and molecular characterization testing methods to comprise the certification data set. The potency must reflect deductions from 100% for moisture and solvent content, ordinary salts, and chemically-related substances (process impurities, degradants). This also must include specificity with respect to solid state morphology, should multiple solid forms be accessible.
   • Stable; isolated and stored under controlled temperature and humidity conditions with unique lot identification and handling vs. Research or regular production materials to maintain its identity and integrity as a certified standard.
3. The standard can be:
   • A sub-lot isolated from a GMP API production batch, a small Research lab lot, or even a lot made using a different synthetic route.
   • Re-certified after the identified re-testing date for the API (given available stability information) is reached, with revised potency factor calculated from the quantitative certification data.
4. The standard should:
   • Be of the highest available purity. Heroic attempts at reaching an arbitrarily high purity factor are not required for a reference standard. What is important is to ensure that the potency factor is accurate, so that consistency in all data evaluations and comparisons where the potency is critical (release and stability for API and drug product, determination of bioavailability, clinical sample blood levels, etc.) is obtained.
   • Be representative of the current API process in terms of impurity profile and scale of manufacturing, so that evolution of the impurity profile and trends in manufacturing variation are more easily revealed.

A Developer should be thinking about securing a supply of API to be dedicated to use as a reference standard when the synthetic process in question is reaching perhaps a 100 gram scale in the lab. If that small scale run is executed according to GMPs and the material is intended for clinical (or GLP tox) uses, then the need for the standard is accelerated. From there, one expects to be making the transition to larger lab/pilot plant glass reactors or fixed plant reactors within a 6 month to 1 year time frame (to make 1 – 5 Kg), given normal Development timelines. GMP batches at these larger scales will obviously also require the availability of the reference standard, so planning to get the reference standard certified as soon as practical given the synthesis scale should be considered.