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By Nageshwar R. Thudi

Nagesh Thudi-finalThe Food and Drug Administration (FDA) conducts inspections of clinical and analytical sites that perform bioequivalence studies to ensure the bioequivalence of a generic drug to its reference product. Although the bioequivalence testing inspections are warranted, the final rule procedures can waste valuable time and resources.

Based on FDA procedures, the organization that conducts the original bioequivalence study is responsible for reserving and sending samples of the test article and the reference drug to the testing facility for randomized testing. The organization also has to send enough samples to meet FDA retention requirements i.e. five times of in vitro testing quantity.

For solid oral dosage forms, (e.g., tablets, capsules), FDA has set an upper limit of 300 units of both the test article and the reference drug. However, drug manufacturers sometimes use site management organizations (SMOs) to conduct pharmacodynamics or clinical endpoint equivalence studies when the usual pharmacokinetic equivalence studies are not appropriate for demonstrating the bioequivalence of two products. Sometimes multiple sites are used by the SMO for testing, and in that situation, each SMO site is required to retain sufficient quantities of the test articles and reference standards for FDA investigation. This process is exhaustive and costly. Are there alternate options for testing bioequivalence without impacting the integrity of the study?

Locally-acting non-solid oral dosage forms (e.g., spray content canisters or bottles) may be distributed in 30 units per batch (think nasal sprays), and additional units may be required to test performance. Hence, the number of sample units that would need to be sent to FDA for testing could exceed 1,000, based on the five-times-quantity rule. So FDA has determined that in lieu of the usual requirement, the quantity of local action nasal/aerosol spray test articles and reference products be at least 50 units for each batch.

However, there are no FDA rules for how to handle nasal/aerosol spray batches that administer less than 30 units. As more pharmacodynamics or clinical endpoint equivalence studies are being conducted for generic approval of locally acting inhalation products, such as for asthma or COPD therapies with recent patent expiries, this FDA issue of sample retention requires a more urgent discussion.

To reduce the unnecessary wastage of investigational products (IPs), I propose that all IPs be gathered at one packaging facility (e.g., SMO-1) and then shipped to an independent facility (e.g., SMO-2) that will randomly pick the retention samples to be sent to FDA investigators. I also propose that all investigations only require 50 units total for all multiple usage containers, like ointments, creams, suspensions, inhalation products, etc.

Implementing these methods will maintain the integrity of the study while reducing the burden on the study’s operations and logistics team. These procedures will also avoid wastage of very useful drug products that can otherwise be available for patient use.

Nageshwar R. Thudi has a Ph.D. in biopharmaceutics and is currently working as a Director of Clinical R&D at Actavis PLC. With close to 17 years of clinical research experience, Thudi has published 20 international publications and is currently serving as a steering committee member of the AAPS Generics focus group.