by Laurie Meehan & Rosanne Sylvia-Heeter
Developing safe and effective drugs requires a coordinated effort across a diverse set of disciplines. This is easier to observe at some points in the process than at others. Once a product is well into human trials, it can be easy to forget that developments on the manufacturing side of the house can affect the clinicians who are conducting the studies.
Trialed Drug vs Marketed Drug
Once researchers are satisfied that animal studies show that an Active Pharmaceutical Ingredient (API) is effective and nontoxic at initial doses, there’s an urgency to get it into the clinic and begin human studies as soon as possible. Though the ultimate product may be marketed in one form, a different form may take less time to manufacture, and so would be the form given to human volunteers in earlier clinical trials.
A tablet, for example, is much harder to manufacture than a 2-piece hard shell capsule because determining the appropriate compression for a tablet takes time. (Tablets that aren’t sufficiently compressed will break apart in the bottle; tablets compressed too tightly may not dissolve as they should, earning themselves the entertainingly accurate moniker “bedpan bullets.”) Rather than wait until a tablet form of the drug can be fully developed, to save time, sponsors would likely begin human studies using a hard shell capsule version.
To ensure that clinical trial data for the Investigational Product (IP) are applicable to the ultimately marketed product, clinicians run bioequivalence for dosage form studies. These small pharmacokinetics studies may result in changes, such as dosage amount or frequency, if people do not metabolize the studied formulation and the final formulation the same way.
Stability Test Failures
When we hear of a pharmaceutical company having to “pull its product,” we typically think of a recall scenario that involves consumers, distributers, and retailers. Recall procedures fall under the GMP umbrella, and are spelled out in great detail in 21 CFR Part 211. However, similar procedures may very well be required of clinical site staff, long before the product ever sees its first drugstore.
Before any clinical trials begin on a drug, manufacturers would have been conducting stability tests for months. But stability testing may continue for years after the start of human trials, and analysts could detect a variety of troubling conditions in the course of their work. Product can change color or break apart. Capsules can crack and leak. Microbes could begin to grow, especially in moister product. The container closure system itself could be problematic; it could leech contaminating material into the product, introducing impurities, or it could extract material from the product, diminishing its potency. Any of these findings could mean that study drug would need to be pulled from clinical sites.
No one expects site staff to have detailed quarantining and recall procedures; the Sponsor will tell site staff exactly what they need to do. But what would this look like?
(1) Adulterated product that cannot be dispensed will need to be moved to a separate, secure area so it won’t be confused with good product. It might need to be stored there for a period of time or shipped back to the Sponsor.
(2) For certain, a site’s drug accountability procedures will be center stage. The only way a site can successfully recall bad product is if it has — all along — closely tracked the amount of IP it has received, dispensed, and still has on hand.
(3) Study participants who have any quantity of the bad product will need to be contacted, told not to use it, and told how to return it. (Note that this pertains to participants on the placebo arm as well, otherwise the blind will be broken.) Phone calls may not be sufficient; sites may need to invoke lost-to-follow-up procedures, such as sending registered letters. Remote, virtual trials, which often ship IP to participants, need to be designed to allow for the tracking and retrieval of bad product.
(4) What should be done if it turns out some participants have already used the bad product? Unfortunately, that’s one SOP you can’t write in advance; it would completely depend on the nature of the IP and the problem it has, the vulnerability of the patient population, the protocol, the participant’s proximity to the site, etc. Perhaps a careful case review to look for AEs associated with affected participants would suffice. More critical situations may require participants to undergo physical examinations or special testing. In some cases, study data associated with the use of the tainted IP would need to be identified and removed from the efficacy analysis.
(5) These quarantining and recall activities must be carefully recorded. IRBs and regulators will want written proof that all suspect IP has been accounted for. Sponsors might consider sending a CRA to ensure adequate documentation.
Stability tests don’t have to fail to trigger action for clinical staff. Should a chemist discover a condition that requires a labeling modification — a new expiry date, for example – all the labels on existing product held at clinical study sites would need to be replaced. In these situations, the Sponsor may dispatch CRAs to replace the labels themselves, or negotiate with individual site staffs to do it instead.
No GxP is an Island…
GMP professionals manufacture, package, and label biopharmaceutical products. GCP professionals conduct clinical trials on those same products. These roles are very different from each other, yet they don’t work in isolation. Formulation changes, stability testing, and re-labeling requirements represent three examples in which activities performed by GMP folks impact their GCP counterparts. Have you experienced any additional examples?
 “By the time clinical trials start, they know what ingredients go in the cookie, they just don’t know how the cookie is going to turn out yet.” – Rosanne Sylvia-Heeter, Polaris Director of GMP Compliance and phenomenal cook
 Expiry dates are not required but are sometimes included on IP labels.
About the Authors
Laurie Meehan is the Social Media Manager for Polaris Compliance Consultants, Inc. She writes the company blog and eNewsletter, manages the company website, social media accounts, and internal training platform. Prior to joining Polaris in 2008, Ms. Meehan worked at a major telecommunication R&D company and taught math and computer science at local university.
Rosanne Sylvia-Heeter is the Director of cGMP at Polaris Compliance Consultants, Inc. She has over 30 years of GxP quality assurance and compliance experience with Active Pharmaceutical Ingredients, Clinical Research Materials, and Finished Product. During her career, Ms. Sylvia-Heeter has developed global quality systems, prepared facilities for FDA Pre-approval Inspections, and interacted with the FDA at both the Headquarters and District levels. She has held positions as Compliance Manager, Quality Assurance Manager, and Global Director at major research-based and generic pharmaceutical companies.