Unchecked supply chain process can degrade a drug's safety, efficacy

Take-home message: Physicians may know how a product is stored once it reaches their offices, but there is no way of knowing the supply chain storage conditions during manufacture and transit.

By Paul S. Koch, MD, Special to Ophthalmology Times

Warwick, RI-Phenylephrine hydrochloride solution has traditionally been used as a topical agent to dilate the pupils. While physicians have had many choices between branded and generic solutions, many do not realize that they had likely been using a non-FDA-approved solution.

The first of these phenylephrine hydrochloride ophthalmic solutions to undergo the FDA’s rigorous approval process belongs to Paragon BioTeck Inc.

Physicians may also be unaware that phenylephrine hydrochloride is a drug that can oxidize and degrade in ophthalmic solutions when exposed to light and higher temperatures.^1-3

This degradation process can often be visibly observed, as the solution may become discolored turning dark yellow or brown.⁴

Even in light-controlled packaging, certain physical and chemical degradation can occur, which has been reported to result in decreased potency.^5-8

To combat this degradation, it has been suggested that minimizing light exposure and higher temperature conditions may be important in optimizing efficacy and performance of this commonly used drug.

During a busy day at the clinic, it may not be practical or efficient to return a bottle of drops that is used on virtually every patient to the refrigerator.

However, maintaining labeled storage conditions when the bottle is out of use at the end of the day may be more important than previously understood. If this is true for the limited amount of time that a drug, such as phenylephrine hydrochloride, is stored in an office setting, then it certainly should be a consideration throughout the entire supply chain.

In a recent online article (http://bit.ly/1DAWrFC) Amy Peak, director of drug information services for Butler University, states that; “the technical definition of room temperature is general storage between 68° and 78° F, but also allowing for temporary excursions as low as 59° F and as high as 86° F.”

The article went on to explain that experts suggest that storing medications over 86° F-a fairly typical summer temperature in many areas of the country-can have a significant effect on their potency.

For example, when stored at temperatures over 98° F, lorazepam and diazepam decrease in potency by 75% and 25% respectively. Insulin and thyroid hormones are widely published as being sensitive to heat, and can lose effectiveness in higher temperatures. Concentrated epinephrine can lose potency by 64% when exposed to cyclical heating (repetitive heating and cooling).

While this may be of less concern in an office setting, what about the multiple warehouses that a product touches prior to its final destination at the clinic? Or, even worse, how about the back of a delivery truck in July?

System of checks and balances

Phenylephrine is just one example of one drug that has been shown to degrade and oxidize under higher temperatures. So for this drug, maintaining refrigerated storage conditions whenever possible-for example, in transition and transport and in the office-may be key.

Leaving the solution unrefrigerated for an undetermined amount of time in unmonitored climate and temperature conditions through the supply chain may be cause for physician and patient concern.

Paragon BioTeck is one such company that has put an entire system of checks and balances into place for appropriate storage procedures that are implemented through distribution. These standards of transport are upheld to ensure the stability of the phenylephrine hydrochloride, as any sort of oxidation or degradation of the product may lead to the drug becoming less stable over time.

Degradation and potency

If degradation occurs and the phenylephrine hydrochloride becomes less active, physicians may experience difficulty with dilation.

In response, this may lead to increased chair time for physicians and their staff, and the use of more drops than the recommended dosage in order to obtain the desired result. Using any product above recommended dosage can contribute to adverse events and should be avoided.

For companies with drug products that are historically stored at room temperature, this means that throughout manufacture and the supply chain, little attention may be paid to maintain optimum temperatures and storage conditions. With the significant distances products like phenylephrine often travel to reach a practice, it is possible they have sat in a truck on a hot tarmac with unregulated temperatures or have gone through a variety of environmental climate and temperature changes.

Physicians may know how a product is stored once it reaches their offices, but there is no way of knowing the storage conditions during manufacture and transit.

When products like phenylephrine are proven to perform with higher efficacy under refrigeration, it stands to reason that they should be maintained in cold storage from start to finish. The increased safety and efficacy of a properly stored product far outweighs the minimal, one-time inconvenience of installing a mini-fridge in the office.

References

1. “Sterile Drug Products: Formulation, Packaging, Manufacturing and Quality.” Michael J. Akers p. 100.

2. “Remington: The Science and Practice of Pharmacy.” Ed. David B. Troy, Paul Beringer p. 1030.

3. US 20090047343 A1

4. “Photochemical Hydroxylation of Phenylephrine to Epinephrine (Adrenaline).” Journal of Pharmaceutical and Biomedical Analysis, Vol. 6, No. 5, pps. 511-514 1988.

5. Douša M, Gibala P, Havlíček J, et al. Drug-excipient compatibility testing-Identification and characterization of degradation products of phenylephrine in several pharmaceutical formulations against the common cold. Journal of Pharmaceutical and Biomedical Analysis. 2011;55:949-956.

6. Luduena FP, Snyder AL, Lands AM. Effect of ultra-violet irradiation of phenylephrine. J Pharm Pharmacol. 1963;15:538–543.

7. Al Taji RAAA, Stanford JB, Sugden JK. Some aspects of the photolysis of aqueous solutions of phenylephrine hydrochloride. Pharm Acta Helv. 1982;57:56–60.

8. El-Shibini HAM, Daabis NA, Motawi MM. The Stability of Phenylephrine: Part I The Rate of Degradation of the Amino Group., 19 (1969) pgs. 676–678.

Paul S. Koch, MD

E: pskoch@kocheye.com.

Dr. Koch is founder and medical director of Koch Eye Associates and has a financial interest in Paragon BioTeck Inc.