Up Close and Personal

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-05-02-2011, Volume 35, Issue 5

Regulators and standard-setting bodies are re-examining over-the-counter drugs.

There are more than 250,000 over-the-counter (OTC) products on the market today with wide access to consumers. But after a series of major OTC drug recalls, regulators and standardsetting bodies seem to be taking a closer look at these readily available products.

Although industry is familiar with the process by which over-the-counter (OTC) products reach the shelves, many consumers may not fully understand the difference between regulatory approvals for prescription products and the majority of nonprescription products. They may not know, for example, that FDA does not perform a prereview of chemistry, manufacturing, and controls (CMC), labeling, or pharmacokinetics for products regulated under the OTC Monograph System. Unlike prescription products, OTC drug products may or may not require clinical studies, and manufacturers of OTC monograph drugs are not required to pay user fees (1). The fact is, OTC drug products have their own rules, and they are approved in various ways depending on when they are (or were) developed and submitted to FDA for marketing approval.


OTC approvals: a brief history

Before the 1960s and 1970s, OTC drug sponsors were not required to demonstrate drug effectiveness. But in 1962, FDA required manufacturers to show effectiveness, and in 1972, the agency began what's known as the OTC Monograph System (also called the OTC Drug Review process), a project that is still underway today. The project involved reviewing in great detail the hundreds of compounds available to consumers in OTC form and developing FDA monograph requirements for drugs to be considered as generally recognized as safe and effective (GRAS/E).

All drugs, including OTCs, for human use in the US market must: adhere to current compendial standards; meet labeling requirements called for in the Code of Federal Regulations (CFR) and in the Federal Food, Drug, and Cosmetic Act; and be manufactured according to cGMPs, which are outlined in 21 CFR Parts 210, 211, and 330 (2). GMP compliance is verified through FDA inspections. Any OTC drug that deviates from a final monograph is not recognized as GRAS/E and requires an approved application (i.e., a new drug or abbreviated new drug application, NDA or ANDA) before it can be marketed (3). OTC drugs that meet final monograph requirements do not require an application approval.

Compendial drug quality monographs, or written standards, are published and maintained for the US marketplace by the US Pharmacopeial Convention (USP) and published in the USPNF. FDA monographs, which are for conditions for market entry, are published in the CFR. An OTC drug monograph includes requirements for the active ingredient's dosage strength and form as well as for the product's labeling and final formulation testing (1).

As part of the OTC Drug Review process, FDA ended up restricting in the 1970s the use of some 500 active ingredients that had previously been on the market because of a lack of sufficient demonstration of effectiveness or lack of general recognition of safety. To date, the agency has completed a review of more than three-fourths of the original monographs proposed at the inception of the program, according to FDA spokesperson Lisa Kubaska. Certain OTC medicines can be reviewed again when a monograph is amended or when a new question of safety or efficacy is raised.

Since about 1984, most new OTC drug products have gone through the NDA/ANDA process for market approval, although companies can still submit applications to get into the monograph system. Figure 1 provides a full historical timeline of OTC drug regulation.

Figure 1: More than 250,000 OTC products are available to consumers. The following timeline provides a detailed look at at the history of OTC regulation (Adapted from an FDA online presentation, from Ref. 1.)

Despite the differences in OTC monograph-drug reviews, NDAs and ANDAs for nonprescription products are examined in the same manner as prescription products. According to FDA, there are 774 OTC products on the market today that were approved by NDA or ANDA.

Another mechanism by which a drug can enter the market as an OTC drug is to undergo a status switch from a prescription drug to a nonprescription drug. The labeling process for this type of switch is quite complex and described later in this article.

Monograph modifications

USP is in the process of updating its compendial monographs and FDA applauds this change, which will help improve the standards companies follow when making drug products. In fact, the agency, along with the Consumer Healthcare Products Association (CHPA), is working closely with USP on the pharmacopeial convention's monograph modernization project, which began in 2010. The aim is to update key USP compendial monographs (to clarify, these are different from FDA's OTC monographs) to incorporate modern analytical methods and technologies.

The most significant gaps reside in USP monographs that have relatively nonspecific identification and/or assay procedures and in monographs lacking procedures for impurities and degradants, says Karen Russo, vice-president for small molecules at USP. In addition to these gaps, methods for certain procedures are outdated (e.g., packed column gas-chromatography and wet-chemistry techniques) and need updating.

Furthermore, USP notes that only about 25% of the monographs targeted for revision are OTC-related. Although, says USP, it's important to note that the same product or active pharmaceutical ingredient can be used in OTC and prescription form based on the dose or other FDA criteria.

Behind the Counter

In February 2011, the standard-setting body said it would be focusing on a few specific OTC monographs based on an FDA request. The agency asked USP to make a priority the monographs for acetaminophen and diphenhydramine (as well as copovidone, crospovidone, povidone, and talc) based on potential health concerns with these drugs (4).

"Acetaminophen- and diphenhydramine-containing drug products are two of the highest-volume selling OTC monograph drugs," explains FDA's Kubaska. "There are known impurities in both of these drugs that represent known (acetaminophen) and theoretical (diphenhydramine) concerns with respect to toxicity. So, the extent of exposure (using sales volume as a surrogate) and toxicity concerns played key roles in the selection of these drugs...."

Adds Russo, "The challenge with diphenhydramine and acetaminophen are the many drug products, particularly those combined with other drugs, and the variety of dosage forms, such as tablets and oral liquids. For example, there are more than 25 acetaminophen-containing dosage form monographs in the USPNF representing primarily OTC drugs."

Another challenge to the project overall, says Russo, is finding the replacement procedures for those monographs that need revision. "We encourage manufacturers to submit their procedures to USP so that the monograph can be revised to incorporate the new procedure(s).... USP is ... using its own laboratory resources to the extent possible to develop and validate procedures to serve as the basis for the monograph revisions; however, we are not able to accomplish this on our own." In addition, says Russo, USP has to find procedures that can accommodate all manufacturers of a given drug substance or drug product.

There is no set deadline for completing the monograph project, according to USP, although a general target is to finish before the 2010–2015 convention cycle ends. USP is hosting an OTC workshop in September 2011 to discuss with industry and FDA some of these compendial issues. (For more details on the monograph modernization project, see the Inside USP column in this issue "Monograph Makeover Requires Industry Input".)

Labeling clarifications

Meeting regulatory requirements and safety standards is only half of the battle for OTC drug manufacturers. As FDA's Kubaska points out, "Like prescription drugs, OTC drugs can cause serious adverse events." And the fact that there is no healthcare provider between a consumer and an OTC drug means that "the consumer must be able to self-diagnose the condition and safely self-medicate," explains Kubaska. For this reason, OTC product labels and information leaflets must be even more clearly identifiable, readable, and understandable to the average consumer than those for prescriptions.

According to David C. Spangler, senior vice-president of policy, and general counsel and secretary for CHPA, "the labeling standards that we have today [for OTCs] have been gone over in painstaking detail by FDA. When putting together a category monograph, the biggest thing FDA is focusing on, in addition to effectiveness and safety of the ingredients, is getting the labeling right. There is always room for improvement, but labeling reviews have been going on for decades."

In terms of improvement, in August 2010, FDA released an OTC guidance for industry on label-comprehension studies (5). These studies determine how well a consumer can read and understand a label. "FDA felt the need to publish this guidance to help industry conduct well-designed studies that provide meaningful data," says Kubaska. Although the guidance is not expected to require major changes in industry practice, it demonstrates that regulators are concerned about making sure OTC manufacturers provide the most clear and accurate information to consumers.

The guidance targets companies planning a label-comprehension study to evaluate a new label or a labeling change, but also applies to drug sponsors trying to switch their already approved prescription drugs to nonprescription status, a trend that seems to be on the rise, says CHPA's Spangler. (See a list of prescription to nonprescription switches at http://chpa-info.org/media/resources/r_4620.pdf.) This type of marketing switch has to be done extremely carefully, not just from a manufacturing and business perspective, but also from the consumer's perspective.

Caution is especially important when considering a complex drug status switch, such as those for cholesterol-lowering products. According to Spangler, these types of status switches involve intense labeling reviews because the products they are based on are generally for asymptomatic conditions. Without obvious symptoms, it is more difficult for a consumer to self-diagnose and self-treat, and so the product labels must be extremely detailed. "We are already seeing this type of switching activity in the UK, and it's more likely for the US in the future."

Across the Atlantic, the European Medicines Agency (EMA) is taking another look at OTC product labels as well. In April 2011, the agency released quality review recommendations for nonprescription-drug packaging design and labeling that would apply across the European Union (6). The new recommendations add to already existing requirements in the European Commission's Directive 2001/83/EC and in the 2009 EMA guideline on the readability of the labeling and package leaflet of medicinal products for human use (7). The new document aims to better harmonize OTC labels across Europe, especially where certain descriptions may use symbols or pictograms. Fonts, colors, text size, and information to be included on the labels and leaflets are addressed. Comments on the recommendations are due to EMA by June 30, 2011.


FDA aims to inspect prescription and nonprescription drug-manufacturing facilities every two years (8). OTC facility inspectors focus on verifying drug-monograph compliance (3). Many of the drug recalls that have occurred during the past 18 months are not tied to FDA approval or labeling, but rather to the manufacturing and supply-chain management of these products, points out Jonathan M. Lewis, a principal at Advanced Biomedical Consulting. "Many OTC drugs are less 'risky' in FDA's eyes," he says, "so these facilities often are not inspected nearly as frequently or with as much focus as compared with prescription products, such as injectables."

Lewis suggests that preapproval inspections, which he says are rarely required for OTC drug products, be implemented. "These inspections would help assess manufacturing conditions and regulatory compliance prior to marketing of these products," he says.

Ravi Harapanhalli, principal consultant and late-stage services lead at Parexel Consulting, agrees. "Over the counter drugs approved via an NDA/ANDA process don't need anything beyond what is currently applied with regard to ensuring product quality. However, for monograph drugs, a requirement for cGMP inspection prior to marketing should be mandated to ensure appropriate product quality and postmarketing recalls. If FDA cannot have the resources to do inspections, it should consider third-party audits as an alternative for OTC drugs marketed under monographs. A system of third-party audits is already accepted for certain low-risk devices."

Also, says Harapanhalli, "OTC drugs approved under an NDA or ANDA pathway seem to have fewer concerns of product quality compared with the OTC drugs marketed under monographs. Because monograph drugs are neither pre-reviewed nor approved, a manufacturer takes full responsibility to attest that their product meets the quality guidelines and requirements described in an OTC monograph."

This responsibility can be more difficult for smaller manufacturers of OTC products, adds Lewis. These smaller firms often turn to outsourcing and do not have the finances or staff to audit their contract manufactures and suppliers. They end up taking "more risk, often at the cost of quality, to produce these products domestically," says Lewis.

Resources are a constant challenge for FDA as well. Harapanhalli points out that many cGMP inspections of OTC sites uncover manufacturing problems and that unfortunately, FDA does not have the resources it needs to perform all of its targeted biennial inspections. As a result, consumer complaints and other triggers often prompt the agency to inspect OTC manufacturing sites.

On the positive side, FDA recently released a guidance for industry on adverse-event reporting that requires manufacturers of OTC monograph drugs to provide safety updates to the agency (9). But until FDA's budget sees a massive increase, inspections of facilities, and seemingly low-risk facilities, may be put on the back burner.

Checking expectations

Many of the ongoing efforts described herein are aimed at improving OTC drug safety for consumers, and says CHPA's Spangler, "It doesn't take a whole lot of sophistication to observe that we're in an era of greater enforcement." These changes are good, he says, because industry ultimately wants to reassure consumers that products on the market are safe and meet quality standards.

That said, it is not official that OTC drug manufacturers will face higher levels of enforcement going forward. According to FDA, the agency's "standards that a marketed drug must have a favorable benefit-to-risk profile remain unchanged."

At the end of the day, consumers play a crucial role in OTC drug safety by their decisions to select and use these products properly. "Consumers should read the product labels carefully and should not throw away the boxes that have the Drug Facts information," points out FDA's Kubaska. Together, consumers, industry, and the authorities can make the drugstore shelf not just an easily accessible place, but a safer place.


1. FDA, "Regulation of Nonprescription Drug Products," presentation www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM148055.pdf.

2. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC), Part 330.

3. FDA, "Compliance Program Guidance Manual," Chapter 61: OTC Drug Evaluation (Rockville, MD May 2007).

4. USP, Letter to USP from FDA, February 2011, www.usp.org/hottopics/monographs.html.

5. FDA, Guidance for Industry: Label Comprehension Studies for Nonprescription Drug Products (Rockville, MD, August 2010).

6. EMA, EMA/275297/2010 3/9 (Apr. 1, 2011).

7. EMA, Guideline on the Readability of the Labeling and Package Leaflet of Medicinal Products for Human Use (2009).

8. FDA, "Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspections Program," Document 7356:002.

9. FDA, Guidance for Industry: Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed without an Approved Application (Rockville, MD, 2010.

Industry Comment:

Albemarle is a leading producer of active pharmaceutical ingredients (API) in the United States but we do not produce any dosage form pharmaceuticals for either prescription or OTC sale. Because of this, Albemarle views FDA’s enforcement efforts regarding OTCs through the eyes of the consumer, and there are several issues that affect OTC drugs that we would like to address.

Monograph modernization can be viewed to have both positive and negative effects. Any effort to replace outmoded and antiquated procedures with methods that are supported by the latest technology may involve the short term inconvenience and cost of conversion to new methods and instruments. However, this will ultimately help assure a safer and better quality product for the consuming public.

There is increased scrutiny by FDA on OTC medications because these products may be consumed without a prescription; thus causing them to be purchased more frequently and in larger quantities. In my opinion, FDA should focus more attention toward assuring the sources of APIs manufactured outside the United States have been produced according to cGMP guidelines and initiate a robust inspection plan to support this effort.

In the past, Western suppliers provided 90% of the active pharmaceutical ingredients to the US market. Today, foreign producers, primary in China and India, produce greater than 80% and this percentage is rising. In 1998, the US Government Accountability Office (GAO) determined that FDA did an inadequate job of performing foreign inspections. In the year 2000, FDA performed only 135 inspections of foreign API producers and since then, globalization has placed an incredible strain on FDA. FDA has made vast improvements to their performance, which is evidenced by their execution of 424 inspections in 2009. However, due to the growing number of foreign producers of APIs, the GAO estimates in a report published in September of 2010, that it would take 9 years for FDA to inspect all of the foreign facilities on its list. In contrast, FDA inspects domestic facilities approximately once every 2.5 years. According to the GAO report, FDA listed a total of 3,765 foreign establishments in its inventory in 2009.

Of this total, 2,394 establishments may never have been inspected because FDA could not identify a previous inspection for those establishments. The percentage of establishments in FDA’s inventory in China that may have never been inspected was 88%.As a consumer, I appreciate FDA’s efforts concerning enforcement and improvement on inspections. However, as the number and sheer volume of imported drugs continue to increase, FDA needs to dramatically improve its program for inspection of foreign establishments.

--Steve LeVan, vice-president of Fine Chemistry Services at Albermarle