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USP Quality ReviewNo. 75, Issued September 2000 Click here for printable version
DPPR—a Final Glance The USP Drug Product Problem Reporting (DPPR) program has worked, for the past 30 years, toward identifying and improving defective and potentially unsafe drug products. As a service to the health community in general, and pharmacy in particular, the program allowed practitioners to quickly and easily report any problems or concerns regarding the quality, performance, and labeling of prescription and over-the-counter drugs, as well as dietary supplements. Since 1971, thousands of health professionals have contributed product problem reports to the program. Many of these reports have led to nationwide—and even worldwide—product recalls, corrective actions, and product improvements by the manufacturers. USP has decided to cease operating the DPPR program as of August 31, 2000, so that its efforts and resources may be concentrated on medication error reporting and prevention. When the DPPR program was first started, it was the only nationally operated program focused on drug quality. After the FDA instituted the MedWatch program, designed to further the effectiveness of postmarketing surveillance of medical products as they are used in clinical practice, USP became a MedWatch partner, sharing reporting and safety information. It is hoped that participants in the DPPR program will continue to report product problems by submitting information to the FDA MedWatch program. Reporting drug product quality issues plays a critical role in improving patient care and protecting public health and allows provision of feedback to the health care community about safety issues involving medical products. This issue of USP Quality Review examines 5,751 DPPR reports received between January 1, 1995 and December 31, 1999. Earlier reports were examined in USP Quality Reviews No. 47, DPPR at a Glance and No. 55, DPPR at a Second Glance. The trends uncovered by the current analysis concerning problem types, route of administration, and dosage form reported are generally consistent with these earlier analyses, however some differences are noted with respect to the specific drug products involved.
Table 1 1995–1999
Reports by Type of Problem USP's health care professionals reviewed reports submitted to the DPPR program and assigned defect codes to the problems described by the reporters. See table 1 on page 1 for problems most commonly identified in the 1995–1999 period. Although DPPR did not actively solicit information about adverse reactions, reports describing an adverse reaction to a medication constitute approximately 20% of all reports. Comparison of the percentage of adverse reaction reports over the years reveals that the proportion of such reports, however, is declining, from a peak of 28.8% in 1994 to 16.6% in 1999. These figures may reflect a downward trend in reporting generally or may be the result of educational efforts targeted at the health care practitioners and the active promotion of the FDA's MedWatch program, which is specifically designed to collect this type of information. Interestingly, physicians and consumers are more inclined to report adverse reactions to the DPPR (57% of all reports from physicians and 42% of all reports from consumers describe an adverse reaction, compared with only 9% of all reports from pharmacists), perhaps reflecting differences in training and/or knowledge regarding how and where to report reactions to medications. The second most frequent type of problem, "Improper fill," accounts for approximately 10% of reports. This defect spans all dosage forms and includes non-uniform fill of ampuls, short fills and overfills of liquid and injectable products, short counts and overcounts of solid oral dosage forms, and bottles or carpujects entirely void of drug. The "Defect/malfunction" category, which comprises about 6% of reports, includes actual mechanical failure of injection systems and inhalers, unit-dose blister packaging that does not open or separate properly, blunt needles, pumps and ophthalmics that clog, and similar complaints. For cases where the packaging or delivery system is lacking or inadequate, the "Missing" code was introduced. This category includes absent or partially defective labeling (for example, lot number and expiration date are not on the label), missing drug delivery devices or their parts (such as injection ports or plungers), as well as missing seals, graduations on bags, etc. Not surprisingly, injectables and associated devices dominate this category. Finally, "Inappropriate design" refers to product or label designs that may lead to an increased potential for medication errors, or to patient or staff inconvenience. Illegible or poorly placed labels, container lids that are difficult to remove, and impractical product design all fall under this category. As an example, several pharmacists reported being unable to place prescription labels on the Prempro® packages, because the manufacturer did not leave any space for it. Although the "Inappropriate design" code was allocated to only about 5% of all reports, these reports served as an important source of information for FDA-initiated corrective actions, such as adjusting inappropriately designed products to help reduce the occurrence of certain types of medication errors. Which Medications Are Most Often Associated with a Specific Problem? When evaluating drug quality concerns, several questions that come to mind include: "what medications are most frequently reported as problematic?" and "what is the nature of the most commonly associated problems?" Table 2 on page 3 lists the 11 medications that were most frequently reported to DPPR during the 5-year period, as well as the most prevalent associated problems. Consistent with previously reported data, controlled substances such as meperidine, morphine, and the combination product, hydrocodone bitartate/acetaminophen, top the list. Because most of the DPPR reporters are hospital pharmacists, medications that are widely utilized in hospital settings, for example cefazolin and sodium chloride for injection, constitute another significant category of reports. Nitroglycerin and heparin, drugs with therapeutic outcomes that may be critical to patient care, are also well represented in the "top eleven." Finally, some problems, like precipitation of calcium gluconate, are inherent to the drug's intrinsic properties. Missing from this list are the top two drugs from the 1993–1994 review, namely, albuterol sulfate solution for inhalation and mesalamine capsules. These products had the specific problems of potential contamination causing severe adverse reaction and unclear/confusing labeling, respectively. No further reports of a similar nature were received post-1994 for these two products. Information captured by the DPPR can be used to identify trends concerning medications commonly associated with particular problems. It is important to note, however, that the number of reported occurrences with a particular medication may indicate not only the prevalence of the problem, but also may reflect reporters' perceptions of the problem's importance, DEA enforcement issues surrounding the medication, product's length of time on the market, and/or widespread use of the product. Some general observations follow:
Table 2
[C] Indicates a controlled substance Reports by Route of Administration
Based on route of administration, products administered orally and via injection comprise more than three-fourths of the reports. This finding may reflect prevalence of use. The practice environment of the DPPR reporters may further influence these figures. Slightly more than half (53.7%) of all reports received were submitted by hospital pharmacists, and nearly one-quarter (23.8%) of all reports received were submitted by community pharmacists. Orally administered dosage forms are implicated in more than one-third (37.8%) of reports submitted by hospital pharmacists and nearly two-thirds (64.4%) of reports submitted by community pharmacists. Pharmacists who practice in hospital settings may currently have more frequent contact with drugs delivered by injection. More than half (50.5%) of the reports submitted by hospital pharmacists involved injectable products, while only about 10% of reports submitted by community pharmacists involved this route of administration. Table 3
DPPR in Action In addition to its role in detecting emerging trends in medication quality and utilization for possible subsequent revisions to the USP–NF, the DPPR program has also served to identify products that do not conform to the current standards of quality, safety, and potency. After evaluating drug product problem reports, USP forwards the data to the FDA, which may subsequently contact the involved manufacturer/ labeler to determine what action, if any, will be taken on the products involved. Since 1987, 78 DPPR reports contributed to FDA recalls, and 263 reports played a role in corrective actions by the pharmaceutical industry. During the most recent time period (1995–1999) alone, information collected by the DPPR program played a role in one market withdrawal, 23 recalls, and 68 corrective actions. Since DPPR was designed to predominantly collect medication quality information, it is not surprising that the majority of recalls and corrective actions attributed to DPPR involve product quality issues. Incomplete, confusing, or inconsistent labeling, inappropriate container or label design, incorrect product or strength information on the labels, foreign material, contamination, and physical disintegration of the product (crumbling, crushing, crystallization) are among the major reasons for recalls and corrective actions. Of the 23 recalls, 6 cited incorrect products in the package. Incomplete labeling was the top reason for initiating corrective action (13 reports), followed by unclear or confusing labeling (10), inappropriate design (7), and inconsistent/discrepant labeling (7). The following synopses recount some of the product recalls and corrective actions that were influenced by DPPR program reports:
DPPR's Impact on USP–NF Standards Occasionally trends in reporting reveal the need for standards to address newly emerging issues. Reports submitted to the DPPR program over the five-year period, 1995–1999, have contributed to several revisions and additions to the USP–NF. These changes serve to raise the standard of drug product quality and may ultimately raise the standard of health care. Storage requirements Reports to DPPR often cited concerns about the effects of storage, including shipping conditions, such as temperature, light, and humidity, on the integrity and potency of medications. An issue of particular concern was the regulation of climate control during the transport process. This includes products shipped directly to the patients as in mail-order situations; the distribution of products from the manufacturer to the wholesaler and then on to individual pharmacies; and also the transport of samples by pharmaceutical sales representatives. (See previous USP Quality Review No. 51, Too Hot to Handle! Too Cold to Hold! and No. 61, Storage Stories.) The General Notices section of the USP–NF, ‘Storage under Nonspecific Conditions,' provides general guidelines for the storage of products where the individual USP monograph does not include specific storage requirements. DPPR reports concerning temperature-related drug integrity problems supported the USP Subcommittee on Packaging, Storage, and Distribution's decision to revise the requirements. The section was modified to state that those requirements must be met during storage and distribution and became effective on November 15, 1998.1 Aerosols, metered-dose inhalers, and dry powder inhalers As a drug delivery system, inhalers continue to be a source of complaints from health care providers and patients alike. During the 1995–1999 period, 48 reports were made to DPPR regarding underfilled or defective aerosol inhalers. Most common were reports of the product failing to deliver the full number of actuations indicated on the label. The reports spanned a number of different manufacturers and products, including albuterol sulfate, triamcinolone acetate, ipratropium bromide, and beclomethasone. Also reported were apparent inconsistencies in amount of drug dispensed with each actuation and variability in patient response to the drug (i.e., it was necessary to use more than the usual number of actuations to achieve the desired effect). Many of the reports specified that the involved patients were long-term, experienced users of aerosol inhalers. Some reports were actually submitted by the patients themselves and contained extensive logs documenting the number of actuations dispensed by each received inhaler. The number and detail of such reports suggested existence of a problem with aerosol inhaler delivery systems. Based in part on information in DPPR reports, two general chapters of USP 23–NF 18 were revised. The changes became official May 15, 1999, with the Tenth Supplement to USP 23–NF 18 and include the following:2 1. The chapter Aerosols <601> was renamed Aerosols, Metered-dose Inhalers, and Dry Powder Inhalers <601> to distinguish between products for inhalation and aerosol spray products for topical use. Within the chapter, distinctions were made between standards for pressurized aerosols for topical application and those for metered-dose and dry-powder inhalers. 2. Some physical methods for testing the products were modified and some new methods were designated. Additionally, specific tests were designated for each particular product type (i.e., aerosols, metered-dose inhalers, dry powder inhalers, etc.). 3. The section, Dose Uniformity Over the Entire Contents, was added to chapter 601. This section, in addition to requiring uniformity of dose dispensed, also "ensures that multidose products supply the total number of discharges stated on the label." 4. Chapter 905, Uniformity of Dosage Units, was revised to include standards for the amount of active ingredient discharged by metered-dose topical aerosols, metered-dose inhalers, and dry powder inhalers. In addition, the First Supplement to USP 24–NF 19 contained 28 monograph revisions to conform to the new requirements under chapter 601. Endotoxin limit in gentamicin sulfate injections In the period covered by this Review, 28 reports were made to DPPR involving gentamicin, 19 of these specifically involving gentamicin injection. In the time period between August 1998 and August 1999, 6 reports involving more than 25 patients cited occurrence of rigors and fever with the administration of intravenous doses of gentamicin sulfate. The FDA received similar reports, and the combined data led to the recall of the involved products. When tested, however, all were found to meet USP standards. As the gentamicin injection monograph existed, a single milligram of gentamicin sulfate could not contain more than 1.70 USP Endotoxin Units.3 This limit was determined using a dosing schedule for an adult with normal renal function in the amount of 3 mg/kg/day administered in three equally divided doses every 8 hours. As many hospitals have adopted protocols for "once daily" dosing of aminoglycosides, it was clear that the endotoxin limit for gentamicin injection needed to be reevaluated to account for the administration of higher doses of the antibiotic and concurrent exposure to higher levels of endotoxin. The endotoxin limit has been revised to 0.71 USP Endotoxin Units per milligram of gentamicin and became official January 1, 2000.4 (See also previous USP Quality Review No. 70, Gentamicin: Reactions, Recalls, and Revision.) References 1. Seventh Supplement to USP 23 and NF 18. U.S. Pharmacopeial Convention, Inc. Rockville, MD: 1997: 3840-3843. 2. Tenth Supplement to USP 23 and NF 18. U.S. Pharmacopeial Convention, Inc. Rockville, MD: 1999: 4933-4949, 4957-4959. 3. Ninth Supplement to USP 23 and NF 18. U.S. Pharmacopeial Convention, Inc. Rockville, MD: 1999: 703, 4553. 4. First Supplement to USP 24 and NF 19. U.S. Pharmacopeial Convention, Inc. Rockville, MD: 2000: 2623.
Acknowledgments: To report product quality problems, call the FDA MEDWATCH program at 1-800-FDA-1088. For your convienience the MEDWATCH program is also available on-line at www.fda.gov. |
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