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U.S. Department of Health and Human Services

Safety

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Communication Dynamics: A Resource in Assuring Drug Quality

"Communication Dynamics: A Resource in Assuring Drug Quality" is a self-study continuing education program for pharmacists that has been developed by the U.S. Food and Drug Administration, Center for Drug Evaluation and Research.

Center for Drug Evaluation and Research is approved by the American Council on Pharmaceutical Education (ACPE) as a provider of continuing pharmaceutical education (and complies with the Criteria for Quality for continuing pharmaceutical education programming).

This program is acceptable for one hour of continuing education credit (0.1 CEU) in states that recognize ACPE-approved providers (#601-000-95-091-C04). Certification will be issued upon successful completion of the post-test (with a score of 70% or better).

Pharmacists completing this program before March 31, 1998 may receive credit


Table of Contents

 

Learning Objectives

Successful completion of this continuing education program will enable the pharmacist to:

  1. Identify the three major participants in assuring the quality of prescription and non - prescription drug products in U.S. distribution.
  2. Obtain an appreciation of the impact an individual report can have in assuring drug quality.
  3. Obtain an appreciation of how drug quality observations are quickly available electronically throughout FDA and immediately shared with the pharmaceutical industry.

Background

One of the U.S. Food and Drug Administration's missions is to assure the quality of prescription and non-prescription drug products in commercial U.S. distribution. The Agency utilizes a variety of information gathering strategies. One of the best ways of acquiring marketplace surveillance information has been through voluntary reporting by the Nation's pharmacists.

This program has had a variety of names over the last 25 years and is currently known as the Drug Quality Reporting System (DQRS) and identifies the type of information the Agency is seeking. DQRS is part of the agency's overall MedWatch system. This approach has provided timely product information and has pinpointed significant product quality issues.

A two-pronged approach of:

  1. freely sharing the reported information with the respective pharmaceutical manufacturer or labeler for inclusion as part of their current good manufacturing practices (CGMP's) into their complaint file system (21 CFR 211.198), and
  2. the investigation of all reports by FDA field investigators

has made for the quick resolution of real problems.

Other improvements are made to many other products through voluntary changes instituted by the pharmaceutical industry for their specific products. The dual action of both FDA and the pharmaceutical industry makes the prescription and non-prescription drug products distributed in the U.S. the best in the world.

The timeliness, specificity of the information provided, especially the product's lot or batch number(s), and the continued professionalism demonstrated by pharmacists and other health care providers make this voluntary surveillance system an unparalleled source of information and helps maximize FDA's limited resources.

To make this system a responsive surveillance tool, the reported information must be freely shared with the pharmaceutical industry, quickly prioritized and be available to the Agency to support current investigations as well as trend analyses. There have been a number of changes in these areas over the past 25 years. First, the reporting mechanisms have been expanded to accommodate four different ways to quickly make individual observations known to the FDA and the pharmaceutical firm - a prepaid U.S. mail reporting form (FDA FORM3500) and three mechanisms for direct electronic reporting:

  • WATTS 24-hour toll-free-telephone number (1-800-FDA-1088),
  • FAX (1-800-FDA-0178), and
  • Modem (1-800-FDA-7737).

Drug Shortage

The dynamics of the pharmaceutical industry has periodically shown problems with the availability of certain drug products. This may have been the result of a lack or limited amount of bulk raw materials, changes in manufacturing procedures or a firm's marketing decision. Whatever the cause, the lack of availability can be a concern for the pharmacist and their patients. To address this problem, DQRS instituted the Drug Shortage Program (DSP) to respond to questions pertaining to the status of drug products that are in short supply.

Drug shortage reports received at DQRS are first reviewed to determine the severity of the shortage. Next, the manufacturer and/or labeler is contacted to determine the reason for the shortage and when the product will be available in sufficient quantity. All reporters of drug shortages are contacted and informed of the findings. A drug shortage report is immediately filed with the FDA and entered into the agency's online DQRS database for tracking.

Drug shortage reports are submitted just as drug quality issues are (by completed FDA form 3500, calling 1-800-FDA-1088, faxing to 1-800-FDA-0178 or by modem to 1-800-FDA-7737).

Data Management

This information is immediately made available to FDA through online entry into the Agency's DQRS database. This availability of the reporter's observations makes the initial evaluation a quicker and simpler process by eliminating the delays incurred by processing and handling hard copy reports. This capability also allows several different segments of the Agency to simultaneously access and review current and previously filed report data.

The managing of drug quality information since the late 1960's has undergone important changes. At that time, computer applications were just making inroads into the FDA's work routine, and the lack of uniformity and the unavailability of standardized dictionaries or terms greatly detracted from the utility and power of these early computer database ventures. Computers and programs have advanced greatly since our early efforts. Some of those developments have met the needs of the DQRS program and now make information from these databases immediately accessible to every FDA investigator at the site of their investigations.

I will address some of the mentioned changes, their impact on inspection and regulatory actions and the daily utility they now provide to the FDA.

Interactive Computer File

 

The DQRS reported information is now easily entered and retrieved using an on-line interactive computer language. The new software designs take advantage of existing Agency databases. These files began in the early 1970's and are mandated by regulation 21 CFR 207, Drug Registration and Listing System (DRLS). The DRLS includes standardized information involving; product name, active and inactive product ingredients, strength, package type and size, and the manufacturer's name and location(s), as some of the data elements. This database provides DQRS with a standardized dictionary, maintained by a separate FDA group and available throughout FDA. The DRLS links and identifies individual products and firms to any DQRS report involving that product via the product's National Drug Code (NDC). This NDC number is all that is necessary for drug and labeler entry of the report information into the DQRS system.

The NDC is a unique number made up of three distinct segments. The first portion is the labeler code. All drug manufacturers or repackagers are required to register with the FDA. The first segment of this unique 11-digit number is assigned by the Agency to each registrant. The second and third segments of this number are related to the product identity and package type or size. The individual firms are allowed to assign whatever numbers they wish for each product and package configuration, but they must conform to the format established by the Agency and must provide to FDA all the required information relating to that specific product. As a result of these filings, the Agency has a database with extensive information on every product distributed in the U.S. This information requirement is ongoing and is supported by regulation. The DRLS file is the primary dictionary for the DQRS program, and the use of NDC numbers allows for rapid and accurate entry of product and labeler information. Secondary dictionaries or tables were developed to meet some special needs of monitoring drug quality issues and facilitate the uniform entry of DQRS reported information.

The concept of "quality" is not promoted as a set or defined term but is left to the reporting pharmacist's or other health care provider's interpretation. This allows for anything the reporter believes to be of concern to him or her in their dispensing or administering of prescription or non-prescription drug products to be reported. However, the variety of terms or phrases used to report an observation are coded in a standardized manner. A system of 10 primary defect categories and a "Thesaurus of Drug Defects," (TODD) has been developed to accomplish this standardization and capture the reported observation(s). These categories are designed to be used in search and retrieval strategies relating to CGMP's inspection needs. The system also has the ability to monitor new or unique dosage or packaging forms, i.e., unit dose, prefilled syringes, aerosols, etc.

DQRS has demonstrated its ability to identify trends in product quality problems, either product specific or industry wide. Several general examples of these trends can be seen from the following: The lack of product stability of certain products manufactured in soft-shelled capsules was identified and reported by individual reporters using a variety of phrases such as "leaking capsules," "capsules sticking together," and "congealed mess." Investigation of these individual reports showed a common problem. The active drug substance inside these capsules had a very long shelf life, but the stability of this drug in this dosage form and marketed container/closure system was much shorter and not reflected in the product's labeled expiration date. The marketed product did not meet the stability requirements (21 CFR 211.166).

Another situation involved a variety of different labelers of antacid products. Many of the labelers were using the same manufacturer for their individual products. What appeared to be isolated contamination problems identified with a variety of differently labeled products was quickly found to be a contamination problem involving a common manufacturer (21 CFR 211.67). These products posed a situation in which their use may cause temporary or medically reversible health consequences and usually resulted in their recall from the market. These examples show that isolated reports from across the nation when entered into a database can immediately interface with other Agency computer files and quickly identify drug quality problems and trends and mitigate situations which can impact on the public's health.

Since starting the drug quality surveillance program (DQRS) and the current data management approaches in 1988, this voluntary reporting of drug quality issues has helped support over 240 recalls and more than 700 corrective actions voluntarily made by the pharmaceutical industry for their respective products.

The development in this on-line data management approach has been to put this file information into the hands of the investigator as quickly and easily as possible. This capability is available to the investigator while on-site at an inspection or in the field office. A system of menu features enables the investigator to obtain detailed or summary reports by such groups as:

  • active ingredient
  • specific labelers
  • specific lot number(s)
  • defect categories
  • combinations of the above

Voluntarily submitted drug quality information can greatly assist the FDA and the pharmaceutical industry in assuring that the highest quality prescription and non-prescription drugs are in U.S. distribution. The original concepts developed in the late 1960's are a viable reality today due to computerization, electronic communications, and most importantly your voluntary reporting of concerns.

Table 1. FDA Recall Classifications

Class I:

A situation in which there is a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death. 
Class II:

A situation in which the use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.

Class III:

A situation in which the use of, or exposure to, a violative product is not likely to cause adverse health consequences.

 

Table 2. Examples of Commonly-Reported Drug Quality Concerns

  • Container defects: leaks, cracks
  • Label damaged, confusing, or missing
  • Insert missing, insert wrong
  • Contamination of product: chemical, insect, microbial
  • Crystallization, gel formation, precipitation
  • Discoloration, mottling, color variation
  • Foreign material in or on dosage form
  • Poor friability, capping
  • Therapeutic effect lacking/potency questioned
  • Similarities in product names or appearances
  • Potential package tampering or drug
  • Drug Shortages