Final FDA Rule on Dietary Supplements (21 CFR Part 111) Guidance

In June 2007, the U.S. Federal Drug Administration issued the Dietary Supplement Current Good Manufacturing Practice (CGMP) Final Rule (21 CFR Part 111). In essence, the final rule requires that the proper controls be in place for dietary supplements during manufacturing, packaging, labeling, and holding operations.

This article discusses:

• The purpose of the CGMP final rule;
• Companies that will be affected;
• Specific requirements of the CGMP final rule and the challenges these requirements present; and
• How automated solutions can help.

Purpose of the CGMP Final Rule

The purpose of the CGMP final rule is to establish quality standards for dietary supplements. Until recently, the FDA has tended to view itself as filling more of a "watchdog" role as far as dietary supplements are concerned, with the FDA's MedWatch consumer complaints hotline serving as the alert system.

"The FDA points out that the final rule addresses only the quality of the manufacturing process for dietary supplements and the accurate listing of ingredients. It does not limit consumers' access to dietary supplements..."

This watchdog role led to the voluntary recall of the dietary supplement Nasutra in September 2006, after it was discovered that the dietary supplement contained an analogue of sildenafil (acetildenafil), the active pharmaceutical ingredient in Viagra. According to the FDA press release announcing the recall:

Acetildenafil is an analogue of sildenafil. Sildenafil is the active pharmaceutical ingredient in Viagra, an FDA-approved drug that is used to treat erectile dysfunction (ED). Acetildenafil is close in structure to sildenafil and is expected to possess a similar pharmacological and adverse event profile.¹

By imposing quality standards, the new ruling will also protect consumers from supplement manufacturers who misrepresent the quantity of a product's active ingredient, or who don't disclose everything about their product's ingredients. The recall of FiberChoice's multivitamin, for example, was initiated after it was discovered that the product contained fish gelatin, a known allergen, which was not disclosed on the product label.²

Moreover, the final rule provides consumers access to dietary supplements that meet quality standards, are free from contamination and are accurately labeled. This will give consumers greater confidence that a dietary supplement has been manufactured to ensure its identity, purity, strength, and composition.

The FDA points out that the final rule addresses only the quality of the manufacturing process for dietary supplements and the accurate listing of ingredients. It does not limit consumers' access to dietary supplements; nor does it address the safety of a dietary supplement's ingredients or effect on health when proper manufacturing techniques are used.³

Nonetheless, cases such as Nastura, in which a previously unknown ingredient (acetildenafil) resulted in potential harm to a group of consumers, obviously would be included under the purview of the FDA's final rule. It is interesting to note that, according to Taiwan's Department of Health, the acetildenafil incident appeared to be an instance of an ingredient's being illegally adulterated into a dietary supplement.⁴

Companies Affected by the Final Rule

The provisions in the CGMP final rule (21 CFR Part 111) apply to manufacturers of nonprescription dietary supplements intended for human use. Nonprescription dietary supplements are a subcategory of nutraceuticals. The latter include a broad category of nutritional products ranging from isolated nutrients and dietary supplements, to genetic engineering products such as broccoflower (a hybrid produced by crossing broccoli and cauliflower).

According to the FDA, the dietary supplements affected by the final rule include:

• Vitamins and minerals;
• Herbs and other botanicals;
• Amino acids;
• Dietary substances for increasing total dietary intake; and
• Concentrates, metabolites, constituents, extracts or a combination of the preceding ingredients that meet other criteria in Section 201(ff)(2)-(3) of the Federal Food, Drug and Cosmetic Act, as amended.

The FDA's CGMP requirements apply to all domestic and foreign companies that manufacture, package, label or hold dietary supplements, including those involved with testing, quality control, and dietary supplement distribution in the U.S.

Specific Requirements of the Final Rule

In addition to requirements having to do with equipment, cleanliness of the facilities and related matters, the final rule requires manufacturers of dietary supplements to:

• Establish procedures for quality control operations;
• Effectively handle deviations and nonconformances (i.e., unanticipated events);
• Employ qualified employees and supervisors;
• Keep a written record of each product complaint related to CGMPs;
• Immediately report serious adverse events to the FDA (this is actually a 2006 FDA requirement); and
• Maintain records.

Staggered Three-Year Phase-In

To limit disruption to small businesses, the CGMP final rule stipulates a staggered three-year phase-in according to the following schedule:

• Companies having 500 or more employees must comply by June 2008
• Companies having between 21 and 499 employees must comply by June 2009
• Companies having fewer than 20 employees must comply by June 2010

Challenges of Establishing/Maintaining Compliance, and How Automated Solutions can Help

Many manufacturers of dietary supplements may face significant challenges in complying with the FDA's final rule. Under the final rule, for example, written procedures must be established for quality control operations. These written procedures must include the steps to be followed when conducting a material review and making a disposition decision.

The final rule requires that quality control personnel conduct the material review and make a decision regarding disposition when, for example, a batch of product deviates from its master manufacturing record, or when an unanticipated event occurs during a manufacturing operation that leads to the adulteration of any portion of a dietary supplement (including its packaging). Quality control personnel are also required to conduct a material review and make a disposition decision in the event that there is a problem with the equipment or how the equipment is calibrated.

Without a centralized, document control/management solution, it can be difficult to establish and maintain written procedures for quality control operations. This is because, with a manual (as well as a decentralized, hybrid) system, it is difficult to ensure that employees are using the most current,up-to-date version of a documented procedure. This can result in confusion, inefficiencies, and poor quality control.

An automated document control/ management solution can help in the following ways:

• A centralized repository that consists entirely of quality procedures that have been routed, approved, and signed off on (via FDA-approved electronic signatures) ensures that every document in the repository is the most recent, up-to-date version. (Any previous version is automatically archived and replaced by the current version.)
• A secure, time-stamped audit trail helps assure compliance by identifying the person who created or modified the electronic record, when the action occurred, and what changes were made.
• It is important that FDA-regulated companies limit access to authorized users and hold them accountable for written policies. Software that automatically locks both login and approval whenever either one is compromised is essential to a quality management system.
• The ability to track documents by status or history also facilitates quality management.

Automated solutions can help in other areas as well--e.g., by effectively handling deviations and nonconformances (i.e., unanticipated events) during the manufacturing process; by making sure that all employees and supervisors are qualified to perform their job functions; by handling customer complaints; etc.

In summary, an automated document control/management system and automated processes can help assure quality, regulatory compliance, and proper documentation. They can also greatly speed up all required FDA CGMPs involved in the production of dietary supplements.

References

1. FDA information about the recall can be found at the following URL, downloaded March 25, 2008: http://www.fda.gov/oc/po/firmrecalls/nasutra09_06.html
2. FDA information about the recall can be found at the following URL, downloaded March 25, 2008: http://www.fda.gov/oc/po/firmrecalls/fiberchoice03_07.html
3. Dietary Supplement Current Good Manufacturing Practices (CGMPs) and Interim Final Rule (IFR) Facts. Downloaded March 25, 2008, from: http://www.cfsan.fda.gov/~dms/dscgmps6.html
4. Mei-Chih Lin, Yoe-Ray Ku, Yi-Chu Liu, Jer-Huei Lin. P-090: Isolation and Identification of a novel Sildenafil analogue adulterated in herbal supplements. Bureau of Food and Drug Analysis, Department of Health, Taipei, Taiwan. Downloaded March 31, 2008, from http://www.phcog.org/AnnualMtg/2006/papers/P_090.pdf