A Closer Look

Originally Published NO July/August 2010

On March 26, a Food and Drug Administration (FDA) directive on Current Good Manufacturing Practices (cGMP) inspections made its way to agency field offices. Part III of the directive, known as the Dietary Supplement Compliance Program, or the Dietary Supplement-Import and Domestic Compliance Program, offers valuable insight on how inspectors will conduct dietary supplement cGMP inspections at both domestic and foreign dietary supplement firms.

The directive also outlines what FDA considers major deviations that could result in the issuance of a warning letter. As of June 25, every firm, regardless of size, engaged in the manufacturing, packaging, holding, and distributing of finished dietary supplements is subject to the cGMP regulations and can be inspected according to this directive.

Although written for FDA field inspectors, the directive is a very useful document for industry. It instructs districts to prioritize inspections as follows:

• 1. Firms that blend and fabricate finished product

• 2. Companies that package and label bulk products

• 3. Firms that label finished products

• 4. Companies that perform other operations not listed above on dietary supplement products

The directive further directs districts to prioritize inspection of manufacturing firms based on the types and combinations of products manufactured. Companies that manufacture supplements such as botanicals, animal and plant extracts, and fats and lipids, as well as vitamins, minerals, and proteins are considered top priority. (Firms that produce products in only one of those groups are given second priority.)

The Inspection

FDA inspectors are instructed to conduct an initial interview to determine the number of employees, the types of operations performed, and the types of products the company handles. Inspectors are also instructed to select a minimum of two products to inspect, including at least one product containing a botanical ingredient (if applicable).

The directive then lists 70 specific items, covering Subparts B–O of 21 CFR Part 111, on which inspectors should focus their attention. Instructions encompass inspecting procedures for personnel, physical plant and grounds, equipment and utensils, manufacturing, production and process-control systems, quality control, laboratory operations, material reviews, equipment and instruments, master manufacturing and batch records, packaging and labeling, holding and distributing, returns, and complaints, among others.

Part V of the directive, Regulatory/Administrative Follow-Up, then provides instructions to inspectors on recommending regulatory action. The directive lists the following six deviations as being of major concern. The directive instructs the district to recommend the issuance of a warning letter for any firm with these deviations:

• 1. Lack of master manufacturing records or significant requirements not included in records

• 2. Failure to meet finished-product specifications that must be met prior to a product's release

• 3. For a product's most significant or prevalent ingredients, failure to establish specifications for incoming materials or failure to conduct identity testing

• 4. No quality-control review of procedures, or significant quality-control procedures not implemented

• 5. No batch records

• 6. Significant physical plant deficiencies

The program also includes instructions to the field force relating to adverse-event reporting. Per the Dietary Supplement and Nonprescription Drug Consumer Protection Act, effective December 22, 2007, inspectors are instructed to review labels for up to five different dietary supplement products manufactured, packed, or distributed by a firm, to ensure that labels bear a domestic address or domestic phone number. Inspectors are then instructed to determine if the firm, 1) has a prominent statement informing consumers that they may report serious adverse events, 2) has an adequate recordkeeping system for adverse events, 3) has a serious-adverse-event reporting process, 4) has submitted any serious-adverse-events reports or has any adverse-events reports that are serious and have not been reported to FDA.

The program also addresses edible ruminant products from countries either affected or at risk for BSE (Bovine spongiform encephalopathy or "mad cow disease"), as well as new dietary ingredients, dietary supplements containing ephedrine alkaloids, import and domestic field exams, import investigations, surveillance sample collection, and analytical testing.

The Current State

As the number of cGMP inspections and issuance of FDA 483s continue to grow, the industry has also seen FDA issue its first two warning letters specifically stemming from cGMP inspections of dietary supplement companies. The first was issued to Coats International Holdings Inc. on March 30, followed by one issued to Atlas Operations Inc., sent on June 4.

Although the Atlas warning letter also cited significant labeling violations, the cGMP violations contained in these first two warning letters reflect the priorities outlined in the compliance program. Among other items, the companies were cited for inadequate documentation, lack of specifications and supporting rationale, insufficient quality-control program, lack of equipment-calibration documentation and review, inadequate sampling, incomplete master manufacturing and batch records, and no theoretical-yields or acceptance criteria. Both of these letters concluded that the violations cause the dietary supplement products to be adulterated under section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act. Failure to correct the violations may result in seizure and/or injunction, without further notice.

It is also important to note that both of these warning letters were issued approximately six months following the actual FDA inspections-and even after the firms had responded to their citations either verbally or in writing. This demonstrates how critical it is for firms to address their violations quickly and completely, and to respond to warning letters thoroughly, in writing, with specific commitments and corrective actions that address the underlying compliance deficiencies. (FDA-issued warning letters can be viewed at www.fda.gov/ICECI/EnforcementActions/WarningLetters/2010/default.htm.)

As a consulting firm that performs independent dietary supplement cGMP audits for companies, we are seeing very similar deficiencies in cGMP compliance. The following is a list of the most common violations that we are finding in firms of all sizes:

Not establishing formalized and approved specifications for raw materials, components, labeling, and finished products Inadequate standard operating procedures (SOP) and failure to establish SOPs for significant areas such as returns, quality-control operations, complaints, adverse events, and material reviews Formulation issues, including failure to formulate to meet 100% of label claims Lack of formal stability programs and data to support expiration dates Insufficient qualifications of quality personnel and formal training programs for staff Inadequate cleaning/sanitation practices Insufficient water monitoring/controls Inadequate formal equipment preventive maintenance and calibration programs Lack of/insufficient master manufacturing records and batch records Inadequate sampling procedures and practices Inadequate supplier-qualification program and procedures Failure to adequately document raw material and in-process product and to perform finished-product analytical testing Failure to comply with good documentation practices

Many of these items are very difficult to address and overcome; however, firms need to proactively and aggressively address these deficiencies, whether it is with their own staff or with the assistance of outside consultants.

What to Do Now

As a first step, dietary supplement companies should be educating themselves by reading warning letters, inspection reports, the FDA Compliance Program, and Part 111 cGMP regulations so they understand FDA's priorities and can quickly begin to identify and address all major violations in their facilities.

In addition, FDA warning letters always contain a statement reminding companies that the list of violations is not all-inclusive and that it is the company's responsibility to ensure their products and facilities are in compliance with all applicable laws and regulations. Therefore, we recommend that companies immediately have qualified experts perform an in-depth cGMP audit of their facilities and products against all subparts of 21 CFR Part 111. Based on the violations and deficiencies found, comprehensive corrective actions should then be aggressively implemented before FDA shows up at the front door.

Finally, companies, regardless of size, need to understand that FDA is taking a very firm and aggressive stance regarding dietary supplement cGMP violations, and that they need to act quickly and effectively to ensure their compliance.

Dean R. Cirotta is the vice president of pharmaceutical, dietary supplement, and tobacco services for EAS Consulting Group LLC (Alexandria, VA). EAS provides regulatory consulting services, including auditing, training, and submissions, to all FDA-regulated industries. Cirotta can be reached at 877/327-9808 or at dcirotta@easconsultinggroup.com. A copy of the Dietary Supplement-Import and Domestic Compliance Program document (7321.008) is available on the EAS website at www.easconsultinggroup.com, under the EAS-e-Docs service.