White Paper on Dietary Supplements

<strong>White</strong> <strong>Paper</strong>: 

Final FDA Rule on 

Dietary Supplements 

(21 CFR Part 111)

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

<strong>White</strong> <strong>Paper</strong> 

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 whitepaper discusses: 

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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. 

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 against supplement 

manufacturers who misrepresent the quantity of a product’s active ingredient, or 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 consumer 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 ruling addresses only the quality of the manufacturing process for dietary 

supplements and the accurate listing of supplement ingredients. It does not limit consumer access to 

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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 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: 

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Vitamins and minerals; 

Herbs and other botanicals; 

Amino acids; 

Dietary substances for increasing total dietary intake; 

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: 

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Establish procedures for quality control operations; 

Effectively handle deviations and nonconformances (i.e., unanticipated occurrences); 

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. 

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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: 

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Companies with 500 or more employees must comply by June 2008 

Companies with between 21 to 499 employees must comply by June 2009 

Companies with fewer than 20 employees must comply by June 2010 

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

This section discusses some of the challenges presented by the final rule’s requirements, and how 

automated solutions can help with these challenges. 

CGMP Requirement to 

Establish Procedures for Quality Control Operations 

Under the final rule, 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 a material review and make a decision 

regarding disposition when, for example, a batch deviates from its master manufacturing record, 

an unanticipated event occurs during a manufacturing operation that leads to the adulteration of 

any portion of a dietary supplement (including its packaging), or when there is a problem with the 

equipment or calibration, etc. 

Difficulties in establishing (and maintaining) procedures for quality control operations: 

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 system 

(as well as a decentralized, hybrid system), there is no foolproof mechanism in place to ensure that 

employees are using the most current, most 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: 

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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. 

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It is important that FDA-regulated companies limit access to authorized users and hold them 

accountable for written procedures. Software that automatically locks both login and approval when 

either one is compromised is essential to a quality management system. 

The ability to track documents by status or history also facilitates quality management. 


Effectively Handle Deviations and Nonconformances 

Under the final rule, quality control personnel must effectively handle deviations and unanticipated 

events (nonconformances) according to their established procedures. 

Difficulties in effectively handling deviations and nonconformances: Any deviation or unanticipated 

event (nonconformance) that can lead to the use of a label in a manner not specified in the master 

manufacturing record must be documented and either justified or investigated. This paperwork can be 

very time-consuming. Even if the justification/investigation process involves a small group of people, 

the paperwork often ends up in a pile on someone’s desk, creating a significant turnaround challenge. 

A related difficulty concerns redundancy. Because in a paper-based or hybrid system, the focus is 

on single deviation or nonconformance events (vs. multiple events over time), trends or patterns 

often remain hidden. As a result the quality control system fails to make the best use of its data. This 

frequently results in redundant effort, inefficiencies, and higher production costs. 

How automated deviation/ nonconformance solutions can help: 

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A deviation or nonconformance solution provides software for entering all relevant data into 

a preconfigured best-practice form, then submitting the form to an automated routing for 

investigation, resolution, and approval. Automated escalation to a higher authority after a 

predetermined amount of time prevents paperwork from piling up on someone’s desk and ensures 

an efficient system. 

A software package for deviations or nonconformances can provide tools for analyzing and 

trending deviations and nonconformances. This helps quality control see the bigger picture, so that 

underlying problems can be resolved. 

A deviation/ nonconformance solution can also be integrated with customer complaints software 

and corrective action/ preventive action software to provide even greater control over quality 

management. 

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Employ Qualified Employees and Supervisors 



Manufacturers of dietary supplements will be required to employ qualified employees and supervisors, 

and they will be held accountable for demonstrating that their employees and supervisors have the 

necessary training and experience for adequately performing their job responsibilities. 

Challenges involved in demonstrating employee competence: The more employees a company 

has, the harder it is to track, follow-up, and verify employee training on all the aspects of their job 

responsibilities, especially if employees are in various locations, working different shifts. A paperbased 

system is likely to result in voluminous paperwork, delays, and incomplete training records. 

How centralized training software solutions can help: 

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Centralized training software solutions for regulated companies automate all CGMP requirements 

related to training. This includes the routing and delivery (via email) of training tasks to all 

personnel affected, e.g., by a change to a standard operating procedure. Once the employee or 

supervisor demonstrates that s/he can successfully perform the training task, his or her training 

record is automatically updated to reflect this. 

With fully integrated solutions, changes to a standard operating procedure can be configured to 

automatically trigger a new training task for all affected personnel. This further expedites the 

process and eliminates the delays and inefficiencies to which manual systems are prone. 


Keep Written Records of Customer Complaints Related to CGMPs 

Manufacturers of dietary supplements are required to document all customer complaints related to the 

requirements of CGMPs. Each written record of a customer complaint must include the following: 

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The name and description of the dietary supplement; 

The batch, lot, or control number of the dietary supplement, if available; 

The date the complaint was received and the name, address, or telephone number of the 

complainant, if available; 

The nature of the complaint including, if known, how the product was used; 

The reply to the complainant, if any; and 

Findings of the investigation and follow-up action(s) taken, if an investigation is performed. 

Challenges involved in maintaining written records of customer complaints: Manually maintaining 

complaint records can lead to misfiled or lost records. This may delay correction of a problem in the 

company’s quality control system, and resolution of the complaint. 

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How customer complaint software can help: 

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Complaint records stored in secure, centralized electronic files can be easily retrieved by authorized 

users. They can also be automatically retrieved by the system to print reports, perform analyses, 

etc., which help companies to see trends and respond proactively. 

Analysis and reporting tools increase management oversight, thereby making it easier to identify 

product issues and incorporate changes into products. Such tools also demonstrate to the FDA that 

the appropriate controls are in place. Examples of useful complaint reports include: 

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Complaint summaries 

In-process complaints 

Complaints categorized by type, product, and department 

Trending categorized by complaint type, product, and department 

2006 FDA Requirement to Report Serious Adverse Events 

Although the requirement is not part of 21 CFR Part 111, the FDA requires manufacturers of dietary 

supplements to report serious adverse events. The FDA defines an “adverse event” as “any healthrelated 

event associated with the use of a dietary supplement that is adverse.” 5 

The FDA defines a “serious adverse event” as an adverse event that: 

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Results in death, a life-threatening experience, inpatient hospitalization, a persistent or significant 

disability or incapacity, or a congenital anomaly or birth defect; or 

Requires, based on reasonable medical judgment, a medical or surgical intervention to prevent an 

outcome described above. 5 

The manufacturer, packer, or distributor whose name appears on the label of a dietary supplement 

marketed in the United States is required to submit to the FDA all serious adverse event reports 

associated with the use of a dietary supplement. 

Customer complaints that represent “serious adverse events” must be reported immediately to the 

FDA’s Adverse Event Reporting System (AERS) using the MedWatch Form FDA 3500A. 6 

Challenges involved in reporting serious adverse events to the FDA: For companies using a manual 

system, the process of physically securing all of the information that must be entered into the FDA’s 

3500A form in order to report an adverse event can be an extremely time-consuming and nerve-racking 

process, particularly when time is of essence. 

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How software solutions can help: 



A customer complaint solution that can be correlated with production data helps provide all the 

information required for reporting an adverse event to the FDA. 

CGMP Requirement to Maintain Records 

Many of the specific FDA requirements for maintaining records have already been discussed in this 

white paper; examples include: 

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Records for quality control operations procedures 

Records of unanticipated events (nonconformances and deviations) 

Training records for employees and supervisors (demonstrating that they are qualified to perform 

their current job functions) 

Records for customer complaints related to good manufacturing practices 

Records documenting serious adverse events (which must be reported to the FDA) 

In addition, manufacturers of dietary supplements must maintain records on packaging and labeling 

operations, qualifications of suppliers, and numerous other issues (having to do with equipment, 

cleanliness of facilities, etc.). 

Challenges involved in maintaining records: Because of the large number of records that manufacturers 

of dietary supplements must maintain, it is difficult and costly to stay up-to-date with the requirement 

of maintaining records if a manufacturer is using a manual system. Decentralized, hybrid systems only 

add to the problem by making it difficult to ensure that a record represents the most up-to-date version. 

How document control /management software can help: 

A document control/management solution can help manufacturers of dietary supplements maintain 

FDA compliance and work more efficiently by providing the following capabilities: 

• Centralized document repository: A centralized document repository ensures that only the most 

current version of a document is available to users; and makes it possible to automate processes 

(which can save an enormous amount of time). 

• Web access: A web-based system gives employees access to documents from virtually anywhere. 

Collaboration capability: 

• This makes it easy for members of a team to revise a document by 

providing a collaboration workspace that allows input from other collaborators, but avoids 

duplicated effort. 

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• Automated routing, escalation and approval: Reduces document revision cycle time by automating 

the routing and approval tasks; items not responded to are automatically escalated to the next level 

of authority after a predetermined amount of time. This process also ensures that only the most 

current version of a document (e.g., a shop floor SOP) is available to users. 

• FDA-approved electronic signoff: Enables documents to be approved or “signed off on” 

electronically. 

Conclusion 

This whitepaper has discussed some of the FDA’s CGMP requirements (detailed in 21 CFR Part 111) 

that apply to all domestic and foreign companies that manufacture, package, label or hold dietary 

supplements in the U.S. The purpose of the CGMP requirements is to establish quality standards for 

dietary supplements. 

The FDA’s CGMP requirements present a number of challenges for manufacturers and companies 

involved in any aspect of the process of bringing dietary supplements to market. These challenges 

range from establishing up-to-date procedures for quality control operations to ensuring that 

all employees and supervisors are qualified to perform the CGMP requirements of their job 

responsibilities. 

Benefits of a document control/management system: A document control/management system with 

version control can set the stage for an effective quality control program by ensuring that any given 

quality control procedure is the most current, up-to-date version available. Automated version control 

avoids confusion and errors as well as inefficiencies and poor quality. This saves time and production 

costs. 

Benefits of deviation/ nonconformance software: Effectively handling deviations and nonconformances 

(i.e., unanticipated occurrences) via an automated solution can also save time and production costs. 

This is accomplished via a preconfigured, best-practice form that prompts the user to enter all relevant 

data. The form is then submitted to an automated routing for investigating, resolution, and signoff. 

Automated escalation to a higher authority after a predetermined amount of time ensures an efficient 

system. 

Benefits of training software: Centralized training software solutions for regulated companies automate 

all CGMP requirements related to training. This includes the routing and delivery (via email) of 

training tasks to all personnel affected, e.g., by a change to an SOP. Once the employee or supervisor 

demonstrates that s/he can successfully perform the training task, his or her training record is 

automatically updated to reflect this. 

With integrated solutions, changes to an SOP can automatically trigger a new training task for all 

affected personnel. This further expedites the process and eliminates the delays and inefficiencies to 

which manual systems are prone. 


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Benefits of customer complaint software: A customer complaint software solution automates the 

process of documenting, reviewing and, when necessary, investigating customer complaints. The 

process of investigating complaints is greatly expedited by the ability to launch a review/approval 

routing (with all relevant documents attached). This prevents delays in resolving complaints due to the 

paperwork not being complete. 

Another benefit is that complaint records stored in secure, centralized electronic files can be easily 

retrieved by authorized users. They can also be automatically retrieved by the system to print reports, 

perform analyses, etc., which help companies to see trends and respond proactively. 

In summary, an automated document control/management system and automated processes can help 

assure quality and regulatory compliance, proper documentation, and greatly speed up the processes 

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, 

from 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, 

from 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 the following URL: 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. Retrieved: March 31, 2008 from http://www.phcog.org/ 

AnnualMtg/2006/papers/P_090.pdf 

5. Guidance for Industry: Questions and Answers Regarding Adverse Event Reporting and 

Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and 

Nonprescription Drug Consumer Protection Act. Downloaded on March 25, 2008, from http://www. 

cfsan.fda.gov/~dms/dsaergui.html#def 

6. Adverse event reporting form. Retrieved March 31, 2008 from the following URL: http://www.fda. 

gov/medwatch/getforms.htm. 

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About MasterControl 

MasterControl Inc. is a global provider of GxP process, quality audit, and document management 

software solutions for life science companies. MasterControl products are easy to use, easy to 

deploy, easy to validate, and easy to maintain. They incorporate industry best practices for automating 

and connecting every stage of the product development cycle, while facilitating regulatory compliance. 

By combining an integrated platform with a continuum of risk-based software validation products 

and services, MasterControl drives down the total cost of ownership and enables customers to extend 

their investment across the enterprise. Hundreds of companies, including 50 percent of the top 20 

pharmaceutical enterprises, currently use MasterControl solutions for easier compliance, faster 

validation, and better process management. For more information about MasterControl, visit www. 

mastercontrol.com, or call 800-825-9117 (U.S.) or +44 118 9812838 (Europe). 


© 2008 MasterControl Inc. All rights reserved. 

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