Overview of the Implementation of the Current Good Manufacturing Practices for Dietary Supplements Guidance for Industry
A Prepared Script for a Satellite Broadcast
October 24, 2007
Monika Samtani: Hello and welcome to the Food and Drug Administration's Overview of the Implementation of the Current Good Manufacturing Practices for Dietary Supplements. I'm Monika Samtani and I'll be your moderator for today's program.
For the next 3 hours we'll be discussing the proper controls manufacturers must now put in place to determine the quality of their dietary supplement. These regulations pinpoint the responsibility manufacturers have in determining that any representations or claims made about their products are substantiated and are not false or misleading. The undertaking of these manufacturing practices will ensure that dietary supplements are processed in a consistent manner, and meet quality standards.
We have three presenters who will discuss and explain these new GMP's and we'll be introducing them in just a little bit. They will provide a general introduction to the rule, the regulation as it applies to manufacturing and other requirements of the final rule. We'll also have a discussion of the rule and its influence on industry and consumers. First, let me explain a little bit about our program.
During the first part of our program, our presenter will go over each new section of the GMP, explaining the guidelines for quality of dietary supplements. After our presentations, we'll take a short break to allow you stretch and get some coffee.
During the second half of the program we'll invite listeners to participate in the discussion by sending us questions or comments by phone, fax or email. Throughout the program we'll be showing you the phone numbers you may use to send in your questions. Those numbers are appearing on your screen right now. If you are watching via satellite downlink, you can call in live at 1-800-527-1401, for faxes its 1-888-361-4011, and our email address is TVquestion@cdrh.fda.gov. You may send in questions at any time during the show.
If you're watching on the web here's what you do. Right above my video panel where you see me is a button with a question mark on it. If you have a question, simply press that button and an email page will appear. Fill in your question and send it as you would any email. Again, you may send in questions at anytime during the conference. If you're listening to this program on the phone bridge only, you can ask a question by pressing STAR 1 and the operator will direct you. Now that's ONLY for those who are listening to this program on the phone bridge. Everyone else should use the question button or the phone & fax numbers.
If you experience any Web-related technical difficulties during this event, talk with your IT folks FIRST to troubleshoot your Web connection. If they cannot solve your problem, call 1-888-626-8730 and we will assist you to the best of our ability. If it appears that the slides are not advancing, you may need to restart your browser and log on again.
If you lose the web cast for any reason and cannot reestablish a connection, we encourage you to access the audio via the phone bridge. The number is 1-888-469-1348, and the conference access code is 5428315.
We also have a live video and audio link with Wiley Auditorium at CFSAN headquarters in College Park Maryland. We invite those watching in Wiley to participate in our question and answer period as well. If you have a questions let your coordinator, Aaron Foster know. He'll then call us we'll recognize you on air and you'll be able to talk directly with our panelists.
OK. With that done, let's begin with some opening remarks from Janice Oliver, Deputy Director, at the Center for Food Safety and Applied Nutrition.
Janice Oliver: (roll-in) Thank you Monika. The final rule was drafted after a public process that included comments from industry and consumers.
We believe publishing a final dietary supplement Good Manufacturing Practice regulation is another critical step in consumer protection and an important public health initiative that touches the lives of millions of Americans.
The GMPs are an important tool to help ensure dietary supplement product quality, purity, consistency, and safety. The regulation helps assure consumers that they get accurately labeled and unadulterated dietary supplements by requiring current good manufacturing practices (CGMPs) in their manufacturing, packing, and holding.
The dietary supplement market has changed significantly since the passage of DSHEA. The industry itself has grown exponentially and so has the number of Americans buying these products. Access to dietary supplements has also changed. Today a wide range of dietary supplements can be purchased in supermarkets or through the Internet. The dynamic nature of this industry underscores the importance of and the necessity for Good Manufacturing Practice requirements for dietary supplements.
This final rule establishes industry wide standards requiring that dietary supplements are manufactured consistently as to their identity, purity, strength, and composition. Accordingly, consumers should have increased confidence in the dietary supplement products they purchase.
The regulation includes requirements for designing and constructing physical plants, establishing quality control procedures, and testing manufactured dietary ingredients and dietary supplements. It also includes requirements for maintaining records and for handling consumer complaints related to dietary supplement products. Thank you.
Monika Samtani: Our first discussion will center on Sections A through C of the final rule. These sections of the final rule focus on WHO is subject to the rule, the requirements for personnel and the requirements for the Physical Plant and Grounds. Let me introduce our first presenter Dr. Vasilios Frankos, the Division Director, in the Division of Dietary Supplement Programs, at the Center for Food Safety and Applied Nutrition here at FDA. Dr. Frankos.
Vasilios Frankos: Thanks Monika. I would like to begin by emphasizing that the majority of the rule's provisions allow the manufacturer to independently determine what specific controls are necessary for their particular operation. The final rule establishes the minimum GMP's necessary for manufacturing, packaging, labeling, or holding dietary supplements. It is one of many actions related to dietary supplements that we are taking to promote and protect the public health.
In an effort to limit disruption for dietary supplement manufacturers, the rule is effective September 2007 but has a staggered three-year phase-in for compliance. Large companies have until June 2008 before FDA will conduct GMP audits; companies with less than 500 employees have until June 2009; and companies with fewer than 20 employees have until June 2010 to comply with the regulations. Thus, small businesses have three years before FDA will conduct GMP Audits.
To better understand the final rule, it is divided into 16 user-friendly question and answer subparts, which focus on specific aspects of the manufacturing process. Each subpart is presented according to its specific operations to make it easier to find the relevant production and process control requirements.
For the next 20 minutes, I will discuss The General Provision under Subpart A, Personnel under Subpart B and Physical Plant and Grounds under Subpart C. Brad Williams will discuss subparts D - P.
Subpart A is divided into 3 sections that define the scope of who is subject to the rule, definitions that apply to the rule, and other statutory requirements.
Section 111.1 explains who is subject to the dietary supplement CGMP requirements. In brief, you are subject to the requirement of this rule if you manufacture, package, label, hold or import a dietary supplement. You would be included if you distribute in bulk to a distributor as well.
The dietary supplement CGMP requirements apply to companies (persons) who manufacture, package, label, or hold a dietary supplement. CGMP compliance also applies to dietary supplements that a company manufactures but are packaged or labeled by another person, or dietary supplements that are manufactured outside the US and then imported for sale into the US. The requirements pertaining to holding dietary supplements do not apply if the dietary supplements are held at a retail establishment for the sole purpose of direct retail sale to individual consumers.
The Final Rule does not apply to dietary ingredient manufacturers or suppliers, but only to persons who manufacture, package, or hold dietary supplements. The manufacturer is thus responsible for ensuring that the ingredients used in the production of a dietary supplement are such that they produce a product consistently meeting CGMPs. It is important to note that excluding raw dietary ingredient producers/suppliers from CGMP does not weaken the rule, but rather shifts the burden for ensuring the quality of dietary ingredients used in dietary supplement to the manufacturer of the final product. A finished product manufacturer still needs to ensure that the dietary ingredients used are the appropriate ones for the manufacturer's final product. This assurance of quality requires, at a minimum, an identify test of each incoming dietary ingredient to verify that the key ingredients are what they are purported to be.
If your activities relate to the harvesting, storage, or distribution of raw agricultural commodities or you are holding dietary supplements at a retail establishment for direct sale to consumers, you are not subject to these regulations - however, you are still subject to Food GMPs.
Although companies that manufacturer dietary ingredients are not subject to this rule, such companies are subject to this Dietary Supplement GMP in certain circumstances: (1) if you manufacture and supply a dietary ingredient directly to consumers as a dietary supplement, or (2) if you sell bulk dietary ingredients to another company who simply packages the ingredient into smaller units for sale as a dietary supplement.
FDA believes that it would be appropriate to exercise enforcement discretion to apply the GMP requirements to certain health care practitioners such as naturopaths, herbalists, or acupuncturists. The agency emphasizes two potential safeguards that could support the exercise of this enforcement discretion: (1) there is evidence of adequate training in the professional practice and (2) there exists an individual client and practitioner relationship. We are not considering exercising our enforcement discretion with respect to practitioners who prepare batches of herbs and sell them to individual consumers without determining whether the dietary supplement is appropriate or safe for each consumer's needs based on a one-on-one personal consultation.
Section 111.3 of Subpart A defines numerous terms used in the final rule and notes that the definitions or interpretations of these terms provide clarity and consistency in interpreting rule. For example - Quality means that the dietary supplement consistently meets the established specifications for identity, purity, strength, and composition and limits on contaminants and has been manufactured, packaged, labeled, and held under conditions to prevent adulteration.
Section 111.5 requires that you comply with any other applicable statutory and regulatory requirements related to dietary supplements.
Subpart B contains 5 sections that address personnel requirements. For example - in Subpart B we will discuss how to establish and follow written procedures, exclude personnel who might be a source of microbial contamination, qualify personnel and supervisors, identify qualified personnel who perform quality control operations and properly separate their quality control responsibilities from other functions they perform, and finally how to make and keep records.
Quality control personnel can be a person or group who perform the quality control operations. We do not require a separate quality control division or office be created. The quality control personnel can have dual functions within the facility but should separately perform the different responsibilities.
Section 111.8 of Subpart B requires that you establish and follow written procedures to fulfill the requirements of Subpart B.
Section 111.10 requires you take measures to exclude from any operations any person who might be a source of microbial contamination due to a health condition.
You are required to instruct your employees to notify their supervisors if they have - or if there is a reasonable possibility that they have - a health condition that could be a source of contamination.
More specifically, you are required to use hygienic practices necessary such as wearing outer garments, washing hands thoroughly, and wearing hair nets, caps, beard covers, or other effective hair restraints.
Section 111.12 requires each person engaged in manufacturing, packaging, labeling, or holding, or in performing any quality control operations, have the education, training, or experience to perform the person's assigned functions.
At this time we have no plans to provide companies with training materials for their employees. However, we expect that most companies already have trained or will train their employees to comply with these regulations.
Section 111.13 requires you to assign qualified personnel to supervise the manufacturing, packaging, labeling, or holding of dietary supplements. You are required that each supervisor you use to be qualified by education, training, or experience. In addition you are required to make and keep documentation of their training including the date of training, the type of training, and the persons trained.
Each person engaged in any activity covered by these CGMP regulations must have the education, training, or experience to perform the person's assigned functions. To show that such training is appropriate to the employee's functions and has in fact occurred, the training must be properly documented.
Finally Section 111.14 of Subpart B requires you to make and keep a record of the written procedures required of subpart B. This would include procedures for keeping the documentation mentioned above.
Subpart C is divided into 4 sections. The 4 sections pertain to the requirements of the physical plant and grounds.
Section 111.15 identifies the sanitation requirements for your physical plant and grounds to protect against the contamination of components, dietary supplements, or contact surfaces.
It addresses the methods for adequate ground maintenance which include:
- How to properly store equipment, removing litter, waste, weeds and grass within the immediate vicinity of the physical plant,
- How to maintain roads, yards, and parking lots,
- and how to adequately drain areas and operating systems for waste treatment.
It also addresses those areas bordered by grounds that are not under your control. If those other grounds are not maintained, you must exercise care by inspection, extermination, or other means to exclude pests, dirt, and filth that may be a source of contamination.
In general, you are to maintain your physical plant in a clean and sanitary condition and in proper repair to prevent contamination.
You are not to use or hold toxic materials in a physical plant unless they are necessary to maintain clean and sanitary conditions or for use in laboratory testing procedures.
Furthermore, you have to identify and hold these materials in a manner that protects against cross contamination.
Specifically, cleaning compounds, sanitizing agents, pesticides, and other toxic materials must be free from microorganisms of public health significance and be safe and adequate under the conditions of use.
You are not allowed animals or pets in any area of your physical plant. Guard or guide dogs are allowed in some areas if it will not result in contamination. You must take effective measures to exclude pests from your physical plant and to protect against contamination.
You are not to use insecticides, fumigants, fungicides, or rodenticides unless you take precautions to protect against contamination.
Although not required to enclose your outside equipment such as storage tanks, vessels, or piping, you are required to take effective measures to exclude pests from your physical plant and to protect against contamination.
The water supply of your plant must provide water that is safe and sanitary, at suitable temperatures, and under such pressure as needed for all uses.
Water used in a manner that becomes a component of the dietary supplement, for example - when such water contacts components, dietary supplements, or any contact surface they must at a minimum comply with the applicable National Primary Drinking Water (NPDW) standard regulations and any State and local government requirements.
Foreign firms are also required to meet these requirements and would need to comply with their own national or local water safety requirements, as well.
Additionally, to emphasize the importance of the water that is used in the manufacture of a dietary supplement, you are required to have documentation and keep records that such water meets the requirements. In contrast, there is no corresponding requirement for documentation for water that is used to clean floors or used in employee bathrooms.
Plumbing components are to be of an adequate size and design, installed and maintained to:
- Carry sufficient amounts of water to required locations,
- Properly convey sewage and liquid disposable waste,
- Avoid being a source of contamination,
- provide adequate floor drainage,
- And not allow backflow between waste piping systems that carry water used for manufacturing dietary supplements.
Sewage must be disposed into an adequate sewage system or other means.
The bathrooms in your physical plant need to be readily accessible and kept clean and not be a potential source of contamination.
Hand-washing facilities are to be designed to ensure that an employee's hands are not a source of contamination and be adequate, convenient, and provide running water at suitable temperatures and pressures.
You are required to convey, store, and dispose of trash to:
- Minimize the development of odors,
- Minimize the potential for trash to attract, harbor, or become a breeding place for pests,
- And protect against contamination of dietary supplements.
It should be emphasized that one or more employees must supervise overall sanitation. Each supervisor must be qualified by education, training, or experience to develop and supervise sanitation procedures.
As always, Section 111.16 of Subpart C requires you to establish and follow written procedures for fulfilling the requirements of subpart C.
Design and Construction requirements are covered in Section 111.20 and require that any plant that you use in the manufacturing, packaging, labeling, or holding of dietary supplements must be suitable in size, construction, and design to facilitate maintenance, cleaning, and sanitizing operations. They must also have adequate space for the orderly placement of equipment and holding of materials for maintenance, cleaning, and sanitizing operations and to prevent contamination and mix-ups.
You must put in place proper precautions to reduce the potential for mix-ups or contamination of components, dietary supplements or contact surfaces, with microorganisms, chemicals, filth, or other extraneous material.
The physical plant must have - and you must use - separate or defined areas of adequate size to receive, identify, hold, and withhold from use, components, dietary supplements, packaging, and labels.
Cosmetic, food, and drug manufacturing must be separated from dietary supplement manufacturing, packaging, labeling, and holding.
You need to have a separate area to perform laboratory analyses and to hold laboratory supplies and samples.
A separate area for cleaning and sanitizing material should also be maintained.
Section 111.20 requires that any physical plant must be designed and constructed in a manner that prevents contamination. This requirement addresses the design and construction of floors, walls, and ceilings.
The final rule provides the flexibility in determining how best to construct your facility in order to prevent contamination and to ensure the quality of the dietary supplements you manufacture.
When fans and other air-blowing equipment are used, those fans and equipment must be located and operated in a manner that minimizes the potential for contamination.
Adequate light must be used in all areas where components or dietary supplements are examined, processed, or held.
You are to use safety-type light bulbs, fixtures, skylights, or other glass materials when they are suspended over exposed components or dietary supplements.
Protective coverings should be used to eliminate pests, infestation, and filth for your outside fermentation or holding vats.
As before, Section 111.23 requires that you make and keep records of the written procedures for cleaning the physical plant, pest control and water quality. Thank you.
Monika Samtani: Thank you Bill for that overview of the general provisions. And now on to the next section.
Our next presentation will spotlight specific portions Sections D through P that apply to the manufacturing of dietary supplements and will include points on quality control procedures, testing and record keeping. Here to present Sections D through P is Brad Williams, Special Assistant to the Division Director, in the Division of Dietary Supplement Programs, at CFSAN. Brad?
Brad Williams: Thanks, Monika. I want to continue with the rest of the final rule, section by section. Of course, since the rule is quite long, I will present the highlights in the time allotted and look forward to your questions later.
Let's begin with Part D of the final rule. This part is divided into four sections and deals with utensils and equipment used in dietary supplement facilities.
First and foremost, a manufacturer must establish written procedures for complying with this subpart under section 111.25. These records must encompass calibration of instruments and controls; calibrating, inspection and checking automated, mechanical and electrical equipments; and maintaining, cleaning, and sanitizing of all equipment, utensils, and any other contact surfaces.
The rule requires that all equipment and utensils used be of an appropriate design, construction, and workmanship to allow them to be suitable for their intended use as well as properly cleaned and maintained. An example would be lubricants from equipment. If a piece of equipment leaked lubricant, this might contaminate the dietary supplement. If, on the other hand, a lubricant is part of a process (such as encapsulation), the integral lubricant will not render that particular piece of equipment non-compliant.
In addition, instruments and controls used in testing or manufacturing dietary supplements or components must be accurate and precise for the intended purpose. As well, they must be properly calibrated, and repaired or replaced if they can't be adjusted to agree with the reference standard.
Refrigerators, freezers and other cold storage equipment must be fitted with temperature measuring or a temperature recording device and must have a device for regulating temperature or an alarm to indicate a significant temperature change.
The rule in section 111.30 requires that automated, mechanical, and electrical equipment be selected that will ensure that dietary supplement specifications are consistently met. The equipment must be capable of operating within the limits specified by the process and must be routinely calibrated, inspected, or checked to ensure proper performance.
Due to their nature, automated mechanical, and electrical equipment must be established such that it functions in accordance with its intended use and that changes to its operating parameters must be approved by quality control personnel. Any software changes must be carefully documented and copies of the software retained.
One important note which will be especially important to some firms is that if your instruments or other equipment are factory calibrated (or calibrated by a third party), you will need to make some assessment or tests to ensure that transportation and installation has not taken the equipment out of calibration. The firm manufacturing the dietary supplement is responsible that calibration is done and maintained.
Subpart E at section 111.55 of the rule sets the Requirement to establish and implement a production and process controls that covers all stages of manufacturing, packaging, labeling and holding of dietary supplements to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record.
The production and process control system must include all requirements of subparts E through L of this regulation, and must be reviewed and approved by quality control personnel. The purpose is that the production and process control system must ensure that you consistently and reliably manufacture what you intend.
Additionally, sections 111.60 and 111.65 requires that your production and in-process control system is designed and implemented to ensure quality control operations in the manufacturing, packaging, labeling and holding operations of the dietary supplement and that the supplement is packaged and labeled in accordance with the master manufacturing record.
Section 111.70: You must establish specifications for any point, step or stage in the manufacturing process where control is necessary to meet identity, purity, strength and composition as well as limits for those types of contamination that may adulterate or lead to adulteration of the finished batch. These include:
- For each component you use in the manufacture of a dietary supplement you must establish both an identity specification and such other specifications.
- In-process specifications for any point, step or stage of the manufacturing and adequate documentation of meeting in-process specification in combination with meeting component specifications. Quality control personnel must review and approve the documentation.
- Specifications for Labels and packaging material that may come in direct contact with the dietary supplement.
- Finished product specifications for the identity, purity, strength and composition of the batch together with limits on those contaminants which may adulterate the finished batch.
- Received products from a supplier for packaging or labeling and distribution (not to be returned to supplier - in this case you are a contractor) you must have specifications to assure that the product received is adequately identified and consistent with your purchase order.
- That you used of specified packaging and that you applied the specified label.
- This part also requires that you determine whether the specifications you have established as required in the preceding discussion are met.
Section 111.75: What must you do to determine whether specifications are met?
Before the use of a component, you must conduct at least one appropriate test or examination to verify the identity of that component. You may petition FDA to be exempt from 100% identity testing of dietary ingredients, which will be discussed in a few minutes.
For a component that is not a dietary ingredient, identity and conformance to other applicable specifications must be determined. But this can be done either with appropriate tests or by relying on a certificate of analysis from a vendor that you have previously 'qualified' to establish the reliability of the certificate of analysis. You must maintain documentation of the qualification and periodically update this qualification. Further, your quality control personnel must review and approve the documentation setting forth the basis for the qualification. You must continue to monitor those in-process points you have identified and determine if in-process specifications are met.
For finished product testing - since in-processing controls require a scheme that measures specification conformance at various stages of the manufacturing process to detect deviations from specifications - the requirement of the rule is that you must verify that your finished batch meets product specifications. But you may exempt one or more product specifications from verification if you carefully document why. This provides needed flexibility as we realize that there may be ingredients which are nearly impossible to analyze in the finished product. However, quality control personnel must review the documentation for this purpose and approve it.
You must visually examine the packaging materials - containers, closures and review all documentation (suppliers invoice, guarantees, certificates of analysis) to ensure packaging specifications are met prior to packaging.
Before labeling, you must, at a minimum, conduct a visual examination of the label and review its documentation to ensure that specifications are met.
Throughout, you must ensure that the methods used are appropriate and scientifically valid - which means that the method is accurate, precise, and specific for its intended purpose.
You must establish corrective action plans for use when an established specification is not met.
What if a specification is not met?
- If a specification is not met for a component, package or label, it must be rejected unless quality control personnel approved a treatment, in-process adjustment, or reprocessing procedure.
- If a specification (especially identity) is not met for a dietary ingredient it must be rejected and must NOT be used in manufacturing a dietary supplement.
- If a specification is not met for a finished product, that product may not be packaged or labeled for distribution as a dietary supplement.
Section 111.80 states that a manufacturer must collect and retain representative samples of all components, packaging, labeling, in-process materials for each batch, a subset of finished batches of each dietary supplement, and of each lot packaged and labeled.
In 111.83 you must also collect and hold reserve samples of each lot of packaged and labeled dietary supplements. This sample must be in the same container and closure system as a finished product. If you don't distribute, package and label the supplement, use a similar container and closure used by the distributor.
Retain for 1 year past the shelf life date (if dating is used) or for 2 years from the date of distribution. And the sample must consist of twice the quantity necessary for all tests or examinations.
111.87 specifies that quality control personnel must conduct all required material reviews and make all disposition decisions.
You must not process a rejected dietary supplement, treat or provide an in-process adjustment to a component, packaging, or label to make it suitable for use in manufacturing a dietary supplement UNLESS:
- It is NOT a dietary ingredient.
- Quality control personnel conducted a material review and disposition decision based on a scientifically valid reason and approves the plan.
- Any batch that is reprocessed, contains components that you have treated, or to which you have made any in-process adjustment must be approved by quality control personnel and in compliance with its specifications.
Section 111.95 states that you must keep records under the provisions of subpart P.
Subpart F requires written procedures be established and followed for quality control operations, which include conducting material reviews, making disposition decisions, and approving or rejecting any reprocessing.
Quality control personnel must ensure that your manufacturing, packaging, labeling and holding operations ensure the quality that the dietary supplement is packaged and labeled as specified in the master manufacturing record. You must:
- Approve or reject all processes, specifications, written procedures, controls, tests, and examinations that may affect the identity, purity, strength, or composition of a dietary supplement.
- Review and approve the documentation.
- Review and approve the documentation of why meeting in-process specifications will ensure that the specifications of the finished product will be met.
- Review and approve the documentation for results of tests or examination for results.
- Review and approve the basis and documentation for why any product specification is exempted and why component and in-process testing, examination, or monitoring will ensure that such exempted product spec is met without verification.
- Ensure required representative samples are collected.
- Ensure required reserve samples are collected and held.
- Determining if all in-process, packaging and labeling specifications are met.
- And review and approve the results of all tests and examinations.
In addition, for laboratory operations, quality control personnel must:
- Review and approve all laboratory control processes.
- Ensure that all tests and examinations required to determine whether established specifications are conducted.
- Review and approve the results of all tests and examinations conducted to make those determinations.
- An example of where these rules don't apply would generally be a research and development laboratory.
Material review and disposition require quality operations described in section 111.113. Quality control personnel must conduct a material review and make a disposition decision whenever any required control specification is not met or there is any unanticipated occurrence during the manufacturing operation that adulterates a component, dietary supplement, or packaging or lead to use of a label not specified in the master manufacturing record. Quality control review is required if a dietary supplement is returned.
Disposition decisions must be based on the material review:
- Quality control personnel must reject the component, dietary supplement, packaging or label unless they approve a treatment, in-process adjustment, or reprocessing as permitted in section 111.77.
- The person (persons) who conducts the review and makes the disposition must document the material review and disposition decision.
There are also detailed requirements in this part for quality control personnel to review all equipment, instruments, and controls; components, packaging and labels; master manufacturing records; and packaging and labeling operations. I refer you to those sections of the rule for further details.
One critical area in which quality control personnel contribute greatly to product quality is the quality control operations required for returned supplements. Quality control personnel must conduct any required material review and make disposition decisions. These are especially important when approving or rejecting any salvage or reprocessing of any returned dietary supplement, determining whether a reprocessed dietary supplement meets product specifications approving, rejecting, and such dietary supplements. Quality control personnel must review and approve decisions about whether to investigate a complaint, as well as reviewing and approving the findings and proposed follow-up action of any investigation performed.
Section 111.140 requires quality control operations to be thoroughly documented and these records retained. Most importantly, included in quality control record keeping are:
- A scientifically valid reason for any reprocessing of a dietary supplement that is rejected or any treatment or in-process adjustment of a component which is rejected.
- The signature of the individuals designated to perform the quality control operation, who conducted the material review and made the disposition decision and each qualified individual who provides information relevant to that material review and disposition decision.
Subpart G: Production and Process Control System requirements for components, packaging and labels, and for product you receive for packaging or labeling as a dietary supplement. Written procedures must be established and followed for this part of the regulation.
You must visually examine each container (or group of containers) for an appropriate content label, container damage, or broken seals to determine whether the container condition may result in contamination or deterioration of the contents.
You must examine the supplier's invoice, guarantee or certification in a shipment.
A certificate of analysis accompanying a component must include a description of tests or examinations and their methods used, limits of the test or examination, and actual results.
You must quarantine components before you use them and collect representative samples.
Quality control personnel must review and approve the results and approve the component for use in the manufacture of a dietary supplement.
You must identify each unique lot that allows you to trace the lot and the status of the component (quarantined, approved, or rejected) to the dietary supplement that you manufactured and distributed.
You must also hold components under conditions that protect against contamination and mix-ups.
Likewise, section 111.160 provides the same requirements for packaging and labeling received for use in your manufacturing operation.
Section 111.165 outlines requirements for a product received for packaging or labeling for distribution rather than return to the supplier. These products, in addition to above, must be approved by quality control personnel for packaging and labeling then again release.
Section 111.170 addresses procedures required for rejected components, packaging, and labeling and to reject products that are received for packaging or labeling.
You must clearly identify, hold and control under a quarantine for appropriate disposition any component, packaging and label as well as any product received for packaging or labeling as a dietary supplement (and distribution rather than return to a supplier) that is unsuitable for use in manufacturing, packaging, or labeling operations. You must keep complete records under this part.
Subpart H Requirements for the master manufacturing record.
You must prepare and follow a written master manufacturing record for each unique formulation of dietary supplement that you manufacture and for each batch size, to ensure uniformity (that specifications established for identity, purity, strength and composition are uniformly met) in the finished batch from batch to batch. This master manufacturing record constitutes the 'master recipe' that a firm follows in producing a dietary supplement product. It must include the name of the dietary supplement to be manufactured and the strength, concentration, weight or measure of each dietary ingredient. It must have a complete list of components and an accurate statement of the weight or measure of each component. Include the identity and weight or measure of each dietary ingredient that will be declared on the supplement facts label and the identity of each ingredient that will be declared on the ingredients list of the dietary supplement. Also include a statement of any intentional overage amounts of a dietary ingredient.
This overage must be limited to that quantity necessary to ensure that labeled content is met, not to provide excess of any ingredient. The theoretical yield of a manufactured dietary supplement expected at each point, step or stage of manufacture where control is needed to ensure the quality of the dietary supplement. Your master record must include a description of packaging and a representative label. You need to have written instructions for each point, step or stage in the process, including procedures for sampling and cross-reference to tests and examinations. Specified actions which are necessary to perform and verify each point, step or stage in the manufacturing process, as well ensure packaging and labeling meet specifications. This must include verifying the weight or measure of any component and that the component was, in fact, added.
For manual operations you must include one person weighing or measuring the component and another verifying the weight or measure. Likewise, one person adds the component and another person verifies the addition. Special notations and precautions are to be followed and corrective action plans specified when specifications are not met.
Subpart I Requirements for the Batch Production Record.
Every time a batch of dietary supplements is manufactured, a batch production record must be prepared. This record must contain complete information regarding the production and control of each batch, and must follow the appropriate master manufacturing record. The batch production record must include the batch, lot, or control number of the finished dietary supplement, as well as any batch number assigned to packaged and labeled dietary supplement, or finished product you distribute to another person for packaging and labeling. There are detailed requirements listed in section111.260 to which you should refer for complete information.
Subpart J: Requirements for Laboratory Operations
First and foremost, laboratory operations must follow written procedures including written procedures for all tests and examinations that you conduct.
You must use adequate lab facilities to perform whatever testing or examinations are necessary to determine components used meet specifications, in-process specifications are met, and dietary supplements you manufacture meet specifications. These laboratory facilities can be your own or a contract laboratory.
You must establish and follow laboratory control procedures that are reviewed and approved by quality control personnel to include criteria for establishing appropriate specifications, sampling plans for obtaining representative samples, criteria for selecting, testing and examination methods, and standard reference material.
The rule specifies that laboratory examination and testing methodologies must be verified as appropriate for their intended use. The methods used must be scientifically valid.
Detailed records must be kept of methods used, documentation of validity or methods established, and results of examinations and tests conducted must be documented at the time of analysis.
Subpart K Requirements for Manufacturing Operations.
Written procedures for manufacturing operations are required under this subpart, which include designing or selecting manufacturing processes that ensure product specifications are met consistently and must be in accordance with sanitation principles.
Manufacturing must take all precautions to prevent contamination of components or dietary supplements.
You must clearly identify, hold, and control under quarantine for appropriate disposition any dietary supplement that is rejected and unsuitable for use in manufacturing, packaging or labeling operation.
Subpart L Requirements for Packaging and Labeling Operations.
You must establish and follow written procedures for packaging and labeling operations.
Remember, packaging and labels are essentially components of the finished dietary supplement, so you must determine whether the packaging meets specifications. You must also control issuance and use of packaging and labels, as well as reconcile issuance and use discrepancies. Examine packaging and labels to determine whether they conform to the master manufacturing record and maintain the ability to determine the complete manufacturing history and control of the packaged and labeled dietary supplement through distribution. One way to do this is with a batch number but that is NOT required.
The rule requires that packaging and labeling operations are conducted in such a way as to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled in accordance with the master manufacturing record.
Dietary supplements can be repackaged and relabeled only after quality control personnel have approved such repacking and re-labeling. Packaged and labeled dietary supplements that are rejected for distribution must be held under quarantine pending appropriate disposition.
Subpart M Holding and Distribution.
A firm must establish and follow written procedures for holding and distribution.
Components, dietary supplements, packaging, and labeling must be held under conditions of temperature, humidity, and light so that the identity, purity, strength, and composition of the components and dietary supplements are not affected.
All must be held under conditions that prevent mix-up, contamination or deterioration.
Reserve samples must be held in a manner that protects against contamination and deterioration -including temperature, etc. specified on the label, if so labeled. Distribution must be done under conditions which protect dietary supplements against contamination and deterioration.
Subpart N Returned Dietary supplements.
You must establish and follow written procedures for complying with this part.
Returned dietary supplements must be identified and quarantined until quality control personnel conduct a material review and reach a disposition decision.
You must destroy or otherwise suitably dispose of any returned dietary supplement unless the outcome of a material review and disposition decision by quality control personnel approves the salvaging or reprocessing of a returned dietary supplement for redistribution.
Returned dietary supplements that are approved for reprocessing must meet all product specifications and be approved (or rejected) for release for distribution by quality control personnel.
If, for any reason, a returned dietary supplement implicates other batches (such as an apparent process failure), you must conduct an investigation of your manufacturing process and each of those other batches to determine compliance with specifications. Quality control personnel must review the results of this investigation as part of a material review.
Subpart O: Product Complaints.
Product Complaints must be reviewed and implicated product(s) investigated (where appropriate) by a qualified person who must review the complaint to determine whether it involves possible failure of a dietary supplement to meet any specification or any other requirement of this rule. Especially any specification which, if not met, could increase the risk of illness or injury. Both the decision to investigate and the findings of an investigation must be reviewed and approved by quality control personnel. The review and investigation conducted for any complaint (including QC personnel review and approval) must be extended to include any relevant batches and records.
Subpart P: Records and Recordkeeping
All records required under the provisions of this rule must be maintained for 1 year past the shelf-life date, if one is used, or for 2 years after the last date of distribution of the last batch associated with those records.
All records must be kept as original records, as true copies (such as photocopies, microfilm, microfiche or other accurate reproduction of the originals) or electronic records.
If electronic records are kept they must comply with FDA regulations for electronic records regulations (part 11 of chapter 21 of the Code of Federal Regulations).
All records required by this rule, or copies of such records, must be readily available during the retention period for inspection by FDA when requested.
If you use reduction techniques, such as microfilming, you must make a suitable reader and photocopying equipment available to FDA. Thank you... Monika.
Monika Samtani: Thank you Brad. Let's now move on to the Interim Final Rule.
In this section we'll discuss the process to petition FDA for exemption from the requirement to test 100 percent of incoming dietary ingredients for identity. And once again we have Brad Williams to do this section. Brad?
Brad Williams: Thanks, Monika. Now we are going to briefly discuss an Interim Final Rule entitled "Petition to Request Exemption from 100 Percent Identity Testing of Dietary Ingredients" which was published at the same time that we published the Final Rule for Current Good Manufacturing Practices for dietary supplements. The comment period for this rule has been extended thru today(ed: October 24, 2007.) However, once the IFR is in effect, the first petitions will not be accepted until a firm's compliance date under the Final Rule for CGMP.
As you may recall, Subpart E of the final rule provides that before you use a dietary ingredient component in manufacturing, you must conduct at least one appropriate test for the identity of that component. This requirement applies whether a dietary ingredient is purchased from a supplier or you manufactured the ingredient for use in your own company.
While FDA believes that establishing identity is critical in ensuring that the dietary supplement is what is says it is, several comments received for the 2003 proposed rule suggested that manufacturers may be capable of demonstrating that a less than 100 percent identity testing method would result in no material diminution of assurance of the identity of the dietary ingredient when compared to the assurance provided by 100% identity testing. Therefore, FDA will consider, on a case-by-case basis, a manufacturer's conclusion that it has developed such a system.
The FDA will consider petitions (under the citizens petition that I will discuss shortly) that, at minimum, must set forth the scientific and statistical rationale for the requested exemption, all supporting data and information, careful documentation and analysis of any variability or errors in incoming materials over time, and an alternative testing proposal.
Under this Interim Final Rule, firms may be granted exemption from 100 percent identity testing only when a manufacturer petitions the agency under section 10.30. And FDA has affirmatively granted the exemption.
Briefly, a citizen's petition filed under section 10.30 must state the following. The action requested, for example - exemption - a statement of the grounds for the request and a statement on environmental impact. Further, a certification that to the best of your knowledge, the petition contains all information and views on which the petition relies. This includes any unfavorable data and information known to you. It should also identify commercial, confidential, or trade secret data and segregate that information from other information in the petition.
An important note - FDA may take into account any other data or information it has in its files, such as information from other manufacturers who use the same suppliers, when reviewing these petitions. While commercial or trade secret information is not available for public disclosure, the agency is not precluded from considering such information when reviewing these petitions.
We have no preconceived notion of what would constitute a successful petition. However, as we gain experience FDA will issue guidance on the information and types of data it recommends for inclusion in these petitions.
The approval of an exemption petition will be only for specific dietary ingredient(s) from specific supplier(s). However, the firm may file petitions containing any number of ingredients from multiple suppliers, so long as there is data specific to each dietary ingredient and each supplier. If a manufacturer changes dietary ingredient(s) or supplier(s), FDA's approval wouldn't extend to that particular changed dietary ingredient.
Once the petition is granted, the section 111.75(a)(1)(i) requires the manufacturer to implement the system identified in the petition. You must use the scientific method developed by the manufacturer with periodic verification testing as approved in the petition. Note - identity may include physical characteristics, state of hydration, or other data. The term identity here refers to the manufacturer's specifications that are used to establish that a supplier's dietary ingredient is suitable for this exemption. The manufacturer is responsible for document all tests, examinations, and other data for the dietary ingredients as specified by FDA in granting the petition, keeping such records under 111.325 and making them available to FDA on request.
In addition, the firm must keep records relating to the petition and FDA's action on that petition.
If periodic testing conducted pursuant to the petition results in a failure of any dietary ingredient to meet its identity specification, the FDA petition approval for that dietary ingredient and supplier would no longer be in effect. This would return that ingredient and supplier to 100 percent identity testing if the firm wished to continue using it and would further require quality control personnel review under the CGMP regulations.
If the firm wished to return to reduced testing for the dietary ingredient from that supplier in the future, it would have to submit a new petition under this process and await approval. Thanks.
Monika Samtani: Thanks again Brad. Let's move on to our final presentation.
Our final presentation will give you and up-close look at what investigators will be looking for upon inspection of dietary supplement manufacturers. Let's say hello to Sara Dent Acosta, Consumer Safety Officer/Investigator with the Los Angeles District Office with FDA. Sara, glad you could be with us today.
SARA Dent-Acosta: Thanks Monika. There are a variety of firms of different sizes and performing different activities that will be subject to the new regulations.
Specifically anyone who manufactures, packages, labels, or holds. The field investigators may find firms that are not aware they are subject to the new regulations or when they come into effect. Please pay attention to the dates.
Many challenges will come from applying the definitions during an inspection, especially the distinction between a finished product, component, and ingredient and verifying if a component is an approved dietary ingredient, a new dietary ingredient, a food substance or in another category such as GRAS substance or approved colors.
Component means any substance intended for use in the manufacture of a dietary supplement including those that may not appear in the finished batch of the dietary supplement.
Ingredient means any substance that is used in the manufacture of a dietary supplement and that is intended to be present in the finished batch of the dietary supplement. An ingredient includes, but is not necessarily limited to, a dietary ingredient as defined in section 201(ff) of the act.
The personnel requirements are similar to what firms should already be doing while preparing foods, including dietary supplements. The difference now is that the procedures must be in writing and firms will have to demonstrate they have trained their employees in the procedures and that the procedures are implemented and followed.
Part of the section on sanitation is similar to what is already required. The new challenge is that written procedures will be in place for all sanitation and pest control activities. If there are sanitation deficiencies observed during an inspection, the investigator may look at the procedures to see if there is a deficiency with the procedure, training, or implementation.
Firms will also need to have records that demonstrate that water used as an ingredient is safe and sanitary. In this case, we would be looking for microbial analysis or other kinds of analysis if there are unusual situations.
There are a series of requirements in this section for having separate and defined areas in the physical plant identified for receiving, in-process and holding activities among others. Investigators will want to look at what system the firm has in place for keeping track of the requirements under this part.
This subpart will require procedures and records of calibration and preventive maintenance. Typical equipment that requires calibration or verification of calibration are: pH meters, thermometers, chart recorders, scales, etc.
Keep in mind that many digital thermometers cannot be adjusted, therefore, calibration can only be verified.
The records of this part will need to be reviewed by quality control personnel. Your quality control personnel must periodically review these calibrations, inspections, or checks. This means investigators will be looking for date and signature of quality control personnel in the calibration records among others. There is also a requirement for backup storage of any electronic records.
The new regulations require a master manufacturing record to be written, implemented, and followed to ensure quality. All requirements of subparts E through L of this part must be reviewed and approved by quality control personnel.
For items that need to be reviewed and approved there should be a signature indicating the review and approval.
Words that will be an important part of inspections are: Specifications - Quality - Identity - Purity - Strength - Composition. Investigators will be looking at how each firm defines their ingredients and products and how they can demonstrate they are achieving their own specifications.
In addition to statements in the regulations that a written SOP is required, investigators will be verifying compliance with areas where it says "review, approve, sign, initial, disposition, identify, document, date, time, test, examine, and cross reference."
Investigators will encounter a variety of SOP's depending on the degree of complexity of the product manufactured.
Here are some suggestions to make the FDA inspection easier:
Make your SOP's easy to understand and not impossible to follow.
Make the records easy to read - inspections are longer and more difficult if there is a lot of information crammed into the same piece of paper and if the information becomes difficult for you to explain. If there is information on a batch record that ties with, for example shipping records, make sure the invoice and B/L numbers match and that they are easy to locate.
Ensure the batch number is clear and easy to follow in all the manufacturing and shipping records.
Make the records easy to fill out by employees. Have an example of what needs to be there - time, temperature, weight, etc. For example: "weight" instead of "Weight of ingredient added in ounces, write time and initials."
Do not have ambiguous blank spaces in your forms. For example a form that says "temperature before" instead of "digital temperature readout from chart recorder."
Finally, take advantage during your next inspection to ask questions about the new regulations and do not wait until after they have come into effect. You can also call your local FDA district if you have any questions.
Begin working on the new procedures now and don't wait until the last minute. If you are overwhelmed by trying to implement the procedures shortly before they come into effect it will be more difficult.
Thank you very much and now back to Monika.
Monika: Thank you Sara, and thanks to all our presenters. Before we get to discussion and questions, let's take a short break to allow you to stretch and get some coffee. When we return, we'll be discussing some of the points talked about in our presentations and begin answering your questions that you've been sending in during our broadcast. Our phone, fax and email lines will be open so please feel free to send your questions if you haven't already done so. We'll see you in about 10 minutes.
Monika: Welcome back. I'm joined on stage by our presenters Bill, Brad, and Sara. Let's jump right into your questions.
Monika: Our time is just about up. I'd like to thank our presenters Bill Frankos, Brad Williams, and Sara Dent Acosta for their wonderful work. Thanks to all of you who participated via phone, fax, and email. For more information on these new rules please feel free to contact CFSAN.
We've received many more questions than we can answer today. We will consider these questions as we develop new documents, such as the Small Entity Compliance Guide that Bill mentioned.
Until next time, I'm Monika Samtani, thanks for watching.
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