GMPs and FDA Oversight of Dietary Supplements Vasilios ...

1. 10/10/2011 1 GMPs and FDA Oversight of Dietary Supplements June 25, 2009 Vasilios H Frankos Ph.D. Director, Division of Dietary Supplement Programs

2. 10/10/2011 2 Current Dietary Supplement Good Manufacturing Practices (CGMP) June 25, 2007 - FDA published the DS CGMP rule. Require proper controls are in place so dietary supplements are processed in a consistent manner and produce a high quality product that is not adulterated with contaminants or impurities, and are accurately labeled. The DS CGMPs should help prevent inclusion of the wrong ingredients, too much or too little of a dietary ingredient, contamination (e.g. natural toxins, bacteria, pesticides, glass, and heavy metals such as lead), and improper packaging and labeling. The DS CGMPs should increase consumers’ confidence in the quality of the dietary supplement products that they purchase.

3. 10/10/2011 3 Requirements Effective August 27, 2007 the final rule codifies (CFR 21 part 111) the specific current good manufacturing practices (CGMPs) that must be used to manufacture dietary supplements. The CGMPs final rule requires that proper controls are in place for dietary supplements so that they are processed in a consistent manner, and meet quality standards. The CGMPs apply to all domestic and foreign companies that manufacture, package, label or hold dietary supplements, including those involved with the activities of testing, quality control, packaging and labeling, and distributing them in the U.S.

4. 10/10/2011 4 Major Requirements Staggered three-year compliance inspection phase-in for small businesses. FDA inspections begin in June 2008 for large companies, June 2009 for companies with 20- 500 employees, and June 2010 for companies with fewer than 20 employees. The final rule is organized into 16 subparts that focus on specific aspects of the manufacturing process or addressing specific issues. Final DS CGMP rule does not apply to raw ingredient manufacturers, although they will continue to need to meet the food CGMP regulations.

5. 10/10/2011 5 Major Points: Final Rule Final DS CGMP rule does not apply to raw ingredient manufacturers, although they will continue to need to meet the food CGMP regulations. Provided more flexibility in determining the qualifications of employees and in design of facilities Reduced testing requirements on final product testing and recognizes Certificates of Analyses (COAs) under certain conditions Requires a written procedure to be in place that governs all recordkeeping requirements where they exist in the rule. Reduced responsibilities of quality control personnel to primarily oversight and final approval.

6. 10/10/2011 6 Major Provisions The requirements include provisions related to: the design and construction of physical plants that facilitate maintenance, cleaning, proper manufacturing operations, quality control procedures, testing final product or incoming and in process materials, 100% testing for identity of incoming dietary ingredients handling consumer complaints, and maintaining records.

7. 10/10/2011 7 Must have adequate laboratory facilities to perform testing and examinations to determine whether: Components meet specifications; In-process specifications are met as specified in the master manufacturing record; and Dietary supplements manufactured meet specifications Production and Process Controls Requirements for Batch Laboratory Operations - Subpart J  Requirements for the Laboratory Facilities §111.310 Subpart C – Physical Plant and Grounds also applies to laboratory operations Subpart D – Equipment and Utensils also applies to laboratory operations If firm uses an outside laboratory, the firm is responsible for ensuring that the test and examinations are adequately performed.Subpart C – Physical Plant and Grounds also applies to laboratory operations Subpart D – Equipment and Utensils also applies to laboratory operations If firm uses an outside laboratory, the firm is responsible for ensuring that the test and examinations are adequately performed.

8. 10/10/2011 8 Production and Process Controls Requirements for Batch Laboratory Operations - Subpart J  Requirements for the Laboratory Facilities §111.310 Ensure lab facilities are designed and suitable to carry out the necessary tests and examinations Suitable size, sanitary, precautions to reduce potential for contamination (Subpart C) Appropriate equipment and calibration of equipment (Subpart D)

9. 10/10/2011 9 reviewed and approved by the quality control personnel unit Use of criteria for establishing appropriate specifications; Use of sampling plans for obtaining representative samples, in accordance with Subpart E, of: Components, packaging, and labels; In-process materials; Finished batches of dietary supplements; Product that you receive for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier); and Packaged and labeled dietary supplements. Production and Process Controls Requirements for Batch Laboratory Operations - Subpart J  Requirements for Laboratory Control Processes §111.315 Sampling plans – subject to approval by quality control personnel but are not developed by quality control personnel 111.80(a) also applies here regarding requirements to collect representative samples of components, packaging and labels. Sampling plans – subject to approval by quality control personnel but are not developed by quality control personnel 111.80(a) also applies here regarding requirements to collect representative samples of components, packaging and labels.

10. 10/10/2011 10 Production and Process Controls Requirements for Batch Laboratory Operations - Subpart J  Requirements for Laboratory Control Processes §111.315 Use of criteria for selecting appropriate examination and testing methods; Mfr may rely on recommendation of contract lab in selecting a test or examination, but the rational must be documented Use of criteria for selecting standard reference materials used in performing tests and examinations; Compendia reference stds do not require characterization Appropriately characterized in-house materials Authenticated plant reference materials Use of test methods and examinations in accordance with established criteria Mfr of dietary supplement has the responsibility to comply with the cGMP requirements to select appropriate tests, regardless of who conducts the tests. Therefore, the mfr may rely on the recommendation of the contract laboratory in selecting an appropriate test or examination. Compendia reference stds do not require characterization Non-compendia reference stds should be of the highest purity that can be obtained by reasonable effort and should be thoroughly characterized to ensure their identity, purity, quality, and strength. Firms should establish appropriately characterized in-house materials prepared from representative lots if no compendia reference std exists. For organoleptic examinations, an authenticated plant reference material would be a material that has been authenticated as the correct plant species and correct plant part(s) by a qualified plant taxonomist (preamble pg 34893) For microscopic and chemical tests (including calibration tests), a reference material is a highly purified compound that is well characterized (preamble pg 34893) Reference stds should be appropriate to the assay procedure for which they are used.Mfr of dietary supplement has the responsibility to comply with the cGMP requirements to select appropriate tests, regardless of who conducts the tests. Therefore, the mfr may rely on the recommendation of the contract laboratory in selecting an appropriate test or examination. Compendia reference stds do not require characterization Non-compendia reference stds should be of the highest purity that can be obtained by reasonable effort and should be thoroughly characterized to ensure their identity, purity, quality, and strength. Firms should establish appropriately characterized in-house materials prepared from representative lots if no compendia reference std exists. For organoleptic examinations, an authenticated plant reference material would be a material that has been authenticated as the correct plant species and correct plant part(s) by a qualified plant taxonomist (preamble pg 34893) For microscopic and chemical tests (including calibration tests), a reference material is a highly purified compound that is well characterized (preamble pg 34893) Reference stds should be appropriate to the assay procedure for which they are used.

11. 10/10/2011 11 Verify that the laboratory examination and testing methodologies are appropriate for their intended use. (May rely on the judgment of a qualified person at a contract lab. Must be documented) Identify and use an appropriate scientifically valid method for each established specification for which testing or examination is required to determine whether the specification is met. Production and Process Controls Requirements for Batch Laboratory Operations - Subpart J  Requirements That Apply to Laboratory Methods for Testing and Examination §111.320 To verify lab exam and test methods are appropriate, firm may rely on the judgment of a qualified person at a contract lab to satisfy the requirements of 111.320(a) To verify lab exam and test methods are appropriate, firm may rely on the judgment of a qualified person at a contract lab to satisfy the requirements of 111.320(a)

12. 10/10/2011 12 Production and Process Controls Requirements for Batch Laboratory Operations - Subpart J Requirements That Apply to Laboratory Methods for Testing and Examination §111.320 Scientifically Valid Method Consistently does what it is intended to do available validated tests and examinations USP AOAC International methods National formulary Note: there is no legal compendial relationship for dietary supplement methods. However, USP, AOAC etc methods are collaboratively validated. May be based on scientific data or results published in scientific journals, references, text books A scientifically valid method is one that is accurate, precise, and specific for its intended purpose. It consistently does what it is intended to do Methods that are based on scientific data or results published in, for example, scientific journals, references, text books, or proprietary research can be scientifically valid even if they are not formally “validated” FDA recommends that a firm use tests and examinations that already have been validated when such tests are available. For example, AOAC International methods are validated in collaborative studies using several laboratories under identical conditions and are often cited as “official validated methods”. If a firm modifies an officially validated method, they should document the reason for the modification and have data to show the modified method produces results that are at least as accurate and reliable as the established method for the material being tested. FDA recommends that firms have complete records of any testing and standardization of lab reference stds, reagents, and std solutions that they use in their laboratory operations. A scientifically valid method is one that is accurate, precise, and specific for its intended purpose. It consistently does what it is intended to do Methods that are based on scientific data or results published in, for example, scientific journals, references, text books, or proprietary research can be scientifically valid even if they are not formally “validated” FDA recommends that a firm use tests and examinations that already have been validated when such tests are available. For example, AOAC International methods are validated in collaborative studies using several laboratories under identical conditions and are often cited as “official validated methods”. If a firm modifies an officially validated method, they should document the reason for the modification and have data to show the modified method produces results that are at least as accurate and reliable as the established method for the material being tested. FDA recommends that firms have complete records of any testing and standardization of lab reference stds, reagents, and std solutions that they use in their laboratory operations.

13. 10/10/2011 13 What type of enforcement action will happen to a manufacturer if they do not follow the CGMPs? When a violation of the law or a regulation arises, FDA can take a number of actions to protect the public The agency may initially work with the product's marketer to correct the problem voluntarily. If that fails, the agency may bring a lawsuit to seize any product and/or enjoin the firm marketing it. When warranted, FDA also seeks criminal penalties – including prison sentences – against parties who break the law. FDA would weigh what action would be appropriate on a case-by-case basis, based on the particular facts and circumstances.

14. 10/10/2011 14 Training FDA had a public rollout of the rule in June of 2007 October 2007: FDA held a 3 hour satellite downlink/webcast for stakeholders to introduce the rule May 2008: FDA held training for Investigators, compliance officers and supervisors Training for State and counterpart Regulators (leverage of inspections) 2009 2 additional sessions for FDA investigators, compliance officers and supervisors 2009

15. 10/10/2011 15 What should global suppliers of dietary ingredients in light of the new DS cGMP regulations? Suppliers need to be “qualified” in order for certificates of analysis to be used by a DS manufacturer. The COA can then be used for determination of the specifications for the product including heavy metals, pesticides, micro, and toxin levels. DS manufacturers must do 100% identity testing. Certificates of analysis cannot be used to meet the 100% identity testing requirements. The DS ingredient supplier should work with the Ds manufacturer to develop appropriate specification for the ingredient. The ingredient supplier is also in the best position to identify a valid and scientifically supported identity test/tests for the ingredient.

16. 10/10/2011 16 Heavy Metal Quality of Dietary Supplements FDA’s DS GMP does not specify limits for heavy metal concentrations in dietary supplements or dietary supplement ingredients. Dietary supplement products vary dramatically in the types of ingredients and the daily serving sizes recommended and are not amenable to a single heavy metal limit. The onus is on the manufacturer to establish specifications for incoming raw ingredients to assure the final product is safe under the recommended conditions of use.

17. 10/10/2011 17 Establishing Heavy Metal Specifications for Dietary Supplements Based on an understanding of the achievable heavy metal content for each raw ingredient in a dietary supplement, the manufacturer must work with their ingredient suppliers to decide how much of each ingredient can be used in the final product so the DS is safe under the labeled conditions of use. Establishing heavy metal specifications for herbal products is especially hard because of the huge variability of environmental levels of heavy metals, variability in growing conditions, and sequestration.

18. 10/10/2011 18 Establishing Heavy Metal Specifications for Dietary Supplements (cont.) The manufacturer is expected to use authoritative sources to determine what is a safe level of exposure for each heavy metal. FDA PTTIL, EPA Integrated Risk Information System (IRIS), government authoritative reviews ( EFSA, WHO, EMEA, Codex Alimenterius, etc.) Raw ingredient specifications are assured through testing of each lot of incoming raw ingredient. A certificate of analysis (COA) can be used if the supplier has been “qualified” and had periodic confirmation. Final product heavy metal specifications is confirmed through testing of each batch of final product or a subset of finished dietary supplement batches based a sound statistical sampling plan

19. 10/10/2011 19 Dietary Supplement and Nonprescription Drug Consumer Protection Act Starting December 22, 2007 any serious adverse events reported to a manufacture must be reported to FDA through MedWatch 15 business days after the report is received Any new medical information must be reported to FDA within 1 year of the initial report and firms are required to maintain records of AERs for six years. Serious AERs are defined as death, a life threatening experience, in patient hospitalization, persistent or significant disability or incapacity, congenital abnormality or birth defect, or requires, based on reasonable medical judgment, a medical or surgical intervention to prevent an outcome described under one of the above examples

20. 10/10/2011 20 AER Status FDA is receiving substantially more AER reports since the implementation of the DS mandatory AER reporting act. The majority of the additional reports are mandatory 3500A reports. Little change seen in the number of voluntary reports submitted FDA is working towards placing all the AER reports online to provide easy public access

21. 10/10/2011 21 Number of voluntary and mandatory Dietary Supplement AER Reports for 2008

22. 10/10/2011 22 Economically Motivated Adulteration (EMA). FDA held a public meeting pertaining to economically motivated adulteration (EMA) on May 1, 2009. The purpose of the meeting was to stimulate and focus a discussion about ways in which industries and regulatory agencies can better predict and prevent economically motivated adulteration. FDA requested interested parties to submit oral and written comments at the meeting or to the public docket.

23. 10/10/2011 23 Economically Motivated Adulteration (EMA). Melamine: In March of 2007, FDA first received reports of kidney failure among cats and dogs and identified melamine contamination of certain brands of pet food as the causative agent. FDA received approximately 18,000 reports of sick pets. Oversulfated chondroitin sulfate (OSCS) in Heparin : January 2008, FDA received reports of U.S. cases of adverse reactions in pediatric dialysis patients. Investigations indicated that the adverse events appeared to be associated with heparin contaminated with oversulfated chondroitin sulfate (OSCS).

24. 10/10/2011 24 Economically Motivated Adulteration (EMA). Adulteration of glycerin, by diethylene glycol (DEG) has resulted in several mass poisonings around the world in the past two decades. Melamine in infant formula: In September 2008, FDA issued a Health Information Advisory in response to reports of melamine contaminated milk-based infant formula manufactured in China. Melamine was apparently added to diluted milk in order to increase measured nitrogen levels (indicators of protein content) and thereby enhance its perceived quality.