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NIA West Fall meeting, Los Angeles, CA October 24, 2014
Daniel Fabricant, Ph.D., CEO & Executive Director
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Distributors responsibility before and after the sale
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� Subpart M--Holding and Distributing � § 111.453 - What are the requirements under this subpart for M written procedures? � § 111.455 - What requirements apply to holding components, dietary supplements, packaging, and labels? � § 111.460 - What requirements apply to holding in-process material? � § 111.465 - What requirements apply to holding reserve samples of dietary supplements? � § 111.470 - What requirements apply to distributing dietary supplements? � § 111.475 - Under this subpart M, what records must you make and keep?
� Subpart N--Returned Dietary Supplements � § 111.503 - What are the requirements under this subpart N for written procedures? � § 111.510 - What requirements apply when a returned dietary supplement is received? � § 111.515 - When must a returned dietary supplement be destroyed, or otherwise suitably disposed of? � § 111.520 - When may a returned dietary supplement be salvaged? � § 111.525 - What requirements apply to a returned dietary supplement that quality control personnel approve for reprocessing? � § 111.530 - When must an investigation be conducted of your manufacturing processes and other batches? � § 111.535 - Under this subpart N, what records must you make and keep?
� Subpart O--Product Complaints � § 111.553 - What are the requirements under this subpart O for written procedures? � § 111.560 - What requirements apply to the review and investigation of a product complaint? � § 111.570 - Under this subpart O, what records must you make and keep?
� Subpart P--Records and Recordkeeping � § 111.605 - What requirements apply to the records that you make and keep? � § 111.610 - What records must be made available to FDA?
Distributors
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� cGMPs � Labeling/AERs
Own Label Concepts
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� Many different models – focus less here � What operations are being performed (or directed/
controlled) – focus more here � What authority does FDA have? � What has the agency done? � What evidence and exhibits are needed to
demonstrate compliance
Own-Label Distributors Are Responsible for cGMP Compliance
• ULTIMATE RESPONSIBILITY
• HOW DOES A FIRM DEMONSTRATE THIS OBLIGATION?
The Basics
� You must comply with the cGMP requirements that apply to your operations related to the manufacture, packaging, labeling and holding of dietary supplements (72 FR 34752 at 34790)
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The Basics
� In cases where a distributor contracts with a manufacturer to manufacture a dietary supplement that the distributor then distributes under its own label, the distributor has an obligation to know what and how manufacturing activities are performed so that the distributor can make decisions related to whether the packaged and labeled product conforms to its established specification and whether to approve and release the product for distribution. (72 FR 34752 at 34790)
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From the Preamble Federal Register Vol. 72, No. 121; Monday, June 25, 2007 p. 34790
We stated under proposed part 111 you would need to comply with those regulations directly applicable to the operations that you perform and provided examples (id.). All activities may not be performed by the same person. For example, a manufacturer may contract with another firm to package and label the dietary supplement in the containers used for distribution to consumers.
Alternatively, a distributor may contract with one firm to manufacture a dietary supplement, and another firm to package and label the dietary supplement that the distributor ultimately distributes under its own name.
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From the Preamble
� Under this final rule, you must comply with the CGMP requirements that apply to your operations related to the manufacture, packaging, labeling, and holding of dietary supplements. It is not practical to list all possible contractual relationships that persons may enter into in the manufacture of a dietary supplement, or to list all businesses or practices that may be subject to the requirements of this final rule in order for persons to know whether they are subject to requirements of this final rule.
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From the Preamble
� In cases where a distributor contracts with a manufacturer to manufacture a dietary supplement that the distributor then distributes under its own label, the distributor has an obligation to know what and how manufacturing activities are performed so that the distributor can make decisions related to whether the packaged and labeled product conforms to its established specifications and whether to approve and release the product for distribution.
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Three Legged Stool
• CONTRACT
• AUDIT
• PRODUCT TESTING
Contract
• ALLOCATED RESPONSIBILITIES • DETAILED • CONTRACT MANUFACTURERS ARE EXPERTS VS. OWN LABEL DISTRIBUTOR IS EXPERT
Contract – Quality Agreement
TESTING SHOULD L IKELY BE PERFORMED ON EACH F IN ISHED BATCH OF THE D IETARY SUPPLEMENT PRODUCED FOR IDENTITY, PURITY, STRENGTH, COMPOSIT ION AND KNOWN OR EXPECTED CONTAMINATION BEFORE RELEASING THE PRODUCT TO BUYER. THESE TESTS SHOULD BE AOAC OFFIC IAL METHODS WHEN THESE ARE AVAILABLE, COMPENDIAL METHODS OR COMPARABLE SCIENTIF ICALLY VALID AND DOCUMENTED ANALYTICAL METHODS. EACH LOT OF PACKAGED F IN ISHED PRODUCT SHOULD BE TESTED FOR MICROBIOLOGICAL ACTIV ITY.
Contract – Quality Agreement
THE CERTIFICATES OF ANALYSIS THAT ACCOMPANY THE FINISHED PRODUCT SHALL REFLECT THE ACTUAL RESULTS OF VALID ANALYTICAL TESTING. A CERTIFICATE OF ANALYSIS THAT INCLUDES “BY INPUT” IS NOT ACCEPTABLE, UNLESS THERE IS NO AVAILABLE ANALYTICAL METHODOLOGY.
Contract – Quality Agreement
VENDOR WILL IDENTIFY THE SUPPLIER OF ALL MATERIALS THAT ARE INCORPORATED INTO THE MERCHANDISE, INCLUDING BUT NOT LIMITED TO THE RAW MATERIAL SPECIFICATIONS, COUNTRY OF ORIGIN AND THE ADDRESS OF THE PLANT WITHIN SUCH COUNTRY FROM WHICH THE RAW INGREDIENTS ARE SOURCED, AND SHALL PROVIDE NOTICE TO BUYER OF ANY PROPOSED CHANGE TO ANY SUCH SUPPLIER AND/OR PLANT .
Contract – Quality Agreement
BUYER WILL BE ALLOWED TO CONDUCT ANNOUNCED AND UNANNOUNCED ON-SITE AUDITS. VENDOR WILL BE EXPECTED TO COOPERATE WITH BUYER’S EFFORTS IN THIS AREA, INCLUDING RESPONDING AND RESOLVING IDENTIFIED CORRECTIVE ACTIONS.
Audit
Maj MinPersonnel 111.10-111.14Physical Plant & Grounds 111.15-111.23Equipment & Untensils 111.25-111.35Production System / Specifications 111.55-111.95Quality Control Requirements 111.103-111.140Component Handling 111.153-111.180Manufacturing Batch Records 111.205 - 111.260QC Laboratory Requirements 111.303 - 111.325Manufacturing Requirements 111.353 - 111.375Packaging & Labeling Requirements 111.403 - 111.430Holding & Distribution 111.453 - 111.475Dietary Supplement Returns 111.503 - 111.535Product Complaints 111.553 - 111.570Records & Record Keeping 111.605 - 111.610OtherTotal Score: 0 0Grand Total: 100
Areas CoveredFindings
21 CFR 111Description of Finding
Opportunities for Improvement
Situational Aspects
� What’s unique to each case? � Are other operations being performed and who is
performing them?
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Who has the ultimate responsibility?
� Think Prohibited Acts
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Inspectional
� Determine who is setting or establishing specifications (both finished and raws) ¡ Who is purchasing raw materials? ¡ Or components? ¡ Who is involved in such decisions?
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Inspectional
� Determine who is setting or establishing specifications ¡ If purchased from a contract mfd or filler is it a “menu” item or is
there more involved direction from the distributor? ¡ What documents speak to the relationships and the degree of
control or direction going between parties? (contracts, agreements, emails, affidavits, catalogues, purchase orders)
¡ Don’t forget labeling specs! (Who established? How?, etc.)
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Inspectional
� Conformance to specifications ¡ Becoming a literal “who done it” ¡ These documents are critical (MMRs, MBRs, testing data) ¡ If firms don’t or claim that they can’t have access to data or
documents (MMRs, MBRs) in a reasonable time frame, are their documents that speak to why that would be the case?
¡ Involvement of “other” third parties (labs, etc.)
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Inspectional
� Client and Distribution Lists ¡ Upwards (Supply Chain) ¡ Downwards (Dist. Chain)
� Makes a compelling reason to inspect Contract Mfd.
� Obtain Labels, Labeling and Website information � Many of these models have “shells”
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Inspectional
� Affidavits – “refresh someone’s memory” � Other items (may not be obligated, but will be
informative) ¡ Who handles AERs and product complaints? ¡ Who trends and tracks product complaints? ¡ Any sort of qualification program in place?
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Private Label Retailer Responsibility
� Private Label ¡ Growth Industry with margin once enjoyed exclusively by national
brand ¡ Past: carried stigma of inferior quality, lower cost, less trust among
consumers) ¡ Evolved from generic product offerings (stigma) to niche proprietary
brand ¡ Retailers in unique position to understand consumer needs/demands
÷ New market branding possibilities and visibility ÷ Local branding can draw in consumers to build trust/brand loyalty
¡ Can exert control over product’s ingredients ¡ Direct CMs to make products according to retailer’s specifications
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Private Label Retailer Checklist: Setting Specifications
� What is the operation? Control & Direction ¡ Do you direct CM as to ingredients used in the formulation? ¡ How were the ingredients for the private label developed ¡ Do you set ingredients specs for the private label CM ¡ Do you set label specs? ¡ Do you exert any control or direction in an email or phone
call to the CM?
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� Handing a National Brand to the CM to replicate their ingredients/serving level is setting specs
Private Label Retailer Checklist: Interstate Commerce
� Do you perform an interstate distribution operation? � Even if distribution within the state, interstate commerce may still apply � Interstate Commerce
¡ Not just shipping the finished product with a technical adulteration (failure in cGMPs) ¡ Components used to make the product can be used as the basis for applying
interstate commerce
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Private Label Retailer Checklist: Warehouse/Storage
� Do you perform any labeling/packaging operations? � Do you operate a warehouse or storage facility that holds DS prior
to their distribution to the retail establishment? � How do you identify each unique lot within each unique shipment
that allows you to trace the lot to the supplier, date received, nameof the packaging/label, status of the packaging and label, and to the DS distributed?
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Private Label Retailers: GMP Responsibilities
� Depends on your operations: QC Operations, Holding/Distribution q Identifying QC personnel responsibility q Procedures for conducting Material review q Approving for release or rejecting any packaged and labeled DS (including re-packaged or re-labeled DS) for
distribution q Written procedures for approval and release by QC q Holding operations q SOP for product distribution q Ensuring DS packaged/labeled as specified in MMR q Prepare/follow MMR for each unique formulation of DS q Ensure uniformity in finished batch for each batch size
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Private Label Retailers: GMP Responsibilities
� Depends on your operations: Product Complaints q Specification Responsibilities to ensure product received is adequately identified and
consistent with purchase order q Establish specs for any point, step, or stage where control is necessary to ensure quality q Establish specs for each component use din the manufacture of the DS product q Written procedures for handling of product complaints, documentation of the findings of
an investigation and follow up q Written procedures on how to investigate complaints
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Private Label Retailers: GMP Responsibilities
� Depends on your operations: Returned DS
q Identifying the responsible person in the organization for receiving product complaints and AERs q Verifying that a domestic address/domestic telephone # is provided on the label q Procedures on how product complaints/AERs are triaged q Documenting medical training for handling product complaint calls/letters q Written procedures for how to classify complaints as serious and non-serious q Written procedures on how/when product complaints will be filed to FDA q Procedures on how QC personnel will be involved in the review/approval process
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Private Label Retailers: GMP Responsibilities
� Depends on your operations: Returned DS
q Making/keeping written procedures for handling returned DS, when returned DS may be salvaged, suitably disposed of or destroyed
q Documenting the person responsible for temp/humidity record keeping q Identifying/quarantining returned DS until QC personnel conduct a material review for disposition q Establishing written procedures for making/keeping records for material review and disposition decision on a
returned DS, results of testing or examination conducted to determine compliance with product specs q Documentation of any DS that is reprocessed q Determination by QC whether reprocessed DS meets product specs
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Private Label Retailers: GMP Responsibilities
� Depends on your operations: Lab Operations q Written agreements with contract lab performing laboratory operation q Verification that the laboratory examination and testing methodologies are appropriate for their intended use q Establishing criteria for selecting standard reference materials q Establishing criteria for selecting appropriate examinations and testing methods q Using test methods and examinations in accordance with established criteria q Demonstrating with science that the lab examination and testing methodologies are appropriate for their
intended use q Documentation from the contract lab that lab methodology was followed q Documentation for laboratory tests and examinations (you must have the results of the testing and examination
in your possession even if a 3rd party performed testing
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Private Label Retailers: GMP Responsibilities
� Depends on your operations: Reserve Samples
q Holding reserve samples under conditions consistent with product labels or under ordinary storage conditions
q Retaining reserve samples for one year past the shelf life date or for two years from the date of distribution of the last batch of DS associated with the reserve sample
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Product Testing
• CONDUCTED AT OUTSIDE INDEPENDENT LAB • PROFICIENCY TEST • RANDOM SAMPLE • METHODS AGREED UPON/DOCUMENTED IN ADVANCE • AUDITED CONTRACT LAB • RESULT INCORPORATED IN SCORECARD OR THE LIKE?
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� http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm404451.htm � Your firm failed to conduct at least one appropriate test or examination to verify the identity of a
component that is a dietary ingredient, prior to its use, as required by 21 CFR 111.75(a)(1)(i) (except in situations where a firm successfully petitions FDA for an exemption from this requirement, pursuant to 21 CFR 111.75(a)(1)(ii)). Specifically, your quality control personnel did not review and approve the results of identity tests conducted by a contract laboratory on dietary ingredient components prior to their use in the manufacture of dietary supplements: (b)(4) powder, lot (b)(4), was used in the manufacture of (b)(4) lot (b)(4), from 03/24/13-03/27/13. However, the identity test results from the contract laboratory were not received until 04/09/13. Your firm used the raw material despite it being only a 41.0% match to your contract laboratory's standard. (b)(4) extract, lot (b)(4), was used in the manufacture of (b)(4) dietary supplement, lot (b)(4), from 03/13/13- 04/15/13. However, the identity test results from the contract laboratory were not received until 04/23/13.
� We have reviewed your response letter, dated May 17, 2013, and have determined your response to be inadequate. You state that you commit to retroactively reviewing and notating on the batch production record acceptance of the identity tests conducted by your contract laboratory for certain products that have already been manufactured. You also state that in the future you intend to comply with 21 CFR 111.75, and that “[i]f any identity test is missing [you] intend to request that test document before using the ingredient or send a sample of the ingredient to [your] test laboratory.” To the extent that your response indicates a plan to rely on a certificate of analysis to verify the identity of your dietary ingredients, please note that such reliance on a certificate of analysis is not permitted under 21 CFR 111.75(a)(1)(i). We would also like to emphasize that review and approval of identity tests of incoming dietary ingredients has to be completed prior to their use in the manufacture of dietary supplements, and not retroactively
Pinnacle Labs
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� The U.S. Food and Drug Administration (FDA) inspected your manufacturing facility, located at 705 McGee St., Kansas City, Missouri, on May 8 through May 15, 2014. During the inspection, our investigators collected labeling for several of your products, which Vitalab Co., Inc. (Vitalab) manufactures, repacks, and labels as dietary supplements for sale by three distributors: V.E. Irons, Inc., Springreen Products, Inc., and Sonne's Organic Foods, Inc. According to statements you made during a telephone call with our investigators, you own the three distributor companies in addition to Vitalab, and all four companies are run as a single enterprise.
Vitalab Co 10/16/2014
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� Even if your MEZOTRACE® Calcium/Magnesium Natural Minerals & Trace Elements, Calcium/Magnesium Natural Minerals & Trace Elements with Vitamin D, and Calcium/Magnesium Powdered Natural Minerals & Trace Elements dietary suplements did not have therapeutic claims which make them unapproved new and misbranded drugs, these products are adulterated dietary supplements within the meaning of section 402(g)(1) of the Act [21 U.S.C. § 342(g)(1)] because the products have been prepared, packed, or held under conditions that do not meet the CGMP regulations for dietary supplements.
� As a distributor that contracts with other manufacturers to manufacture dietary supplements that your firm releases for distribution under your firm’s name, your firm has an obligation to know what and how these activities are performed so that you can make decisions related to whether the products conform to established specifications and whether to approve and release the products for distribution [72 Fed. Reg. 34752, 34790 (June 25, 2007)]. Your firm introduces or delivers, or causes the introduction or delivery, of dietary supplements into interstate commerce for distribution to consumers. As such, your firm has an overarching and ultimate responsibility to ensure that all phases of the production of that product are in compliance with dietary supplement CGMP requirements.
Mezotrace WL
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� Although your firm may contract out certain dietary supplement manufacturing operations, it cannot, by the same token, contract out its ultimate responsibility to ensure that the dietary supplement it places into commerce (or causes to be placed into commerce) is not adulterated for failure to comply with dietary supplement CGMP requirements (see United States v. Dotterweich, 320 U.S. 277, 284 (1943) (explaining that an offense can be committed under the Act by anyone who has “a responsible share in the furtherance of the transaction which the statute outlaws”); United States v. Park, 421 U.S. 658, 672 (1975) (holding that criminal liability under the Act does not turn on awareness of wrongdoing, and that “agents vested with the responsibility, and power commensurate with that responsibility, to devise whatever measures are necessary to ensure compliance with the Act” can be held accountable for violations of the Act). In particular, the Act prohibits a person from introducing or delivering for introduction, or causing the delivery or introduction, into interstate commerce a dietary supplement that is adulterated under section 402(g) for failure to comply with dietary supplement CGMP requirements [see 21 U.S.C. §§ 342(g) and 331(a)]. Thus, a firm that contracts with other firms to conduct dietary supplement manufacturing, packaging, and labeling operations is ultimately responsible for ensuring that the product complies with the dietary supplement CGMP requirements, regardless of who actually performs the dietary supplement CGMP operations.
Mezotrace WL
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� You failed to establish and follow written procedures to fulfill the requirements related to product complaints, as required by 21 CFR 111.553. Specifically, you did not have written procedures for reviewing and investigating product complaints received. Additionally, you did not keep written records of product complaints related to good manufacturing practice received by your firm associated with your Mr. Energy 8-HR Energy pill, as required by 21 CFR 111.570(b)(2). Moreover, you informed our investigator that you did not review and investigate the product complaint you received from a women experiencing vomiting after taking your product, Mr. Energy 8-HR Energy Pill, on an unknown date, as required by 21 CFR 111.560(a).
� Your product complaint procedures must specify that a qualified person review and investigate any product complaint that involves the possible failure of a dietary supplement to meet any of its specifications, or any other requirement of 21 CFR Part 111 (see 21 CFR 111.560(a)), quality control personnel review and approve decisions about whether to investigate a product complaint and review and approve the findings and follow up action of any investigation performed (see 21 CFR 111.560(b), and the review and investigation of the product complaint must extend to all relevant batches and records (see 21 CFR 111.560(c)).
� We have reviewed your response dated August 21, 2013, which states that you have now established written procedures for requirements to review and investigate product complaints. However, we find your response inadequate in that you have not established your firm’s own procedures to address product complaints associated with your products nor have you established procedures to investigate those complaints. You simply provided a written recitation of the requirements of 21 CFR 111.560 and 111.570, rather than establishing written procedures to fulfill these requirements.
Bhelliom WL - 8/1/2014
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� However, you informed our investigator that you do not have a designated quality control employee, do not have designated procedures describing their responsibilities, and have not established procedures for ensuring the quality of dietary supplements received from your contract manufacturer(s) to ensure the quality of the dietary supplements you distribute or that they are packaged and labeled according to the master manufacturing record of your contract manufacturer(s).
� We have reviewed your response dated August 21, 2013, which includes “Procedures for Qualification of Contract Manufacturers” and states that additional written quality control procedures have been added to specifically require inspection of incoming contract manufactured dietary supplements and components for quality control. However, you did not provide FDA with any documentation of such written quality control procedures. Therefore, we cannot determine the adequacy of your proposed corrective action at this time.
� 3. You failed to establish specifications for your dietary supplement products, as required by 21 CFR 111.70. Specifically: � •You failed to establish specifications for dietary supplement labels (labeling specifications) as required by 21 CFR 111.70(d).
Specifically, you failed to establish labeling specifications for your Growth RX HGH Enhancer dietary supplement product, Lot #2070576, and your Thermolene Body Sculptor dietary supplement product, Lot #111299.
� •You failed to establish specifications to provide sufficient assurance that products you receive from a supplier, for packaging or labeling and distribution as dietary supplements, are adequately identified and are consistent with your purchase order, as required by 21 CFR 111.70(f).
� •You failed to establish specifications for the labeling of the finished labeled dietary supplements, including specifications that ensure that you applied the specified label, as required by 21 CFR 111.70(g). Specifically, you have no written specifications with which to compare your finished products after you have applied labels to containers of your Growth RX HGH Enhancer and Thermolene Body Sculptor dietary supplement products.
� We also note that once you have established the above specifications, you must determine whether the specifications have been met, as required by 21 CFR 111.73.
� We have reviewed your response dated August 21, 2013. We find your response inadequate. Although you have created some verification procedures and specifications for receipt of some for your dietary supplements, you have not provided documentation showing that you have established labeling specifications for your dietary supplement products, as required by 21 CFR 111.70(d) and 21 CFR 111.70(g). Therefore, we are unable to verify the adequacy of your proposed corrective actions at this time.
Bheliom WL
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� You failed to establish and follow written procedures for the responsibility of quality control operations, including written procedures for conducting a material review and making a disposition decision, as required by 21 CFR 111.103 and 21 CFR 111.140(b)(1). Your quality control personnel must approve for release, or reject, any packaged and labeled dietary supplement (including a repackaged or relabeled dietary supplement) for distribution, as required by 21 CFR 111.127(h).
� As a distributor that contracts with other manufacturers to manufacture, package, or
label dietary supplements that your firm releases for distribution under your firm’s name, your firm has an obligation to know what and how these activities are performed so that you can make decisions related to whether your dietary supplement products conform to established specifications and whether to approve and release the products for distribution [72 Fed. Reg. 34752, 34790 (Jun. 25, 2007)]. Your firm introduces or delivers, or causes the introduction or delivery, of dietary supplements into interstate commerce in their final form for distribution to consumers. As such, your firm has an overarching and ultimate responsibility to ensure that all phases of the production of those products are in compliance with dietary supplement CGMP requirements.
Bheliom WL 8/1/14
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� Although your firm may contract out certain dietary supplement manufacturing operations, it cannot, by the same token, contract out its ultimate responsibility to ensure that the dietary supplement it places into commerce (or causes to be placed into commerce) is not adulterated for failure to comply with dietary supplement CGMP requirements (see United States v. Dotterweich, 320 U.S. 277, 284 (1943) (explaining that an offense can be committed under the Act by anyone who has “a responsible share in the furtherance of the transaction which the statute outlaws”); United States v. Park, 421 U.S. 658, 672 (1975) (holding that criminal liability under the FD&C Act does not turn on awareness of wrongdoing, and that “agents vested with the responsibility, and power commensurate with that responsibility, to devise whatever measures are necessary to ensure compliance with the Act” can be held accountable for violations of the FD&C Act)). In particular, the Act prohibits a person from introducing or delivering for introduction, or causing the delivery or introduction, into interstate commerce a dietary supplement that is adulterated under section 402(g) for failure to comply with dietary supplement CGMP requirements (see 21 U.S.C. §§ 342(g) and 331(a)). Thus, a firm that enters into a contract with other firms to conduct certain dietary supplement manufacturing, packaging, and labeling operations for it is responsible for ensuring that the product is not adulterated for failure to comply with dietary supplement CGMP requirements, regardless of who actually performs the dietary supplement CGMP operations.
� You must also establish a system of production and process controls to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record (21 CFR 111.55). You must establish and follow written procedures for the responsibilities of the quality control operations (21 CFR 111.103). The quality control personnel must ensure that your manufacturing, packaging, labeling, and holding operations ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record (21 CFR 111.105). Further, you must have documentation of the quality control personnel review and approval for release of any packaged and labeled dietary supplement (21 CFR 111.127(h) and 111.140(b)(2)).
Bheliom WL 8/1/14
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403(y) Compliance
Labeling 101
Intervening Material
Statement of Identity
Net Quantity of Content Serving Size – Maximum
Ordering of ingredients (b2 vs. b3)
DI nomenclature and units
Inner and Outer Packaging
Nutrition Information
Use of “Fresh”
Breathable/Inhalation/Nasal spray/Sublingual
Labeling for Bulk DIs
Export Labeling
Claims (fortified, antioxidant, nutrient content, structure fxn, dz claims
Labeling 101
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21 CFR 101.3
21 CFR 101.2(e)
21 CFR 101.5
21 CFR 101.9(b), 101.12(b) (Table 2)
21 CFR 101.4
21 CFR 101.9(c)(8)(iv)
21 CFR 101.15(c)
21 CFR 101.36
21 CFR 101.54
21 CFR 101.93
21 CFR 101.95
21 CFR 101.100
21 CFR 101.105
21 CFR 101.17(e)
21 CFR 189.5
Labeling 101
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� Expiration dating � Part 11 Compliance � Social Media � Adverse event reporting
¡ Records ¡ Communication ¡ Tracking and Trending ¡ Four basic criteria: an identifiable patient; an identifiable
reporter; a specific product; and a symptom or effect
Other thoughts
Take Away
• O W N L A B E L D I S T R I B U TO R S A R E U LT I M AT E LY R E S P O N S I B L E F O R G M P C O M P L I A N C E O N S O M E L E V E L
• F I R M S M U S T B E A B L E TO D E M O N S T R AT E H O W T H E Y K N O W T H AT M A N U FA C T U R I N G A C T I V I T I E S A R E B E I N G P E R F O R M E D I N A G M P C O M P L I A N T M A N N E R
• C L A R I T Y W I T H PA R T N E R S S P E C I F I E D I N A G R E E M E N T S A N D C O N T R A C T S
• T H I N K C O N T R O L A N D D I R E C T I O N
DS GMP Overview 2008-2013 v 285 Dietary Supplement Warning Letters Issued
for GMP Inspections (2008-2013) v 675 domestic DS inspections in FY 2014 v 88 Foreign Inspections in 2014 v 2,752 domestic DS inspections since GMP Final
Rule v 150+ foreign DS inspections since GMP Final Rule
Enforcement Overview and GMP Metrics
2014 major regulatory actions
� BioAnue Injunction for Claims and cGMPs ¡ http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm411390.htm
� Triceutical cGMP Injunction ¡ http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm404417.htm
� Mira Health Injunction ¡ http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm403845.htm
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Metrics
Enforcement Overview and GMP Metrics
DS NC OAI VAI NAI FY 2007 0 FY 2008 158 41.1% 15.2% 25.9% 58.9% FY 2009 162 43.2% 14.8% 28.4% 56.8% FY 2010 228 61.4% 25.4% 36.0% 38.6% FY 2011 353 75.0% 36.8% 38.2% 30.6% FY 2012 591 63.8% 27.9% 35.9% 34.5% FY 2013 585 69.4% 28.0% 41.4% 30.6% FY 2014(qtr1) [675](140) (72.1%)(34.3%) (37.8%) (27.9%)
FY 2012 – Actions for PAC 21008/21008A
Totals: Warning Letter 91 Untitled Letter 6 Regulatory Meeting 6
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FY 2011 – Actions for PAC 21008/21008A
Totals: Warning Letter 73 Untitled Letter 14 Regulatory Meeting 12
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FY 2010 – Actions for PAC 21008 & 21008A
Totals: Warning Letter 28 Untitled Letter 3 Regulatory Meeting 2
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DS GMPs 2009-2012
Ins NC RM UL WL SZ INJ ResR
� FY 2009 162 43.2% 1 1 9 0 1 50.0% � FY 2010 228 61.4% 2 3 28 0 2 60.3% � FY 2011 353 75.0% 12 14 73 3 5 82.3% � FY 2012 591 63.8% 6 6 91 1 7 67.3%
Net Effect from Increased Inspections?
Are DS More Regulated?
Interven;on Ini;ated (3 yr roll out of GMP Final Rule)
Volume
Time
A B
Source: Malcolm K. Sparrow. The Character of Harms: Opera&onal Challenges in Control. Cambridge Univ Press. 2008
Are we at slope “A” or “B” in terms of GMP Compliance?
Net Effect from Increased Inspections?
Regulatory Actions Moving the Needle
v How do you know if you are at slope “A” or slope “B”? v Is the Agency s;ll seeing firms with no GMPs?
v (no GMPs = Not even establishing specifica;ons to the kitchen sink) v What are the top 10 or so GMP charges and are they changing? v In the early days … no GMPs (establishing specs -‐-‐ 111.70) v Where is that charge today? v Agency is wri;ng more Warning Leeers v Agency Response Rate or “Efficiency Rate” is going down over the past few years v For every VAI or OAI, an Agency ac;on has not been taken
What Can We Say for DS GMP Regulation?
Are DS More Regulated?
v slope “B” represents the firms having no GMPs in place? v slope “A” represents the firms with deficiencies noted on inspec;ons but have some
GMPs in place (have not implemented all of part 111) v Why is the Response Rate not 100%?
q Fewer “easy” cases where no GMPs in place (quick turnaround by FDA) q Second layer cut on the GMPs (those with GMPs in place but lack full
implementa;on) q You may need two or more inspec;ons of a firm for a Warning Leeer
ü More cases where the Agency needs more ;me to agree on what to charge ü More cases that require addi;onal evidence collec;on to support the
charge? ü Evidence considered “stale” aker 6 months … strains resources of the Field
q In the ;me the Agency has been evalua;ng the case evidence, the firm came into compliance, obvia;ng the need to send a Warning Leeer
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Ø What Makes the Warning Letter
Top 10 Violations
111.70(a)(1) – Failure to Establish Iden;ty Specifica;on
Identity Testing of Dietary Ingredients
What is the FDA finding? ¡ No testing performed
÷ No idea of what ingredient is actually used. Could result in product mix-up and hazard to health. ÷ Several firms rely only on the identity stated by the supplier of the ingredient. ¢ FDA has no way of knowing what a firm is actually using. This is our only positive control on identity ¢ Firm: No actual knowledge of what is being bought and sold in manufactured product. ¢ Consumer: has no basis for confidence in the product being “what you see is what you get’
¡ Inadequate/lack of appropriate standards ÷ May have no standard of identity to establish what is being tested. ¢ One firm that uses an FT-NIR for identity with correlation to previous lots as the specification. 1st lot received is correlated
to “new” with no reference to a standard ¢ No one has any scientific basis to rely on this ID test ¢ Manufacturing firm has no way of detecting substitutions or ‘tampering’ with ingredient (s) ¢ Consumer has no way of knowing whether the label is correct. Faith in knowledge of manufacturer is incorrect.
¡ Inadequate records of testing performed to allow proper documentation of material, method used or results
÷ If no records are kept, what evidence is there that testing occurred, the method was adequate and the results were legitimate?
Didn’t establish finished product specifications/Didn’t verify that you meet specifications
¡ Not setting any specifications and/or verifying that specifications are met:
÷ Extreme of this observation is more common than expected. ¢ FDA needs assurance that components are used that meets some measure of quality before they are used in a firm’s product. ¢ Industry needs specifications to ensure the ingredients and components us ¢ Consumers need to be able to rely on product labels
¡ Specifications not set for contaminants based on product, history, country of origin or changes in science, technology or other findings
÷ Salmonella from milk products ÷ Sibutramine for weight loss or ÷ Sildenafil for male enhancement ingredients. ÷ Heavy metals/pesticides/microbiological specifications for field grown source components. ¢ FDA needs to look for records that firm is aware of potential adulterants in their products ¢ Industry needs to know that their ingredients, components and finished products are not adulterated. ¢ Consumers need to be able to rely on the manufacturers to protect them from adulterants.
¡ Rationale not documented why conformance to component and in-process specifications ensure adequate conformance to finished product specifications
÷ You are allowed to do skip lot and reduced testing, but a statistically based plan reviewed and approved by QC personnel must be used.
÷ Risk is always that non-conforming product enters the marketplace ¢ FDA needs evidence that firms are following rationale to reduce testing which ensures that products meet specifications ¢ Industry needs to assure themselves that the efforts they expend to analyze their products are sufficient to demonstrate
compliance with specifications ¢ Consumers need reassurance that the products contain what the label states.
