Inspections, Compliance, Enforcement, and Criminal Investigations

Exclusive Supplements, Inc. - Company Response Letter 3/10/14

EXCLUSIVE SUPPLEMENTS, INC.
3000 CASTEEL DRIVE-CORAOPOLIS-PENNSYLVANIA, 15108 • TOLL FREE: 866.429.2600 • TEL: 412.787.2770 • FAX: 412.787.6304
 

Anne Johnson
Acting District Director
Food and Drug Administration
PHILADELPHIA DISTRICT
900 U.S. Customhouse
2nd and Chestnut Streets
Philadelphia, PA 19106


Date: March 10th, 2014


Re: Response to the FDA-Warning Letter 14-PHI-03 received on February 3rd, 2014.
 

Dear Acting Director Johnson:


This is our response to the FDA-Warning Letter 14-PHI-03 that we received on Monday February 3rd, 2014. In this letter we will offer detailed responses to each observation and provide supporting documentation. Before we offer our detailed responses, we would like to provide some Insight into the work that we have already completed to address the deficiencies that were cited in the Form FDA 483 dated March 21st, 2013. We respectfully request that this response be posted online along with the Warning Letter.


The inspection in 2013 was the first FDA inspection of our facility. Since that time we have taken steps to correct the deficiencies cited in the Form FDA 483. As you will read, we have implemented improvements Standard Operating Procedures (SOPs) to address the calibration and complaint handling deficiencies and we have also concluded our investigation into the Certificate of Analysis issue regarding Androbolix Lot #C071185. Also, after the inspection, we enrolled our new Chief Operations Officer (COO) and Quality Control Manager (QCM) in the following NSF courses: 21 CFR 111 Dietary Supplement GMP Overview, Vendor Qualification & Audit Training, SOP & Record Keeping, and FDA Inspection Readiness. They also attended two (2) speaking presentations given by Dr. Fabricant, the Director, Division of Dietary Supplement Programs. We strive to be compliant with all FDA regulations and FDA Guidance Documents, so continued education and training of our personnel is an example of our commitment to quality and compliance to 21 CFR 111. We have included their certificates of attendance at these NSF cGMP courses for your review. [see APPENDIX A].


Furthermore, we have worked to address all of the deficiencies related to the Master Manufacture Records (MMRs) and product specifications. As part of these improvements, we are reformulating and re-labeling all of our products. All production on our current products will cease on March 31st, 2014, and the first of our new products will begin production on April 7th, 2014. As you will read, we have created product specifications and MMRs that are compliant with 21 CFR 111.70. We have included a copy of a few of these specifications along with an MMRs for your consideration. We have also included detailed information as to specification limits for identity, purity, strength, and composition and the testing that will be used to determine if the specifications have been met.


I assure you that we take the FDA and 21 CFR 111 with the utmost seriousness. As this response will show, we have addressed all of the issues outlined in the Warning Letter. We have provided excerpts from the Warning Letter followed by our detailed response to each observation below:
 

Excerpt from Warning Letter 14-PHI-03


Unapproved New Drugs


We reviewed your website at the Internet address http://biorhythm-ads.com/index.cfm In January 2014, and we have determined that you take orders there for your BioRhythm Olio and ReGenerate products, which the website promotes for conditions that cause the products to be drugs under section 201(g)(1)(B) of the Act [21 U.S.C.§ 321 (g)(1)(B)]. The therapeutic claims on your website establish that the products are drugs because they are intended for use in the cure, mitigation, treatment, or prevention of disease. As explained further below, Introducing or delivering these products for introduction into Interstate commerce for such uses violates the Act.


Examples of some of the website claims that provide evidence that your products are intended for use as drugs Include:


BioRhythm Olio product, under the Quick Facts tab:
• "Supports reduction of 'bad' cholesterol"


BioRhythm Olio product, under the Description tab:
• "Research Indicates a diet that includes olive oil yields less overall disease and lower mortality rates"
• "Supports reduction of "bad" cholesterol"


BioRhythm ReGenerate product, under the Quick Facts tab:
• "Decrease bone fracture healing time and lessen joint pain"

BioRhythm ReGenerate product, under the Ingredients tab:
• "Cissus Quadrangularis [an ingredient in the product] ... has already proven to be an excellent healing aid by significantly reducing the average recovery time in major injuries as well as reducing the pain associated with minor tears or inflammation"


Your BioRhythm Olio and ReGenerate products are not generally recognized as safe and effective for the above referenced uses and, therefore, the products are "new drugs" under section 201 (p)(1) of the Act [21 U.S.C. § 321 (p)(1)]. New drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the Act [21 U.S.C § 355(a)]; see also section 301(d) of the Act [21 U.S.C. § 331(d)]. FDA approves a new drug on the basis of scientific data submitted by a drug sponsor to demonstrate that the drug is safe and effective. 


Furthermore, your BioRhythm Olio product is offered for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, adequate directions for use cannot be written so that a layperson can use the drug safely for its intended purposes. Thus, your BioRhythm Olio product is misbranded within the meaning of section 502(f)(1) of the Act [21 U.S.C. §352(f)(1)], in that its labeling fails to bear adequate directions for use. The introduction of a misbranded drug into Interstate commerce is a violation of section 301(a) of the Act [21 U.S.C. § 331(a)].


RESPONSE:


We take extreme care to ensure that the statements on our labels are not misleading. After reading Warning letter 14-PHI-03, we reviewed our website at the Internet address http://biorhvthmads.com/index.cfm. We are pleased to report that all of the statements mentioned in Warning letter 14-PHI-03 have been removed. we have provided screen shots of the pages and tabs from our website as verification [see APPENDIX B).


Excerpt from Warning Letter 14-PHI-03


New Dietary Ingredient


During the inspection, our Investigators collected labeling for your BioRhythm Androbolix product, which you market as a dietary supplement. The labeling for this product declares 4-etioallocholen-3,6, 17-trione as a dietary ingredient. The term "dietary supplement is defined in section 201(ff) of the FD&C Act [21 U.S.C. § 321 (ff)]. Assuming that 4-etioallocholen-3,6, 17-trione is a dietary ingredient under section 201 (ff)(1) of the Act, it would also be a "new dietary ingredient for which a notification is required under section 413(a)(2) of the Act [21 U.S.C. § 350b(a)(2)] and 21 CFR 190.6.


Under section 413 of the Act, a dietary supplement that contains a new dietary ingredient (i.e., a dietary ingredient not marketed in the United States before October 15, 1994) shall be deemed adulterated under section 402(f) of the Act [21 U.S.C. § 342(f)] unless it meets one of two requirements:


1. The dietary supplement contains only dietary ingredients that have been present in the food supply as an article used for food in a form in which the food has not been chemically altered; or

2. There is a history of use or other evidence of safety establishing that the dietary ingredient, when used under the conditions recommended or suggested In the labeling of the dietary supplement, will reasonably be expected to be safe and, at least 75 days before being introduced or delivered for introduction into interstate commerce, the manufacturer or distributor of the dietary ingredient or dietary supplement provides FDA with information, including any citation to published articles, which is the basis on which the manufacturer or distributor has concluded that a dietary supplement containing such dietary ingredient will reasonably be expected to be safe.


FDA is not aware of any information demonstrating that 4-etioallocholen-3,6, 17 -trione was lawfully marketed as a dietary ingredient in the United States before October 15, 1994, nor is FDA aware of any information demonstrating that this dietary ingredient has been present in the food supply as an article used for food in a form in which the food has not been chemically altered. In the absence of such information, 4-etioallocholen-3,6, 17 -trione is subject to the notification requirement for a new dietary ingredient in section 413(a)(2) of the Act [21 U.S.C.§ 350b(a)(2)] and 21 CFR 190.6. Because the required notification has not been submitted, your BioRhythm Androbolix product is adulterated under sections 402(f)(1)(B) and 413(a) of the Act
 

RESPONSE:


The ingredient 4-etioallocholen-3,6,17-trione was only used as an ingredient in our original formulation of Androbolix. We have provided a copy of the original Androbolix label along with its formula for your consideration [see APPENDIX C). In February of 2011, we began offering a reformulated version named Androbolix300 and started phasing out Androbolix. The formulation for Androbolix300 does not contain the ingredient 4-etioallocholen-3,6,17-trione. We have provided a copy of the Androbolix300 label along with its formula for your consideration [see APPENDIX C].


Our Androbolix product was officially discontinued on November 30th, 2012 and any remaining units, and bulk capsules were destroyed on that day. After reviewing our inventory report for these items, you will see that we do not have any Androbolix units in our inventory with the exception of the units that we kept for retains in accordance with 21 CFR 111.80 and 111.83. We have provided copies of our inventory records for these items along with the material destruction logs for the remaining units. [see APPENDIX C]. We have not distributed Androbolix or any other products containing 4-etioallocholen-3,6,17-trione since November 30th, 2012.


Excerpt from Warning Letter 14-PHI-03


Dietary Supplement CGMP Violations


Even if your BioRhythm Olio and ReGenerate products did not have therapeutic claims which make them unapproved new and misbranded drugs, these products would be 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 Current Good Manufacturing Practice (CGMP) regulations for dietary supplements, Title 21, Code of Federal Regulations, Part 111 (21 CFR Part 111) these. In addition, your BioRhythm Androbolix 300, Androbolix, Whole Gains Mango, Olio, and ReGenerate products are adulterated dietary supplements within the meaning of section 402(g)(1) of the Act for the same reason.


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.


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 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. Specifically, during the inspection, our investigators observed the following violations:


1. You did not establish product specifications for the identity, purity, strength, and composition of your finished dietary supplements, and for limits on those types of contamination that may adulterate, or that may lead to adulteration of, the finished batch of dietary supplements, as required by 21 CFR 111.70(e). Specifically, during the inspection, you stated that you create and approve product formulations, which you provide to other manufacturers for the manufacture of your products In bulk. You also stated that you do not provide any additional specifications for the products. Further, in your response letter, dated April 10, 2013, you provided a Standard Operating Procedure (SOP) entitled "Specifications Setting Policy," which specifies that "Exclusive Supplements must establish specifications for the finished batch of the dietary supplement." While you stated that your firm will review the specifications that you have in place for finished products and establish finished product specifications where necessary, you failed to provide documentation of such finished product specifications. As such, we are unable to determine the adequacy of your proposed corrective actions at this time.
 

RESPONSE:


Improving our product specifications and MMRs have been our firm's top priority. We have written a new SOP for Specifications (ESI-SOP-019) that is compliant with 21 CFR section 111.70, 111.77, and 111.90. We have included a copy of ESI-SOP-019 for your consideration [see APPENDIX D). As you will read, ESI-SOP-019 requires that we establish written specifications for the Identity, purity, strength, and composition of every finished batch of every dietary supplement. Specifications must also be established for the limits of those types of contaminants that may adulterate, or that may lead to adulteration of, the finished batch of the dietary supplement.


We have been working on reformulating and relabeling our entire product line since May of 2013. On March 31st, 2014 all production of our current products will be discontinued. Production on our new reformulated products is slated to begin on April 7th, 2014. All products packaged, labeled, and distributed by ESI after March 31st, 2014, will be in accordance with SOP ESI-019. We have included a copy of one of these specifications for our finished dietary supplements for your consideration [see APPENDIX E). We have also written a new SOP for the sampling of all incoming materials (ESI-SOP-020). As part of ESI-SOP-020, we have developed testing schedules for each incoming material utilizing ANSI/ASQ Z1.4 tables to ensure a statistically sound testing program. We have included a copy of ESI-SOP-020 for your consideration [see APPENDIX F).


Excerpt from Warning Letter 14-PHI-03


2. You did not prepare a written Master Manufacturing Record (MMR) related to your packaging and labeling operations, as required by 21 CFR 111.205. An MMR must include, among other things, 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 and a description of packaging and a representative label, or cross-references to the physical location of the actual or representative label (21 CFR 111.210). However, your firm did not prepare an MMR for the packaging and labeling operations conducted at your firm. We note the records provided as part of your firm response, dated April 10, 2013, are Batch Product Records and not MMRs. You must prepare MMRs for each of your products for the operations you perform.


RESPONSE:

As we stated before, improving our product specifications and MMRs have been our firm's top priority. We have written a new SOP for MMRs (ESI-SOP-026) that is compliant with 21 CFR section 111.205 and 111.210. We have included a copy of ESI-SOP-026 for your consideration [see APPENDIX G]. As you will read, ESI-SOP-026 requires that we document 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. ESI-SOP-026 also requires a description of packaging and a representative label.


As we stated before, we have been working on reformulating and relabeling our entire product line since May of 2013. On March 31st, 2014 all production of our current products will be discontinued. Production on our new reformulated products is slated to begin on April 7th, 2014. All products packaged and labeled by ESI after March 31st, 2014, will be in accordance with ESI-SOP-026. We have also included a copy of a MMR for your consideration [see APPENDIX H).
 

Excerpt from Warning Letter 14-PHI-03


3. You did not establish specifications to sufficiently assure that the product you receive for packaging and labeling as a dietary supplement is adequately identified and is consistent with your purchase order, as required by 21 CFR 111.70(f). Specifically, you stated during the inspection that you do you do not have written specifications for the packaging and labeling of your dietary supplement products, packaging, or labels that you receive for packaging and labeling. You also stated that you perform a visual examination of incoming products, but you stated that you do not document the visual examination you perform of incoming products. We note that a visual examination generally cannot sufficiently assure that dietary supplement products are adequately identified and consistent with your purchase order as a visual examination only provides information about the appearance of a product and such information alone generally cannot be used to verify the identity of product, particularly a product in capsule or tablet form.


We have reviewed your response letter, dated April 10, 2013, and determined your response to be inadequate. Your response states that you "will review the specifications [you] have in place for product [you] receive for packaging and labeling as a dietary supplement. Where necessary, these will be revised, approved and implemented." However, you have not provided FDA with any documentation of such specifications, including those you have in place. As such, we are unable to determine the adequacy of your proposed corrective actions at this time.


RESPONSE:


It should be noted that we do not blend our various powders in-house. We receive blended powders from contract manufacturers. Confirming the identity of a blended powder is not as straightforward as establishing the identity of a single pure ingredient. In 2013, we began looking for the most appropriate method for identity testing for our various blended powder and capsule products. A feasibility study was conducted by Bruker Optics to determine which method would provide the most reliable results. It was concluded that Fourier Transform Near lnfared Analysis (FT-NIR) is the most suitable analysis for blended powders and capsules. We have included a copy of the feasibility study and supporting information for your consideration [see APPENDIX 1]. We have purchased a new Bruker Optics MATRIX-1-FT-Near Infrared Spectrometer unit and we are awaiting delivery.


As you know, FT-NIR analysis requires that an "analysis reference standard" be created to determine the identity of blended powder or capsule. As our formulas are new and unique, we must first build the "analysis reference standards" before utilizing this method. We will be utilizing an independent third party lab to analyze our products to confirm their identity and composition until our "analysis reference standards" have been created for each product. Our new MMRs detail the specific tests and third party analysis that will be utilized to verify the identity and composition, so that we may create our "analysis reference standards" for identity. We have also Included a copy of a MMR for your consideration [see
APPENDIX H
).


Excerpt from Warning Letter 14-PHI-03


4. Your quality control personnel approved and released for distribution product received from a supplier for packaging and labeling as a dietary supplement for which sufficient assurance was not provided to adequately identify the product to determine that the product Is consistent with your purchase order, as required by 21 CFR 111.123(b)(4). Specifically, two products that you receive from a supplier for packaging and labeling are similar in name: BioRhythm Androbolix 300 capsules and BioRhythm Androbolix capsules. Your quality control personnel approved and released for distribution your BioRhythm Androbolix 300 capsules, lot# (b)(4), which you received from your contract manufacturer on 8/20/11. However, the Certificate of Analysis (COA) for this product lists ingredients that are not listed in your Androbolix 300 product Master Formula or product label. Rather, the ingredients listed on this COA are the ingredients listed In the Master Formula and product label for the other product, BioRhythm Androbolix capsules. Lot# (b)(4) was used to repack and label a total of (b)(4) - 120 capsule bottles of Androbolix 300 with finished product lot# (b)(4) and lot# (b)(4).
 

We note your firm's response, dated April 10, 2013, concludes that the product received for packaging and labeling as Androbolix 300 was, indeed, Androbolix 300; your conclusion is that the COA included typographical errors. You base this conclusion on the fact that the product you received had the appropriate visual characteristics, namely color. You also submitted documentation in the form of a Master Batch Record from your contract manufacturer for your Androbolix 300 product. However, the listing of ingredients in this batch record further calls into question the identity of the product in that the ingredients are not consistent with either the Androbolix 300 Master Formula or the product label. Further, you did not submit the complete Batch Product Record, and there is no information as to how this product was manufactured or any other information that would assist in determining the Identity of this product, such as results of identity testing. Reliance upon visual characteristics is not adequate to verify the identity and ensure quality of a dietary supplement product.


Furthermore, we note that the violations described above with respect to not preparing MMRs for your packaging and labeling operations under 21 CFR 111.205, not establishing specifications under 21 CFR 111.70(f), and the failures in your quality control operations under 21 CFR 111.123(b)(4) to ensure the products you receive from contract manufacturer(s) are consistent with your purchase order demonstrate a pervasive problem with your facility's operations. It is critical that your firm have a system of production and process controls in place along with sufficient quality control operations to ensure the quality of your dietary supplements and that the dietary supplements are packaged and labeled as specified in the MMR (21 CFR 111.55 and 111.65). MMRs, applicable specifications, and quality control measures that relate specifically to your packaging, labeling and distribution operations are necessary to ensure the quality of your dietary supplement products, and to be compliant with the regulations under 21 CFR Part 111.


RESPONSE:


We assure you that we have taken this incident with the utmost seriousness. Upon being made aware of this incident, we contacted our customers who had purchased lot #C071185 in an attempt to retrieve any units that could still be in circulation. Lot #C071185 of Androbolix300 was bottled on September 7th of 2011, so it is not surprising that we were unable to locate a single bottle of lot #C071185 in circulation.


We also contacted the contract manufacturer that produced lot #C071185. The contract manufacturer provided us with a copy of their Batch Production Record (BPR) for lot # C071185 and asserted that it was simply a typographical error on the Certificate of Analysis that caused the information from Androbolix to be listed on the documentation for Androbolix300. We feel that this oversight should have been detected by ESI but also by the contract manufacturer, so we immediately discontinued the use of this contract manufacturer for our Androbolix300 product. On March 16th, 2013, we began purchasing Androbolix300 from another contract manufacturer.


We agree with the FDA that relying on the contract manufacturer's BPR and visual verification were not sufficient. We began looking for a way to scientifically prove that lot # C071185 was Androbolix300 and not Androbolix. We determined that the best way to differentiate between the two formulas would be to test for an ingredient that would be present in Androbolix300 and not in Androbolix. While there are several differences between the two formulas, we determined that the most obvious difference is that Eurycoma Longofolia is present in Androbolix300 but not in Androbolix. If we were to detect the presence of Eurycoma Longofolia In Lot #C071185 it would confirm that it was Androbolix300 and not Androbolix. We contracted Alkemist Labs to perform the analysis. We sent Alkemist Labs samples of both Androbolix and Androbolix300 along with Lot #C071185 of Androbolix300. They analyzed the samples using High Performance Thin-Layer Chromatography and concluded that Eurycoma Longofolia was present in Androbolix300 Lot #C071185. We feel that these analyses results confirm that Lot #C071185 was indeed Androbolix 300. We have included the results from these tests for your consideration. [see APPENDIX J]. On September 30th, 2013, after reviewing the findings of Alkemist Labs, we concluded our investigation into this incident.


We have taken steps to prevent this from happening in the future. We have implemented improved SOPs for Specifications (ESI-SOP-019) [see APPENDIX D] and MMRs (ESI-SOP-026) [see APPENDIX G]. We have also implemented improved SOP for Quality Control (ESI-SOP-024). We have included a copy of ESI-SOP-024 for your consideration [see APPENDIX K]. ESI-SOP-024 clearly states:


Excerpt from Quality Control (ESI-024)


The Quality Unit shall not approve and release for distribution:
 

1. Any batch of dietary supplement for which any component In the batch does not meet its identity specification.


2. Any batch of dietary supplement, including any reprocessed batch which does not meet all product specifications.


3. Any batch of dietary supplement, including any reprocessed batch which has not been manufactured, packaged, labeled, and held under conditions to prevent adulteration.


4. Any product received from a supplier for packaging or labeling as a dietary supplement (and for distribution rather than for return to the supplier) for which sufficient assurance is not provided to adequately identify the product and to determine that the product is consistent with the purchase order.


Excerpt from Warning Letter 14-PHI-03


5. A qualified person did not Investigate product complaints that involved possible failures of dietary supplements to meet specifications, or other requirements as required by 21 CFR 111.560(a)(2). Specifically, you did not investigate several complaints, including, but not limited to the following;


• A serious adverse event, dated 2/19/13, regarding BioRhythm brand Whole Gains Protein Watermelon in which the complainant experienced a rapid heart rate and dizziness after using the product.


• A serious adverse event, dated 4/5/11, regarding BioRhythm brand Olio softgels in which the complainant experienced rectal bleeding.


Furthermore, you failed to make and keep records related to product complaints, as required by 21 CFR 111.570. Specifically, you stated during the inspection that you remembered Investigating two complaints related to your BioRhythm brand product, AfterGlow, in which the complainants stated that the product did not mix, and that the product tasted like sour milk; however, you did not document the investigation. You must investigate product complaints and document the investigation in order to comply with 21 CFR 111 Subpart O - Product Complaints.
 

RESPONSE:


We have since adopted an improved SOP for handling of customer complaints that is compliant with 21 CFR 111.560 (ESI-SOP-036). As part of the new SOP, any customer service personnel that receives a complaint must gather initial information regarding the incident. This information is then given in writing to the Quality Control Manager. We have attached copies of ESI-SOP-036 along with a copy of a completed complaint record for your consideration [see APPENDIX L].


Excerpt from Customer Complaints (ESI-036)


A. A qualified employee of the Quality Unit must review each consumer complaint to determine whether the complaint involves a possible failure of a dietary ingredient or dietary supplement to meet any of its specifications, or any other requirements which may render the product non-conforming, and a possible risk of illness or injury to the consumer.


B. The Quality Unit must review and approve decisions to investigate a product complaint, and they must review and approve the findings and follow-up action of any investigation performed.


C. Review, investigations, and follow-up action for product complaint must extend to all relevant batches and records.


D. If the review indicates that the product is a possible risk to consumer safety, the consumer complaint must be fully investigated, and the need to recall the product must be evaluated.


E. The investigator must review the batch records associated with the dietary supplement involved in the consumer complaint. In addition, the investigator must review batch records for other dietary supplements that may have also been affected and could also pose a threat to consumer safety.


F. The Quality Unit must maintain a written record of every consumer complaint, whether the complaint relates only to product quality, or to concerns about a possible health hazard.
 

Excerpt from Warning Letter 14-PHI-03


6. You did not make and keep documentation of calibrations for instruments or controls that you use in manufacturing or testing a component or dietary supplement as required by 21 CFR 111.35(b)(3). Specifically, you do not document that your scales have been calibrated.


We have reviewed your response letter, dated April 10, 2013, and determined your response to be inadequate. Your response states that you will establish a more detailed written procedure for Calibration of Scales and will complete the implementation by May 13, 2013. However, you failed to provide documentation of such procedures. As such, we are unable to determine the adequacy of your proposed corrective actions at this time. We note that your scales should be calibrated as often as specified by the manufacturer of these scales
 

RESPONSE:


In September of 2013 we implemented our Equipment Calibration (ESI-SOP-017) that is compliant with 21 CFR sections 111.25, 111.27, 111.30, and 111.35. We have attached a copy of ESI-SOP-017 along with our calibration log sheets for your consideration [see APPENDIX M]. Furthermore, all of our scales have been calibrated by WISCO calibration Services and their accuracy is now tested on a weekly basis. It should also be noted that our improved MMRs document which ESI scales are used at every step during our packaging and labeling process.
 

Excerpt from Warning Letter 14-PHI-03


Misbranded Dietary Supplements


Your BioRhythm brand Androbolix 300, Androbolix, and Whole Gains Mango dietary supplement products are misbranded under section 403 of the Act [21 U.S.C. § 343] in that the labeling for these products does not comply with labeling requirements for dietary supplements, including FDA's regulations under 21 CFR Part 101. In addition, even if your BioRhythm Olio and ReGenerate products did not have therapeutic claims, which make these products unapproved and new misbranded drugs, they would also be misbranded for the same reason.


1. Your BioRhythm brand Androbolix 300, Androbolix, Whole Gains Mango, Olio, and ReGenerate dietary supplement products are misbranded within the meaning of section 403(q)(5)(F) of the Act [21 U.S.C. § 343(q)(5)(F)] in that the nutrition information does not comply with 21 CFR 101.36. For example,


• Your BioRhythm brand Androbolix 300 label does not list zinc, niacin and Vitamin B6 in the correct order. Niacin, vitamin B6 and zinc should be listed in that order before the other dietary ingredients in accordance with 21 CFR 101.36(b)(2) and 101.36(b)(3).


• In accordance with 21 CFR 101.36(b)(2)(ii)(B), your Whole Grains Protein label fails to include the total quantitative amount by weight per serving for dietary ingredients declared under 21 CFR 101.36(b)(2)(i)(B) using the units of measurement and the levels of significance given in § 101.9(c)(8)(iv). Furthermore, the enzymes declared on the label should not be listed after the terms "Ingredients" or "Other Ingredients". The enzymes Pancreatin; amylase, protease, and lipase should be declared using their common or usual name and listed with their quantitative amount by weight per serving in metric units in the nutrition information within the Supplement Facts panel in accordance with 101.36(b)(3).


• Your Whole Grains Protein label fails to declare the dietary ingredients iodide, chloride, and potassium, their amounts in one serving of the product, and the percent of the daily value. Vitamins or minerals listed in 101.9(c)(8)(iv) shall be declared when they are added to the product for purposes of supplementation, or when a claim is made about them. Your label makes the claim to contain potassium iodide and potassium chloride.


In addition, the listing for "Other ingredients" on the labels of your BioRhythm brand Androbolix 300, Androbolix, Whole Gains Protein, Olio, and ReGenerate products must be listed outside of
the Supplement Facts box in accordance with 21 CFR 101.4(g).


2. Your BioRhythm brand Androbolix and Androbolix 300 products are misbranded within the meaning of section 403(s)(2)(C) because the label fails to identify the part of the plant from which the ingredients are derived in accordance with 21 CFR 101.4(h). For example,


• Your Androbolix and Androbolix 300 labels fail to include the part of the plant from which Tribulus is derived.


• Your Androbolix 300 label fails to include the part of the plants from which Eurycoma longifolia and Cimicifuga racemosa are derived.


RESPONSE:


Thank you for making us aware of these issues with our label format. I would like to address each of these issues individually:


In regards to Androbolix and Androbolix 300 labels, as we stated previously we have discontinued production of Androbolix in November of 2012. As of March 30th, 2014, the Androbolix300 will no longer be produced and is being replaced with Androbolix300-XL. We have corrected these issues on our new label for Androbolix300-XL. We have attached a copy of the label proof for the Androbolix300-XL for your consideration [see APPENDIX N]. As you will read, the Androbolix300-XL label list zinc, Niacin, and Vitamin B6 in the correct order in accordance with 21 CFR 101.36(b)(2) and 101.36(b)(3). The Androbolix300-XL label also clearly lists the part of the plant from which the Tribulus, Eurycoma Longifolia, and Cimicifuga racemosa are derived in accordance with CFR 101.4(h).


In regards to our Whole Gains Mango label, as of March 30th, 2014, we will no longer produce our Whole Gains Mango product using its current label. Production will resume for this product after April 7th, 2014 with a new formulation and a new label. The new Whole Gains label will include the total quantitative amount by weight per serving for dietary ingredients declared under 21 CFR 101.36 (b)(2)(i)(B). The new label will also include the amount of iodide, chloride, and potassium along with their Daily Value. The other ingredients will also be listed outside of the Supplement Facts box in accordance with 21 CFR 101.4(g). We will update the FDA with a label proof once it has been completed and approved.


In regards to our Olio and Regenerate labels, as of March 30th, 2014, we will no longer produce either of these products using their current labels. Production will resume after April 7th, 2014 with new formulations and new labels. The other ingredients will be listed outside of the Supplement Facts box in accordance with 21 CFR 101.4(g). We will update the FDA with a label proof once it has been completed and approved.
 

Excerpt from Warning Letter 14-PHI-03

Adverse Event Reporting Violations


1 . You failed to submit a Serious Adverse Event Report (SAER) for a dietary supplement within 15 business days after receiving a report about the adverse event, as required by section 761(c) of the Act [21 U.S.C. §§ 379aa-1 (c)]. Specifically you did not submit an SAER for the following serious adverse events until April 11, 2013:


• A serious adverse event, dated 2/19/13, regarding BioRhythm brand Whole Gains Protein Watermelon in which the complainant experienced a rapid heart rate and dizziness after using the product.


• A serious adverse event, dated 4/5/11, regarding BioRhythm brand Olio softgels in which the complainant experience rectal bleeding.


This letter is not intended to be an all-inclusive list of violations that may exist at your facility. You are responsible for ensuring that your firm is operating in compliance with the Act and applicable FDA regulations,
 

RESPONSE:


As we stated before, we have since adopted an improved SOP for handling of customer complaints that is compliant with 21 CFR 111.560 (ESI-SOP-036) [see APPENDIX L]. ESI-SOP-036 requires the Quality Control Manager to review and investigate all complaints to determine if there is a failure of a dietary supplement to meet any of its specifications, or any other requirements of 21 CFR 111, including those specifications and other requirements that, if not met, may result in a risk of illness or injury and determine if the incident warrants reporting to FDA Med Watch.


It should be noted that, since receiving the FDA Form 483 on March 21st, 2013, we have reported two (2) adverse events to Med Watch in accordance with ESI-SOP-036. It should also be noted that, although it was outside of the required fifteen (15) day period, we have since reported the above referenced incidents to MedWatch.


Excerpt from Warning Letter 14-PHI-03


Additionally, we have the following comment:


1. You state on page (b)(4) of your Standard Operating Procedures Manual (under the subheading 4.


EXPIRATION DATING:


"The expiration date is the recommended shelf life date of the product as provided by the vendor/manufacturer of the bulk product. This information provided by the manufacturer is entered on the original receiving report for raw materials and must always be listed on the bulk containers as received by the manufacturer. If bulk materials are received by any vendor without the expiration date the bulk material will be refused by the shipping/receiving personnel and returned to the vendor."


Please note that the term "shelf life date includes expiration dating and "best if used by" dating [See 72 Fed. Reg. 34912, 34856 (Jun. 25, 2007)]. Any expiration, shelf life, or "best if used by" date you place on a product label should be supported by stability data [See 72 Fed. Reg. 34752, 34856 (Jun. 25, 2007)].


RESPONSE:


As you know, we receive our blended powders from contract manufacturers. The expiration dating has been determined by our contract manufacturers. We have requested the supporting stability data from our contract manufacturers for all of our new product formulations. In the event that our contract manufacturers are unable to provide us with stability testing data, we will have stability analysis performed.
 

We assure you that we are determined to continue implementing required Good Manufacturing Practices and training our personnel in these requirements. Please be assured of our strong commitment to keeping our operations in compliance. We hope that our timely and thorough response demonstrates our desire to correct and proactively prevent any compliance issues.


Sincerely,

/S/
Mark A. Mangieri
President/CEO

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