| | |
 Department of Health and Human Services
| Public Health Service
Food and Drug Administration |
| | Denver District Office Building 20 – Denver Federal Center P.O. Box 25087 Denver, Colorado 80225-0087 TELEPHONE: 303-236-3000 |
May 27, 2011
WARNING LETTER
VIA UPS PRIORITY
Robert McNamara, President
Columbine Specialty Products Inc.
4880 East 41st Ave.
Denver, CO 80216-440
Ref: # DEN-11-13-WL
Dear Mr. McNamara:
On December 1 - 10, 2010, the U.S. Food and Drug Administration (FDA) conducted an inspection of your manufacturing facility at which you manufacture dietary supplements, located at
4880 East 41st Ave., Denver, Colorado. The inspection revealed serious violations of FDA’s Current Good Manufacturing Practice (CGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements (Dietary Supplement Regulations), Title 21, Code of Federal Regulations, Part 111 (21 CFR Part 111). At the conclusion of the inspection, you were issued a Form FDA 483, List of Inspectional Observations, which listed a number of the violations that cause your dietary supplement products to be adulterated within the meaning of section 402(g)(1) of the Federal Food, Drug and Cosmetic Act (the Act) [21 U.S.C. § 342(g)(1)] in that the products have been prepared, packed, or held under conditions that do not meet CGMP requirements for dietary supplements. Also, our investigators collected and reviewed samples of the labeling of your (b)(4) during the inspection of your facility. FDA concluded that this product is misbranded under section 403(e) of the Act [21 U.S.C. § 343(e)]. You can find the Act and the Dietary Supplement Regulations through links on FDA’s home page at http://www.fda.gov.
The significant violations documented during the inspection include, but are not limited to, the following:
Adulterated Dietary Supplements
1) Your firm failed to provide records to show the established product specifications for each dietary supplement you manufacture for the identity, purity, strength, and composition of the finished batch of dietary supplement, as required by 21 CFR 111.70(e). Specifically, you were not able to provide any records to show established product specifications for the identity, purity, strength, and composition of the following finished dietary supplement products, including all lots manufactured since June 25, 2010:
(b)(4)
2) Your firm failed to verify, for the finished batches of your dietary supplement products, identified below, that either every finished dietary supplement batch or a subset of the finished dietary supplement batches that you identify through a sound statistical sampling plan meet the finished product specifications for identity, purity, strength, and composition as required by 21 CFR 111.75(c).
Specifically, you informed us, during the inspection, that your firm does not test any finished goods (b)(4). It is not clear whether your firm receives established specifications from your customers or whether your firm establishes specifications for your customers. Nevertheless, your firm’s status as a contract manufacturer does not exempt you from having to comply with those regulations in 21 CFR Part 111 that are directly applicable to the operations that you perform, such as ensuring that the final product meets established specifications for identity, purity, strength and composition. Our review of your records revealed that you did not establish specifications or conduct any finished product testing to ensure that specifications for identity, purity, strength, and composition were met for the following finished dietary supplement products, including all lots manufactured since June 25, 2010:
(b)(4)
We acknowledge the corrective actions you have identified in your response letter, dated February 1, 2011. Your response under observation 2 appears to indicate that you are taking steps towards establishing specifications and implementing a finished product testing program; however, your response is inadequate because you did not provide supporting documentation with your response to demonstrate the steps you took towards establishing finished product specifications and implementing a finished product testing program. Your response, also, does not include documentation of established specifications for the dietary supplement products you manufactured and documentation of finished product testing. In addition, in your response letter, under observation 2, you stated the adequacy of the in-process blend step will be verified by testing for (b)(4), but these tests do not meet the requirements, which require you to verify that your finished batch of dietary supplement meets product specifications for identity, purity, strength, and composition. However, you may exempt one or more product specifications from the verification requirements under circumstances set forth in 21 CFR 111.75(d)(1). For any such exemption, you must document why, for example, any component and in-process testing, examination, or monitoring, and any other information, will ensure that such exempted product specification is met without verification through periodic testing of the finished batch.
3) Your firm failed to make and keep records of the established component specifications, as required by 21 CFR 111.95(b)(1), to show that component specifications were established to ensure that the specifications for the identity, purity, strength, and composition of the dietary supplements manufactured using the components are met, as required by 21 CFR 111.70(b)(1) and (b)(2).
Specifically, your firm used the following components to manufacture your dietary supplement products: (b)(4), but you failed to provide records showing the established component specifications for each of these components.
We acknowledge the corrective actions you have identified in your response letter, dated February 1, 2011, under observation 3. However, your response is inadequate in that it did not address your commitment to establish component and finished product specifications to ensure that specifications for the identity, purity, strength, and composition of the component and dietary supplements manufactured at your facility are met. Further, you provided no documentation to show that these specifications were established. Your response also did not indicate whether you would establish limits on any types of contaminants that may adulterate or may lead to adulteration of a finished batch of dietary supplement to ensure the quality of the dietary supplement.
4) Your firm failed to include the following information in your master manufacturing records (MMR):
a) A statement of theoretical yield of a manufactured dietary supplement expected at each point, step, or stage of the manufacturing process where control is needed to ensure the quality of the dietary supplement, and the expected yield when you finished manufacturing the dietary supplement, including the maximum and minimum percentages of theoretical yield beyond which a deviation investigation of a batch is necessary and material review is conducted and disposition decision is made for (b)(4) brand dietary supplement products, as required by 21 CFR 111.210(f). Specifically, your MMRs for the dietary supplement products you manufacture failed to include this information. A statement of theoretical yield is necessary at each such point, step, or stage, where control is needed to ensure the quality of the dietary supplement, and the expected yield of the finished dietary supplement so that you will know whether the manufacturing process is proceeding as expected or whether something is wrong.
b) A description of packaging and a representative label, or cross-reference to the physical location of the actual or representative label for (b)(4) brand dietary supplement product varieties, as required by 21 CFR 111.210(g). Specifically, your MMRs for the dietary supplement products you manufacture failed to include this information.
c) Specifications for each point, step, or stage in the manufacturing process of your (b)(4) brand dietary supplement products, where control is necessary, to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the MMR, as required by 21 CFR 111.210(h)(1). Specifically, your MMRs for the dietary supplement products you manufacture failed to include this information.
d) Procedures for sampling and a cross-reference to procedures for tests or examinations in the MMRs for (b)(4) brand dietary supplement product varieties, as required by 21 CFR 111.210(h)(2). Specifically, your MMRs for the dietary supplement products you manufacture failed to include this information.
e) Corrective action plans for use when a specification is not met for the (b)(4) brand dietary supplement products, as required by 21 CFR 111.210(h)(5). Specifically, your MMRs for the dietary supplement products you manufacture failed to include this information.
We acknowledge the corrective actions you have included in your response letter, dated February 1, 2011, under observation 1. Your response indicates you are taking steps to address the deficiencies in your MMRs; however, your response is inadequate because you fail to provide documentation to demonstrate the actual changes you have made to your MMRs.
5) Your batch production records (BPR) did not include complete information relating to the production and control of each batch of your (b)(4) brand dietary supplement products manufactured since June 25, 2010, as required by 21 CFR 111.255(b). Your BPR did not include the following required information:
a) The date and time of the maintenance, cleaning, and sanitizing of the equipment and processing lines used in producing the batch, or a cross-reference to records, such as individual equipment logs, where this information is retained, as required by 21 CFR 111.260(c). Specifically, your BPR for the dietary supplement products you manufacture failed to include this information.
b) A statement of the actual yield and percentage of theoretical yield at appropriate phases of processing, as required by 21 CFR 111.260(f). Specifically, your BPR for the dietary supplement products you manufacture failed to include this information.
c) Results of any testing or examination performed during the batch production, or a cross-reference to such results, as required by 21 CFR 111.260(h). Specifically, your BPR for the dietary supplement products you manufacture failed to include this information.
d) Documentation of the manufacture of the batch at the time of performance, as required by 21 CFR 111.260(j) Specifically, the following information was not documented in your BPR at the time of performance:
· the date on which each step of the master manufacturing record was performed;
· the initials of the person responsible for weighing or measuring of each component used in a batch;
· the initials of the person responsible for verifying the weight or measure of each component used in the batch;
· the initials of the person responsible for adding the component to the batch; and
· the initials of the person responsible for verifying the addition of components into a batch.
e) Documentation at the time of performance, of packaging and labeling operations as required by 21 CFR 111.260(k). Specifically, the following information was not documented, in your BPR, at the time of performance:
· the unique identifier that you assigned to packaging and labels used, the quantity of the packaging and labels used;
· an actual or representative label or a cross-reference to the physical location of the actual or representative label specified in the master manufacturing record; and
· the results of any tests or examinations conducted on packaged and labeled dietary supplements (including repackaged or relabeled dietary supplements), or a cross-reference to the physical location of such results.
f) Documentation at the time of performance that quality control personnel reviewed the batch production record, as required by 21 CFR 111.260(l). Specifically, your BPR for the dietary supplements you manufacture failed to include this information.
g) Documentation at the time of performance of any required material review and disposition decision, as required by 21 CFR 111.260(m). Specifically, your BPR for the dietary supplements you manufacture failed to include this information.
We acknowledge the corrective actions you have identified in your response letter, dated February 1, 2011, under observation 7. However, your response is inadequate because you did not provide documentation demonstrating the actual corrections made to your BPR. Further, you did not address the theoretical yields at appropriate phases of processing and your responses to specific areas of deficiencies did not adequately address the deficiency. For example, your response stated that you are now recording cleaning and maintenance in your Sanitation log book; however, under 21 CFR 111.260(c), cleaning activities that are documented in independent logs, must be cross-referenced in your BPR. You also did not include these logs for our review.
6) Your firm failed to establish and use appropriate controls to ensure that equipment functions in accordance with its intended use, as required by 21 CFR 111.30(e). You must document such controls, as required by 21 CFR 111.35(b)(6).
Specifically, you did not establish blending times for your (b)(4) to demonstrate that components you add are mixed sufficiently to assure that your product is thoroughly mixed prior to your filling operation. Blending/mixing times must be established, checked, and adjusted as necessary during this operation of your manufacturing process.
We acknowledge the corrective actions you have identified in your response letter, dated February 1, 2011, under observation 8. However, your response is inadequate because you did not explain how (b)(4) measurements will demonstrate that the batch is mixed adequately and that all vitamins and minerals are evenly distributed throughout the liquid blend.
7) Your firm did not confirm the identity of other components (not including dietary ingredients) and determine whether other applicable component specifications established in accordance with 21 CFR 111.70 are met by conducting appropriate tests or examinations; or relying on a certificate of analysis (COA) from the supplier of the component that you receive, provided that, among other requirements, you first qualify your component suppliers by establishing the reliability of the suppliers’ COA through confirmation of the results of the suppliers’ tests or examinations, as required by 21 CFR 111.75(a)(2)(ii)(A).
Specifically, as you stated during the inspection, your firm is a contract manufacturer that produces dietary supplement products (b)(4) As stated previously, your firm’s status as a contract manufacturer does not exempt you from having to comply with those regulations in 21 CFR Part 111 that are directly applicable to the operations that you perform, such as qualifying each supplier of raw material components, not including dietary ingredients, which are used in your dietary supplement products so that you may rely on each supplier’s COA to confirm other component specifications are met, including the identity of supplied raw material components. To qualify a supplier you must establish the reliability of the supplier’s COA through confirmation of the results of the supplier’s tests or examinations. Instead of complying with this requirement, you rely on your suppliers’ COAs without qualifying any of your (b)(4) suppliers. Therefore, you cannot rely on these suppliers’ COAs to assure the identity of your raw material components.
We acknowledge the corrective actions you have identified in your response letter, dated February 1, 2011, under observation 5. However, your response is inadequate because you provided no documentation of how you would qualify your suppliers. Further, in your response you state you will “set a program in place to qualify vendors;” however, you do not describe the program you intend to put into place. In addition, you state a review procedure is being implemented, but you do not state exactly what will be reviewed or when the review procedure will be in place.
8) You do not collect representative samples of each unique lot of components, packaging, and labels that you use to determine whether the components, packaging and labels meet specifications established in accordance with 21 CFR 111.70(b) and (d), and as applicable, 21 CFR 111.70(a), as required by 21 CFR 111.80(a).
Specifically, you had no representative samples collected for each unique lot of components, packaging, and labels.
We acknowledge the corrective actions you have identified in your response letter, dated February 1, 2011, under observation 10. Your response indicated that you are now keeping samples from all incoming raw materials; however, your response is inadequate because it did not address whether you are collecting representative samples of packaging (e.g., bottles/caps) and labeling.
9) Your firm failed to clearly identify, hold, and control under a quarantine system for appropriate disposition any dietary supplement that is rejected and unsuitable for use in manufacturing, packaging, or labeling operations, as required by 21 CFR 111.370.
Specifically, components, including raw materials, are not held in a quarantine system for review or approval prior to use in manufacturing.
10) Your firm failed to conduct at least one appropriate test or examination to verify the identity of a dietary ingredient, prior to its use, as required by 21 CFR 111.75(a)(1)(i).
Specifically, your firm uses (b)(4), but you did not perform an identity test or examination on any of the (b)(4) dietary ingredients in the (b)(4) blend/premix and any of the (b)(4) dietary ingredients in your (b)(4) blend/premix, respectively, used in these dietary supplements.
We acknowledge the corrective actions you have identified in your response letter, dated February 1, 2011, under observation 4. Your response indicates that you send samples to an outside lab for identity testing; however, this response is inadequate because you did not provide supporting documentation about how your quality control unit will oversee the testing performed by the outside lab in order to ensure that the appropriate tests and examinations of incoming materials are being performed. Ultimately, it is your responsibility to confirm the identity of the dietary ingredients you intend to use in your product and determine whether these specifications are met.
11) Your quality control personnel failed to ensure that your manufacturing, packaging, labeling, and holding operations ensure the quality of the dietary supplements, including approving all processes, specifications, written procedures, controls, tests, and examinations, and deviations from or modifications to them that may affect the identity, purity, strength, or composition of the dietary supplement, as required by 21 CFR 111.105(a).
Specifically, a review of COAs and batch records found that you used several expired dietary supplement components during production. For example:
(b)(4).
12) Your firm failed to provide receiving records (including records such as COAs, suppliers’ invoices, and suppliers’ guarantees) for components, packaging and labels, as required by 21 CFR 111.180(b)(2).
Specifically, you were unable to provide Certificates of Analysis (COA) for the components used in the manufacture of your dietary supplements. For example, you were not able to provide the COAs for (b)(4).
Misbranded Food
13) Your (b)(4) is misbranded under section 403(e) of the Act [21 U.S.C. § 343(e)] in that the label fails to bear the name and place of business of the manufacturer, packer or distributor, as required by 21 CFR 101.5.
The above violations are not intended to be an all-inclusive list of violations in your plant. It is your responsibility to ensure that all of your products are in compliance with all requirements of the Act and implementing regulations.
Failure to promptly correct the violations specified above may result in enforcement action without further notice. Enforcement action may include seizure of violative products and/or injunction against the manufacturers and distributors of violative products.
In addition, we have the following comment. During the inspection, you volunteered to reseal the floor of the production area and to locate and install a filter to protect against the inclusion of metal or other foreign material in your dietary supplement products. We acknowledge your voluntary corrections; however your response letter, dated February 1, 2011, did not include documentation that these corrective actions were completed.
We request that you notify this office in writing within 15 working days from your receipt of this letter of the current status of your corrective actions and the specific steps you have taken to correct the noted violations. Your response should include any documentation necessary to show that correction has been achieved. If you cannot complete all corrections before you respond, state the reason for the delay and the date by which you will complete the corrections.
Your written response should be directed to the U.S. Food and Drug Administration, Attention: Nancy G. Schmidt, Compliance Officer, at the above address. If you have questions about this letter, please contact Ms. Schmidt at (303) 236-3046.
Sincerely,
/S/
Howard E. Manresa
Acting Denver District Director
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