Inspections, Compliance, Enforcement, and Criminal Investigations
Cascadia Manufacturing, Inc. 06-Aug-08
Department of Health and Human Services
Public Health Service
August 6, 2008
VIA CERTIFIED MAIL
RETURN RECEIPT REQUESTED
In reply refer to Warning Letter SEA 08-30
Jeffrey T. Haley, President
Cascadia Manufacturing, Inc.
13440 Southeast 27th Place
Bellevue, Washington 98005
Dear Mr. Haley:
During an inspection of your manufacturing facility, located at 13440 Southeast 27th Place, Bellevue, Washington, on January 31, 2008, and. February 1, 4, 11, 13, and 22, 2008, an investigator from the United States Food and Drug Administration (FDA) documented significant violations of Current Good Manufacturing Practice (CGMP) regulations in Title 21, Code of Federal Regulations, Parts 210 and 211 (21 CFR §§ 210 and 211): These deviations cause your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 351(a)(2)(B)) in that the methods used in, or the facilities or controls used for their manufacturing, processing, packing, or holding, do not conform or are not operated or administered in conformity with CGMP. In addition, this inspection also revealed your firm is marketing unapproved new drugs in violation of Section 301(d).and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)].
The CGMP violations include, but are not limited to, the following:
1. Appropriate laboratory testing is not performed on each batch of drug product to determine satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release [21 CFR § 211.165(a)]. For instance, you have sampled only one lot of the CankerMelts Natural Product ("CankerMelts") out of [(b)(4)] produced since 2006 for the percentage of active ingredient. In addition, appropriate finished product testing for the strength of Glycyrrhiza Herbal Extract in this product is not performed.
2. There is no appropriate laboratory testing of each batch of drug products required to be free of objectionable microorganisms [21 CFR § 211.165(b)]. Microbial limits testing is not performed on each batch of oromucosal drug products. Only one batch of the CankerMelts has been tested for microbial limits since the previous inspection of October 2005.
3. Failure to establish acceptance criteria for the sampling and testing conducted by the quality control unit that are adequate to assure that batches of drug products meet each appropriate specification and appropriate statistical quality control criteria as a condition for their approval and release [21 CFR § 211.165(d)]. For instance, your firm has not established any acceptance criteria or specifications for microbial limits testing on the CankerMelts other than a visual examination for mold.
4. Failure to establish written procedures describing in-process controls, tests, or examinations to be conducted on appropriate samples of in-process materials for each batch of drug product to monitor the output and validate the performance of manufacturing processes that may be responsible for causing variability in the characteristics of in-process materials or finished drug products [21 CFR § 211.110(a)]. For instance, there are no control procedures established for CankerMelts for the uniformity and homogeneity of the in-process mixed batch materials, heating and drying steps, pH, weight and shape variations of the finished product, and disintegration/dissolution time and rate.
5. Failure to conduct microbiological tests on drug components that are liable to microbial contamination that is objectionable in view of their intended use [21 CFR § 211.84(d)(6)]. For instance, your firm is not testing [(b)(4)] or [(b)(4)] under appropriate microbiological analysis to determine the suitability of the component as compared to the finished drug product.
6. Failure to conduct at least one specific identity test for each drug product component [21 CFR § 211.84(d)(1)]. Specifically, your firm has failed to conduct specific identity tests on any of the components of your drug products other than the Glycyrrhiza Herbal Extract.
7. Equipment and utensils are not cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product [21 CFR § 211.67(a)]. For instance, peeling paint and apparent residual drug product material were observed on the CankerMelts disk filling/dispensing equipment (Ml).
8. Failure to establish adequate written procedures for cleaning and maintenance of equipment, including utensils used in the manufacture, processing, packing, or holding of drug products [21 CFR § 211.67(b)]. For instance, your firm has not demonstrated that the cleaning procedures are capable of removing residual disinfectant compounds, such as Chlorite and Quaternary Ammonia, from the product contact surfaces of production equipment.
9. Failure to maintain records of cleaning and sanitization of equipment as specified in 21 CFR § § 211.180 and 211.182 [21 CFR § 211.67(c)]. For instance, the "Preparation and Cleanup Checklist" used by your firm does not address or record the cleaning of production equipment.
10. Components are not retested or reexamined, as appropriate, for identity, strength, quality, and purity, and approved or rejected by the quality control unit after storage for long periods of time [21 CFR § 211.87]. For example, Glycyrrhizic acid, [(b)(4)] which are currently used to manufacture CankerMelts, were received between June and July 2004, and Magnesium/Calcium Stearate currently used to manufacture Avamin Melts was received in August 2002. These components have not been retested or reexamined to verify the suitability of their continued use.
11. Equipment used in the manufacture, processing, packing, or holding of a drug product is not of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance [21 CFR § 211.63]. For instance, the drying chamber is constructed of painted, rough, compressed wood and 2X4 wood supports, and the mixing area is constructed of plastic tarp and rough wood-framed walls.
12. Written procedures for production and process control are, not followed and the deviations are not justified [21 CFR § 211.100(b)]. For instance, the Batch Production Record used for the lots of CankerMelts produced since 2006 does not match the Master Production and Control Record for the percentage of potassium hydroxide and the amount of water. For the Avamin Melts product, the amount of Methylcobalamin was adjusted on Lots #101 and #103 from that reflected in the Master Production and Control Record.
13. Failure to establish a quality control unit that has the responsibility and authority to approve or reject all components, in-process materials, drug products, and all procedures or specifications impacting on the identity, strength, quality, and purity of the drug products [21 CFR §§ 211.22(a) and (c)]. Although you stated during the inspection that you are the Quality Control Unit, you could provide no documentation that the responsibilities and authority of the Quality Control Unit have been established, written, and followed for products manufactured and distributed [21 CFR § 211.22(d)].
14. There are no laboratory controls established to include scientifically sound and appropriate specifications and test procedures designed to assure that components and drug products, conform to appropriate standards of identity, strength, quality, and purity [21 CFR § 211.160(b)]. For instance, there are no laboratory test methods in place to assure that each disc of CankerMelts delivers the active ingredient in a time-release of 2-6 hours, as claimed in the product's labeling.
15. There are no written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR § 211.198(a)]. For instance, your firm maintains an "Adverse Event" file but does not have written procedures for the handling of these or any other type of complaints.
16. Unexplained discrepancies and failures of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed, are not thoroughly investigated [21 CFR § 211.192]. For example, Lot #331, representing [(b)(4)] batches of the CankerMelts, was rejected and destroyed reportedly due to quality reasons [(b)(4)], yet there was no documentation that an investigation was conducted.
17. Master production and control records do not contain the strength of the product, a description of the dosage form, complete manufacturing and control instructions, sampling and testing procedures, and specifications to ensure drug product uniformity from batch to batch [21 CFR § 211.186(b)(1) and (b)(9)]. For instance, master production and control records are deficient in that they do not identify the strength and describe the dosage form of the finished drug product, CankerMelts Natural. They also fail to include the steps to be followed during the drying and foil closure/heat sealing operations and the packaging process for CankerMelts.
18. Batch production and control records do not include complete information related to the production and control of each batch, nor are they an accurate reproduction of the appropriate master production and control record [21 CFR § 211.188]. For instance,
a) the amount of [(b)(4)] for use in Avamin Melts was not specified on the batch production and control records for Lot #101;
b) the lot numbers of methylcobalamin [(b)(4)] Xylitol, and [(b)(4)] are not recorded for Avamin Melts Lot #102;
c) there is no description of the drug product containers and closures for CankerMelts and Avamin Melts on the batch production records; and
d) there is no documentation that the packaging and labeling area is inspected before and after use.
19. Automatic, mechanical, or electronic equipment is not routinely calibrated, inspected, or checked according to a written program designed to assure proper performance [21 CFR § 211.68(a)]. For instance, the mixer, scales, filling/dispensing machine, water distiller, foil heat sealing machine, drying chamber, and tablet press are not calibrated and inspected in accordance with a written program.
20. Drug products do not bear an expiration date determined by appropriate stability testing [21 CFR § 211.137(a)]. For instance, the 10-year shelf life claimed on the, labeling for the CankerMelts is not supported by stability testing performed consistent with 21 CFR § 211.166.
21. There are no written procedures describing in detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials [21 CFR § 211.122(a)]. For instance, your firm has no written procedures covering the receipt, examination, storage, and handling of labeling and packaging materials used to produce the finished drug products, CankerMelts Natural and Avamin Melts.
This inspection also revealed that your firm is marketing unapproved new drugs in violation of Section 301(d) and 505(a) of the Act [21 U.S.C. §§ 331(d) and 355(a)]. CankerMelts, Avamin Melts, and XyliMelts are drugs offered for sale as defined by section 201(g) of the Act, 21 U.S.C. § 321(g), because they are intended for the diagnosis, cure, mitigation, treatment, or prevention of disease and/or to affect the structure or any function of the body of man under section 201(g) of the Act.
Evidence of intended use for these products includes promotional statements found on your website, www.orahealth.com, where CankerMelts, Avamin Melts, and XyliMelts are offered for sale.
These claims include:
• "ACTIVE INGREDIENT (in each disc) . . . Glycyrrhiza (Licorice Root) extract (GX) 30 mg . . . INACTIVE INGREDIENTS: Hydrophilic gums and potassium . . .."
• "For ordinary mouth sores: canker sores (ophthous ulcers), sores from braces, dentures, minor cuts and abrasions . . . Heals most canker sores in 1-5 days . . . Provides anti-inflammatory relief without numbing . . . Hours of Pain Relief . . . Using CankerMelts for 6-12 hours after getting a cut from braces or biting the lip or cheek may prevent a canker sore from occurring . . .."
• "CankerMelts is the first product on the market to combine a patented time-release oral medicated patch with the natural clinically-proven remedy Glycyrrhiza (licorice) extract . . . Pain Relief (not numbing of the mouth) is achieved in roughly 10 minutes and the all-natural disc dissolves slowly in the mouth, providing 2-6 hours of time-released medication exactly in the needed spot . . .. "
• "After 7 days of use 8 hours per day, canker sores treated with CankerMelts shrank to one-tenth their original size while untreated canker sores grew larger . . .. "
• "ACTIVE INGREDIENT: Avamin (methylcobalamin) bioactive B 12 500 mcg . . . INACTIVE INGREDIENTS: Xylitol, vegetable gum, and calcium stearate . . . . "
• "All natural canker sore prevention . . . Reduces incidence, duration and pain of mouth sores . ..."
• "Natural time-release bioactive B 12 . ..."
• "Incorporates patent-pending time-release technology . . .."
• "ACTIVE INGREDIENTS: Xylitol 500 mg released over 30 to 120 minutes (carbohydrate, 1.4 calories, raises blood glucose half as much as typical carbohydrates) . . . INACTIVE INGREDIENTS: vegetable gums, natural peppermint flavor, calcium stearate, and nothing else ...."
• "Inhibits growth of unwanted bacteria ... Inhibits plaque build up . . . Natural adhering domes deliver time-released xylitol, which is clinically proven to reduce tooth decay, gum disease, plaque, dry mouth, and ear infections . . . . "
• "Reduce plaque in the mouth ... which helps reduce tooth decay, gum disease, and bad breath .. .."
•"Reduce inner ear infections (behind the ear drum) by suppressing the common causative bacteria, Streptococcus pneumoniae (SP) and Haemophilus influenzae (HI) and reducing their adherence to human tissues . . . . "
Drug products intended for indications such as those promoted for CankerMelts, Avamin Melts, and XyliMelts are being evaluated under the developing monographs for OTC Oral Health Care Drug Products within the agency's OTC Drug Review. The Tentative Final Monograph (TFM), published in the Federal Register on September 24, 1991 (56 Fed. Reg. 48302), did not include the ingredients glycyrrhiza, the active ingredient in CankerMelts, or methylcobalamin, the active ingredient in Avamin Melts, nor were these ingredients evaluated in the developing monograph. The Advance Notice of Proposed Rulemaking (ANPR), published in the Federal Register on May 29, 2003 (68 Fed. Reg. 32232), did not include the ingredient xylitol, the active ingredient in Xylimelts, nor was this ingredient evaluated in the developing monograph.
Further, we are unaware of any evidence that any products formulated and labeled like CankerMelts and Avamin Melts were marketed in the United States on or before the date of the inception of the OTC Drug Review, making them ineligible for inclusion in the agency's OTC Drug Review. Additionally, CankerMelts and Avamin Melts have not been recognized by qualified scientific experts as safe and effective for their labeled oral health care uses. Accordingly, CankerMelts and Avamin Melts are new drugs as defined by section 201(p) of the Act, 21 U.S.C. 321(p). Since CankerMelts and Avamin Melts are not the subject of approved new drug applications, their marketing in the United States violates section 505(a) of the Act, 21 U.S.C. § 355(a).
For XyliMelts, because the labeled indications, "Streptococcus pneumonia (SP) and Haemophilus influenzae," are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners, adequate directions cannot be written so that a layman can use this product safely for its intended uses. Thus, Xylimelt's labeling fails to bear adequate directions for its intended uses, causing it to be misbranded under section 502(f)(1) of the Act, 21 U.S.C. § 352(f)(1).
Moreover, FDA considers all timed-release dosage formed drug products to be new drugs under section 201(p) of the Act, because a timed-release dosage form is not generally recognized by experts to be safe and effective for any uses, 21 U.S.C. § 321(p), and 21 CFR §§ 310.3(h)(5) and 310.502. Therefore, CankerMelts, Avamin Melts, and XyliMelts, which claim to be in timed-release dosage forms, are new drugs under the Act and its implementing regulations. For this additional reason, since CankerMelts, Avamin Melts, and XyliMelts are not the subjects of approved new drug applications, their marketing in the United States violates section 505(a) of the Act, 21 U.S.C. § 355(a).
The issues and violations cited in this letter are not intended to be an all-inclusive statement of violations that exist in connection with your products. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to assure that your firm complies with all requirements of federal law and FDA. regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice, including, without limitation, seizure, and injunction. Until FDA confirms correction of the deficiencies observed during the most recent inspection, this office can recommend disapproval of any new applications listing this site as a manufacturer of drugs. Federal agencies are advised of the issuance of all Warning Letters about drug products so that they may take this information into account when considering the award of contracts.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction.
During the course of this inspection, your firm disclosed that Xylimelts are manufactured by a third-party firm. As part of your response, please include the name and address of the manufacturer of Xylimelts. If the firm from which you receive the products is not the manufacturer, please include the name of your supplier in addition to the manufacturer.
Please address your reply to the U.S. Food and Drug Administration, Seattle District Office, 22201 23rd Drive SE, Bothell, Washington, 98021-4421, to the attention of Lisa M. Althar, Compliance Officer. Should you have any questions concerning this letter, you can contact Ms. Althar at (425) 483-4940.
A description of the new drug approval process can be found on FDA's internet website at http://www.fda.gov/cder/regulatory/applications/default.htm. Amy questions you may have regarding this process should be directed to the Food and Drug Administration, Division of Drug Information (HFD-240), Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, Maryland 20857.
Charles M. Breen