International Laboratories (Canada) Ltd. 10/23/12
| || |
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||Silver Spring, MD 20993 |
VIA UPS MAIL
October 23, 2012
Mr. Erik Larsen
International Laboratories (Canada) Ltd.
63 Skyline Crescent NE
Calgary, Alberta T2K 5X2
Dear Mr. Larsen:
During our February 13 through 16, 2012, inspection of your pharmaceutical manufacturing facility, International Laboratories (Canada) Ltd. located at 63 Skyline Crescent NE, Calgary, Alberta, investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug product(s) 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 manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We acknowledge receipt of your firm’s correspondence dated April 2, 2012.
Our investigator(s) observed specific violations during the inspection, including, but not limited to, the following:
1. Your firm has not established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals [21 C.F.R. § 211. 84(d)].
For example, the inspection found the following regarding components used in the manufacture of drug products:
a. Your firm accepts and relies upon the suppliers’ Certificates of Analysis (CoAs) for drug components without conducting adequate vendor qualification.
b. Your firm does not conduct specific identity tests of incoming components to be used in drug product manufacture.
Without establishing the reliability of vendors, there is no assurance that drug product components, containers or closures are appropriate for their intended use. In your response to this letter, please provide a detailed plan to establish vendor qualification for drug components, containers and closures. The plan should include standard operating procedures and test methods. Your response should also include plans for implementation of specific identity tests for all incoming components to be used in the manufacture of drug products, including a timeline for validation of each of the analytical methods. Also, provide specific plans for ongoing (b)(4) quality testing that will ensure that (b)(4) used in your finished drug products is appropriate for its intended use. Finally, include a plan for an appropriate retrospective review of retain samples of drug components previously used in manufacture of drugs at your facility.
2. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. [21 C.F.R. § 211.160(b].
Two examples of this violation include:
a. Your firm has not established finished product specifications for your (b)(4) product.
b. Your firm did not have identity and assay test procedures for the (b)(4) finished product.
In response to this letter, provide copies of all drug product specifications, as well as sampling plans and all test methods including the identity and assay for (b)(4) active pharmaceutical ingredients. Provide a plan for validating the accuracy, sensitivity, specificity, and reproducibility of each test method that will be employed. Your firm should also include a plan to promptly address the quality of lots already on the US market. At minimum, you firm should promptly provide testing results for retain samples of all drug product lots within expiry and distributed to the US.
3. Your quality control unit (QCU) has not approved or rejected all procedures or specifications impacting the identity, strength, quality, and purity of the drug product. Secondly, the QCU lacked the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products. Finally, the QCU failed to exercise its authority to review production records to assure that no errors occur or, if errors occur, that they are fully investigated. [21 C.F.R. § 211.22].
Four examples of this violation include:
a. Your firm has not established standard operating procedures (SOPs) describing the responsibilities of the QCU.
b. There is no QCU oversight for the review of finished products before release and distribution.
c. Your firm has not established specifications for the release of drug product components.
d. Your firm has not followed the procedure for testing (b)(4) used in the manufacture of drug products.
In response to this letter, provide your SOP for the QCU and specifications for drug product components, containers, and closures. When preparing your SOPs, please note that a CGMP-compliant quality system supports a sustainable state of control. This includes but is not limited to systems to ensure proper raw materials, vigilant quality monitoring, and appropriate corrective and preventive actions. FDA expects your firm to perform a comprehensive assessment of manufacturing operations to ensure that drug products conform to FDA requirements.
4. The master production and control records did not contain all the information necessary for the manufacture of the product and specifically required by regulation [21 C.F.R. § 211.186(b)].
Three examples include:
a. The master production record does not include an accurate statement of weight for each component.
b. The master production record does not include a statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which an investigation is required.
c. The control records do not contain complete manufacturing and control instructions, sampling and testing procedures, special notations or precautions to be followed.
We also note that your firm has not established a change management program for manufacturing operations. In your response, provide copies of your revised master production and control records, as well as your change management procedures.
5. Your firm failed to ensure that employees received training in current good manufacturing practices, as well as in particular operations assigned to the employees [21 C.F.R. § 211.25(a)].
Your employees were not adequately trained in CGMPs as evidenced by the deficiencies listed in this letter. In your response to this letter, provide a plan to develop an ongoing and robust CGMP training program for your personnel, including an explanation of how you will assess training effectiveness.
In addition to the items listed above, the investigator found other deficiencies that lead us to question the effectiveness of your current quality system to achieve overall compliance with CGMP at your over-the-counter (OTC) drug product manufacturing facility. For example, there is no procedure for evaluating drug product containers and closures. We recommend that you seek the advice of a third-party consultant for assistance with a comprehensive evaluation to determine the improvements that you will need to make to meet the CGMP requirements for the manufacture of drug products.
COSMETIC LABELING VIOLATION
Your firm failed to list the (b)(4) net contents in terms of (b)(4) pound and ounce, or the U.S. gallon, quart, pint, and fluid ounce [21 C.F.R. § 701.13(c)].
Specifically, the net contents is listed only in metric units. Metric units may be included along with the English units.
Please note, the product's website, (b)(4) which appears on the product label, contains claims, such as (b)(4). This claim presents the inactive ingredient (b)(4) as an active ingredient as defined under 21 C.F.R. § 201.66(b)(2). (b)(4) is not considered an active ingredient under the OTC monograph rulemaking for external analgesics. In addition, the website includes claims for uses, such as "anti-inflammatory" and "pain due to tendinitis," that are also not addressed under the OTC monograph rulemaking for external analgesics. Such claims should be revised so that the product remains subject to the OTC Drug Review rather than the "new drug" provisions of the Act.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, your failure to correct these violations may result in FDA refusing admission of articles manufactured at 63 Skyline Crescent NE, Calgary, Alberta into the United States. The articles are subject to refusal of admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).
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 and prevent the recurrence of violations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug product(s) at issue, provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3005256547.]
Please send your reply to the following address:
Allison A. Aldridge, Ph.D.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51, Room 2258
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-0483
Fax: (301) 847-8741