INTERNATIONAL LABORATORIES (CANADA) LTD RECEIVES FDA (CDER) WARNING LETTER (10/23/12)

NO FDA EXPORT BAN (REFUSAL OF ADMISSION) IS ISSUED

The FDA conducted an inspection of International Laboratories from February 13 – 16, 2012 at their facilities in Calgary, Alberta.  While the Company responded within 15 business days, the responses to the audit were unsatisfactory and a Warning Letter containing five Observations was issued.

Selected cGMP violations are listed below and include:

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.

COMMENT 

In-coming components, i.e., raw materials, containers and closures, require that sampling plans be established (ASQ), to determine frequency and quantity for testing as well as whether skip lot testing may be initiated.  Critical components suppliers should receive periodic on-site visits, and other less critical vendors be visited on a periodic basis as required.  In addition, finished drug products may include a requirement for validation of both analytical and/or microbiological methods.   

Identity testing usually is initiated during the development of Phase 1, 2 and 3 – such that by the initiation of the PAI, all raw materials should be qualified.  Following the establishment of each raw material which typically requires three unique lots, a plan should be in place to permit specific identity testing to assure the C of A can be confirmed.  Plans should be in place to assure that an approved and detailed rationale is followed with all components.  

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:

1. Your firm has not established finished product specification for your (b)(4) product.

2.  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. 

COMMENT 

Observation #2 mimics Observation #1 in many of its features, but now requires drug product specifications as well as identity and assay for the Active Pharmaceutical Ingredients (API).  Observations #1 and #2 also request a retrospective review of retain samples of drug components previously used in the manufacture of drugs as well as provide testing results for retain samples of all drug product lots. 

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:

1. Your firm has not established standard operating procedures (SOPs) describing the responsibilities of the QCU.
2. There is no QCU oversight for the review of finished products before release and distribution.
3. Your firm has not established specifications for the release of drug product components.
4. 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.

COMMENT 

Standard Operating Procedures (SOPs) and/or Policies describing the responsibilities of the Quality Control Unit are basic requirements for any pharmaceutical manufacturing operation.  One must inquire as to how product is being released if the QCU has no oversight for the review and release of finished product. 

As previously noted within Observations 1 and 2 above, specifications for the release of drug product components must be established and procedures for testing the various components used in the manufacturing and testing of drug products must be followed. 

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.

COMMENT

On-going cGMP training is essential to assure that Observations 1 – 4 can be effectively executed. 

Please visit the complete Warning Letter at http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm326621.htm