Department of Health and Human Services
Public Health Service
Minneapolis District Office
September 8, 2006
Refer to MIN 06 – 36
RETURN RECEIPT REQUESTED
John R. Hawkins
Chairman and CEO
3 100 E . Hennepin Avenue
Minneapolis, MN 55413
Dear Mr. Hawkins:
On March 28-31 and April 5, 7, and 10, 2006, an investigator from the Food and Drug Administration (FDA) inspected Hawkins, Inc., located at 3100 E. Hennepin Avenue, Minneapolis, MN. The inspection disclosed that your firm receives active pharmaceutical ingredients (API) from manufacturers and distributors, and that you subsequently repackage and re-label these for further distribution for use by pharmacies for compounding of drug products.
The inspection revealed significant deviations from current good manufacturing practice (CGMP) in the repacking and re-labeling of APIs. These deviations cause these APIs 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 they are not manufactured and held according to CGMPs.
These deviations include, but are not limited to:
1. Failure to demonstrate the adequacy of the retest dating assigned to the 155 APIs that are repackaged by your firm for use by compounding pharmacies. Your firm routinely assigns to your repackaged APIs retest dates that are either provided by your API suppliers on their certificates of analysis (COA), derived from expiration dates provided by your API suppliers on their COAs, or derived from stability data provided by API manufacturers. The retest date assigned by your firm is stated in the certificate of quality (COQ), a COA (which you term COQ, as hereinafter referred to as COQ) you include with the repackaged APIs. However, you have not demonstrated that the container closure systems into which these APIs are repackaged are identical or equivalent to those in which the APIs are received.
Furthermore, in the absence of any container-closure equivalency data, there is no stability testing program designed to assure that these APIs will be stable throughout the retest period indicated on your COQs. For example:
a. Acyclovir HCL – The manufacturer supplied stability data for polyethylene bags sealed in triple laminate aluminum bags, which then were stored in closed, fiber board drums. Your firm repackaged this API into HDPE (plastic) containers. In addition, you assigned a 5-year retest date to this repackaged API, contrary to the 3-year expiration date determined by the manufacturer.
b. Amitriptyline HCL – The manufacturer supplied stability data for polyethylene bags placed in an aluminum laminate bag. Your firm repackaged this API into HDPE containers and assigned a retest date equal to the expiration date determined. by the manufacturer.
c. Cyclosporine A – The manufacturer supplied stability data for heat-sealed double polyethylene bags with a 1-gram desiccant canister between the first and second double polyethylene bags, which then were encased in an aluminum can in a foil bag. Your firm repackaged this API into HDPE containers and assigned a retest date equal to the expiration date applied by the manufacturer.
d. Dexamethasone Sodium Phosphate – The manufacturer supplied stability data for transparent polyethylene bags with outer packing of black colored polyethylene bags. Your firm repackaged this API into HDPE containers and assigned a retest date equal to the expiration date determined by the manufacturer.
e. Gentamicin Sulfate – The stability data provided for this API had no information regarding the container/closure system, nor was any expiration or retest date indicated in the stability data. Your firm repackaged this API into HDPE containers which are irradiated after repackaging. You assigned retest dates that you indicate were based on retest dates determined by stability studies performed by the API supplier. These stability studies were for a different container-closure and performed prior to this additional manufacturing step (irradiation).
2 . Failure to show on the COQ that you issue with the repackaged APIs the name, address, and telephone number of the laboratory that performed the analysis. Furthermore, you fail to reference on your COQs the name and address of the original manufacturer and the original batch certificate, which you fail to attach to the new certificate of analysis.
3. Failure to validate the authenticity of supplier’s COAs of a periodic basis in lieu of full compendia testing of APIs that you package.
4. Failure to conduct audits of contract laboratories that perform testing-of-incoming API. Your SOPs indicate that these audits are to be conducted every two years.
5. Failure to maintain written procedures that describe the responsibilities and procedures applicable to the quality control unit.
6. Failure to retain reserve samples of each batch of each API that you repackage. There were a number of instances your firm received complaints regarding product integrity. Your firm failed to conduct complete investigations into these complaints regarding the APIs that you repackage because no reserve samples were available to examine.
7. Failure to document that the pre and post-filters on the air handling units in your repackaging suites are changed according to the frequency specified in your SOP.
Please note that if your firm repackages any APIs for resale, your firm must establish a stability testing program designed to determine appropriate retest/expiration dates for the repackaged APIs. In lieu of stability testing, your firm can use the manufacturer’s original retest/expiration date provided that you obtain and have on file data demonstrating that the API(s) is repackaged into an equivalent container/closure system that is at least as protective as or more protective than the manufacturer’s original container-closure system. This would include data demonstrating equivalence (for protection against oxidation, moisture and light) and to ensure compatibility with the container-closure system (e .g., plastic bottle). System equivalency would also extend to any special protective materials, such as container seals or desiccants associated with the original container-closure system in which the API is marketed. Additionally, there must be appropriate controls in place to prevent any inappropriate exposure of the API to oxygen, moisture or light during repackaging operations. Your firm could then utilize the retest/expiration date(s) on the manufacturer’s original container-closure system.
There was no documentation available to demonstrate that the expiration dates assigned to your repackaged APIs were appropriate because there were no data to demonstrate equivalence of the container-closures used by your firm with the original container-closure systems used by your suppliers of the APIs. Additionally, in the absence of any container-closure equivalency data, there was no independent stability data to support the validity of the expiration date assigned to your repackaged APIs.
We acknowledge receipt of your April 21, 2006, letter in response to the Form FDA-483, Inspectional Observations, in which you concur with the observations in the Form FDA-483 and promise corrections. As a general comment, please note that because no documents were provided to support your proposed corrective actions, the effectiveness of these corrections can be evaluated only during a future inspection. We have reviewed your response and have the following comments.
Observations 1 and 2
Your response indicates that your firm intends to have a first draft of a new stability plan completed by May 31, 2006, and that your firm would like to submit the plan to our office for review and comment prior to implementation. We are amenable to reviewing your firm’s plan, however, the proposed plan should include specific timeframe for completion. The effectiveness of your plan cannot be evaluated until after you have successfully implemented the complete plan and FDA has had an opportunity to observe the corrections during a future inspection of your facility.
Although not provided, your response indicates that a procedure for collecting and retaining samples of repackaged API will be implemented by July 31, 2006. You should describe and fully document your procedures for obtaining and storing retain samples of your repackaged API.
The corrective action, if implemented as proposed, appears to address this observation. However, the response does not specifically describe the additional training that will be given to all employees.
The response does not completely describe the changes to your complaint handling system. In addition, the response does not specifically describe the training that will be given to employees.
The above violations are not intended to be an all-inclusive list of deficiencies at your facility. As Chairman and CEO of your company, you are responsible for ensuring that all of your drug products are in compliance with the Act and its implementing regulations. Federal agencies are advised on the issuance of all Warning Letters about drugs and devices so that they may take this information into account when considering the award of contracts.
You should take prompt action to correct the above violations and to establish procedures whereby such violations do not recur. Failure to promptly correct these violations may result in enforcement actions being initiated by the Food and Drug Administration without prior notice. The Federal Food, Drug, and Cosmetic Act V provides for the seizure of adulterated products and for injunction against the repacker and distributor of adulterated products.
You should be aware that the FDA has concerns about the sterilization of drugs via irradiation. Although the current inspection did not specifically focus on your processing of Gentamicin Sulfate, we suggest that you evaluate this processing in light of the regulation found at Title 21, United States Code of Federal Regulations (21 CFR), Section 310.502 entitled: Certain drugs accorded new drug status through rulemaking procedures, particularly 21 CFR 310.502(a)(11).
You should notify this office in writing of the steps you have taken to bring your firm into compliance with the law within fifteen working days of receiving this letter. Your response should include each step that has been taken or will be taken to correct the violations and prevent their recurrence. If corrective action cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be completed. Please include copies of any available documentation demonstrating that corrections have been made.
Your written response should be sent to Brian D. Garthwaite, Ph.D., Compliance Officer, at the address in the letterhead. If you have any questions about this letter, please contact Dr. Garthwaite at (612) 758-7132.
W. Charles Becoat
This page was posted on November 8, 2008.