Inspections, Compliance, Enforcement, and Criminal Investigations
Pragmatic Materials, Inc. 17-Jun-05
Department of Health and Human Services
Public Health Service
Cincinnati District Office
June 17, 2005
VIA FEDERAL EXPRESS
David A. Camiener, President
Pragmatic Materials, Inc.
c/o Amresco, Inc.
30175 Solon Industrial Parkway
Solon, 0H 44139
Dear Mr. Camiener:
This letter is in reference to an inspection of your firm, Pragmatic Materials, Inc., 27100 Richmond Rd., Unit 3, Solon, OH, conducted on February 8, 15 & 18, 2005, by Investigators from the Food and Drug Administration. The inspection disclosed that your firm receives active pharmaceutical ingredients (APIs) and subsequently repackages and relabels these for further distribution for use by pharmacies for compounding of drug products.
The inspection revealed significant deviations from current good manufacturing practice in the repacking and relabeling of active pharmaceutical ingredients (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)]. Section 501(a)(2)(B) of the Act requires that all drugs be manufactured, processed, packed and held according to current good manufacturing practice (CGMP).
These deviations include, but are not limited to:
1. Failure to demonstrate the adequacy of the expiration dating assigned to the APIs that are repackaged by your firm for use by compounding pharmacies. Your firm routinely assigns to your repackaged APIs, the same expiration dates provided by your API suppliers on their container labels or certificates of analysis. However, you have not demonstrated the container closure systems into which these APIs are repackaged are identical or equivalent to those in which the APIs are received. Additionally, 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 expiration period applied to these repackaged containers. For example:
a. NADH (nicotinamide-adenine dinucleotide, reduced sodium salt) - The manufacturer supplied data for a glass container with a nitrogen overlay and determined that plastic containers could not be used. Your firm repackaged this APIs into HDPE (plastic) containers and applied the same expiration date used on the original container
b. Oxytocin - The manufacturer supplied data for a glass container with nitrogen overlay. Your firm repackaged the APIs into glass containers with no nitrogen overlay.
c. Streptomycin Sulfate USP- The manufacturer supplied data for an aluminum container with an oxidation barrier film. Your firm repackaged API into a double polystyrene bag, which was tied off and placed into a plastic pail.
d. Polymyxin B Sulfate - The manufacturer supplied data for an airtight aluminum container with an intermediate polyethylene stopper and a screw cap. Your firm repackaged the API into an HDPE (plastic) bottle.
e. Gentamycin Sulfate - The manufacturer supplied data for a sealed aluminum drum with a plastic bag liner. The manufacturer gave instructions that the container must be airproof. Your firm repackaged this API into a double polyethylene bag (that was tied off) inside a plastic pail.
f. Cromolyn Sodium - The manufacturer supplied data for a sealed aluminum container with polyethylene bag liner, provided information that the product would have a stability problem if water was absorbed, and instructed that it must be kept in the original container. Your firm repackaged the API into a tied double polyethylene bag inside a plastic pail.
2. The expiration date for Cromolyn Sodium lot [redacted] was extended by 18 months based solely on tests for appearance, acidity/alkalinity, water content, and clarity of solution. The supplier reported in a November 2003 correspondence that the indicated tests to check the stability of Cromolyn Sodium include: 1) appearance, 2) potentiometric assay, 3) HPLC purity, 4) water content, and 5) clarity of solution. Your firm did not perform 2 of the 5 required tests (i.e., potentiometric assay and HPLC purity test).
3. Technical grade EDTA Disodium was repackaged and labeled as EDTA Disodium Salt, Dihydrate USP grade with a statement that it was for prescription compounding. The supplier's label stated that it was not for food or drug use. While your firm performed several USP tests for the product, you failed to perform the USP test for nitrilotriacetic acid.
4. A lot of EDTA Disodium was to be reconditioned by sifting the material to remove brown and black particulate matter. This lot was later released to a customer without documenting: a) who had performed the reconditioning, b) when it was done, c) who reviewed the work, d) whether the lot was accepted or rejected, e) quantity to inventory, or f) whether the QC review had been performed.
Please note that if your firm repackages any APIs for resale, you must establish a stability testing program designed to assure the stability characteristics of the repackaged APIs. In lieu of stability testing of the APIs in the repackaged container, your firm could provide data demonstrating that the APIs are repackaged into an equivalent container/closure system that is at least as protective as or more protective than the manufacturer's system. For example, this would include data demonstrating equivalence regarding water vapor permeation (protection against oxidation and moisture) and compatibility with the drug substance (e.g ., ingredient migration from the container to the drug substance).
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 dating assigned to your repackaged APIs.
We acknowledge the receipt of your March 10, 2005, letter in response to our Form FDA 483, Inspectional Observations. We have reviewed your response and have the following comments:
1a. NADH - Your response indicates you changed your container closure system to use a glass bottle. However, although the manufacturer packaged NADH with a nitrogen overlay, there is no indication that your firm repackages NADH with a nitrogen overlay. Additionally, although you now indicate that you are repackaging NADH into glass bottles, you provide no information indicating that the closures used by your firm on the containers of repackaged drugs are equivalent, or at least as protective as or more protective to the product than the closures used by the manufacturer. As such, your response provides no assurance that NADH is repackaged into a container- closure system that is equivalent or exceeds the protective features of the original manufacturer's container, and there is no basis for applying the manufacturer's stability data and expiration dating to the NADH repackaged by your firm.
1b. Oxytocin - You indicate you will implement changes in the packaging system based on your evaluation of the manufacturer's recommendations for a nitrogen overlay system and will implement corrective actions no later than June 30, 2005. However, you provide no commitment to cease repackaging this API until such time as these corrections are implemented.
1c. Streptomycin - You indicate that you provided documentation of a "Pressure test and Leakproofness test" to the investigators during the inspection and that they verbally communicated this test was "an acceptable packaging configuration." Our Investigators refute this statement. They indicate they saw no evidence showing: 1) your leak test is equivalent to the USP test for a tight container and 2) the plastic bag/plastic pail system would be an adequate moisture barrier, and otherwise non-reactive with the active drug substance.
1d. Polymyxin - Again, you indicate that you will investigate this matter with the manufacturer and will implement corrective action by June 30, 2005. However, you make no commitment to cease repackaging of this API until your corrective actions are implemented.
1e. Gentamycin - Again, our investigators refute your claim that they found your leak test and internal hydrostatic pressure test to be acceptable evidence of the equivalency of your plastic container to the manufacturer's aluminum container closure system.
If. Cromolyn - Again, your response makes no commitment to cease repackaging this API further until adequate stability data are obtained to support the labeled expiration date.
Regarding the Cromolyn Sodium lots [redacted] extension of expiration date by 18 months, we have reexamined the November 4, 2003 letter supplied by your supplier. This was the documentation provided to our investigators to support your 18 month extension of the expiration date.
The document states:
" .. . Cromolyn Sodium is stable for at least five years if packed and stored in the relevant product DMF Nevertheless the material needs to be retested after 18 months from production and can be used if the results are within specifications reported in the product certificate of analysis. This can also apply to material which is older that (sic) 5 years . . .(The supplier) can therefore guarantee the quality of the product if the . . . tests performed just before the use of the product comply with the specification in . . . DMF."
Based upon a plain reading of this letter, we do not interpret this document to mean that the expiration date can be extended for an additional 18 months if it can pass the specified stability protocol. Rather, taken literally, this statement implies that the product must be tested after 18 months from the date of production or " . . .just before use of the product. . ." if it has passed the 5 year expiration date, in order to assure that it will comply with the specifications.
It appears that this letter was intended to provide instructions to the end user that the product should be retested immediately before use if it is older than 18 months from production . It does not appear to be intended for establishing stability criteria for a repackager that utilizes an entirely different container closure system from the original container closure system.
Technical Grade EDTA repacked and labeled as USP. In order to be labeled as "USP" the product must not only be able to pass USP finished product testing but must be manufactured in accordance with current good manufacturing practice (CGMP). These CGMP controls distinguish the official compendial "USP" products from the "Technical Grade" products. Please refer to the applicable section(s) in the current United States Pharmacopoeia (e.g., General Notices - Ingredients and Processes).
Your response to the fourth item on the Form FDA 483 concerning the removal of black and brown particulates from a specified lot of EDTA Disodium does not address the underlying failure of your quality system to perform and document adequate out-of-specification investigations and subsequent corrective actions for a non-conforming product lot.
Your letter also requests copies of the full establishment inspection report and digital images of all photographs taken by the Investigators. FDA normally provides courtesy copies of establishment inspection reports to firms after an inspection has concluded and the regulatory file has been closed. These copies would not automatically include digital copies of photographs taken during the course of the inspection. You may submit a written Freedom of Information Act (FOIA) request via facsimile (fax) or mail to:
U.S. Food & Drug Administration
Division of Freedom of Information
5600 Fishers Lane, Room 12A16 (HFI-35)
Rockville, Maryland 20857
Fax: (301) 443-1726
The above violations are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to assure that all 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.
We request you take prompt action to correct these violations. 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 provides for the seizure of adulterated products and for injunction against the repacker and distributor of adulterated products.
Please notify this office in writing within fifteen (15) working days of receipt of this letter as to the specific steps you have taken to correct the stated violations, including an explanation of each step being taken to identify and make corrections to assure that similar violations will not recur. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the time within which the corrections will be implemented.
Your reply should be sent to the attention of Charles S. Price, Compliance Officer, U.S. Food and Drug Administration, 6751 Steger Drive, Cincinnati, Ohio 45237-3097. If you have any questions regarding this letter, you may call Mr. Price at telephone (513) 679-2700 extension 165.
Carol A. Heppe