| Public Health Service Food and Drug Administration |
| San Juan District 466 Fernandez Juncos Avenue San Juan Puerto Rico 00901-3223 Telephone: 787-474-9500 FAX: 787-729-6851 |
Department of Health and Human Services
WARNING LETTER
11-SJN-WL-04
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
January 20, 2011
Mr. Robert L. Parkinson
Chairman, President, and CEO
Baxter Healthcare Corporation
One Baxter Parkway
Deerfield, IL 60015-4633
Dear Mr. Parkinson:
During our July 14 to August 26, 2010 inspection of your pharmaceutical manufacturing facility, Baxter Healthcare Corporation, located at No. 250 Road No. 144 Jayuya, Puerto Rico, investigators from the 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.
The inspection at Jayuya, Puerto Rico, also identified that your products are misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)].
In addition, the inspection at Jayuya, Puerto Rico, and our September 21 - 30, 2010 inspection at the Baxter Healthcare Corporation, located at Route No. 3 KM 142.5 Guayama, Puerto Rico, identified your firm’s failure to submit NDA Field Alert Reports (FARs) to the FDA as required by 21 C.F.R. § 314.81(b)(1)(i) and (ii), and section 505(k) of the Act [21 U.S.C. § 355(k)].
We have reviewed your firm’s response of September 15, 2010, and October 20, 2010, and note that they lack sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
I. The Jayuya Facility (Puerto Rico)
A. CGMP Violations
1. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].
For example, investigations, (b)(4) and (b)(4) identified an equipment malfunction as the root cause of discolored product. These investigations did not address the possibility of carryover of solution due to the equipment malfunction. Additionally, the investigations did not extend to other lots manufactured on the non-dedicated filling line. Subsequently, your firm released 17 lots of product that were at risk of cross contamination to the market.
Furthermore, your firm failed to thoroughly investigate and correlate consumer complaints for discolored drug product distributed by your firm. On September 7, 2010, your firm initiated a recall of 17 lots of drug product associated with the equipment failure but only after our inspection identified deficiencies in your investigation and management of consumer complaints. Your firm identified the root cause of the discoloration that occurred on October 30, 2009, approximately one year prior to initiating a recall.
Lastly, your investigation concluded that the administering health care professionals (i.e., pharmacist, nurse, or physician) would identify any discoloration and prevent the usage of the drug product. It is unacceptable to rely upon the health care professional to fulfill your Quality Control Unit responsibilities.
This is a repeat observation from the March 2008 inspection.
2. Your firm failed to ensure your container closure system provided adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product [21 C.F.R. § 211.94(b)].
For example, your firm identified 542 incidences through consumer complaints of product defects such as, leaks, bursts, and premature activation during the period of January 2008 to August 2010. These are critical defects that can impact sterility and stability of your product. Your firm identified that the probable cause was the result of defective materials used in the manufacture of the container closure system.
Your response is not adequate since the sampling plans described are not based on appropriate statistical criteria to sufficiently identify these known potential defects, especially given the history of the supplier for this container closure system.
Furthermore, your final product inspection procedure and use of a (b)(4) does not appear to be effective in preventing shipments of product with critical defects to the marketplace. Additionally, our data indicates there may be other cases of foreign substances in products manufactured at your facility such as an insect found in the intravenous solution of Sodium Chloride and dirt reported inside of (b)(4) and the (b)(4) of Travasol®. Please provide an evaluation of the suitability of any of these potentially affected lots.
B. Misbranding
Besides the approved labeling of your products, you developed and distributed a color chart to provide instructions to the end user when to use or not to use your products based on the discoloration of the solution. During the inspection, our investigator requested information provided to the FDA in relation to the subject color chart. No analytical data was provided in support of the color chart development, nor was this labeling submitted as part of the New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) process as a supplement. The failure to do renders your product(s) misbranded under section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)], because the approved labeling fails to bear adequate directions for use. The end user should not be expected to make a determination of product safety and effectiveness based on a color chart that was not reviewed and approved by the Agency. It is your responsibility to ensure that your products comply with their predetermined specifications to ensure their quality, safety, and effectiveness.
II. The Jayuya and Guayama Facilities (Puerto Rico)
A. Post Marketing Reports
1. Your firm failed to submit NDA Field Alert Reports (FARs) within three (3) working days of receipt of information concerning a product defect. This includes any bacteriological contamination, any significant chemical, physical, or other change, any deterioration in the distributed drug product, or any failure of one or more distributed batches of drug product to meet the specifications established for it in the application [21 C.F.R. §314.81(b)(1)(ii)]. For example:
Since February 2010, your Jayuya facility has received approximately 43 incidences of consumer complaints related to discoloration in your product 15% Clinisol Sulfite Free (Amino Acid) Injection, 500 ml, lot # P244269. The complaint reports document variability in color intensity of the product from dark yellow to dark brown. Although an internal investigation confirmed a correlation between the broken damper and the discolored amino acid samples solutions, no FAR was submitted to the Agency as required under the regulations.
In 2001, your Guayama facility became aware of a product defect with its inhalation anesthesia Suprane: discoloration and particulate matter. Your firm began receiving complaints in 2004 and has received at least 199 complaints since then.
Beginning in 2008, your firm has received at least 39 complaints regarding particulate matter in the product prompting a Health Hazard Assessment for these problems in 2009. Again, no FAR was submitted to the Agency as required under the regulations.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facilities. 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. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations within your corporation.
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. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
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 and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction.
Your reply should be sent to the following address: Food and Drug Administration, Attention: Carlos A. Medina, Compliance Officer, 466 Fernández Juncos Avenue, San Juan, Puerto Rico 00901-3223.
Sincerely,
/S/
Maridalia Torres
San Juan District Director
cc:
Mr. Eladio Alvárez, Plant General Manager
Baxter Healthcare SA
PO Box 518
Jayuya PR 00664
Mr. Eidiol Ghigliotty, General Manager
Route No. 3 Km. 142.5
PO Box 1290
Guayama, PR 00785
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