DATE

EVENT

1972

Per Baxter, SPL is first listed as an approved supplier of heparin for ESI Lederle (ESI), a division of Wyeth, later acquired by Baxter. (03/05/08 Baxter: Heparin Press Update.)

1976

Per SPL, SPL is created by Oscar Mayer to process pancreatin and heparin. (It is later sold to various companies including A.H. Robins [1983], AHP [1989], Wyeth [2002], Arsenal Capital Partners [2004], and American Capital Strategies [2006]). (SPL timeline: http://www.spl-pharma.com/timeline.htm)

1990s

SPL begins to explore sourcing its crude heparin from China . (03/05/08 Baxter: Heparin Press Update.)

1996

SPL begins producing regular shipments of finished heparin API processed at its Wisconsin facility and sourced from Chinese crude heparin material. (03/05/08 Baxter: Heparin Press Update.)

1999

SPL creates a joint venture with Techpool Bio-Parma Co., Ltd. called Changzhou-SPL (“SPL-CZ”), (which later opens a facility in China for processing crude heparin). (SPL timeline: http://www.spl-pharma.com/timeline.htm and 03/05/08 Baxter: Heparin Press Update.)

SPL contends that they discussed the Changzhou joint venture with the FDA. (04/29/08 Written Testimony of David G. Strunce before Comm. On Energy and Commerce.)

2000

SPL builds a heparin API manufacturing facility in Changzhou , China . (04/29/08 Written Testimony of Robert L. Parkinson before Comm. on Energy and Commerce.)

March, 2000

SPL contends that it formally notified the FDA of the SPL-CZ joint venture. (04/29/08 Written Testimony of Robert L. Parkinson before Comm. on Energy and Commerce.)

June, 2002

Baxter signs a definitive agreement to acquire ESI Lederle (ESI), a division of Wyeth, which receives their API from SPL for approximately $305 million. (03/05/08 Baxter: Heparin Press Update;12/20/02 Baxter: “Baxter Completes Its Acquisition of ESI Lederle;” 10/17/02 Baxter: “Baxter’s Sales, Earnings to Grow in Third Quarter”)

Dec. 12, 2002

Baxter acquires ESI for approximately $305 million in cash (03/05/08 Baxter: Heparin Press Update; 12/20/02 Baxter: “Baxter Completes Its Acquisition of ESI Lederle”)

As part of the agreement, Baxter acquired ESI Lederle's generic injectable products and patent-expired branded products, such as Phenergan® (promethazine), Ativan® (lorazepam), heparin, midazolam and fentanyl to expand its anesthesia and critical care portfolio. Baxter also acquired the 330,000-square-foot facility for manufacturing injectable, small-volume drugs located in Cherry Hill , New Jersey , and 1,000 employees. (12/20/02 Baxter: “Baxter Completes Its Acquisition of ESI Lederle” and 10/17/02 Baxter: “Baxter’s Sales, Earnings to Grow in Third Quarter”)

Wyeth Global Compliance begins the first audit of the SPL-CZ facility. (03/05/08 Baxter: Heparin Press Update.)  The 2002 inspection, however, is only for manufacturing two drugs: a simple, well-known, and well-characterized diuretic, hydrochlorothiazide, and a simple, semi-synthetic antibiotic, doxycycline.  (The manufacturing process for each of these drugs is very different from the extraction process required to produce crude heparin, which is not produced until 2004.) (04/29/08 Written Testimony of David Nelson, Senior Investigator for the Committee on Energy and Commerce )

2002

SPL contends that it submitted DMF detailing the quality control and manufacturing processes for heparin API produced at the SPL-CZ facility to the FDA. (04/29/08 Written Testimony of Robert L. Parkinson before Comm. on Energy and Commerce.)

2003

Wyeth’s Global Compliance Division finishes conducting its qualification audit of SPL-CZ. (03/05/08 Baxter: Heparin Press Update.)

Sept. 2003

Baxter contends it conducted a plant inspection of the SPL-CZ facility. (03/05/08 Baxter: Heparin Press Update.)

Feb. 6, 2004

Baxter submits a NDA Prior Approval Supplement (“PAS”) for use of the SPL-CZ facility as an alternate supplier for heparin API.  Baxter’s NDA PAS references the Drug Master File (“DMF”) that SPL submitted to the FDA for the SPL-CZ facility. (03/05/08 Baxter: Heparin Press Update and 04/29/08 Written Testimony of Robert L. Parkinson before Comm. on Energy and Commerce.)

June 8, 2004

Per Baxter, the FDA sends letter approving SPL-CZ as an alternate supplier for heparin. (03/05/08 Baxter: Heparin Press Update.)  It is later learned, however, that prior to said approval, the FDA failed to inspect the Chinese facility that did not have any history of producing a complex, biological-based product for exportation to the United States . (04/29/08 Written Testimony of David Nelson, Senior Investigator for the Committee on Energy and Commerce )

Baxter’s records indicate that they were aware that this plant had never been inspected by the FDA. (04/29/08 Written Testimony of David Nelson, Senior Investigator for the Committee on Energy and Commerce )

Nov. 2004

The SPL-CZ facility first begins to process crude heparin for Baxter. (03/05/08 Baxter: Heparin Press Update.)

Sept. 20, 2007

Baxter claims to have performed an audit of the SPL-CZ facility and approves its continued production of API pending satisfactory responses to the observations included in the report, (which SPL-CZ produces on 01/19/089.) (03/05/08 Baxter: Heparin Press Update.)  (However, the results of this audit differ significantly from those reported by the FDA, which inspected the Chinese facility only five months later and found multiple serious violations so severe that all imports were halted from the facility. (04/29/08 Written Testimony of David Nelson, Senior Investigator for the Committee on Energy and Commerce )

Nov. 19, 2007

Pediatric hemodialysis patients at St. Louis Children's Hospital begin to experience allergic-type reactions. (CDC MMWR Report: “Acute Allergic-Type Reactions Among Patients Undergoing Hemodialysis --- Multiple States, 2007—2008.”)

End of Dec. 2007

Baxter purposes to have first noticed an increase in the rate of allergic-type reactions associated with its 1,000 unit/ml 10 ml and 30 ml multi-dose heparin products, “as part of [its] normal pharmacovigilance process.” (03/05/08 Baxter: Heparin Press Update)  Baxter is notified of problems by physicians (other than Dr. Alex Elward at St. Louis Children’s Hospital, see 01/04/08 entry below) and some dialysis centers notify equipment makers, thinking it is a problem with contaminated dialysis machines. (03/13/08 Baltimore Sun, “MD. Native’s expertise led to drug recall.”) 

Jan. 4, 2008

St. Louis Children's Hospital call in its infectious-disease specialist, Dr. Alexis Elward, to diagnose a mysterious spike in allergic reactions to kidney dialysis. (03/13/08 Baltimore Sun, “MD. Native’s expertise led to drug recall.”) 

Baxter contends that it begin an investigation of heparin adverse events at this time. (03/05/08 Baxter: Heparin Press Update.)

Jan. 7, 2008

The Missouri Department of Health and Senior Services (MDHSS) notifies the CDC of the allergic-type reactions among pediatric hemodialysis patients since November 19, 2007, at St. Louis Children’s Hospital. The CDC then solicits reports of similar allergic-type reactions among hemodialysis patients nationally through nephrology e-mail lists and public health notifications. (CDC MMWR Report: “Acute Allergic-Type Reactions Among Patients Undergoing Hemodialysis --- Multiple States, 2007—2008.”)

Jan. 08, 2008

Baxter’s pharmacovigilance group travels to Fargo , ND to investigation adverse events. (03/05/08 Baxter: Heparin Press Update.)

Jan. 09, 2008

In response to its case-finding measures, CDC is contacted by an unidentified dialysis supply company that had received reports during the previous 2-week period of approximately 50 similar reactions among adult hemodialysis patients at dialysis facilities in six states. A second unidentified supply company reports learning of similar reactions from dialysis facilities as early as December 10, 2007. CDC alerts the Food and Drug Administration (FDA) to the nationwide reports of allergic-type reactions. (CDC MMWR Report: “Acute Allergic-Type Reactions Among Patients Undergoing Hemodialysis --- Multiple States, 2007—2008.”)

Baxter places inventory for both the 1,000 unit/mL 10 mL and 30mL products on hold. (03/05/08 Baxter: Heparin Press Update.)

Jan. 11, 2008

Baxter contacts the FDA about increased adverse drug experience reports at some dialysis centers. (03/05/08 Baxter: Heparin Press Update.)

Jan. 14, 2008

Baxter suspends the manufacturing of its 1,000 unit/mL multi-dose products. (03/05/08 Baxter: Heparin Press Update.)

Jan. 16, 2008

Baxter communicates additional complaints to the FDA and informs that it is initiating a recall. (03/05/08 Baxter: Heparin Press Update.)

Jan. 17, 2008

Baxter issues a press release recalling nine lots of Heparin Sodium Injection multiple-dose vials in 1000 units/mL concentrations of 10mL and 30mL vials, 5000 units/mL concentration of 10mL vials, and 10,000 units/mL for 4mL vials. (01/25/08 Baxter News Release, “Baxter Issues Urgent Nationwide Voluntary Recall of Heparin 1,000 Units/ML 10 and 30mL Multi-Dose Vials.”)

Baxter issues its first “Customer Letter” to heparin “customers/wholesalers/distributors.” (01/17/08 Baxter Customer Letter)

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 18, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 19, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 22, 2008

Baxter issues its second “Customer Letter” to “dialysis center nephrologists.” (01/22/08 Baxter Customer Letter)

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 23, 2008

Baxter issues its third “Customer Letter” to “renal home patients.” (01/23/08 Baxter Customer Letter)

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 24, 2008

Baxter issues its fourth “Customer Letter” with an update to heparin “customers/wholesalers/distributors.” (01/24/08 Baxter Customer Letter)

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 25, 2008

Baxter and FDA issues a press release regarding Baxter’s recall. (01/25/08 Baxter News Release, “Baxter Issues Urgent Nationwide Voluntary Recall of Heparin 1,000 Units/ML 10 and 30mL Multi-Dose Vials.” and FDA 1/25/08 Press Release: “Baxter Issues Urgent Nationwide Voluntary Recall of Hepain 1,000 Units/ml 10 and 30ml Multi-Dose Vials;”)

Jan. 27, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 28, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 29, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 30, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Jan. 31, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 1, 2008

CDC posts its MMWR (Morbidity and Mortality Weekly Report) “Acute Allergic-Type Reactions Among Patients Undergoing Hemodialysis --- Multiple States, 2007—2008” reporting on the outbreak of acute allergic-type reactions among patients who have undergone hemodialysis since November 19, 2007.

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 4, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 6, 2008

Baxter contends that it contacted the FDA to report that the company was contemplating an expanded recall on the multi-dose vials. (03/05/08 Baxter: Heparin Press Update.)

Feb. 7, 2008

Baxter initiates hold on all single and multi dose vials. (03/05/08 Baxter: Heparin Press Update.)

Feb. 8, 2008

Baxter reports to the FDA that there had been 348 unique adverse reaction case reports, with 94% of the reports related to 1,000 unit mulit-dose vials, 4% related to the 5,000 unit and 10,000 unit multi-dose vials, and 2% of the reports related to the 5,000 unit single dose vial (8 total).  Three of these eight single dose reports concerned situations where multiple singe dose vials were used to create a large bolus dose. Since Baxter supplies approximately half of the multi-dose vials of heparin used in the U.S. , Baxter & the FDA decide not to proceed with an expanded recall. (03/05/08 Baxter: Heparin Press Update.)

Feb. 9, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 11, 2008

Baxter and FDA issue press releases indicating that Baxter has temporarily stopped manufacturing multiple-dose vials of injectable heparin due to the potentially life-threatening adverse and allergic reactions and incidents of hypotension that were reported and re decision not to proceed with expanded recall. (Baxter 2/11/08 News Release, “Baxter Provides Update on Heparin Reactions.” and FDA 2/11/08 Press Release: “Baxter’s Multiple-dose vial Heparin Linked to Severe Allergic Reactions.”)

FDA also holds its first press conference on the same issue, (2/11/08 FDA Press Conference Transcript), issues a Public Health Advisory and posts a “Question and Answers” webpage.

Baxter issues its fifth and sixth “Customer Letters” to renal home patients and health care professionals entitled “Important Heparin Safety Information.” (02/11/08 Baxter Customer Letter to Renal Home Patients and 02/11/08 Baxter Customer Letter to Health Care Professionals)

Feb. 13, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 14, 2008

Zoll, Kranz & Borgess, LLC is the first law firm in the nation to file suit against Baxter Healthcare Corporation and other related companies regarding the contaminated heparin. (For sample complaint, click here.)

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 15, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 18, 2008

FDA holds its second heparin press conference. (2/18/08 FDA Press Conference Transcript.) The FDA admits that the SPL-CZ Chinese facility was never inspected by the FDA.

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 19, 2008

APP announces its ability to meet the heparin demand. In response, Baxter assembled info on its own supply situation, including supply that might become available from non-SPL sources. (03/05/08 Baxter: Heparin Press Update.)

Feb. 20, 2008

International Compliance Team for the U.S. FDA begins a five day inspection of the Changzhou SPL facility.

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 21, 2008

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 22, 2008

Baxter claims to have had a conference call with the FDA on this date to discuss expansion of the recall in light of APP’s announcement about their ability to supply the market.  Baxter claims the FDA (including the Office of Drug Shortage) wanted some time to examine the issue including market supply of all heparin products. (03/05/08 Baxter: Heparin Press Update.)

Feb. 26, 2008

The International Compliance Team for the U.S. FDA releases its inspection report of the Changzhou SPL facility. The partially redacted report of the inspection establishes severe deficiencies in the companies manufacturing and inspection processes.

Baxter claims to have had contact with the FDA regarding adverse event reports on this date. (03/05/08 Baxter: Heparin Press Update.)

Feb. 27, 2008

Baxter claims to have received clearance from the FDA to recall all of its heparin products from the market. (03/05/08 Baxter: Heparin Press Update.)

Feb. 28, 2008

In light of continuing reports of comparable adverse events associated with the use of multiple-dose heparin vials not within the initial recall, Baxter and the FDA issue additional press releases recalling all remaining lots and doses of its multiple-dose vials, single dose vials, and HEP-LOCK heparin flush products. (FDA 2/28/08 Press Release: “Baxter to Proceed with Recall of Remaining Heparin Sodium Vial Products” and Baxter 02/28/08 Press Release: “Baxter to Proceed with Recall of Remaining Heparin Sodium Vial Products.”)

The same day, the FDA holds its third heparin press conference providing an update of the ongoing investigation (2/28/08 FDA Press Conference Transcript), updates its Public Health Advisory and creates a “Public Health Update.”

Feb. 29, 2008

Baxter issues three “Customer Letters” to renal home patients, customers/wholesalers/distributors/dialysis centers, and one entitled “HEP-LOCK (Heparin Lock Flush Solutions, USP) and HEP-LOCK U/P (Preservation-Free Heparin Lock Flush Solution, USP”). (02/29/08 Baxter Customer Letter to Renal Home Patient, 02/29/08 Baxter Customer Letter to Customer/Wholesaler/Distributor/Dialysis Center, and 02/29/08 Baxter Customer Letter: “HEP-LOCK (Heparin Lock Flush Solutions, USP) and HEP-LOCK U/P (Preservation-Free Heparin Lock Flush Solution, USP”)

March 05, 2008

The FDA holds its fourth heparin press conference providing an update of the ongoing investigation, including an announcement that the contaminate is a “heparin-like substance.” (03/05/08 FDA Press Conference Transcript.)

Baxter releases its first “Press Update” on the heparin investigation. (03/05/08 Baxter: Heparin Press Update.)

March 06, 2008

The FDA holds its fifth heparin press conference providing an update of the ongoing investigation, including an announcement that German Regulatory authorities had recalled heparin manufactured by a German company after reports of similar adverse events. (03/06/08 FDA Press Conference Transcript.)

The FDA also posts webpages regarding screening methods to detect the contaminate including “Impurity Evaluation of Heparin Sodium by Capillary Electrophoresis” and “Impurity Evaluation of Heparin Sodium by H-NMR Spectroscopy,” (later updated on 4/8/08).

March 07, 2008

The FDA updates its “Questions and Answers” webpage.

March 10, 2008

The FDA announces that all heparin coming into the U.S. from SPL-CZ is subject to an import alert (import alert 66-40). (04/29/08 Written Testimony of Janet Woodcock, M.D. before Comm. On Energy and Commerce.)

March 11, 2008

Three Japanese companies recalled Heparin made with USP Active Pharmaceutical Ingredient supplied by SPL. (3/11/08 NY Times Article: “Japan: Heparin Recalled as Precaution.”)

March 14, 2008

The FDA publishes online three demonstrative exhibits for the public entitled, Adverse Reactions, Analyzing the Contaminant, and Import Alert.

The same day, the FDA also holds its sixth heparin press conference announcing that 20 of the 28 samples taken from Changzhou SPL plant had contained the contaminant and describing the preventative steps that the FDA is putting in place at America ’s borders. An import alert is issued and new testing procedures are put in place. (03/14/08 FDA Press Conference Transcript.)

The FDA also issues an assignment to its field staff requiring examination and sampling of all heparin sodium API coming into the U.S. , except sodium heparin API being shipped to firms where the FDA “knows the recommended tests will be conducted.” (04/29/08 Written Testimony of Janet Woodcock, M.D. before Comm. On Energy and Commerce.)

Baxter releases its second “Press Update” on the heparin investigation. (Baxter 03/14/08 Press Release.)

March 17, 2008

SPL-CZ submits its response to the FDA’s 483 (inspection). (04/29/08 Written Testimony of David G. Strunce before Comm. On Energy and Commerce.)

March 19, 2008

FDA announces in it seventh heparin press conference that it had identified the contaminant as over-sulfated chondroitin sulfate (“OSCS”). (03/19/08 FDA Press Conference Transcript.)  Per the FDA, it costs approximately $20/kilogram (kg) to produce OSCS versus $2,000/kg to produce crude heparin. It is later learned, however, that the FDA failed to inspect the Chinese facility prior to approval. (04/29/08 Written Testimony of David Nelson, Senior Investigator for the Committee on Energy and Commerce .)

Baxter releases its third “Press Update” on the heparin investigation.