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Request to HHS to investigate charges against Schering-Plough for possibly knowingly shipping millions of asthma drug inhalers that may not have contained any active ingredient (HRG Publication #1559)

ATTACHMENT (pages of External Audit Report by AAC & FDA Inspection Report) * Note: You will need Adobe Acrobat Reader to open and read this document. If you do not have Acrobat Reader, you can access this free software by clicking on the graphic. You will only have to complete this process once.

March 1, 2001

Tommy Thompson,  Secretary,
Department of Health and Human Services
200 Independence Avenue, SW
Washington, D.C. 20201

Dear Secretary Thompson:

During the past 15 months, 59 million asthma inhalers manufactured by Schering-Plough for treating acute attacks of asthma had to be recalled because of dangerously sloppy manufacturing procedures which resulted in many units failing to contain the active ingredient, albuterol (brand name Proventil⁽¹⁾). We have obtained a confidential external audit by the AAC Consulting Group of Rockville, Maryland, contracted for by Schering-Plough, conducted at Schering-Plough's manufacturing facility at Kenilworth NJ, where these life-sustaining products were manufactured. This audit took place from February 28, 2000 to April 14, 2000⁽²⁾. The auditors were extremely critical of the general attitude of management personnel who described to them--- "an imbalance between quality and production, leaning considerably toward production". They also found serious specific problems with the quality control of the production of the asthma inhalers such as the fact that "An in-process assay for the active ingredient in Proventil is not performed." Managers told the auditors that "aerosol products are a major money maker for the company". But, the auditors concluded, "significant manufacturing problems have been experienced with this product class, which is indicative of insufficient technical expertise and managerial oversight...."

In addition, we have obtained the summary of a very recent 31-day FDA inspection of the same plant completed January 19th of this year in which FDA inspectors found a persistence of many of the same kinds of problems with the quality of manufacturing uncovered one year ago during the private audit of Schering. The FDA investigators concluded that "The process validation for many products fails to support claims that manufacturing processes were capable of consistently producing products with the same quality, purity and safety."⁽³⁾

We urge you to launch an investigation into criminal charges against Schering-Plough based on the possibility that the company knowingly shipped millions of the 59 million units of albuterol-containing asthma drug eventually recalled between the time the company became aware of the seriously flawed manufacturing processes and the time the recall was finally accomplished. We also urge that you investigate the company for continuing to ship other prescription drug products while fully aware of the serious violations of FDA good manufacturing practice (GMP) regulations during their production.

The current quality control problems found in that manufacturing plant during the recent FDA inspection are so serious that there has been a "temporary interruption of some production lines"⁽⁴⁾ and it will not be allowed by the FDA to gain approval or start shipping its new allergy drug, Clarinex, a metabolite of the active ingredient in its top-selling Claritin, which it had previously planned to ship very soon. During that inspection, FDA investigators found that "There was no assurance that the manufacturing process, parameters, equipment or protocols...conducted at multiple sites for the production of Clarinex (Desloratidine tablets, 5 mg) are equivalent or capable of producing product of the same quality." No other new Schering-Plough products will be approved until these serious manufacturing problems are resolved.

SCHERING'S PRIORITY OF PRODUCTION OVER QUALITY: A FORM OF CONTEMPT FOR THE SAFETY OF PATIENTS

Added to the findings of Schering-Plough's own consultants and the results of the FDA's most recent inspection of the Kenilworth NJ facility, is the fact that the FDA has issued at least five Warning Letters to the company since June, 1998 detailing serious GMP problems in its manufacturing facilities in New Jersey, Puerto Rico, and Ireland.

Table 1 below summarizes the five Warning Letters directed at various Schering-Plough plants since June 29, 1998 for serious deviations from GMP guidelines.

Six months before the FDA began their most recent inspection of the Kenilworth NJ facility on November 1, 2000, Schering-Plough's consultants, AAC Consulting Group, noted in their audit of this plant on April 27, 2000:

Upper management needs to demonstrate its long term commitment to product quality, such as through increased staffing/budget resource allocations and investments in new equipment, in order to supplant the traditional emphasis on production and firmly establish a company culture in which quality is, in fact, the number one priority.⁽¹⁰⁾

AAC Consulting found that "Most units fail to have documentation demonstrating that operators are qualified in all required critical tasks. Some areas also lack approved training procedures." The consultants noted that although Schering-Plough's upper management had recently placed some emphasis on quality " there is staff concern that this commitment to quality may not be long term."⁽¹¹⁾

The consultants asked supervisors, managers, and operators if they perceived a real change in the company's commitment to improving product quality since the aerosol recalls and problems with the FDA in late 1999. The consultants observed:

Most managers/supervisors have adopted a wait and see attitude, to determine if upper management will "walk the talk" with respect to long term commitment to product quality. They state that for many years they have been under significant pressure to get production out and don't feel they have had enough time or people to do a quality job. They indicated that there has been in the past a continual push for increased production and decreased down time sometimes at the expense of quality work and GMP compliance. They believe there has been an imbalance between quality and production, leaning considerably toward the side of production.⁽¹²⁾

After five Warning Letters for serious GMP violations in a period of only two years and an audit conducted by outside consultants of the Kenilworth NJ facility, a plant that had previously had been issued two Warning Letters, serious GMP violations were found seven months later by the FDA. The first point in the FDA's report referred to the quality of products produced at this facility. The FDA inspectors observed:

The Quality Control Unit failed to assure that drug products were manufactured in compliance with cGMPs and therefore have the safety, quality, and purity that they purport, or are represented to possess.⁽¹³⁾

CHRONOLOGY AND REPEATED MANUFACTURING DEFECTS WITH IMPORTANT DRUGS

Appendix 1, at the end of this document, is the chronological sequence of important events in the Schering-Plough affair.

ALBUTEROL (PROVENTIL) ASTHMA INHALERS

Two of the Warning Letters, 10/23/98 and 7/21/99, involve manufacturing problems with albuterol (PROVENTIL) aerosol inhalers. Albuterol is a drug of vital importance for asthmatics. It is frequently used to stop acute asthma attacks.

The 7/21/99 Warning Letter also reveals meetings and communications between Schering-Plough and the FDA's Center for Drug Evaluation and Research (CDER). On 6/25/99, CDER informed Schering-Plough's Vice President for Worldwide Regulatory Affairs of a four phase prior approval program for the release of albuterol inhalers by the company.

Defective manufacturing of albuterol led to almost 60 million canisters of this drug being recalled because some canisters did not contain the active ingredient. The first recall took place on 9/9/99 and involved 190,679 units of the drug. The second, on 3/29/00, recalled 58,936,179 canisters of albuterol.

Schering-Plough knew of problems with the production of albuterol inhalers during the July 30, 1998 inspection of the Kenilworth NJ facility that resulted in the October 23, 1998 Warning Letter. By late June of 1999, the company had to agree to prior approval by the FDA before any albuterol inhalers could be distributed by the company.

The AAC Consulting Group began their audit at Kenilworth NJ on February 28, 2000 and submitted its final report to Schering-Plough on April 27, 2000. After two Warning Letters and two recalls involving albuterol inhalers, the consultants made the following observations regarding the manufacturing of albuterol inhalers:

• Evaluation of this manufacturing area disclosed significant changes in both procedures and record keeping practices. Overall, these were found to be positive, but some observations did reflect potential problem areas and perhaps even some degree of over-reaction to the recent aerosol product recalls.⁽¹⁴⁾
• It is our understanding, based on interviews with supervisors and managers, that aerosol products are a major money make for the company. In addition, significant manufacturing problems have been experienced with this product class, which is indicative of insufficient technical expertise and managerial oversight. This production area does not have the visibility and importance from an organizational standpoint that it needs in order to quickly and effectively recover from past problems, maintain satisfactory regulatory compliance, attract and retain necessary expertise, and grow in the future.⁽¹⁵⁾
• Some components, such as aerosol valves from 3M Neotechnic, are received for testing already pre-sampled by the vendor. There is no assurance that the samples provided to Schering were collected by the vendor according to accepted sampling procedures and are representative of the entire lot.⁽¹⁶⁾
• Updating aerosol test procedures should be given the highest priority in light of past problems with this product class and the intense scrutiny Schering operations in this area is currently undergoing by FDA.⁽¹⁷⁾
• An in-process assay for the active ingredient in Proventil is not performed. Reportedly, R&D has been trying for several years without success to shorten the Proventil final release assay procedure, so that it is suitable for in-process testing.⁽¹⁸⁾
• An in-process assay method for Proventil should be developed and validated as soon as possible so that the active ingredient is quantified in-process as is done for all other Schering aerosol products.⁽¹⁹⁾

The AAC audit was completed six months before the FDA's most recent inspection of Kenilworth NJ. Still the FDA observed deficiencies in the manufacture of albuterol inhalers:

• Aerosol Manufacturing Line 76 with the online stress testing heating blocks was validated in that the two validation attempts have failed to meet the validation protocol acceptance criteria.⁽²⁰⁾
• Validation Summary Report #Val-9-184, (validation for the use of the heating blocks for on-line stress testing for Proventil/Albuterol) was inadequate in that 1 out of 3 original Validation Batches, #9-BBS-640, was rejected for excessive downtime and rejected canisters (purged cans). An additional Validation Batch, #9-BBS-643, was also rejected due to out-of-specification leak test results.⁽²¹⁾
• A second validation attempt of the heating blocks for on-line stress testing was executed under Validation Summary Report #VAL-00-48. This validation was inadequate in that Validation Batch #'s 0-BBS-572m 0-BBS-573 & 0-BBS-574 failed to meet the process validation acceptance criteria for total content of Albuterol. Additionally, the rinse method utilized by the laboratory to retest the total content of Albuterol per canister was never validated.⁽²²⁾
• The Product Quality Review (PQR) methods for the Delivery of Albuterol through the Actuator and Particle Size for Proventil Aerosol Inhaler were inadequate in that the methods exhibit various unidentified extraneous peaks. PQR Methods for Total Content of Albuterol per Can Assay and Estimation of Degradation Products were also inadequate in that there was a lack of resolution between typical unknown peaks from neighboring active or placebo peaks. These methods were used to test and release product batches, as well as stability samples, from 10/11/99-12/7/00.⁽²³⁾

LORATADINE WITH PSEUDOEPHEDRINE (CLARITIN D)

Problems with the production of the antihistamine loratadine in combination with pseudoephedrine (CLARITIN D) were identified in the July 30, 1998 inspection of the Kenilworth NJ plant that resulted in the October 23, 1998 Warning Letter.

Eighteen months later AAC Consulting continued to find problems with the production of Claritin-D:

• Previously filed validation reports for Claritin-D (Once-a-Day), with the same product ID (GJKS), were performed in 1993. The protocols and final reports were reviewed and approved by production and quality in 1995. One of the batches manufactured failed final blend specifications, but this validation was approved by management nearly two years later. There was no statement as to the batch's disposition.⁽²⁴⁾  
• The annual product review for Claritin-D 24 reflected 45 of 752 finished tablet batches were rejected. Of those there were 35 rejected for high moisture, 5 for variable loratadine content. This would seem to reflect that the process is not validated. There also were 44 batches that had low granulation yield based on product hang-up in the equipment. This same issue has been seen with other products and it is not apparent that there has been a for cause investigation done to determine why product is hanging up in the equipment. There also were 307 batches that had low yield. This has caused variance and MRB reports. It appears that the specs may not be appropriate and/or the process is not validated. Addressing this issue could cut down on a lot of unnecessary investigation time.⁽²⁵⁾

The FDA also continued to find deficiencies in the production of Claritin-D in their most recent inspection of the Kenilworth NJ plant:

• Validation of the Claritin D-24hr. ER Tablet process, using a drug substance from a new source (Schering, Singapore) was not adequate in that only one batch was manufactured. Change Authorization #CA-99-248 allows for the use of this alternate source. The new drug substance was used to manufacture batch #'s 0-DCS-257 through 0-DCS-340, approximately 95 batches.⁽²⁶⁾
• The current revalidation Protocol, #VAL-0-61, for Claritin D-24 hr. ER Tablet Cores contained incorrect acceptance criteria, but was signed and approved by Validation, QC, and Manufacturing Departments. Specifications for two finished product tablet tests were erroneously included as the acceptance criteria for the tablet cores.⁽²⁷⁾

DESLORATADINE (CLARINEX)

Desloratadine (CLARINEX) is Schering-Plough's replacement for its overpriced antihistamine loratadine (CLARITIN). Desloratadine is the major metabolic breakdown product of loratadine. It appears from the FDA's recent Kenilworth NJ inspection that there are serious problems with the production of desloratadine that will prevent final approval of the drug. The FDA observed the following in their recent inspection:

• There was no assurance that the manufacturing process, parameters, equipment, or protocols and acceptance criteria, conducted and generated at multiple sites for the production of Clarinex (Desloratadine Tablets, 5 mg) are equivalent, or capable of producing product of the same quality.
• The test method transfer from Schering, Kenilworth to Schering, Puerto Rico failed to demonstrate that accurate and reliable results could be obtained from the QC laboratory.
• There was insufficient comparability data for the drug substance, Desloratadine, manufactured at the firm's Ireland and Singapore sites to assure equivalence of the drug substance supply.⁽²⁸⁾

In conclusion, it is clear that there are an extraordinary variety of serious problems at the Schering-Plough manufacturing plant in Kenilworth, New Jersey which threaten the safety of drugs already shipped out of the facility and bespeak the need for extreme caution in allowing any further products to be shipped from that plant. In addition, we hope you insist that the FDA investigate the possibility of criminal behavior on the part of those Schering-Plough officials who may have knowingly shipped defective pharmaceutical products for use in unsuspecting patients. We expect a prompt response to this urgent request.

Sincerely,

Larry Sasich, Pharm.D., MPH
Research Associate

Sidney M. Wolfe, M.D., Director
Public Citizen's Health Research Group

1. The first recall, 9/9/99, involved 190,000 units and the second, 3/29/00, involved 58.9 million units. Some units manufactured by Schering in the same New Jersey facility were sold under the name of their subsidiary, Warrick, as generic albuterol. In a Q & A accompanying the second recall, Schering-Plough explained that the purpose of the recall was to "address the remote possibility that an aerosol container may not contain active drug" and said, in an extraordinary and reckless understatement of what could be a life-threatening situation, "Proventil and Warrick brand albuterol patients using a canister without active drug will not obtain their usual relief from asthma symptoms."

2. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000. Final report is dated April 27, 2000.

3. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 1.

4. Schering-Plough press release, February 15, 2001.

5. Warning Letter addressed to Mr. Francisco R. Rodriquez, General Manager, Schering-Plough Products Inc., Las Piedras, Puerto Rico from Samuel Jones, District Director, Puerto Rico District, Food and Drug Administration dated June 29, 1998.

6. Warning Letter addressed to Mr. John E. Nine, President, Technical Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ 07033-0503 from Douglas I. Ellsworth, Food and Drug Administration, District Director, New Jersey District dated October 23, 1998.

7. Warning Letter addressed to Colman Casey, Ph.D., Managing Director, Schering-Plough (Brinny) Co., Innishannon, Couny Cork, Ireland from Jerome A. Donlan, M.D., Ph.D., Acting Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, Food and Drug Administration dated November 23, 1998.

8. Warning Letter addressed to Mr. John E. Nine, President, Technical Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ 07033-0503 from Douglas I. Ellsworth, Food and Drug Administration, District Director, New Jersey District dated July 21, 1999.

9. Warning Letter addressed to Mr. John E. Nine, President, Technical Operations, Schering Laboratories, Schering-Plough Corporation, Kenilworth NJ 07033-0503 from Mildred R. Barber, District Director, Food and Drug Administration dated May 2, 2000.

10. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 6.

11. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 5.

12. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 76.

13. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 1.

14. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 36.

15. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 65.

16. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 91.

17. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page106.

18. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page106.

19. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page106.

20. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.

21. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.

22. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.

23. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 12.

24. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 9.

25. Audit of Schering Laboratories Manufacturing Facility Kenilworth, NJ, Audit Report, AAC Consulting Group, February 28, 2000 ­ April 14, 2000, page 85.

26. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 2.

27. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 3.

28. Department of Health and Human Services, Food and Drug Administration. Form FDA 483 (8/00) Inspectional Observations, Schering-Plough Corporation, 2000 Galloping Hill Road, Kenilworth, NJ 07033, dated January 19, 2001, page 15.

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