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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Merck & Company, Inc. 22-Jul-05

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration


Rockville, MD 20857

July 22, 2005





Richard T. Clark
CEO and President
Merck and Company, Inc.
Two Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889

Dear Mr. Clark:

The Food and Drug Administration (FDA) conducted an inspection of Merck and Co., Cherokee Plant, 100 Avenue C, Riverside, Pa., from February 15-18, 2005. During the inspection, the FDA Investigators documented violations of 21 U.S.C. 351(a)(2)(B) (Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic (The Act)), 42 U.S.C. 262(a) (Section 351(a) of the Public Health Service Act (The PHS Act)), and deviations from the applicable requirements within the Code of Federal Regulations (CFR), Title 21, Subchapter F, Parts 600-680. At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations, that described a number of significant objectionable conditions relating to the facility's compliance with CGMPs. Significant deviations in the manufacture of Asparaginase intermediate observed during the inspection include, but are not limited to, the following:

1. Failure to submit a supplement for a change in the production process and quality controls that has a substantial potential to have an adverse effect on the identity, strength, quality, purity or potency of the product [21 CFR 601.12]. Specifically, you failed to notify FDA upon establishing a new working cell culture from a pro-existing working cell culture. Your records referenced that each new lyophilization series is sequentially prepared from the previous lyophilization series. There has been no evaluation or comparability study to support this practice. You prepared production cell culture [redacted] from a pre-existing production cell culture [redacted] instead of preparing it from master cell culture [redacted]. This is a significant departure from your biologics license application and requires the submission of a prior approval supplement.

Additionally, you have instituted a re-isolation procedure for selecting cells for use in production of Asparaginase intermediate. You re-isolated production cell culture [redacted] and selected re-isolate [redacted] for use in the production of Asparaginase intermediate. You did not characterize this isolate prior to use in production. This re-isolation procedure amounts to re-cloning and requires the submission of a prior approval supplement.

Furthermore, because you have not fully characterized the new WCBs and re-isolated cell lines to determine whether their attributes were consistent with the cell lines in the MCB, there is no assurance that your product meets the quality and purity characteristics that they purport, or are represented, to possess. Therefore you are in violation of 21 U.S.C. 351(a)(2)(B) of the Act.

We have evaluated your written response dated March 15, 2005, and have the following comments:

FDA Observation #lA: Your response is not adequate. You do not reference any analysis/characterization of working cell culture [redacted] as part of your evaluation, nor do you compare it to the master cell culture [redacted]. You only reference testing and comparison of the column feeds and bulk Asparaginase between working cell culture [redacted] and working cell culture [redacted]. The tests for the Intermediate Column Feed material consist of [redacted], and [redacted]. For the bulk Drug Intermediate, you perform [redacted] tests. We note that there are significant differences for Intermediate Column Feed [redacted] ([redacted] higher for Cell Bank [redacted] lots compared to [redacted] and for Drug Intermediate [redacted] ([redacted] times lower with Cell Bank [redacted] lots compared to [redacted]). We believe that these tests are limited in their ability to characterize the protein. Additionally, no direct comparison has been made between Working Cell Bank [redacted] and Master Cell Bank, [redacted]. The industry currently uses more thorough and reliable tests to characterize proteins, such as gene copy number determination and sequencing, mRNA level evaluation, and Western blotting to assess the Asparaginase protein characteristics and potential speciation. These sequence analyses will allow for the assessment of possible mutations that may have occurred in the Asparaginase protein coding sequence during propagation. Currently, you fail to perform any [redacted] on Asparaginase. Since beginning Asparaginase manufacturing in [redacted] you have developed [redacted] generations of E Coli cell cultures, the latest of which is called [redacted].

Furthermore, we find the improper preparation of [redacted] from [redacted] [redacted] occurred at your culture management facility located in Rahway, NJ. You did not reference any corrective actions that your firm would implement for the Rahway, NJ location.

FDA Observation #1B: Your response is not adequate. We disagree with your statement that re-isolation of production culture [redacted] does not constitute a culture change. It is our position that you have re-cloned the production cell culture and created a [redacted] generation E.Coli strain. This re-cloning requires characterization of the cell culture and notification/approval from the Agency. It is apparent that the performance of [redacted] was not optimal as referred to in your [redacted] study which specifically referenced heterogeneity, variability and inconsistency within working cell culture [redacted] stock. In this same document, you reference differences in morphological and performance characteristics of various re-isolates of working cell culture [redacted].

Your reasons for selecting re-isolate [redacted] included the fact that it was a superior producer of Asparaginase as compared to its parental control. Therefore, subsequent selection and propagation of re-isolate [redacted] for manufacture is a direct change in the starting culture for production fermentation of Asparaginase intermediate.

Additionally, your [redacted] response to the FDA-483 stated that you have performed an assessment of [redacted] for the Intermediate Column Feed for the"[redacted] Reisolate." We acknowledge that there appear to be no appreciable differences in the comparison of the average values for these tests, between the [redacted] Intermediates prepared from the Cell Bank [redacted] and the [redacted] Intermediates from the "[redacted] 'Re-isolate." However, these are a very limited range of tests performed; industry consistently uses a far more robust comparability program for assessing such proteins. We note that in the response, you stated that you have relied on the CBER guidance document Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description for a Vaccine or Related Product (January 1999). However, this guidance pertains to small molecule fermentation. Asparaginase is not considered to be a small molecule; this enzyme is a 142 kDa tetramer of identical 348 amino acids protein chain, each of which has one potential disulfide bond. The applicable guidance document is ICH Q6B (August 1999) Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products. Please clarify the steps that your firm will take toward modernizing your specification/characterization procedures and practices. Currently, you have produced [redacted] lots of Asparaginase Intermediate Column Feed material (material prior to column purification). Please clarify how you will assure that these in-process lots of Asparaginase will meet their specifications for identity, strength, quality, and purity.

Furthermore, we note that in a recent correspondence during [redacted] from the Division of Therapeutic Proteins (HFD-122) within the Center for Drug Evaluation and Research to your firm regarding exemptions from the General Safety Test, the Agency communicated recommendations regarding expanding and modernizing the Asparaginase characterization tests. These recommendations include the use of Peptide Mapping, RPHPLC, SE-HPLC, SDS-PAGE (Coomassie and/or Silver staining), Western blotting using anti-E. Coli and [redacted]. Particulate analysis, and Bioburden as release tests to confirm the identity of Asparaginase. Other suggestions include carefully monitoring process-related (e.g. host cell proteins and adventitious microbial contaminants) and product-related (degradation products and aggregates) impurities. Mass spectroscopic molecular weight determination and analysis of free sulhydryls are also recommended to the firm.

Neither this letter nor the observations noted on the Form FDA 483 are intended to be an all-inclusive list of the deficiencies that may exist at your facility. It is your responsibility, as a drug intermediate manufacturer, to ensure that your operations are in full compliance with all applicable requirements of the federal regulations.

Please notify us in writing within 15 working days of receipt of this letter, of any steps you have taken or will take to correct the noted violations and to prevent their recurrence. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Failure to promptly correct these deviations may result in further regulatory action, such as license suspension, license revocation, seizure and/or injunction, without further notice.

Your response should be sent to the Food and Drug Administration, ORA/OE/Division of Compliance Management and Operations, HFC-210, 5600 Fishers Lane, Rockville, MD, 20857.

If you have any questions regarding this letter, please contact Dr. Jacqueline Little, Team Leader, Team Biologics Compliance, Division of Compliance Management and Operations, at (240) 632-6854.


David K. Elder
Office of Enforcement