Inspections, Compliance, Enforcement, and Criminal Investigations
Balchem Corporation 12/22/09
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
550 West Jackson Blvd.,
Chicago, Illinois 60661
December 22, 2009
RETURN RECEIPT REQUESTED
Mr. Dino Rossi, President and CEO
52 Sunrise Park Road
New Hampton, New York 10958
Dear Mr. Rossi:
This is regarding our May 20 to June 10, 2009 inspection of your pharmaceutical manufacturing facility, Balchem Corporation, located at 24708 West Durkee Rd. Channahon, IL. The inspection identified significant violations from the Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations (CFR), Parts 210 and 211. These violations cause your drug products 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.
We determined that your firm manufactures granulated calcium carbonate in various concentrations. You sell this granulated calcium carbonate to finished pharmaceutical manufacturers for use in antacids and a postmenopausal medication. Your firm also sells granulated calcium carbonate for use in a dietary supplement. Your granulated calcium carbonate is deemed in-process material as defined in 21 CFR 210.3(b)(9), meaning any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the drug product. In-process materials are "drugs" as defined by Section 201 (g)(1) of the Act [21 U.S.C. 321(g)(1)], because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.
In addition, dietary supplements and their components are deemed to be foods within the meaning of the Act, pursuant to the definition set forth in section 201 (ff) of the Act [21 U.S.C. 321 (ff)]. The inspection revealed that these products are adulterated within the meaning of section 402(a)(1) of the Act [21 U.S.C. 342(a)(1)], in that a food shall be deemed to be adulterated if it bears or contains any poisonous or deleterious substance which may render it injurious to health.
We reviewed your firm's response of August 3, 2009, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm failed to reject in-process materials required to be tested as appropriate, and approved or rejected by the quality unit [21 CFR 211.110(c)]. In addition, your firm has not established written procedures designed to prevent objectionable microorganisms in drug products not required to be sterile [21 CFR 211.113(a)].
a. Lot E8143A of Modified Calcium 58B was released and distributed although laboratory analysis showed (b)(4) of (b)(4)
b. Ninety-four (94) lots of Modified Calcium 58B and Calcium Carbonate 1551-95 (P) were released and distributed despite findings of coliform bacteria in the purified water and potable water systems, which are used in the manufacture of these products.
Your response concerning the lots that were released despite finding coliform bacteria is inadequate. Proper identification of microbial contamination is critical in your evaluation of such findings. A confirmation test result of "coliform bacteria" is not adequate to determine the hazard that might be posed by the contaminating microbes. A proper course of action is greatly based on the identification (i.e., species) of the coliform(s), and consequently identity of the bacteria is an essential part of an investigation. Also note that, as a general principle, your firm should consider the finding of bacterial coliform contamination to be an indication of unsanitary conditions that may pose a risk to the consumer.
In addition, your response states that you plan to include in SOP 121 that all product manufactured since the last "passing" potable/purified water samples will be submitted for analysis to confirm the absence of coliforms. This plan is not adequate. Microbiological testing of the product, or of water, while providing some information, should not be relied upon as the sole justification for the release of a batch or scope of an investigation.
Also, we note that the response does not specifically describe the additional training that will be given to the employees.
2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that in-process materials conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)].
For example, your Quality Variance Report (QVR-8012) documents that samples of Modified Calcium 58B from lots E8064A and E8064B were submitted to the contract microbiological laboratory for testing. The samples contained (b)(4) of (b)(4) Additional samples from the batch were submitted for testing in an attempt to confirm the original result of (b)(4) of (b)(4). Based merely on passing results for the additional batch samples, your firm's investigation concluded the contamination in the two initial batch samples was due to a sampling problem. Lots E8064A and E8064B were intended to be released as in-process materials (for use in drug products), but were instead released for use in the bulk dietary supplement Vitasmooth 041 (which your firm refers to as "downgrading").
This practice of "testing into compliance," is unscientific and objectionable under CGMPs. Although the FDA Guidance for Industry entitled, "Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production," applies to chemistry based laboratory testing, we recommend review of this guidance for some basic principles regarding conduct of OOS investigations. The guidance states that when no laboratory errors are identified in the initial test, there is a lack of scientific basis for invalidating initial OOS results in favor of passing retest results. In addition, the guidance notes that all test results should be reported and considered in batch release decisions. Your response does not specifically describe a predefined retesting plan or protocol to address additional testing and scientific handling of the data, nor does your response describe additional training to be given to your employees.
3. Your firm failed to use equipment in the manufacture, processing, packing, or holding of a drug product of appropriate design to facilitate operations for its intended use and for its cleaning and maintenance [21 CFR 211.63].
For example, your firm failed to ensure your water system was of adequate design. We note your firm also has not performed a formal validation of the purified water system, although you collected data that indicates your firm is now apparently producing purified water of adequate quality for your products. We acknowledge your firm's commitment to upgrade the design of their USP Purified Water System, replace all existing stainless steel piping and filter housing, and conduct a performance qualification of the purified water system.
The inspection revealed that your current practice of "downgrading" Calcium Carbonate 58B and Calcium Carbonate 1551-95 (P) to dietary supplement ingredients when they do not meet pharmaceutical specifications is objectionable.
Specifically, your firm issued several Quality Variance Reports in 2008 and 2009 because your firm found growth of various gram-negative organisms of the family (b)(4) in lots of Modified Calcium 58B, E8009A, E8010A (b)(4) E8010B (b)(4) E8011A, E8064A, E8064B, E8281A (b)(4) E9005A (b)(4) and E9029A. Even though you had evidence of microbial contamination in the above lots of products, you released them based on acceptable specifications for the dietary supplement ingredient Vitasmooth 041.
Your calcium carbonate ingredients are intended for use in dietary supplements, a subset of foods as defined under section 201 (ff) of the Act, and also as articles used for food as defined under section 201(f) of the Act. Consequently, the above lots of Calcium Carbonate 58B are adulterated within the meaning of section 402(a)(1) of the Act in that they contain an added poisonous or deleterious substance, namely the bacteria identified from your Quality Variance Reports, which may render them injurious to health.
Your response does not adequately address the above violation. You stated in this response that you resampled and analyzed the retained sample, and three additional samples from individual granulation batches. Your investigation concluded that the results could not be verified, and determined that the original sample results were contaminated because of poor sampling techniques. However, this response does not adequately address the widespread contamination of the various lots identified above that were manufactured in 2008 and 2009, and in instances where your root cause was undetermined.
Further, based on your corrective actions in the response letter, our comments are as follows for the specifications of your two dietary supplement ingredients: For the Vitasmooth 041, we recommend Salmonella being negative in a 25 gram sample and Enterobacter being negative in a 25 gram sample. For the Vitagran 040, we recommend Salmonella being negative in a 25 gram sample.
We acknowledge that you rejected lots E8031A, (b)(4) and E8032A (b)(4) and (b)(4) and that they remain under your control and stored in the encapsulation warehouse. Please provide your rationale for selling these lots as "specialty chemicals" as indicated in your response.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. 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.
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 as a manufacturer 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. Additionally, your response should state if you no longer manufacture or distribute granulated calcium carbonate, and provide the date(s) and reason(s) you ceased production.
Your response should be sent to: Lorelei Jarrell, Compliance Officer, Food and Drug Administration, 550 W. Jackson Blvd., 15th Floor, Chicago, IL 60661. If you have any questions about the content of this letter, please contact Ms. Jarrell at 312-596-4216.
Scott J. MacIntire