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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Braintree Laboratories Inc 5/10/10




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

Public Health Service
Food and Drug Administration
 New England District
One Montvale Avenue
Stoneham, Massachusetts 02180
(781) 596-7700
FAX: (781) 596-7896




VIA UPS Next Day Air

May 10, 2010
Mr. Harry P. Keegan
Braintree Laboratories, Inc,
60 Columbian Street
Braintree, MA 02185

Dear Mr. Keegan:

During our December 3, 2009 through January 22, 2010 inspection of your pharmaceutical manufacturing facility, Braintree Laboratories, Inc., 270 Centre Street, Holbrook, Massachusetts, investigators from the United States 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 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 have received your firm's responses dated February 10, 2010 and March 19, 2010 and note that these responses lack sufficient corrective actions.

The specific violation observed during the inspection include, but is not limited to the following:

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, our investigator noted the following three investigation failures.

a. Your firm received 21 consumer complaints in 2008-2009 for the presence of foreign materials in five finished products (e.g., insects, insect parts, and spiders). Upon receipt of these complaints, you concluded that the foreign material could not be attributed to your firm's manufacturing practices. However, you did not conduct a thorough investigation to assess whether facility or raw material quality problems were at the root of these complaints.

Your responses are inadequate. In your February 10, 2010 response, you state, "We believe that the foreign matter reported [some not verified] in the complaints do not present inherent health hazard." FDA considers contamination of finished drug products with foreign material (e.g., insects) a significant product quality issue. You also conclude in your March 19, 2010 response that contamination with foreign matter could not have occurred while the product was in storage, but did not provide your rationale for this conclusion.

We acknowledge your commitment to the following four corrective actions:

• Conduct thorough investigations of foreign matter complaints.
• Increase pest control monitoring at your firm.
• Review complaints for trends.
• Identify foreign matter to determine origin.

However, this response is incomplete. In addition to the corrective actions listed in your above response, you should include a plan for determining additional potential sources of these foreign matter complaints and may need to audit your suppliers of raw materials and packaging components.

b. PhosLo Gel caps (Calcium Acetate), 667 mg, lot 1308016, Expiration 02/2011, failed to meet dissolution specifications for accelerated stability samples 40°C/75% RH at the 2-, 3-, and 6-month time points. The results were not appropriately invalidated based on a documented test event that could reasonably be determined to have caused the OOS result. Accordingly, your firm failed to conduct an adequate investigation.

Further, passing results for the 2- and 3-month stability time stations were obtained with both a) water and pepsin, and b)(b)(4), as dissolution medium for part of the OOS investigation. Our investigator noted four additional OOS events dating back to 2005 in which passing (b)(4) dissolution test results were reported and an investigation into (b)(4) was not conducted. Your response is inadequate because it does not address the use of (b)(4) in dissolution testing by your firm. This is a significant departure from the PhosLo Gel new drug application and requires submission of a prior approval supplement.

In addition, as highlighted in the chart below, your firm released lot 1308016 (which was on accelerated stability studies) although failing results were obtained at the 6-month time point, using the (b)(4) dissolution medium. Please clarify how you will assure that lot 1308016 will meet its specifications for identity, strength, quality, and purity.


Summary of PhosLo Gel caps 667mg, lot 1308016 Dissolution Tests


Time PointDissolution MediumPossible Cause

2 month


Water - Failed S3
Water and Pepsin -
Passed S1
(b)(4) Passed
3 monthWater - Failed S3
Water and Pepsin -
Failed S3
(b)(4) Passed S1



6 monthWater - Failed S1
Water and pepsin - Failed
(b)(4) Failed S3




6 month (caplets)Water-Passed S1N/A
8 month retain (gelcaps)Water-Passed S1N/A
24 month retain (gelcaps)Water-Passed S1N/A

Your February 10, 2010 response discusses the information regarding additional passing dissolution test results for retain samples at the 6-month time point as well as results from the accelerated stability testing (see table above). However, your response does not address the failing result at the S3 stage after using (b)(4) dissolution medium, which would indicate that (b)(4) was not the cause of the dissolution failure. Your response states that a) 6 inner caplets were removed from the gelcaps (gelatin capsules) and met S1 specifications at the 6 month time point, and b) retain gelcaps (gelatin capsules) passed at 8 and 24 month time points and met the S1 specifications. You conclude that additional data your firm provided supports quality of the marketed product. FDA disagrees with your conclusion because your response fails to address the failing results of the gelcaps (gelatin capsule), which is the marketed product, not solely the inner caplet itself.

Further, your response cites the (b)(4) phenomenon of the gelatin capsules as the reason for dissolution failures. You state that the (b)(4)formation was due to chemical interactions and elevated temperature and humidity of the packaged PhosLo Gel caps. However, your response is inadequate because you do not propose acceptable corrective action to prevent gelcap (gelatin capsule) (b)(4).

c. PhosLo Gel caps (Calcium Acetate), 667 mg, lot 1308035, Expiration 02/2011, accelerated stability samples 25°C/60% RH failed to meet the stage S3 specification for stability testing at the 12 month time point. This stability failure occurred when one sample had a dissolution test result of (b)(4) at the S3 stage. As stated above, your firm also cites (b)(4) of gel capsules as the reason for this dissolution failure; however, you performed no further analysis to confirm this conclusion.

Your March 19, 2010 response revealed failing stability testing results (dated February 9, 2010) for three samples from lot 1308035 at the 15-month time period. These three samples apparently failed stage S3 dissolution testing. Your response states an investigation is currently in progress but your response lacks the following three items:

• Test results and data for the above noted failed 15 month stability test.
• Timeframe for completion of the OOS investigation.
• Rationale for continued distribution of this lot.

Your response is also inadequate because it is unclear if your firm has determined the root cause of the problem and attempted to resolve it.

Additionally, we have concerns about your firm's fundamental understanding of the regulatory expectations and requirements when conducting OOS investigations. Please review the FDA Guidance entitled, "Investigating Out-of-Specification Test Results for Pharmaceutical Production," which explains FDA's policy on how to evaluate chemistry-based laboratory OOS test results. This guidance can be found on FDA's webpage at http:www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U

The violations cited in this letter are not intended to be an all-inclusive list of deficiencies that exist at your facility. You are responsible for investigating and determining the causes of the violation 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, 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 specific drug products, and provide the date(s) and reason(s) you ceased production.

Your reply should be sent to the Food and Drug Administration, One Montvale Avenue, 4th floor, Stoneham, MA 02180, Attention Karen Archdeacon, Compliance Officer, 781-596-7707.


John R. Marzilli
District Director
New England District



Cc: Mr. Adel Kheir-Eldin
Vice President Quality and Compliance
Braintree Laboratories, Inc.
270 Centre Street
Holbrook, MA 02343