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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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PCI Synthesis 12/2/10


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 United Parcel Service

December 2, 2010

Mr. Edward S. Price
PolyCarbon Industries, Inc., d.b.a. PCI Synthesis
9 Opportunity Way
Newburyport, MA 01950-4044

Dear Mr. Price:

During our May 11, 2010 to June 11, 2010 inspection of your Active Pharmaceutical Ingredient (API) manufacturing facility, PolyCarbon Industries, Inc., d.b.a. PCI Synthesis, located at 9 Opportunity Way, Newburyport, MA, investigators from the Food and Drug Administration (FDA) identified significant deviations from the Current Good Manufacturing Practice (CGMP) for the manufacture of APIs. These deviations cause your API(s) 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 reviewed your firm’s response of July 2, 2010, and note that it lacks sufficient corrective actions.

Specific deviations observed during the inspection include, but are not limited to, the following:

1. Your firm failed to investigate critical deviations or a failure of a batch to meet its specifications or quality standards. For example:

a. Your firm failed to investigate an Out-of-Specification (OOS) impurity result obtained in the Methscopolamine Nitrate API (lots 313001N09 and 313001N10). Specifically, your firm did not conduct testing to determine the identity of the impurity and the possible impact to the API quality prior to releasing the lots.

We acknowledge your commitment in your letter dated May 28, 2010, to stop distribution of the Methscopolamine Nitrate API. However, in your response dated July 2, 2010, you state that you did not conduct an investigation because of the “regulatory status” of Methscopolamine Nitrate API. Your response is inadequate because any drug you manufacture intended to be used in a finish drug product for use in humans must be manufactured in accordance with appropriate standards of CGMP, irrespective of the drug’s regulatory status.

b. Your firm failed to conduct an adequate investigation concerning an OOS for Loss of Drying (LOD) in a lot of Podophyllotoxin Crude (lot 081031) on November 19, 2008. This lot was used to manufacture three lots of Podophyllotoxin API (lots 802001N09, 802002N09 and 802003N09), which were released on February 18, 2009.

In your response, you state that the established LOD specification was not scientifically sound and that you will conduct additional experiments to ensure that the LOD specification for Podophyllotoxin Crude is adequate. However, lot 081031 was released solely on the results of a test that is only intended to be used for clinical trial material. You did not conduct additional experiments to ensure the adequacy of the LOD specification. Please note that our records indicate that Podophyllotoxin API (DMF No. 18862) is not associated with an Investigational New Drug (IND) application.

2. Your Quality System failed to provide assurance that your API manufacturing processes will consistently yield a product meeting its intended specifications.

For example, your firm did not validate the manufacturing processes for Flecainide Acetate API.

Your response is inadequate because you failed to provide scientific evidence to explain your rationale of asserting “batches manufactured since Spring 2008 are within acceptable scale-up parameters.”

3. Your QCU failed to adequately review batch records.

For example, Sodium 4-Phenylbutyrate API, lots 230001N09, 230002N09, and 230003N09, were manufactured, reviewed and approved by Quality Assurance (QA) and released although a step in the manufacturing process was omitted.

We acknowledge your commitment to revise your batch records, however your response is inadequate because you failed to indicate the training you will provide to QA to ensure that batch records are complete, accurate and the product meets established specifications prior to release.

It is essential that your firm establish and maintain a corporate commitment to an effective pharmaceutical quality system. Your firm’s management should demonstrate leadership and ultimate responsibility by participating in the design, implementation, and monitoring for quality throughout the company. Management should establish policies that describes your firm’s overall approach to ensuring drug quality and communicates your expectation of compliance with all requirements of applicable federal law and FDA regulations.

In addition to the items listed above, our inspection uncovered violations that indicate your firm’s management failed to exercise its responsibilities and take appropriate actions to ensure an effective pharmaceutical quality system. These violations include, but are not limited to, the following:

• QCU’s failure to initiate change control and to assess possible impact to product quality after changes to the Master Processing Record.

• QCU’s failure to follow the procedure for annual product review.

The deviations cited in this letter are not intended to be an all-inclusive statement of deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.

You should take prompt action to correct the deviations detailed in this letter. Failure to promptly correct these deviations 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 deviations 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 deviations. Include an explanation of each step being taken to prevent the recurrence of deviations 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 APIs manufactured at this facility and provide the date(s) and reason(s) you ceased production.

Your reply should be sent to the following address: Todd Maushart, Compliance Officer, Food and Drug Administration, One Montvale Avenue, 4th Floor, Stoneham, Massachusetts 02180. If you have any questions about the content of this letter please contact: Todd Maushart at (781) 596-7844.



Mutahar S. Shamsi
District Director
New England District