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Pine Pharmaceuticals, LLC MARCS-CMS 500724 —

Pine Pharmaceuticals, LLC

United States

Issuing Office:
New York District Office

United States



Black HHS-Blue FDA Logo



New York District
158-15 Liberty Ave
Jamaica, NY 11433 


November 7, 2016
Mr. Alfonse J. Muto, Co-Owner and Quality Manager
Pine Pharmaceuticals
100 Colvin Woods Parkway., Suite 300
Tonawanda, NY 14150
Dear Mr. Muto:
You registered with the U.S. Food and Drug Administration (FDA) as an outsourcing facility under section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA) [21 U.S.C. § 353b] [1] on June 17, 2014, and again on October 7, 2015.  From October 5, 2015, to October 9, 2015, FDA investigators inspected your facility, Pine Pharmaceuticals, LLC, located at 100 Colvin Woods Parkway., Suite 300, Tonawanda, NY 14150.  During the inspection, the investigators observed that you failed to meet the conditions under section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain requirements under the FDCA.  FDA issued a Form FDA 483 to your facility on October 9, 2015.  FDA acknowledges receipt of your facility’s undated response on October 28, 2015, and your further response dated April 25, 2016. 
Based on this inspection, it appears your facility is producing drugs that violate the FDCA.  
A. Compounded Drugs under the FDCA
The Drug Quality and Security Act (DQSA) was enacted on November 27, 2013. Title I of the DQSA, the Compounding Quality Act (CQA), added a new section 503B to the FDCA. Under section 503B(b), a compounder can register as an outsourcing facility with FDA. Drug products compounded by or under the direct supervision of a licensed pharmacist in an outsourcing facility can qualify for exemptions from the drug approval requirements in section 505 of the FDCA [21 U.S.C. § 355(a)], the requirement in section 502(f)(1) of the FDCA [21 U.S.C. § 352(f)(1)] that labeling bear adequate directions for use and the Drug Supply Chain Security Act requirements in section 582 of the FDCA [21 U.S.C. § 360eee-1] if the conditions in section 503B of the FDCA are met.
An outsourcing facility, which is defined in section 503B(d)(4) of the FDCA [21 U.S.C. § 353b(d)(4)], is a facility at one geographic location or address that — (i) is engaged in the compounding of sterile drugs; (ii) has elected to register as an outsourcing facility; and (iii) complies with all of the requirements of this section. Outsourcing facilities must comply with other provisions of the FDCA, including section 501(a)(2)(B) [21 U.S.C. § 351(a)(2)(B)], regarding current good manufacturing practice (CGMP), and section 501(a)(2)(A) [21 U.S.C. § 351(a)(2)(A)], regarding insanitary conditions. Generally, CGMP requirements for the preparation of drug products are established in Title 21 of the Code of Federal Regulations (CFR) parts 210 and 211.
B. Violations of the FDCA
The FDA investigators observed significant CGMP violations at your facility, causing your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.
In addition, the FDA investigators observed that your facility failed to meet the conditions of section 503B. For example, during the inspection, FDA investigators noted:
1.    Some of your facility’s drug products do not include the following either on the label or the container: a list of the inactive ingredients, identified by established name and the quantity or proportion of each ingredient.  Additionally, the containers for some of your drug products do not include the following information to facilitate adverse event reporting: www.fda.gov/medwatch and 1–800–FDA–1088 [Section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)]].  
2.    The June 2015 product report submitted to FDA by your facility failed to identify all drug products that you compounded during the previous 6-month period as required by section 503B(b)(2) of the FDCA [21 U.S.C. §353b(b)(2)]].
Because your compounded drug products have not met all of the conditions in section 503B, they are not eligible for the exemptions under section 503B from the FDA approval requirements in section 505, the requirement under section 502(f)(1) that labeling bear adequate directions for use, and the Drug Supply Chain Security Act requirements described in section 582 of the FDCA.[2] 
Specific violations are described below.
Adulterated Drug Products
FDA investigators noted CGMP violations at your facility, causing your drug product(s) to be adulterated within the meaning of section 501(a)(2)(B) of the FDCA.  The violations include, for example:
1.    Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
2.    Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release  (21 CFR 211.165(a)).
Outsourcing facilities must comply with CGMP requirements under section 501(a)(2)(B) of the FDCA. FDA’s regulations regarding CGMP requirements for the preparation of drug products have been established in 21 CFR parts 210 and 211. FDA intends to promulgate more specific CGMP regulations for outsourcing facilities. FDA has issued a draft guidance, Current Good Manufacturing Practice — Interim Guidance for Human Drug Compounding Outsourcing Facilities under Section 503B of the FD&C Act. This draft guidance, when finalized, will describe FDA’s expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 until more specific CGMP regulations for outsourcing facilities are promulgated.  
Under section 301(a) of the FDCA [21 U.S.C. § 331(a)], the introduction or delivery for introduction into interstate commerce of any drug that is adulterated is a prohibited act. Further, it is a prohibited act under section 301(k) of the FDCA [21 U.S.C. § 331(k)] to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being adulterated.
Unapproved New Drug Products
You do not have any FDA-approved applications on file for your drug products.[3] Under sections 301(d) and 505(a) of the FDCA [21 U.S.C. §§ 331(d) and 355(a)], a new drug may not be introduced or delivered for introduction into interstate commerce unless an application approved by FDA under section 505 of the FDCA is in effect for the drug. 
Misbranded Drug Products
You compound drug products that are intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, and adequate directions for use cannot be written so that a layman can use these products safely for their intended uses. Consequently, their labeling fails to bear adequate directions for their intended uses, causing them to be misbranded under section 502(f)(1) of the FDCA, and they are not exempt from the requirements of section 502(f)(1) of the FDCA (see, e.g., 21 CFR 201.115).  The introduction or delivery for introduction into interstate commerce of these products therefore violates section 301(a) of the FDCA.  Further, it is a prohibited act under section 301(k) of the FDCA to do any act with respect to a drug, if such act is done while the drug is held for sale after shipment in interstate commerce and results in the drug being misbranded.
Failure to Report Drugs
As noted above, your facility failed to submit a complete report to FDA, identifying the drug products that you compounded during the previous 6-month period (Section 503B(b)(2) of the FDCA [21 U.S.C. § 353b(b)(2)]).  The failure to report drugs by an entity that is registered with FDA in accordance with section 503B(b) is a prohibited act under section 301(ccc)(3) of the FDCA [21 U.S.C. § 331(ccc)(3)].
C. Corrective Actions
In your responses, one received on October 28, 2015, and one dated April 26, 2016, you described certain corrective actions in response to the Form FDA 483 observations.
Although some of your proposed corrective actions appear adequate, others are deficient or cannot be evaluated due to a lack of documentation.  For example, in your response, while you commit to correct the observed 503B labeling deficiencies by including “the quantities and proportions of each individual active drug and/or chemical contained in all preparations,” as well as adverse event reporting information, some of the revised labels submitted with your response are inadequate because some of the information required to be on the product label instead appears to be included on the container. Specifically, some of the product labels submitted do not include the statement, ‘This is a compounded drug,’ the firm’s address and phone number, or the statement ‘Not for resale’, and ‘Office Use Only.’
In addition, your April 26, 2016 response indicated that your out-of-specification (OOS) investigations would include a review of laboratory and production processes; however you did not indicate whether a retrospective review of previous OOS investigations would be conducted to verify that all root causes had been identified.   Further, we note that your responses did not state what interim measures would be taken while potency test methods were being developed.  
During our June 2014 and October 2015 inspections of your facility, our investigators collected portions of the stability study for the sterile bevacizumab drug product distributed in syringes. However, the documents collected do not clearly state the product quality criteria used to determine the (b)(4) beyond use date (BUD) (under refrigeration) currently assigned to this sterile drug product including whether particulate matter in the final container closure was evaluated as part of this study. We note that your firm voluntarily recalled more than (b)(4) units of sterile bevacizumab syringes on November 4, 2015 due to the presence of particulate matter caused by silicone oil microdroplets. Outsourcing facilities should perform stability studies with pre-determined specifications that include product quality attributes such as appearance, pH, color, clarity, visible particles, sub-visible particles, protein content, purity, potency, and endotoxin to establish BUD. Please provide FDA with a copy of this stability study, including study design, product quality attributes evaluated and raw data used to determine the BUD.
FDA strongly recommends that your management immediately undertake a comprehensive assessment of your operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess your aseptic processing operations. A third party consultant with relevant sterile drug manufacturing expertise could be useful in conducting this comprehensive evaluation. You should fully implement necessary corrections in order to ensure that the drug products produced by your firm conform to the basic quality standards that ensure safety, identity, strength, quality, and purity.
In addition to the issues discussed above, you should note that CGMP requires the implementation of quality oversight and controls over the manufacture of drugs, including the safety of raw materials, materials used in drug manufacturing, and finished drug products.  See section 501 of the FDCA, as amended by the Food and Drug Administration Safety and Innovation Act (Pub.L. 112-144, Title VII, section 711). We note that you have chosen to hire a contract testing laboratory to perform some of the required testing of your finished drug products. If you choose to contract with a laboratory to perform some functions required by CGMP, it is essential that you select a qualified contractor and that you maintain sufficient oversight of the contractor’s operations to ensure that it is fully CGMP compliant. Regardless of whether you rely on a contract facility, you are responsible for assuring that drugs you introduce into interstate commerce are neither adulterated nor misbranded. [See 21 CFR 210.1(b), 21 CFR 200.10(b).]
D. Conclusion
The violations cited in this letter are not intended to be an all-inclusive statement of violations at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure that your firm complies with all requirements of federal law, including 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. FDA intends to re-inspect your facility 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 you have taken to correct violations.  Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you do not believe that the products discussed above are in violation of the FDCA, include your reasoning and any supporting information for our consideration. If the corrective actions cannot be completed within fifteen working days, state the reason for the delay and the time frame within which the corrections will be completed.  Your written notification should refer to the Warning Letter Number above (NYK-2017-2). Please address your reply to CDR Frank Verni, Compliance Officer, at the address above.
If you have questions regarding the contents of this letter, please contact CDR Verni at (718) 662-5702.
Matthew R. Palo
Lieutenant Commander, U.S. Public Health Service
District Director (Acting)
New York District 
New York State Education Department (via email)
Office of the Professions
State Board of Pharmacy
Attn: Kimberly Leonard, Executive Secretary
89 Washington Avenue
Albany, New York 12234-1000

[1] See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).
[2] See, e.g., section 503B(a)(11) of the FDCA [21 U.S.C. § 353b(a)(11)].
[3] The specific products made by your firm are drugs within the meaning of section 201(g) of the Act, [21 U.S.C. § 321(g)] because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases and/or because they are intended to affect the structure or any function of the body. Further, they are “new drugs” within the meaning of section 201(p) of the FDCA [21 U.S.C. § 321(p)] because they are not generally recognized as safe and effective for their labeled uses. 
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