Source: https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm529217.htm
Timestamp: 2019-04-22 06:41:44+00:00

Document:
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]  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.
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.
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.
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)]].
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.
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)].
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.
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.
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.

References: § 353
 § 355
 § 352
 § 360
 §353
 §353
 § 353
 § 331