WARNING LETTER
Stokes Healthcare Inc. dba Epicur Pharma
MARCS-CMS 677624 —
April 02, 2024
Delivery Method:
VIA Electronic Mail
Product:
Drugs
Recipient:
Recipient Name
Michael Tursi
Recipient Title
CEO
Stokes Healthcare Inc. dba Epicur Pharma
8000 Commerce Parkway, Suite 600
Mount Laurel
,
NJ
08054-2211
United States
mtursi@stokespharmacy.com
Issuing Office:
Division of Pharmaceutical Quality Operations I
United States
WARNING LETTER
WL # 677624
April 2, 2024
FEI: 3002815949
Dear Mr. Tursi:
You registered your facility 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 January 30, 2018, and most recently on October 11, 2023.  From September 26, 2023, to October 25, 2023, FDA investigators inspected your facility, Stokes Healthcare Inc. dba Epicur Pharma, located at 8000 Commerce Parkway, Suite 600, Mount Laurel, NJ 08054.  During the inspection, the investigators collected evidence indicating that drug products you produced failed to meet the conditions of section 503B of the FDCA necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain provisions of the FDCA.  In addition, the investigators noted serious deficiencies in your practices for producing drug products intended or expected to be sterile, which put patients at risk.
FDA issued a Form FDA 483 to your facility on October 25, 2023.  FDA acknowledges receipt of your facility’s response, dated November 15, 2023.  Based on this inspection, it appears you produced drugs that violate the FDCA.
A.  Compounded Drug Products under the FDCA
Under section 503B(b) of the FDCA, 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 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. § 360eee1] if the conditions in section 503B of the FDCA are met.
2
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 applicable 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.
For a compounded drug product to qualify for the exemptions under section 503B, the labeling of the drug must include certain information (section 503B(a)(10) of the FDCA [21 U.S.C. §353b(a)(10)]).
In addition, for a compounded drug product to qualify for the exemptions under section 503B, it must be compounded in an outsourcing facility that is in compliance with the registration and reporting requirements in section 503B(b), including the requirement to submit adverse event reports to FDA “in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor  regulations)” (section 503B(a)(1), (b)(5) of the FDCA [21 U.S.C. § 353b(a)(1), (b)(5)]).
B.  Failure to Meet the Conditions of Section 503B
During the inspection, FDA investigators collected evidence indicating that drug products produced by your facility failed to meet the conditions of section 503B.  For example, the investigators collected evidence indicating:
1. Some of your facility’s drug products, such as various strengths of Tacrolimus (Aqueous) Ophthalmic Suspensions did not include the following information on the label: The quantity or proportion of each inactive ingredient.  Additionally, some of your facility’s drug products, such as Tacrolimus (AQ) 0.5% Ophthalmic Suspension 10mL and Fluorouracil (AQ) PF 50mg/mL Injection Solution 50ms, did not include the following information on the container: Information to facilitate adverse event reporting: www.fda.gov/medwatch and 1-800-FDA-1088.
2. Your facility did not submit adverse event reports to FDA in accordance with the content and format requirements established through guidance or regulation under section 310.305 of title 21, Code of Federal Regulations (or any successor regulations).
3
For example, your documented Standard Operating Procedures (SOPs) for reporting adverse events do not state that a follow-up report is to be submitted to FDA within 15 calendar days of receipt of new information or as requested by FDA (21 CFR 310.305(c)(2)).
Because your compounded drug products have not met all of the conditions of section 503B, they are not eligible for the exemptions in that section from the FDA approval requirements of 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.
Specific violations are described below.
C.  Violations of the FDCA
Adulterated Drug Products
FDA investigators noted that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA.  For example, the investigators observed that:
1. Your firm failed to conduct
(b)(4)
testing on
(b)(4)
used to sterilize the human drug product Fluorouracil PF.  Therefore, you do not have assurance that the
(b)(4)
was integral throughout use.
2. Your media fills were not performed under the most challenging or stressful conditions.  Therefore, there is a lack of assurance that your firm can aseptically produce drug products within your facility. Specifically, your firm did not include higher risk production steps in your media fills, such as
(b)(4)
mixing of drug components in large vessels and
(b)(4)
to the finished drug product suspension. Additionally, sealed
(b)(4)
were used during media fills to protect media bottles during transfer from the
(b)(4)
to the ISO 5 classified critical areas, but these
(b)(4)
were not used during human drug production.
3. Your firm failed to perform adequate smoke studies under dynamic conditions to demonstrate unidirectional airflow within the ISO 5 classified critical area, in that you did not include production steps that may impede airflow such as mixing drug lots in
(b)(4)
vessels. Therefore, your products intended to be sterile are produced in an environment that may not provide adequate protection against the risk of contamination.
4. Your firm failed to ensure an adequate contact time for your sporicidal agent used to disinfect your aseptic processing areas.  According to the
(b)(4)
label, the required dwell time for
(b)(4)
is
(b)(4)
, but your firm's SOP only requires a
(b)(4)
dwell time.  Further, the investigators observed that a
(b)(4)
dwell time is not always achieved during cleaning and disinfection.
FDA investigators also noted CGMP violations at your facility, that caused your drug products 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 establish written responsibilities and procedures applicable to the quality control unit and to follow such written procedures (21 CFR 211.22(d)).
2. Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)).
3. Your firm’s quality control unit 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).
4. Your firm failed to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
5. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
6. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
7. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).
8. Your firm failed to establish an adequate air supply filtered through high-efficiency particulate air filters under positive pressure in the aseptic processing areas (21 CFR 211.42(c)(10)(iii)).
9. Your firm failed to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions (21 CFR 211.42(c)(10)(v)).
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 revised draft guidance,
Current Good Manufacturing Practice — 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.
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.
Misbranded Drug Products
You compound drug products that are intended for conditions not amenable to self-diagnosis and treatment by individuals who are not medical practitioners; therefore, 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.
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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.
D.  Corrective Actions
We have reviewed your facility’s responses to the Form FDA 483.
Regarding your responses related to the insanitary conditions and CGMP violations, some of your proposed corrective actions appear adequate.  However, the following corrective actions appear deficient:
1. In your response regarding your Quality Unit failing to prevent numerous significant deficiencies, you did not assess the need and develop plans to strengthen quality oversight to ensure deficiencies do not reoccur.
2. Concerning the release of non-conforming human drug products, you did not commit to improving Quality Unit training and oversight to prevent recurrence.  Additionally, your response did not consider the unsuitability of:
a. Modifying the potency test method to obtain passing potency results without scientific justification and revalidation, and without assessing the impact of these changes on the accuracy of the potency results for all previously distributed batches within expiry;
b. Invalidating original potency results based on resampling results without scientific justification.
3. Regarding process validation for your human drug products, you stated that you would execute the necessary validations; however, you did not perform a risk assessment to determine the impact of failing to perform process validations on the quality of the drug products that you previously and continue to distribute.  Additionally, you did not provide validation plans or executed validation studies for FDA’s evaluation.
4. In your response, you provided an executed potency test method validation protocol for your Tacrolimus AQ human drug products; however, this test method remains unvalidated because the validation study:
a. Lacked scientific rationale to justify establishing some of the relative standard deviations limits at
(b)(4)
;
b. Documented significant intra-batch potency variability;
c. Did not record chromatography column temperature information for specificity, limit of quantification, limit of detection, linearity, accuracy, precision, intermediate precision, and stability testing;
d. Concluded that the analytical results meet all acceptance criteria, although some sample results failed to meet specifications.
Additionally, you did not consider the impact of these test method changes on the accuracy of the potency results for all previously distributed batches within expiry.
5. In your response, you commit to completing new media fill studies; however, the provided media fill protocol does not include simulating the high-risk step of
(b)(4)
drug product suspension.
6. In your response, you stated that you provided a smoke study capturing the missing production activities cited in the FDA observation.  However, our review of this new smoke study finds it to be inadequate because it does not include simulating the higher risk production steps of diluting and mixing the drug components using large volume vessels.
7. Regarding your environmental monitoring program response, you indicated in your response that historical data will be used to justify sampling locations; however, you have not performed a risk assessment to determine if historical sampling sites meaningfully represent high risk operating conditions.  Further, you did not provide the referenced change control CC-23-021 or details about your proposed risk assessment.
8. In your response, you stated that your firm’s media fill studies, smoke studies, and environmental monitoring program are supporting indicators that your HEPA filter airflow velocities are adequate; however, the current FDA inspection found deficiencies in each of these areas. As such, you have not provided scientific evidence to demonstrate that the wide ranges of airflow velocities generated by your HEPA filters do not adversely impact the airflow patterns inside your ISO 5 classified critical areas.
9.  You did not provide a response regarding your investigations failing to include root cause analysis and extension to other lots that may have been associated.
Additionally, we are unable to fully evaluate some of your corrective actions due to lack of adequate supporting documentation:
1. In your response, you commit to improving the timely closing of your investigations; however, you did not provide the referenced revised standard operating procedures and the Interim Status Report form.
2. In your response, you commit to performing
(b)(4)
testing; however, your firm did not provide evidence that you have purchased the referenced
(b)(4)
Tester, or revised your standard operating procedures and master batch records.  Additionally, while you stated you would perform additional sterility testing, the sterility test in itself is not indicative that the batch is sterile, because when contamination is present, it is not uniformly distributed throughout the batch.  Therefore, aseptic processing controls, such as
(b)(4)
testing, are critical for ensuring the sterility of the finished drug products.
3. We acknowledge that you commit to performing a disinfection efficacy study; however, you did not provide information about the study goals and the protocol details.
Furthermore, our review of data collected during the inspection revealed that your firm detected an adverse trend of
Mucor circinelloides
fungal contamination between November 3, 2022, and July 10, 2023, in your ISO 8 classified cleanrooms C715, C711, and C735.  The
(b)(4)
located in cleanroom C715 is used to sterilize the drug components for Tacrolimus AQ, a human drug product intended to be sterile, which are then transported through C711 and C735 on route to the cleanrooms C704 and C706 where aseptic mixing and filling operations occur.  Your Quality Unit did not investigate this adverse trend to determine and correct the root cause of the contamination and the impact the contamination may have had on the human drug product components that were exposed to these cleanrooms, and instead produced and distributed
(b)(4)
lots of Tacrolimus AQ during this period.
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.  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 produce are neither adulterated nor misbranded.  [See 21 CFR 210.1(b), 21 CFR 200.10(b).]
In addition, regarding observations related to the conditions of section 503B of the FDCA, some of your corrective actions appear adequate: You state that the adverse event reporting information will be added to the packaging for the drug product.
You did not address certain observations related to the conditions of section 503B of the FDCA, for example: You state that you list inactive ingredients proportionally from largest to smallest on your product labels and that each label states “INACTIVE(S) (proportional from largest to smallest amount)”, but such a list does not provide the quantity or proportion of each inactive ingredient.
With respect to your documented SOPs for reporting adverse events, FDA expects to evaluate compliance with section 503B(b)(5) of the FDCA upon reviewing any updated copy of your adverse event reporting SOPs that you submit in response to this letter.
Should you continue to compound and distribute drug products that do not meet the conditions of section 503B, the compounding and distribution of your drugs would be subject to the new drug approval requirement, the requirement to label drug products with adequate directions for use, and the Drug Supply Chain Security Act requirements.
FDA strongly recommends that your management undertake a comprehensive assessment of operations, including facility design, procedures, personnel, processes, maintenance, materials, and systems.  In particular, this review should assess your aseptic processing operations.  A third-party consultant with relevant sterile drug manufacturing expertise should assist you in conducting this comprehensive evaluation.
E.  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 any violations 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 address any violations.  Failure to adequately address any violations may result in legal action without further notice, including, without limitation, seizure and injunction.
Within fifteen (15) working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to address any violations.  Please include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation.  This letter notifies you of our concerns and provides you an opportunity to address them.  If you believe your products are not in violation of the FDCA, include your reasoning and any supporting information for our consideration.  If you cannot completely address this matter within fifteen (15) working days, state the reason for the delay and the time within which you will do so.
Your written notification should refer to the Warning Letter Number above (
WL #677624
). Please address your reply to: CAPT Liatte Closs, Acting Director of Compliance, orapharm1_responses@fda.hhs.gov.
If you have questions regarding the contents of this letter, please contact Compliance Officer, Juan Jimenez, at orapharm1_responses@fda.hhs.gov and juan.jimenez@fda.hhs.gov or at 973-832-9409. Please identify your communications with
FEI: 3002815949
.
We appreciate your acknowledgement in receipt of this communication.
Sincerely,
/S/
Lisa Harlan
Program Division Director
Office of Pharmaceutical Quality Operations Division I
_________________
1
See Pub. L. No. 113-54, § 102(a), 127 Stat. 587, 587-588 (2013).
2
We remind you that there are conditions, other than those discussed in this letter, that must be satisfied to qualify for the exemptions in section 503B of the FDCA.
3
For more information, see, FDA’s guidance, “Adverse Event Reporting for Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act,” which can be found at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM434188.pdf.
4
Your compounded drug products are not exempted from the requirements of section 502(f)(1) of the FDCA by regulations issued by the FDA (see, e.g., 21 CFR 201.115).
Content current as of:
10/22/2024
Regulated Product(s)
Drugs