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  5. Sofie Co., dba Sofie - 583034 - 10/10/2019
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Sofie Co., dba Sofie MARCS-CMS 583034 —

Delivery Method:

Recipient Name
Patrick W. Phelps
Recipient Title
President and Chief Executive Officer
Sofie Co., dba Sofie

21000 Atlantic Blvd., Suite 730
Dulles, VA 20166
United States

Issuing Office:
Division of Pharmaceutical Quality Operations II

4040 North Central Expressway, Suite 300
Dallas, TX 75204-3128
United States

October 10, 2019



Dear Mr. Phelps:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Sofie Co., d.b.a. SOFIE (FEI 3008302967), at 136 Commerce Way, Sanford, Florida, from April 3 to 12, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for positron emission tomography (PET) drugs. See 21 CFR, part 212.

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your PET drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your May 3, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

Your firm's facilities are not adequate to ensure the prevention of contamination of equipment or product by environmental conditions that could reasonably be expected to have an adverse effect on product quality (21 CFR 212.30(a)).

You manufacture sterile PET drug products for parenteral administration. From September 2018 to March 2019, your environmental monitoring program repeatedly recovered microorganisms including several fungal species from your facility's ISO 5 areas. The persistent, adverse trend of fungal contamination indicates that you did not have adequate control over these critical areas. You continued PET drug production operations without adequate interim measures to address the persistent microbial contamination in your ISO 5 environments that could pose a risk to product safety.

In 2018, your environmental monitoring trend data frequently identified fungal contamination on operator glove, air, and surface samples. Examples of such contamination included Penicillium decumbens, Penicillium steckii, and Penicillium decaturense. Although you identified several potential causes of the environmental monitoring trend, including a water leak in your material acceptance room, your corrective actions were inadequate.

You continued to have an adverse pattern of fungal contamination in your facility including the ISO 5 areas and operator glove samples. Specifically, you recovered Penicillium decumbens in over 40 environmental and glove monitoring samples from September 2018 through March 2019. You failed to appropriately conduct a thorough assessment of the scope of the fungal contamination in your facility and the potential routes by which fungi had entered your ISO 5 areas.

These findings indicate a loss of environmental control that requires substantial remediation efforts. Breaches in aseptic control represent a direct hazard to the sterility of the finished drug product. Robust, ongoing control over your ISO 5 areas is critical to ensure the sterility of your PET drug products because these areas are used to conduct aseptic manipulations.

An ongoing goal for environmental control of ISO 5 areas is to remain free of microbial contamination. An adverse pattern of microbial recovery in the ISO 5 areas should result in prompt, appropriate attention and effective and sustainable corrective action. PET drug manufacturing requires vigilant environmental control, and robustly designed andmaintained facilities to prevent contamination.

In your response, you indicated that a "Mold Risk Assessment, Risk Mitigation, and Internal Remediation Plan" had been developed, and you provided estimated dates for the execution of the plan. You stated that you would shut down production operations for approximately (b)(4) to perform remediation and you expected the majority of the remediation to be completed by May 31, 2019.

Your response is inadequate in that you did not provide adequate information to assure that your proposed remediation plan is sufficient and will be effective.

In response to this letter, provide:

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide an independent assessment that includes, but is not limited to:

o All human interactions within the ISO 5 area
o Equipment placement and ergonomics
o Air quality in the ISO 5 area and surrounding room
o Facility layout
o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)
o Adequacy of procedures to ensure ongoing maintenance and control of your facility

• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

• Your action levels for ISO 5 surfaces, air, and operator gloves, and revised procedures that describe appropriate response to contamination (i.e., 2:1 CFU) in critical environments.

• A list of all results outside action limits for ISO 5 and ISO 7 areas since April 1, 2019. Also include all organism identifications and the location(s) where microbe(s) were recovered. Also include investigations associated with any action level excursions in your classified environments.

Repeat Violations at Multiple Sites

FDA cited similar CGMP violations at another facility in your company's network: N-Molecular Inc. d.b.a. SOFIE, that received a Warning Letter (CMS #553833) issued September 24, 2018. These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate.

Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company's global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.

Guidance on Positron Emission Tomography (PET) Drugs

See FDA's guidance document, PET Drugs-Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing PET drugs, at https://www.fda.gov/media/71013/download. This guidance document also references FDA's guidance document, Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice for additional concepts and expectations that may apply to PET drug manufacturing.


The violation cited in this letter is not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violation and for preventing the recurrence or the occurrence of other violations.

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER's Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Correct the violation cited in this letter promptly. Failure to promptly correct the violation may result in legal action without further notice including, without limitation, seizure and injunction. An unresolved violation in this warning letter may also prevent other Federal agencies from awarding contracts.

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violation is corrected. We may re-inspect to verify that you have completed your corrective actions.

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Your written notification should refer to the Warning Letter Number above (Case # 583034). Please electronically submit your signed reply on your firm's letterhead to CDR John W. Diehl, M.S., Director, Compliance Branch, at john.diehl@fda.hhs.gov and orapharm2_responses@fda.hhs.gov.

If you have questions regarding the contents of this letter, you may contact Mr. Thao Ta, Compliance Officer, via phone at 214-253-5217 or e-mail at thao.ta@fda.hhs.gov.

Monica R. Maxwell
Program Division Director
Office of Pharmaceutical Quality Operations, Division II


Melissa Moore, Ph.D.
Chief Technology Officer
Sofie Co., d.b.a SOFIE
6162 Bristol Parkway
Culver City, California 90230

Kirk McCall
Facility Manager
Sofie Co'., d.b.a SOFIE
136 Commerce Way
Sanford, Florida 32771

Patrick W. Phelps
President and Chief Executive Officer
Sofie Co., d.b.a. SOFIE
6162 Bristol Parkway
Culver City, California 90230

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