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  5. N-Molecular Inc. d.b.a. SOFIE - 553833 - 09/24/2018
  1. Warning Letters


N-Molecular Inc. d.b.a. SOFIE MARCS-CMS 553833 —

Delivery Method:
Certified Mail

Recipient Name
Patrick W. Phelps
Recipient Title
President and Chief Executive Officer
N-Molecular Inc. d.b.a. SOFIE
SOFIE and SOFIE Biosciences

6162 Bristol Parkway
Culver City, CA 90230
United States

Issuing Office:
Center for Drug Evaluation and Research

10 Waterview Blvd
3rd FL
Parsippany, NJ 07054
United States

(973) 331-4900

Dear Mr. Phelps:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, N-Molecular Inc. (d.b.a. SOFIE) at 11 Rogers Rd, Suite 6, Haverhill, Massachusetts, from February 12, 2018 to February 28, 2018.

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

We reviewed your March 20, 2018, response in detail and acknowledge receipt of subsequent correspondence.

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

1.    Your firm failed to take appropriate corrective action when a failure of a production batch or any component of the batch failed to meet any of its specifications. (21 CFR 212.20(d))

You failed to take corrective actions following bacterial contamination of an injectable product batch that you released. You opened a sterility failure investigation on May 31, 2016, after finding Bacillus pumilus/safensis in your finished sterile injectable drug product fludeoxyglucose F-18 (FDG). You failed to complete the investigation in a timely manner, and it had not been formally approved by the quality assurance vice president, as per your SOP, at the time of our inspection over a year and a half later.

Although no errors were found in laboratory testing, your investigation postulated that the FDG could have been contaminated with B. pumilus/safensis during sterility testing. You stated that the disinfection program might need to incorporate more frequent use of sporicidal agents. However, there was no indication that more frequent use of sporicidals was implemented.

Your investigation also lacked a thorough evaluation of potential manufacturing causes of the non-sterility test result. For example, your review of environmental monitoring data was minimal. You failed to address the active air sampling that found the same spore-forming genus as the sterility test isolate (Bacillus, sp.) and (b)(4) in the ISO 7 cleanroom location immediately adjacent to the Dispensing Hot Cell the day after the batch that failed sterility testing was produced. You had not performed active air monitoring in this area on the previous day.

In your response, you stated that you would provide training and implement director-level sign off for all investigations. You lacked evidence of your corrective actions, including but not limited to revised disinfection procedures and your remediated investigation procedure.

In response to this letter provide:
• a thorough assessment of the adequacy of your facility, equipment, and process (including both production and testing laboratory) design and controls.
• a comprehensive corrective action and preventive action (CAPA) plan that identifies microbial contamination risks throughout your operations and describes improvements to assure higher confidence in the sterility of products made at your facilities.
• a revised cleaning and disinfection program that ensures an environment suitable for aseptic processing and sterility testing.
• an assessment of your overall system for investigations into deviations, discrepancies, complaints, OOS results, failures, and verification of effectiveness of corrections. Include an action plan to fully remediate this system throughout your company’s network.

2.    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))

Your facility was in a state of disrepair and lacked cleanliness. Floor tiles were observed to be cracked and stained in the hallway that permits access to the classified areas. The sticky floor mat at the entry to the gowning room was visibly soiled with filth, including hair. The floor beneath the door that separates ISO 7 and ISO 8 areas had black streaks and stains. PET drug manufacturing requires adequately designed, controlled, and maintained facilities to prevent contamination.

In your response, you provided a timeline for cleanroom floor remediation and stated that you will implement a procedure for changing the sticky floor mat. You also submitted environmental monitoring trend data for the fourth quarter of 2017 and indicated that there were no environmental excursions during the fourth quarter of 2017 and first quarter of 2018.

However, your data included fungal and bacterial spore formers in critical environments (e.g., operator glove, ISO 5 sterility testing hood). It is unclear whether you initiated a deviation report in response to these findings.

Your response is inadequate because you did not provide a detailed plan for remediation activities that will adequately control your production areas.

In response to this letter, provide:
• your alert and action levels for ISO 5 surfaces, air, and operator gloves, and improved procedures that address appropriate responses to contamination at these levels.
• your investigations for any recovery of microbes in ISO 5 hoods and on operator gloves, and any results outside alert or action levels for the ISO 7 environment since January 2017. Also include all organism identifications performed for these two clean areas during this period, and the location where microbes were recovered.
• evidence that cleaning and disinfecting agents used in all classified areas are effective.
• your firm’s procedures for ensuring ongoing maintenance and control of your facility.

3.    You failed to approve or reject proposed changes to existing processes, before they were implemented, to ensure that they maintain the identity, strength, quality and purity of a PET drug, and you failed to demonstrate that any change does not adversely affect the identity, strength, quality, or purity of any PET drug. (21 CFR 212.20(c))

Your firm changed your manufacturing process by (b)(4). You did not adequately manage this change to ensure that it would not adversely affect the identity, strength, quality, or purity of your PET drug prior to being implemented.

Furthermore, your firm acknowledged to our investigator that you had not adequately validated this sterile filtration change. Your firm manufactured and distributed multiple batches of finished drug products using (b)(4).

In your response, you stated that you have discontinued the practice of using (b)(4). You provided a corporate risk assessment that included a retrospective review of this practice across all your manufacturing facilities. You concluded that patient safety was not compromised, based on the absence of patient adverse events reported during this period.

We acknowledge that you returned to the practice of using a (b)(4) as of February 28, 2018, upon conclusion of our inspection. However, your response is inadequate because you failed to address your deficient change management system. Further, you cannot rely on the absence of adverse events as evidence of sterility.

In response to this letter, please provide your procedures to evaluate all production and testing changes prior to implementation, including specific steps to ensure appropriate technical evaluation. Also provide a retrospective analysis to determine whether any other changes, particularly changes related to aseptic processing and sterility assurance, were implemented without adequate change management, and determine whether they adversely affected the quality of your PET drugs.

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 using aseptic processing, at


Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations for determining the causes, for preventing their recurrence, and for preventing other violations in all your facilities.

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) and 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 violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

Until these violations are corrected, we may withhold approval of pending drug applications listing your facility. We may re-inspect to verify that you have completed your corrective actions. We may also refuse your requests for export certificates.

After you receive this letter, respond to this office in writing within 15 working days. Please 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.

Please send your electronic response to orapharm1_responses@fda.hhs.gov. Please reach out to Compliance Officer, Yvette Johnson, at yvette.johnson@fda.hhs.gov with any questions.


Diana Amador-Toro
Program Division Director/District Director
OPQO Division I
New Jersey District Office

CC: N-Molecular Inc. d.b.a. SOFIE
Philip Nielson, R.Ph.
11 Rogers Rd, Ste 6
Haverhill, MA 01835

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