Mr. Wayne Shafer
125 Titus Ave, Suite 200
Warrington, PA 18976-2424
CMS # 607662
September 15, 2020
Dear Mr. Shafer:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Coupler Enterprises, FEI 3003734940, at 125 Titus Avenue. Suite 200, Warrington, Pennsylvania, from February 26 to March 10, 2020.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your 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 March 31, 2020, response to our Form FDA 483 in detail.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm does not adequately inspect the packaging and labeling facilities immediately before use to assure that all drug products have been removed from the previous operations (21 CFR 211.130(e)).
Your firm operates as a human drug repackager. During the inspection walk-through, our investigator observed a variety of different tablets and capsules on and under the (b)(4) and (b)(4) packaging area. Your batch records indicated that line clearance was performed and the “Repackaging Room Cleaning Checklist” indicated the room was fully cleaned on February 14, 2020. The presence of tablets and capsules of various drugs on and under the packaging machinery indicates that line clearance was not adequately performed and increases the risk for potentially dangerous drug product mix-ups.
In your response, you stated that operators had been re-trained on line-clearance and a timelier cleaning schedule for the production area was developed. However, the standard operating procedure (SOP) for line clearance was not provided and your SOP for Production Room Cleaning Requirements lacks sufficient detail.
In your response to this letter, provide your SOP for line clearance and a comprehensive written evaluation of packaging and labeling operation, with emphasis on failure modes, capability, and design sufficiency. Provide an analysis including but not limited to, all human interactions with equipment before, during, and after (e.g., clearance) operations to identify all points with potential for human error.
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
You failed to demonstrate that your cleaning practices are adequate to remove residue from shared equipment used to manufacture your drug products. You were unable to provide scientific justification for the selection of drug products used in your cleaning validation studies. You stated that the “most powdery” products were selected for cleaning validation studies rather than selecting products based on adequate scientific rationale.
Although you committed to working with your third party consultant to address your deficiencies, you have not provided adequate details on your progress.
In your response to this letter, provide the following:
• Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
o drugs with higher toxicities
o drugs with higher drug potencies
o drugs of lower solubility in their cleaning solvents
o drugs with characteristics that make them difficult to clean
o swabbing locations for areas that are most difficult to clean
o maximum hold times before cleaning
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
• A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
During the inspection, our investigator observed that your quality unit (QU) did not provide adequate oversight for the manufacture of your drug products. Your QU failed to ensure that all deviations were investigated. For example, contrary to your firm’s Deviation SOP, you lacked adequate investigations into 11 deviations. Instead, the 11 batch records in question were placed in a folder labeled “deviations” without appropriate deviation forms or adequate investigation. Additionally, your QU failed to ensure all equipment was qualified. For example, you did not adequately qualify the air compressor used in your operations.
In your response you provided a master list of 11 investigations. However, you did not provide the completed individual investigations. You also failed to address the product impact of the 11 deviations. Additionally, the qualification of your air compressor was still pending.
In response to this letter, provide the following:
• A risk analysis to show quality impact of inadequate equipment qualification on currently distributed drugs.
• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
o A determination of whether procedures used by your firm are robust and appropriate
o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices
o A complete and final review of each batch and its related information before the QU disposition decision
o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
The violations cited in this letter are 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 these violations and for preventing their recurrence or the occurrence of other violations.
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.
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 violations are 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.
If you believe that your products are not in violation of the FD&C Act (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.
Send your electronic reply to [email protected] Your written notification should refer to the Warning Letter CMS # 607662 and reference FEI 3003734940.
If you have any questions, contact Compliance Officer CDR Liatte Closs at [email protected]
Program Division Director/District Director
OPQO Division I/New Jersey District