FDA Warning Letters Week of 12/15/2019: Independent Assessment Requests

Lots of enforcement this week.  FDA published five GMP drug warning letters and one to a device maker.

Note that frequently for the information that FDA requests from the firms below, they want an “independent” assessment indicating that they do not think the firm itself is capable or has enough knowledge to perform this activity internally.

DEVICE | Conformis Inc.

Conformis Inc. (Billerica, MA) received a warning letter on December 10, 2019 based on the outcome of an inspection ending November 15, 2019.  The firm manufactures Class II sterile orthopedic implants.

Deficiencies include but are not limited to:

• Adequate procedures are not established for corrective and preventive actions.  The example given is the failure to identify actions needed to correct and prevent recurrence of problems in the Class II new implants.  The actions implemented to date have not resolved the problem.

DRUG | Pharmalab Enterprises, Inc

Pharmalab Enterprises, Inc (Hialeah, FL) received a warning letter on December 10, 2019 based on the outcome of an inspection ending June 17, 2019.  The firm manufactures drugs and dietary supplements.  The firm is a contract manufacturer for OTC drug products.  The firm also was cited for adulteration of dietary supplements, misbranded foods, and misbranding of dietary supplements.  FDA recommends that the firm hire a qualified consultant to assist them in coming into GMP compliance.

Drug violations include but are not limited to:

• Microbiological limits for drug product are “far in excess of appropriate limits for drug products intended for oral use.”  In their response the firm failed to provide a risk-based assessment of their microbiological limits nor could they justify why the current limits were acceptable based on the intended use of the product.
• The firm failed to perform adequate investigations into high microbial counts in drug product.  Values ranged in the two lots cited from 1900 cfu/mL to 2,800 cfu/mL.  These lots were distributed.  In their response to FDA, the firm indicated that additional testing resulted in lower values, not a response that sat particularly well with FDA.  Further, the anti-microbial effectiveness testing showed that the preservative levels were not adequate.
• The firm did not adequately qualify equipment and validate the manufacturing process.  They failed to identify and assess process variables such as “blending speeds, in-process hold times, and temperatures.”  The firm’s response did not identify and evaluate all variables that may impact reproducibility of manufacture.  Furthermore, when the active ingredient concentration was doubled there was no assessment of this on the manufacturing process.

DRUG | Wild Child WA Pty Ltd

Wild Child WA Pty Ltd (Australia) received a warning letter on December 6, 2019 based on the outcome of an inspection ending May 31, 2019.  The firm manufactures OTC drug products.   FDA suggests the firm hire qualified consultant(s) to assist them in coming into compliance with GMP requirements.

Deficiencies include but are not limited to:

• Product was released without testing for identity and strength of the active ingredient.  Further, the firm uses tests that are inferior to those in the USP, nor is a minimum fill test performed.  The response given by the firm addressed actions that will be taken in the future but did not address any analysis or consideration of product that is already made and in distribution channels.
• The firm does not have adequate ongoing monitoring of process controls.  Further, investigators identified instances where batches were manufactured using significantly different parameters.  The firm’s response in committing to process validation was not adequate because it lacked information on the planned validation activities and did not include timelines for completion or draft protocol development.
• The firm failed to test incoming components and raw materials for identity.  They state that Australia does not mandate this, and the inactive ingredients are accepted on the basis of the supplier’s CoA.

DRUG | Unipharm, LLC

Unipharm, LLC (Tamarac, FL) received a warning letter on November 6, 2019 based on the outcome of an inspection ending May 7, 2019.  The firm manufactures OTC drug products.  FDA states that the firm also manufactures a misbranded product and an unapproved new drug product.

Deficiencies include but are not limited to:

• The firm has a trend of Burkholderia cepacia contamination in their water (I’m assuming purified water for an OTC oral product).  This adverse trend was not adequately investigated.  Further, the story that FDA provides strongly suggests a water system that is far from operating in a state of control.
• The firm failed to conduct process validation for their drug products.  The activities of qualification that were performed did not include appropriate acceptance criteria for all significant steps.  The processes are not robust and reproducible.  The firm stated they “inadvertently released” unvalidated product to the US market.
• The firm does not have stability data to support 2-year labeled expiry.  For example, there were failing assay results during accelerated studies and long-term studies have not been conducted.

DRUG | LNK International, Inc.

LNK International, Inc. (Hauppauge, NY) received a warning letter on September 26, 2019 based on the outcome of an inspection ending February 8, 2019.  FDA indicates that the firm’s inspection history indicates that the quality unit is not fully exercising their authority and responsibility and states “Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.“  FDA encourages them to hire qualified consultant(s) to assist them in coming into GMP compliance.

Deficiencies include but are not limited to:

• The firm released four lots of oral liquid diphenhydramine with OOS results for total aerobic microbial count, and total yeast and mold that ranged from high double-digit to four-digit values of CFU/mL.  They were released on the basis of testing results from additional samples.  There was not an adequate investigation into the events.
• The firm did not establish specification or analytical testing procedures for dissolution, and also failed to test for the impurity 4-aminophenol in acetaminophen-containing drug products.

DRUG | Dercher Enterprises Inc DBA Gordon Laboratories

Dercher Enterprises Inc DBA Gordon Laboratories (Upper Darby, PA) received a warning letter on September 13, 2019 based on the outcome of an inspection ending March 29, 2019.  The firm also manufactures OTC drugs.  FDA also cited the firm for distribution of unapproved new drugs and misbranded drugs.  Further, they recommend that the firm hire a qualified consultant(s) to assist them in coming into GMP compliance.

Deficiencies include but are not limited to:

• The FDA tested a hemostatic agent meant to be applied to skin that is not intact and found it to be super-potent.  The firm recalled the product after receiving the result from FDA but failed to conduct an adequate investigation.  The firm’s contract laboratory confirmed the 2018 OOS results but the firm continued to manufacture and distribute the product.
• The firm failed to establish specifications for microbiological quality of drugs applied to non-intact skin.  Further, the firm failed to test final product for microbiological quality.
• The firm did not establish an adequate quality unit, nor did they have or follow adequate procedures describing the quality units’ responsibilities.
• The firm does not have an adequate program for ongoing monitoring of process controls to ensure consistent and stable manufacture.  FDA points them to the Guidance on Process Validation.