FDA warns US firms over inadequate testing, lax process controls

The US Food and Drug Administration (FDA) recently issued warning letters to three domestic companies for multiple violations of good manufacturing practices (GMPs) in their production of over-the-counter drugs. The warning letters cited several common issues, including the companies’ failure to conduct adequate testing of incoming components and ensuring that their manufacturing processes were in a state of control.

All three warning letters were posted to FDA’s website on 7 October.

Naturich Cosmetique Labs

Naturich Cosmetique Labs, a manufacturer of OTC drugs based in Garland, Texas, was cited for several GMP issues following an inspection last Spring. The company produces skin protectants designed for use on irritated and broken infant skin.

The firm was cited for failing to validate its water production process, which should ensure that the system consistently produces water of appropriate quality.

“Your firm uses water as a component to manufacture topical over-the-counter (OTC) drug products including skin protectants applied to irritated and potentially broken skin of infants. You failed to adequately validate your water production process to ensure the system was consistently producing water of appropriate quality for its intended use,” said the warning letter.

Also, investigators stated that the company did not validate its processes for manufacturing OTC drug products and failed to provide sufficient documentation and control over critical processing steps used in its manufacturing.

As a result, a lot of sub-potent acne moisturizing lotion was released without adequate justification for their initial failing result. Furthermore, there was a lot of super-potent SPF 30 lotion that repeatedly failed both in-process testing and finished product release testing.

The warning letter states that “process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs.”

Furthermore, the water system was not properly maintained or regularly sanitized, and it lacked adequate monitoring to ensure compliance with chemical and microbial quality standards.

The investigators stated that the company failed to address multiple microbiological out-of-limit (OOL) results from its water system, which is used to manufacture topical drug products. This included the detection of objectionable microorganisms at multiple points of use. These microorganisms included Enterobacter cloacae, a common fecal microbiota, Burkholderia cepacia, and multiple species of Pseudomonas sp.

The company also failed to adequately test incoming component ethyl alcohol at risk of methanol contamination before using it as an active pharmaceutical ingredient (API) in manufacturing its OTC topical drug products. FDA reminded the company that “use of ethanol contaminated with methanol has resulted in various lethal poisoning incidents in humans worldwide.”

FDA said the company also failed to adequately test its incoming components at high risk of diethylene glycol (DEG) or ethylene glycol (EG) contamination for identity before using them to manufacture its drug products.

FDA recommended that the firm hire a GMP consultant. The company was notified that if it fails to address the violations, the FDA may withhold the issuance of export certificates and may delay the approval of new applications or supplements until the issues are resolved. The company has 15 days to correct these violations.

Dixon Investments Inc.

FDA sent Dixon Investments, based in Orchard Hill, GA, a warning letter for multiple GMP violations tied to its topical first aid antiseptic and external analgesic drug products following an inspection in March.

Inspectors said the company had not performed process validation for its OTC aerosol drug products, which the agency said is a repeat violation found in previous inspections. FDA reminded the company that “process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs.”

In addition, the company failed to conduct adequate stability testing on drug product batches as defined by its written stability procedures. This was another repeat violation noted in previous inspections.

Also, the quality unit did not establish adequate procedures for change controls, batch record release, and Corrective and Preventive Actions (CAPA).

FDA recommended that the firm hire a GMP consultant. Failure to correct these violations may prompt the FDA to withhold the issuance of Export Certificates and the approval of new applications or supplements. These issues must be resolved within 15 days.

Creative Essences Inc.

Creative Essences, Inc., located in Santa Fe Springs California, received an FDA warning letter following an inspection in March for failing to conduct thorough investigations into batch failures associated with its manufacturing of OTC drugs for oral, nasal, rectal, and topical use.

For example, the quality unit failed to investigate an out-of-specification (OOS) result for an incoming lot of the API benzocaine, which was subsequently used in the final drug product. Additionally, the company did not address several microbial OOS results from its water system, which is a component in its drug products. Lastly, the quality unit overlooked multiple OOS stability failures related to pH and viscosity for a released batch of Nutrascreen Color Balanced SPF30 sunscreen.

Investigators also said there were “multiple instances” where the company also failed to perform adequate sampling to ensure that drug products conform to appropriate standards of identity, strength, quality, and purity.

FDA said that “the ability of microbial testing methods to detect objectionable microorganisms in the presence of each drug product must be established and validated. Results generated using unverified or unvalidated methods may put consumers at risk.”

The company also failed to adequately test each shipment of each lot of glycerin and propylene glycol for identity, components at higher risk for DEG and EG contamination.

The company also lacked process validation data to demonstrate that demonstrate it processes are reproducible and controlled to consistently yield drugs of uniform character and quality.

Naturich warning letter; Creative Essences warning letter; Dixon warning letter;

FDA warns US firms over inadequate testing, lax process controls

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