GMP Problems Stop Canadian Firms’ Topical OTC, Homeopathic Imports

Homeolab USA’s and Cellex-C’s imports were stopped earlier in 2017 following GMP inspections at their facilities, and FDA warns that approvals for marketing of additional products in the US could be withheld until each firm is GMP-complaint. Homeolab trips up by trying to prevent FDA photography inside plant.

Two Canadian firms marketing OTC drugs in the US learned one of the basics of good manufacturing practices: their contract manufacturers or test labs are not responsible for their GMP compliance. Both received FDA warning letters that their imports are stopped until their GMP problems are corrected.

One of the firms, homeopathics marketer Homeolabs USA Inc. in Montreal, also learned that preventing FDA officials from taking photographs during GMP inspections could lead to their products being considered adulterated (see box below).

In warning letters submitted Aug. 2 to Homeolabs and to Toronto firm Cellex-C International Inc. in, the manufacturing quality and compliance offices in FDA’s Center for Drug Evaluation and Research explained problems found during inspections at both firms’ facilities and why each firm’s response to inspectors’ Form 483 findings was inadequate to assure the agency that it had become GMP compliant (see table below).

Both firms were added to FDA Office of Regulatory Affairs’ list of “detention without physical examination” import alerts earlier in 2017 following the inspections at their facilities in January. (Also see "Aloe Drug Claims Land Indian Firm On FDA Import Alert List" - HBW Insight, 5 Jun, 2017.)

“Failure to correct these violations may also result in FDA continuing to refuse admission of articles” each firm manufactures, CDER officials stated in each letter. Additionally, failing to become compliant, as determined by FDA, could prevent each firm from gaining “approval of any new applications or supplements listing your firm as a drug manufacturer.”

Homeolab USA’s Kid’s Relief teething tablets are among the products FDA noted in a warning letter on GMP violations.

Import alerts are an effective complement to warning letters for getting manufacturers’ attention about problems with their products, food and drug attorney Anthony Young observed. “That’s the ultimate authority FDA has over these foreign suppliers. ‘Boom, your product isn’t coming into the US,’” said Young, a partner at Kleinfeld, Kaplan & Becker LLP in Washington, in an interview.

Same Address, Same Responsibilities

Homeolabs, a business of Homeocan Laboratories Inc., responded by stating in part that it tests samples of each component of its products for identity and conformity with specifications for purity, strength, and quality “according to the requirements of the Homeopathic Pharmacopeia,” the standards body FDA recognizes for homeopathic product formulations and manufacturing.

However, FDA officials state in the warning that the Homeopathic Pharmacopeia of the US “requires multiple analytical identity tests” and Homeolab’s “response failed to adequately describe whether each lot of components will be fully and appropriately tested for identity prior to use in manufacturing, and whether other attributes will also be tested.”

FDA’s Candid Photo Authority

Homeolab’s problems weren’t limited to omitting GMP compliance steps, but also extended to an activity during the inspection. A representative of the firm prevented an FDA investigator from photographing “excess material clinging to the sides” of machinery used to make drugs, according to the letter.

The letter points out that if a firm “delays, denies, limits, or refuses an inspection,” including taking photographs, “the drugs may be deemed adulterated.”

CDER’s 2014 guidance, “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection” lists examples of conditions or practices effectively documented by photographs including evidence of rodents or insect infestation; faulty construction or maintenance of equipment or facilities; product storage conditions; product labels and labeling; and, visible contamination of raw materials or finished products.

The guidance also states that preventing photography during an inspection would not render products adulterated when the “chemical properties of products manufactured at the facility are such that taking photographs would adversely affect product quality.”

Young said the 2012 FDA Safety and Innovation Act clarified FDA’s authority to deem products adulterated when agency officials believe someone is obstructing their inspection authority. The authority includes taking photographs and, as the guidance states, allows limited exemptions. (Also see "How FDA Will Use Its New Authority against Denying, Limiting or Refusing Inspections – And Why Industry is Still Worried" - Pink Sheet, 21 Nov, 2013.)

“It’s very specific,” Young said, adding that Homeolab’s warning letter “spells out very carefully” why inspectors took a photograph.

Homeolab’s explanation that it is not a manufacturer but a distributor that contracts with Homeocan for its finished product also did not assuage FDA’s concerns.

The warning notes that Homeolab and Homeocan “share the same address, facility, and personnel, including the chief executive officer and the head of quality,” who “signs email correspondence with “Homeocan Inc./Homeolab USA” as the firm’s identity.

“In terms of drug manufacturing, Homeolab USA Inc. and Homeocan Inc. have no significant separation, so we are treating Homeolab/Homeocan as a single entity,” CDER’s manufacturing quality and compliance offices stated.

The warning also pointed out that Homeolab provided powder blends that contract manufacturer Raritan Pharmaceuticals Inc., of East Brunswick, N.J., used in homeopathics for use by infants and children that were determined to be adulterated. Homeolabs’ Kids' Relief Ear Relief Oral Liquid and two other children’s homeopathic products made by Raritan were recalled in November 2016 due to GMP violations. (Also see "Recent FDA Health And Wellness Product Recalls" - HBW Insight, 30 Jan, 2017.)

Homeolabs’ warning and import alert link to FDA’s concerns about the safety of belladonna, an ingredient in the firm’s Infants’ Teething Tablet. (Also see "Teething Tablets, Toothpaste Recalls: Consumer Health Industry News Roundup" - Pink Sheet, 17 Apr, 2017.)

The warning states some of Homeolab’s “powder blend mixtures are manufactured from ingredients that pose potentially toxic effects,” and including belladonna Raritan uses in drug products for infants and children, “a population vulnerable to the toxic effects of belladonna.”

Suppliers’ COA Not GMP-OK

Cellex-C, which markets OTC topical drugs indicated for skin care, responded to FDA that “it is not feasible” for the firm to perform component identification testing and it would rely on its supplier’s certificate of analysis for each incoming component’ identity.

Cellex-C International’s manufacturing of Skin Hydration Complex, High Potency Serum and other products didn’t get a clean GMP report following an FDA inspection.

The response, FDA stated, is inadequate because Cellex-C did not indicate how it would address its failure to test all incoming components for specifications other than identity and because GMP regulations require manufacturers to conduct at least one specific identity test on all incoming components. “You may not rely on your supplier’s COA to verify the identity of your components,” the warning said.

Similarly, Cellex-C said it would resolve its violation of failing to have appropriate laboratory determination of the identity and strength of active ingredients by having “a contract laboratory test all finished drugs for active ingredients.”

However, the response “lacks sufficient detail about the selection, qualification, and oversight procedures [the firm] will use to engage [its] contract testing laboratory.” The firm also did not provide an action plan and timelines for conducting tests to determine the identity and strength of active ingredients in all its drug products within expiry that it previously released without performing the testing.

GMP Problems For Toronto’s Cellex-C And Montreal’s Homeolab
GMP violation for failing to:	Firm cited:
have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient.	Cellex-C International
test samples of each component for conformity with all appropriate written specifications for identity, purity, strength, and quality.	Cellex-C International Homeolab USA
establish written responsibilities and procedures applicable to the quality control unit.	Cellex-C International
establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess.	Cellex-C International
prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced.	Cellex-C International
establish and follow adequate control procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.	Homeolab USA

From the editors of the Tan Sheet.