Warning Letters

FDA Sent These 8 Warning Letters for Pharma Companies | September 2016

We took a snapshot of the 8 warning letters the FDA sent to pharmaceutical companies last month.  Drug manufacturing violations ranged from a product containing “hair and a black spider” to management failing to “document laboratory controls.”

From pharmaceuticals in Japan, Brazil, and more, here they are (starting with the most recent):

  • Delarange Cosmetics & Healthcare BV, Zeewolde, The Netherlands – 3 violations:
    • Failed to 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, prior to release. (21 CFR 211.165(a))
    • Failed to establish a quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products. (21 CFR 211.22(a)) 
    • Failed to establish and follow written procedures for cleaning and maintenance of equipment. (21 CFR 211.67(b))
  • Laboratoire Sintyl S.A., Carouge Ge, Geneva – 6 violations:
    • Failed to establish written responsibilities and procedures applicable to the quality control unit, including the review of out-of-specification results and customer complaints. (21 CFR 211.22(d)). During the inspection, site indicated that it have no independent quality unit.
    • Failed to test finished batches of drug products for the identity and strength of active ingredients. (21 CFR 211.165(a))
    • Failed to ensure the identity of components sourced from various suppliers, including (b)(4) active ingredients. (21 CFR 211.84(d)(1) and (2))
    • Failed to clean and maintain (b)(4) at appropriate intervals to prevent malfunctions or contamination of drug products. (21 CFR 211.67(d)). During the inspection, we observed reddish brown discoloration consistent with rust (b)(4).
    • Failed to establish written procedures for production and process controls, including validation protocols and reports, designed to assure that drug products have the identity, strength, quality, and purity they purport or are represented to possess. (21 CFR 211.100(a)). During the inspection, site acknowledged that firm has no procedures for process validation.
    • Failed to have data to demonstrate that the chemical and physical properties of products remain acceptable throughout their shelf lives. (21 CFR 211.166(a))
  • Nippon Fine Chemical Co., Takasago City, Japan – 3 violations:
    • Barred access to areas. The quality control manager directed employees to stand shoulder-to-shoulder, barring the investigator from accessing portions of the laboratory and the equipment used to analyze drugs for U.S. distribution.
    • Refused to provide copies of documents.  During the inspection, the investigator reviewed complaints received about drugs from the site’s customers, including complaints that drugs contained glass, hair, cardboard, metal, product discoloration, and a black spider.  The firm limited the inspection by refusing to provide FDA copies of these records.
    • Limited photography.  The quality assurance manager impeded the inspection by preventing the investigator from photographing a piece of equipment.
  • Yangzhou Hengyuan Daily Chemical Plastic Co., Yangzhou, China – 2 violations:
    • Failed to provide adequate written production and control procedures which are designed to assure that the drug products produced have the identity, strength, quality and purity they purport or are represented to possess (21 CFR 211.101).
    • Failed to 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, prior to release (21 CFR 211.165(a)).
  • Cheng Fong Chemical Co. Ltd., Taoyuan City, Taiwan – 3 violations:
    • Failed to have an adequate maintenance procedure to prevent contamination or carry-over of a material that would alter the quality of the API.
    • Failed to adequately conduct investigations and extend the investigations to other batches that may have been associated with the failure or deviation.
    • Failed to properly maintain buildings used in the manufacture of API in a clean condition.
  • Mappel Industria de Embalagens, Diadema, Brazil – 4 violations:
    • Failed to approve or reject all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product (21 CFR 211.22(c)).
    • Failed to 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, prior to release (21 CFR 211.165(a)).
    • Failed to follow written procedures for production and process control designed to assure that the drug products manufactured have the identity, strength, quality, and purity they purport or are represented to possess. (21 CFR 211.100(b)).
    • Failed to maintain production, control, or distribution records associated with a batch of a drug product for at least one year after the expiration date of the batch (21 CFR 211.180(a)).
  • Ajes Pharmaceuticals, Copiague, NY – 3 violations:
    • Failed to establish product specifications for the identity, purity, strength, and composition of finished batches of the dietary supplements, and for limits on those types of contamination that may adulterate, or that may lead to adulteration of, the finished batches of dietary supplements to ensure the quality of the dietary supplements, as required by 21 CFR 111.70(e).
    • Failed to establish any of the following specifications for the (b)(4) Capsule, Lot #(b)(4) product that is manufactured, such as identity specifications for each component that is used in the manufacture of a dietary supplement, as required by 21 CFR 111.70(b)(1); and component specifications for each component that is used in the manufacture of a dietary supplement that are necessary to ensure that specifications of the purity, strength and composition of dietary supplements manufactured using the components are met, as required by 21 CFR 111.70(b)(2).
    • Failed to collect and hold reserve samples of each lot of packaged and labeled dietary supplements that the site distributes, as required by 21 CFR 111.83(a). For each lot of packaged and labeled dietary supplements that is distributed, the firm must collect reserve samples and hold the samples in accordance with 21 CFR 111.83(b). 
  • Hebei Yuxing Bio-Engineering Co. Ltd., Hebei, China – 3 violations & 3 recommendations:
    • Failed to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure compliance with established specifications and standards.
    • Failed to follow and document laboratory controls at the time of performance, and failure to document and explain any departures from laboratory procedures.
    • Failed of the quality unit to ensure that all critical deviations are investigated and resolved.
  • With this last warning letter, the FDA clearly listed necessary “next steps” for Hebei.  We’ve included them below:
    • A comprehensive investigation into the extent of the inaccuracies in data records and reporting.
    • A current risk assessment of the potential effects of the observed failures on the quality of drugs. The assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.
    • A management strategy for the firm that includes the details of global corrective action and preventive action plan.

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