FDA Enforcement Actions Against Firms in South Korea
by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief
Several years ago, the FDA began, in earnest, to take more enforcement actions against sites outside the US than they did against sites within the US. This was simply because the majority of drugs and APIs are produced outside the US. If we look at warning letters, we initially see a distinct focus on dosage form and API sites in India followed by a similar focus on sites in China. Now we see the FDA focusing warning letters and import alerts against multiple sites in the Republic of (South) Korea.
Eight of nine Import Alerts 66-40 (failure to meet drug GMPs) on the FDA website that identify firms in South Korea are from 2017 — the other one is from 2013. Five of the 2017 import alerts were issued to firms of similar names in different locations. Import Alert 66-41 identifies six firms that offered unapproved new drugs for sale in the US in 2017. This includes cosmetics that appear to have made drug-like claims. In addition, products have been added in 2017 to firms placed on import alert in preceding years. And, finally, one firm in Korea was placed on Import Alert 99-32 for refusing an FDA foreign establishment inspection.
The following table identifies the warning letters (posted on the FDA website) issued to firms in the Republic of (South) Korea in CY2017. All of the warning letters from 2017 were issued to firms manufacturing finished pharmaceuticals — none were issued to API firms or device firms. Whenever ‘contract manufacture’ is noted in the table, it means that the firm is either a contract manufacturer or employs a contract manufacturer for its own products. Three of the six identify instances of contract manufacture associated with the warning letter.
Table 1: 2017 Drug Warning Letters Issued to Sites in South Korea
|Amaros Co., Ltd||Drugs, Finished Pharmaceuticals
OTC, Contract Manufacture
|AN Co. Ltd||Drugs, Finished Pharmaceuticals
|Dae Young Foods Co., Ltd||Drugs, Finished Pharmaceuticals, Homeopathic Drug, Contract Manufacture|
|Dasan E&T Co., Ltd||Drugs, Finished Pharmaceuticals,
|Frison Co., Ltd.||Drugs, Finished Pharmaceuticals,
Aseptic Manufacture of Sterile Drug
|Seindni CO., Ltd||Drugs, Finished Pharmaceuticals
OTC, Contract Manufacture
Table 2 shows that no device firms in South Korea received warning letters in 2017. In 2016, 3 warning letters were issued to device firms, and none were issued to pharmaceutical or API firms. In the years between 2011 and 2015, only two warning letters were issued to pharmaceutical firms and 16 were issued to device firms. We seem to be seeing a shift from warning letter enforcement actions against device firms to warning letters issued to pharmaceutical firms.
Table 2: Warning Letters Issued to South Korea
|CY YEAR(s)||WARNING LETTERS TO PHARMA FIRMS||WARNING LETTERS TO DEVICE FIRMS|
In conclusion, three of the six warning letters issued in 2017 to firms in South Korea cite manufacture of over-the-counter (OTC) products and one cites homeopathic drugs which are most frequently also OTC products. Only one letter cites aseptic manufacturing of sterile drugs — though the products in question may be topical creams rather than injectables. Redaction makes it difficult to tell. Another cites manufacturing of a ‘cream’ product which is likely a topical dosage form. The focus on OTC drugs reflects the FDA’s concern about the number of individuals potentially impacted by this category of products that are generally oral or topical dosage forms rather than injectables. Mentioning that contract manufacture is associated with three of the six warning letters reflects the FDA’s continued focus on these operations and their oversight (or lack thereof!) by drug sponsors.
Below are details on each of the warning letters issued to drug firms n South Korea in 2017:
- Amaros Co, Ltd (Seongnam-si, Korea) received a warning letter dated December 13, 2017 based on the outcome of an inspection ending May 12, 2017. The firm responded to the FDA on May 26, 2017 but did not ‘commit to any specific corrective actions.’ The firm was placed on Import Alert 66-40 on August 23, 2017. The FDA also recommends they hire a consultant to help them come into GMP compliance. Deficiencies include but are not limited to:
- The firm uses contract manufacturers for their OTC products released to the US and have a quality agreement in place. Some products, however, have been released for which neither the contract manufacturer or the sponsor have conducted tests for identity and strength of the active ingredient.
- Packaging and labeling materials have been released without a governing SOP.
- AN Co. Ltd (Gyeonggi-do, Korea) received a warning letter on December 13, 2017 based on the outcome of an inspection ending May 30, 2017.
- The firm did not conduct an investigation for an OOS event but rather simply rejected the product.
- Stability samples are not stored in the commercial packaging configurations.
- Process validation has not been conducted for products, and there is no ongoing program to monitor process controls.
- Dae Young Foods Co., Ltd (Seoul South Korea) received a warning letter on November 20, 2017 based on the outcome of an inspection ending March 17, 2017. The firm manufactures homeopathic drugs. The warning letter deficiencies address both adulteration items and misbranding. The firm is identified as a contract manufacturer and the FDA reminds them that “You and your customer, (b)(4), have a quality agreement regarding the manufacture of (b)(4). You are responsible for the quality of drugs you produce as a contract facility, regardless of the quality agreements in place. You are required to ensure that drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act.” The FDA also suggests they employ a GMP consultant to help bring them into compliance with GMPs. Deficiencies include but are not limited to:
- The firm accepted at least one shipment of a drug component without ensuring it was properly labeled. Further labels on in-process drums did not identify any of the active ingredients or their concentrations.
- The firm does not test incoming drug components for identity or any quality attributes prior to use. The FDA states the active ingredients are potentially toxic and present a safety hazard if present in levels higher than the labeled content.
- The firm lacks a quality control unit and some basic procedures. The quality unit does not review complete batch records prior to product release.
- Dasan E&T Co., Ltd (South Korea) received a warning letter on September 22, 2017 based on the outcome of an inspection ending January 26, 2017. The FDA suggests they hire a qualified consultant to assist them in coming into compliance with CGMPs. Further, they identified that the firm submitted a number of ‘inadequate procedures’ with their response. Procedures lacked dates, version number, and evidence of Quality Unit review and approval. Deficiencies include but are not limited to:
- Drug products are released without testing for each active ingredient identity and strength.
- The firm failed to show that microbial limits test methods can detect microorganisms in the presence of drug product. The FDA is looking for suitability testing to ensure the drug product does not inhibit microbial detection.
- The firm does not perform validation studies to ensure that microbial limits and specification can be met.
- The firm failed to test glycerin raw material from their supplier prior to releasing it for use in drug product manufacture.
- Firson Co., Ltd. (Korea) received a warning letter on August 31, 2017 based on the outcome of an inspection ending November 11, 2016. The firm was placed on import alert 66-40 on May 11, 2017. The FDA requested thirteen specific actions be taken in responding to the letter. Deficiencies include but were not limited to:
- The firm’s media fill program was inadequate in that they were not performed at sufficient frequency and were not representative of worst case conditions.
- The firm did not have smoke studies to confirm unidirectional airflow over the aseptic processing line.
- Sterilization validation was inadequate in that it provided only for minimum lethality.
- Complaint management is inadequate and includes inadequate investigations, lack of critical elements that would be useful to identify root cause, and samples from complaint lots were not tested for relevant quality attributes. The materials from “storage samples” of the lots subject to complaints for irritation, burning, and pain were tested on employees as ‘test subjects.’
- The firm does not perform adequate identity tests upon incoming materials. It seems the firm used the Korean Pharmacopoeia method which the FDA deemed inadequate to ‘discriminate between the chemical structure of similar compounds.’
- Seindni Co., Ltd (Seoul South Korea) received a warning letter on December 5, 2017 based on the outcome of an inspection ending May 26, 2017. This is yet another recent warning letter issued to a firm in South Korea that manufactures OTC drug products. The firm did not respond to the FDA inspection. The firm was placed on Import Alert 66-40, on August 23, 2017. Deficiencies include but are not limited to:
- The firm does not have an adequate Quality Unit.
- The firm employs contract manufacturers for their OTC products that admittedly do not manufacture under CGMPs. For example, some drugs are not tested for identity or strength of the active ingredient.
- The firm makes lot release decisions over the phone with their contract manufacturer. There are no procedures covering your batch release process and there is no documented evidence to demonstrate acceptability of the lots.
- The FDA reminds them of their responsibilities regarding the use of contract manufacturers. The firm also manufactures ‘skin protectant’ where labeling does not meet requirement.
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