FDA Warning Letters for International APIs in 2011

January 8, 2012

API FDA Warning Letter International firms

API Warning Letters to International Manufacturers

FDA issued at least ten Warning Letters to international manufacturers of active pharmaceutical ingredients in FY-2011. Manufacturers in both China and India, the world’s largest exporters of APIs, received three Warning Letters each from FDA. Manufacturers in Spain, the UK, Canada, and Japan each received one Warning Letter from FDA. These metrics show both the domination of China and India in the API market as well as the continued dependence on international manufacturers for APIs destined for the U.S. market.

Deficiency Categories:

The violation that dominated the charges cited by FDA in FY-2011 related to quality control, cited in four Warning Letters, two to China and one each to Canada and Japan.

FDA API Warning Letters in 2011

Failure to Have Procedures for Cross Contamination

Another violation that is sure to cause concern with FDA is the failure to prevent cross-contamination. When I attended FDA API inspection training in 2000 cross-contamination, particularly with anti-biotics, was a major concern. It continues to be with API manufacturers in both India and China being cited for the “Failure to have appropriate procedures in place to prevent cross-contamination.”

Out of specification (OOS) laboratory results are always a concern of FDA and landed on Warning Letters to manufacturers in India and Spain. Other citations include:

= Water purification for APIs used in parenterals

= Failure to establish a stability program to monitor APIs

= Failure to perform at least one identity test of each batch of incoming material

= Validation of analytical methods used to test APIs

There are no big surprises here but it shows that regular surveillance of API vendors is an absolute necessity for the manufacture of quality drug products. What is of interest is that GxP Perspectives couldn’t find any domestic Warning Letters for APIs. That doesn’t mean they don’t exist, only that they couldn’t be easily located. Unfortunately, FDA lists API Warning Letters in any number of classifications for GMPs for finished pharmaceuticals. However, they don’t seem to list them for APIs. With all the razzle-dazzle taking place on FDA’s website, you would think they could come up with a consistent way to list API Warning Letters. Who knows, maybe next year.

by Carl Anderson, GxP Perspectives
Research by Francesca Carreras-Perez, GxP Perspectives

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Two articles of interest regarding APIs:

Indian API Manufacturers want anti-dumping duties

API Product List (note countries of origin)

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FDA Issues 5 New International Warning Letters

May 15, 2011

FDA international warning letters

FDA's Increased International Presence

The “Most Recent Warning Letters” section of the FDA website lists five Warning Letters to international firms. The Warning Letters were posted on May 10 and will disappear into the Warning Letter labyrinth on the website in a few days (see previous post). They are to firms in both Europe and Asia and come from four different centers: the Center for Devices and Radiological Health; the Center for Drug Evaluation and Research (Active Pharmaceutical Ingredient (API); the Center for Biologics Evaluation and Research; and the Center for Food Safety and Applied Nutrition (two Warning Letters for Seafood HACCP).

The Warning Letters do not state if the inspections were conducted by one of the FDA’s new International Resident Posts- but it is likely that the FDA’s increased global presence contributed to the enforcement actions. FDA now has offices in China, India, Belgium, and Costa Rica. This is addition to FDA’s International Inspection Cadre which is primarily drawn from FDA Field Investigators (Consumer Safety Officers) working for the 20 FDA District Offices across the country. The fact that different offices are issuing Warning Letters around the world at the same time gives a clear indication of FDA’s increased international enforcement efforts.

FDA International Resident Posts

Read the Warning Letters:

Hong Kong – Medical Devices

Spain – Active Pharmaceutical Ingredients

Sweden – Biologics cGMP

Korea – Seafood HACCP

On the Blogroll: Last week we had the FDA Lawyer’s Blog. This week I want to highlight a recent article on the FDA Law Blog on “FDA Warning Letter ‘Close Out’ Process Not Working.”

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FDA Warning Letters to International Companies for CAPAs & Complaints

November 28, 2010

FDA warning letter CAPA complaint

Warning Letters for CAPAs & Complaint Investigations

In the past 90 days FDA issued five Warning Letters to international firms for GMP failures to adequately investigate complaints. Whether it is GMPs, GCPs, or GLPs FDA is making the case that when things go wrong, it is a company’s responsibility to investigate and implement the necessary corrective and preventative action (CAPA), In the past, FDA was hesitant to issue Warning Letters to firms outside the United States. That clearly is changing as both the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) have issued Warning Letters to companies in Canada, Switzerland, China, Sweden, and India. Although the companies are from diverse locations and range from medical devices, active pharmaceutical ingredients (APIs), and finished pharmaceuticals, one issue connects them all: the failure to adequately address complaints. For the medical device Warning Letters, corrective and preventative actions (CAPAs) figured prominently.

FDA first opened international offices in 2008 in India and China and now has offices in Europe and Latin America as well. The international offices are predominantly focused on GMPs for food, drugs, and medical devices. FDA has also stepped up its inspections of clinical trials in international locations including Russia and Eastern Europe. However, there has not been the corresponding surge in Warning Letters. At least not yet. Here are charges that FDA made in the international Warning Letters:

CAPA complaint FDA warning letter

Failure to Investigate Bacterial Contamination

Claris (India): On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large volume parenteral and examined it.

Storz Medical (Switzerland): Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, no protocol, including acceptance criteria, was established for the validation of Change Request (b)(4). Additionally, there was no documentation showing that this change was validated. The change was implemented to fix cracked cooling pumps in the Modulith SLX-F2.

The Warning Letter goes on to say:

international complaint investigation failure FDA

Failure to Establish Procedures for Complaints

Failure to establish and maintain adequate procedures to ensure that any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c).

Neoventa Medical AB (Sweden): 1. Failure to establish and maintain adequate procedures for implementing corrective and preventive action that include requirements for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device and that all activities required under this section and their results be documented, as required by 21 CFR 820.100(a)(4) and (b).

2. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).

Once again the direct connection between the failure to investigate complaints and the failure of a system of CAPA.

FDA Warning Letters CAPA

Chinese API Manufacturer Hit with FDA Warning Letter

Yunnan Hande (China): Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.

Pega Medical (Canada): Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)… For example, Complaint NCR No. (b)(4) reported…”

Read the Warning Letters:

Storz Medical, AG Warning Letter

Yunnan Hande Biotech Warning Letter

Claris India Warning Letter

Pega Medical Warning Letter

Neoventa Medical AB

FDA International Resident Posts

And What About Clinical Trials?

At a recent FDANews conference FDA representative Ann Meeker-O’Connell, M.S., Division of Scientific Investigations, Office of Compliance CDER/FDA, said,

FDA warning letter international complaint investigations

Clinical Trial CAPAs Face Different Challenges

“But, clinical trials are inherently variable systems with a goal of producing reliable data for regulatory decision-making . . . How can this be reconciled with a quality system framework originating in mass manufacturing?”

That is a very good question and one that many of us have been wrestling with. However, it is clear that FDA has been taking on the question of the international nature of the drug and device industry, including manufacturing and clinical trials.

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Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

UPDATE: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.

Public Comment Period is Open for New FDA Draft Guidance:
FDA Draft Guidance on Electronic Source Data in Clinical Investigations

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Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

On FDA’s Website there are Two New Warning Letters from FDA to Clinical Investigators that show the need to effectively respond to a Form FDA 483, Inspectional Observations, with a well thought out CAPA Plan.


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