Warning Letters for CAPAs & Complaint Investigations
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:
Failure to Investigate Bacterial Contamination
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:
Failure to Establish Procedures for Complaints
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.
Chinese API Manufacturer Hit with FDA Warning Letter
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
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,
Clinical Trial CAPAs Face Different Challenges
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.
Posted by GxP Perspectives 
REACH: The EU Approach to Regulation of Chemicals
November 14, 2010REACH: The EU Approach to the Regulation of Chemicals
In this Guest Commentary Sid Olufs, a professor at Pacific Lutheran University, discusses REACH, which is a new program in the EU for the regulation of chemicals. You can read book reviews by Sid on the page at the top of the blog on topics of regulation, food safety, and public health policy.
GUEST COMMENTARY: REACH—A New Approach to Regulation of Chemicals.
By Sid Olufs
The European Union (EU) has embarked on a far reaching regulatory undertaking—to investigate the chemicals we release into the environment, and move toward enactment of a precautionary approach. This means that some chemicals could be used only for specific applications, after being tested for effects on the environment and human health. REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) was passed in 2007, and is now in the early stages of implementation.
The European Chemicals Agency (ECA) is empowered to enact REACHs many provisions, including choosing a list of “substances of very high concern” (SVHC) that will be the first targets of scrutiny. This has been a focus of intense political conflict, as chemical companies want a very small list of SVHCs, while groups that favor regulation want a large list. The current list of the ECA contains 34 chemicals, several of them alternative versions of a single substance. The NGOs that favor stronger regulation are advocating a list that contains 356 chemicals at present, and is likely to grow.
One surprising feature of REACH is how little attention it receives in US media outlets. This is unfortunate, because it is a big deal for US chemical companies, manufacturers, exporters, farmers, and food companies.
Problems in the Regulation of Chemicals
• The EU is a large market for companies that manufacture or use chemicals in their products. The EU has half again as many people as does the US.
• The US imports many chemicals and items containing chemicals from the EU. The possible effects on the availability and labeling of these substances could be large.
• Existing US law (TOSCA, for example) contains triggers for more aggressive regulation that may be set off by REACH. For example, currently the EPA may require investigation of a chemical that it reasonably expects to cause harm, but usually it may not conduct the research that would produce those reasonable expectations. Yet the giant pile of data produced under REACH will doubtless contain grounds for such expectations. Environmental groups will probably resort to courts to require the EPA and other agencies to launch more aggressive regulation, particularly if the party controlling the White House is against enhanced regulation.
• Agencies that regulate chemicals and substances for which chemicals are used in their production will be faced with that giant pile of data from REACH. As a recent report on the FDA noted, for example, the agency is not prepared to deal with its present responsibilities for managing information. This will get much worse without substantial change, and money.
Differences in the Interpretation of Data?
We can also expect a well-financed effort to produce material that will cast doubt on efforts to regulate, perhaps as intense as in the case of climate change.
For those interested in reading more about REACH and its possible effects on the US, please check this web page—it has links to websites of the ECA, industry associations and NGOs interested in policy. It also links some of the best research comparing REACH and US approaches to regulation.
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In news from GxP Perspectives. I will be participating in the conference, Developing CAPAs in the GCP Environment on January 18-19, 2011 in Arlington, VA.
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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 The Blogroll: FDA as a political football? Read the latest from Steven Grossman at:
FDA Matters
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