mdi ConsultantsFDA compliance has been much more difficult to deal with
By Alan Schwartz
What is going on with the FDA? Is the FDA on a war-path judging by the ever increasing number of facility inspections? Or is it like any bureaucracy, they have taken on too much work without clearly assessing the consequences for companies, especially foreign companies, many of which are in jeopardy of financial ruin as a result of present FDA policies. The situation is having a rippling effect on the domestic companies as well, since most domestic companies have a critical supply linked to at least one foreign supplier. So when a foreign supplier is shut down and their products are not allowed to be imported in the USA, then the U.S. company is also hurt financially having to lay off staff or possibly close down.
Now most U.S. companies and consumers would feel that it is about time that FDA takes a closer compliance look at foreign manufacturers since so many products are presently being made elsewhere and then imported into the U.S. It is not that all foreign manufacturers are producing poor quality medical devices and/or drugs, but there are some foreign manufacturers that are not as familiar with specifics of FDA regulations such as QSR or cGMPs. So while their products may be meeting local country standards, they may not always meet FDA compliance and as a result, get involved in possible adverse events and product recalls.
Until recently, the FDA foreign inspection program had always relied on the FDA’s staff of domestic investigators to volunteer to conduct foreign inspections. Under this structure, when a domestic investigator volunteers to conduct a foreign inspection, the foreign trip would be for three weeks and the investigator’s domestic work was still his responsibility. Such approach made it difficult to find experienced investigators to volunteer and this was putting strain on the FDA’s ability to audit foreign companies at the numbers the Agency would like.
To remedy this situation, the FDA had decided to get investigators to commit to a year’s assignment as a full time foreign inspector only, with no responsibility for domestic inspections. I was told that there were 20 such positions and these 20 investigators would do 18 inspections each for the year, a total of 360 inspections of medical device and pharmaceutical companies.
So far, this changed approach to foreign inspections sounds only fair since the domestic medical device and pharmaceutical companies must always be open to an FDA inspection. Many domestic companies know they could count on the FDA visiting every 2 years.
There are however several differences in the domestic audit and a foreign one. The first difference is the scheduling of the audit. Domestic medical device companies can get 1 to 3 day pre-notice of a pending inspection (and that is only if the company has no compliance issues). A foreign company is now getting a three months (yes, I said 3 months) prior notice of an upcoming visit. That gives the foreign company a big edge on being prepared for the audit.
The second difference: The FDA only spends 4 days on-site for a foreign inspection, where an FDA inspection of a domestic company can go on for weeks even months at a time. Of course there is a major difference, the U.S. audit is based on investigation of violations to the FD&C Act, where foreign inspections are just to determine if the company is in compliance or not. There is no need to document criminal violations for foreign based companies. The FDA has no right to prosecute a foreign company if they violate the U.S. laws. This again gives foreign companies a big edge on dealing with FDA inspection. If the investigator is only on site for 4 days, there is less opportunity for the FDA to find potential problems.
The third thing and the most important difference between domestic and foreign inspection is that if a foreign company is found to be out of compliance, the FDA would issue a warning letter and notify the company that they have put all future shipments on automatic detention list (ADL) preventing shipments from entering the USA. On the other hand, when the FDA finds a U.S. company out of compliance, the FDA would issue the U.S. company a warning letter, but they would be allowed to continue to operate and sell their products while they deal with the FDA compliance office and work on bringing their operations into compliance. Of course, for a domestic company, the FDA could proceed with possible product seizures, company injunctions, prosecution and monetary penalties if a U.S. company continues to violate the regulations. As explained previously, the FDA does not have these options for foreign companies.
If a foreign manufacturer received a warning letter and was put on the ADL, the shipments are not allowed entry into the USA till the FDA-483 and warning letter issues are addressed and that the corrective actions are verified by the FDA in a subsequent company re-inspection.
Recently, we also learned of another internal FDA policy that the FDA has started to use in dealing with foreign pharmaceutical companies. We have observed that the FDA has put companies that are found to be out of compliance with the FDA cGMPs on an Import Alert. The Import Alert allows the FDA to Detain Without Physical Examination (DWPE) all shipments being imported into the USA. This regulatory action is being done without fore warning, i.e. the issuance of a warning letter. This appears to be a new FDA internal policy and it has been used on several foreign companies in the last few months. This is the first time we have observed this new policy.
All these FDA activities would appear to be positive in furthering U.S. consumer protection while making sure that foreign companies are in compliance with all the FDA regulations and that the products they ship meet their specifications. But what is happening now is that to get the FDA to review these foreign company’s responses and corrective actions to the FDA-483s and warning letters in a timely fashion is becoming nearly impossible since the FDA is stuck in a tremendous backlog. It appears that while the FDA has increased their foreign inspection staff, they did not increase their compliance support staff which is responsible for the issuance of the warning letters, reviewing the responses and corrective actions, and setting up the re-inspections. This is causing havoc for both the foreign company as well as their U.S. partners and customers.
With the dramatic increase in the FDA number of foreign inspections, we also see a dramatic increase in the time it takes FDA to assist these companies in getting back into commerce. We have been involved with companies waiting 7-8 and 9 months to have a warning letter detention lifted. This is just way too long for some small companies to survive as well as for the U.S. companies that depend on these suppliers and are also being put in serious financial condition by these delays.
The situation has gotten so bad that in one case a Canadian generic drug giant Apotex Inc. says a U.S. “import alert” that blocked shipments from two of its Toronto plants in 2009 “decimated” its U.S. business and cost the company at least $520-million (U.S.).
We recently had a case involving a Pakistani company that was on the FDA Automatic Detention List (ADL) because of quality issues, for almost a year. It has been FDA policy involving Pakistani companies, that the FDA will not send investigators into Pakistan because of the high level of risk. The import alert is requiring that Pakistani companies need to retain the services of a third party GMP expert to provide a certification of GMP compliance. For this company we were involved with, the certification audit was completed and the documentation was submitted to the FDA in July of 2011. In February of 2012 the company was finally taken off the ADL and allowed to start shipping again to the USA. The U.S. importer whose business was very hurt by this unnecessary delay had to get his U.S. Congressman involved with the FDA to check on what was causing the long and damaging delays.
We are involved in a case now with a foreign medical device manufacture in Asia. They received their W/L in the last quarter of 2011. The FDA-483 and the W/L were not that serious in terms of the GMP deficiencies. The FDA however was in an awkward position since they had issued this company a W/L several years earlier but at that time the violative conditions at the company were not so serious and the company was allowed to continue to export (the FDA does have the option to issue foreign W/L and still allow companies to ship devices to the USA as well as preventing entry of shipments to the USA). The company, like many foreign companies, was not that familiar with the FDA-483 observations and how to respond to the 483 with the proper corrective actions and supportive documentation. The FDA decided to issue a second W/L and this time the company was put on the ADL. It has been over 4 months since the FDA received the company’s response to the W/L with the corrective actions. As of last week, the FDA has told the company they do not have a timeframe when they would finish the review and could schedule the company for re-inspection. The way it looks it can be another 4 to 5 months. This has been devastating to the company along with their U.S. operations where they had to lay off most of their staff.
We recently heard from another foreign company that was inspected by the FDA in August 2011 and just this past week, the FDA put them on the an import alert and the products are on the DWPE list, without being pre-warned. We expect it could take this company maybe 6 to 9 months before they could get this situation rectified. The FDA official stated that the FDA will be sending out a follow up letter to the company on what the company needs to do to rectify the situation. This FDA official stated this will not be a “warning letter” but it appears to be a “post FDA action” letter. As we stated this is a very new policy by the FDA.
How long will it take to get this backlog of foreign company W/L reviews through the system to give these companies a reasonable time frame to be allowed to get back into business, is anyone’s guess. We have had discussions with the various directors of the foreign compliance branches and they say that they just don’t have the staff to deal with the paper work in a timely matter. It would appear that if the FDA does not renew these foreign investigator’s special assignments for 2013, the number of foreign audits should be slowed down and the W/L backlog should be diminished.
That is not good news for companies that are already in this regulatory quagmire.
What can foreign companies do about this situation? It does not appear that they have many options. These companies should make sure that they do the following to try to avoid this problem before it occurs but using the following tips:
- That they are in full FDA compliance
- If they get notified of a pending FDA audit, get a pre-audit by an expert in FDA QSR and/or cGMP compliance and address all issues to get into compliance before an actual FDA inspection. (Please note: that many foreign companies use foreign based consultants for FDA compliance. Be sure if you use these consultants that they are up to date with all the FDA policies and interpretation of the regulations. These can be changed on a regular basis and many foreign based consultants do not keep up with these changes.)
- Make sure that you have a consultant expert in FDA audits available just prior to and during the audit to:
– assist with final preparation for the audit
– provide guidance during the audit
– provide immediate assistance for addressing any corrective actions - If an FDA- 483 is issued, make sure you understand the observations and how they need to be responded to. Your response to the FDA-483 is the last opportunity a company has to prevent the issuance of a warning letter. Most foreign companies and many consultants do not know how to respond to the FDA-483 observations properly and effectively.
- Make sure your corrective actions and responses to the FDA-483 are sent to the FDA within 10 days after the audit with all corrective actions completed and in documented.
Lastly, it cannot be said how important it is to understand the U.S. FDA regulations and what is needed to assure full compliance and have a strategic plan for dealing with the FDA. (Please note that the strategic plan could be critical to your ultimate survival in the event you are placed on the ADL or DWPE). This could be the only way to survive a future FDA audit.