Anatomy of an FDA Warning Letter

When a company receives a warning letter, it is usually an exciting event – in every sense of the word. The letter could show up unexpectedly. It does not matter if you have spoken with the FDA investigator ‘just last Thursday’ and ‘everything looked good’. It is also entirely possible that your company was expecting it (depending on how bad things are going with the FDA and how open they were with you during their visit).

What ever the case may be and no matter how experienced your management is in dealing with the FDA, a warning letter guarantees you that you will live in interesting times (as the Chinese blessing goes). Depending on how you look at it, you can turn this in to an energetic wake-up call and drive you to get all your compliance ducks in the row, or you curse your ‘bad luck’. Like any such event, your company will go through the initial denial phase, before it matures into an acceptance phase. In this post, we shall examine and analyze warning letters, how it impact your company, how to read, how to respond to such letters and of course turn this into an organizational learning experience.

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What is a Warning Letter? – A Warning Letter is a communication to the firm that has been reviewed within several levels of the FDA, including the district office and the Center at FDA headquarters. The Warning Letter generally states that the firm has made products that are adulterated, violating the Food, Drug, and Cosmetic Act and that the firm has a very limited amount of time to address the problem(s) before the FDA takes further regulatory action against the firm, the adulterated product, and responsible individuals. These further actions could be anything from just a follow-up review of your system or a seizure, which could mature into a much larger liability. So for starters, let’s review some examples of warning letters, just click here:

FDA Warning Letters.

Explore the site, and read a few of these until you get a feel for it. Don’t dwell too much on the specifics at first but look at the beginning of each sentence. When you are ready, lets continue.

Here is an example of a typical Warning Letter, fully dissected:

 Part I –
How the Letter is sent –
February 7, 2009CERTIFIED

FDA never sends the Warning Letter by regular First Class mail. They want to make sure that you have received it. Your company can’t say you never received it. Post
office keeps records – hence the certified mail. Your company’s SOP on receiving mail should be followed with regards to such important communication. Yes, there should be an SOP or at least a formal communication policy.

Since the letter is often addressed to the most responsible person in the company, the
letter should find its way to the addressee promptly. If that person is out of office, the administrative person should have the authority to pass it on to a designee (typically a Senior Manager in Regulatory Affairs or Quality).Preferably a time-log should be started as to when the letter was received, who was informed, who reviewed it etc. Note that the fact that the letter is sent by certified mail, it bears legal importance.

Part II – Who the Letter is addressed to –Mr. CEO/President (Typically the Most Responsible Person at this company)
ABC Pharma
123 As It Where Lane
Anytown, NL 01234

As discussed, the letter is often addressed to the top management. It may not show
up at the actual site where deviations were found, but typically the site
manager or at least the Quality Operations leadership is also copied.
Rightfully, FDA understands that the CEO or the President is the person most
responsible to effect change and most liable in some cases.

Part III – Background info – What prompted this Letter

Dear Mr. CEO:

The Food and Drug Administration (FDA) conducted an inspection of xxx site
located at [Address] between January 20 and January 27, 2009. During
the inspection, FDA investigators documented a number of
significant deviations from current good manufacturing practices
(CGMP) in the manufacture of XXX Products.

These deviations from CGMP include deviations from the applicable requirements of section [Section Reference] of the Federal Food, Drug, and Cosmetic Act (FD&C Act) as well as requirements of your license/registration under section xxx of the Public Health Service Act (PHS Act) and Title 21, Code of Federal Regulations (21 CFR) Part

At the close of the inspection FDA issued a Form FDA 483, Inspectional
Observations, which described a number of significant deviations in
the manufacture of your XXX Products. Specific areas of concern
include, but are not limited to: ….

This is a scope or background section. Here the FDA is coming straight out in telling
they visited your site on such an such a date and they found ‘numerous’ deviations. Note that the Warning letter is not always preceded by an FDA visit or a 483. It could be that you may have been communicated verbally about some of your practices, may it be advertising, manufacturing, or handling of a customer complaint. Typically, though a significant event must have occurred to prompt the FDA to write this warning letter.

For the sake of this example, the language states that they visited you and found these
problems. In this case, you would have most likely received an FDA-483, and in some cases you may have even responded the 483. While the FDA may acknowledge some efforts from your end, their overall thinking is that if the deviations are both numerous and significant and somehow somewhere, they got the feeling that you are not really paying attention then you should be warned. Note that the FDA is also legally responsible to enforce compliance so they are obligated compelled to warn you.

This section also specifies sections of the regulations that are being violated. Additionally , the letter points to the specific deviations that follow in the next section. However, the last sentence is important because it states that Specific areas of concern include, but are not limited o”. Here FDA wants to tell you that while these deviations are described below, it is not all inclusive. In fact, the FDA is alluding to the fact that their audit may
not have discovered all the deviations and that what they found is essentially symptomatic of wider issues. These wider issues may not be specific to the site where the FDA visited, but could also include other sites where such practices or deviations could potentially exist. While reading this section, it is imperative to visualize a broader scope,
while looking at the specifics.

Part IV – What are the specifics of discrepancies?


  1. The sterility of XXXX could not be assured, yet final product lots that used XXX were further processed and submitted to FDA for lot release. For example…..:

[Multiple Examples]

The root cause for sterility failures of both lots was determined to be contaminated with XXX, yet XX additional lots that came into contact with XXX did not undergo a second test as was performed during the investigation of previously manufactured lots.

  1. “Master
    Validation Plan of…” is inadequate in that ……… were not defined, and the rationale for determining ……. Also, the ………..
  2. Stability study conducted to establish an expiry period for XXXX, is inadequate in that containers and closure systems used for stability sample storage are not representative of the final container. In study No. …
  3. Validation study for XXX did not address the reason for the deviations
    or the potential effect of the deviations on the study. For example:
    [Multiple Examples]
  4. You failed to follow written procedures to assure XXXX


  1. Sterility Failure investigations are incomplete. For example:
    [Multiple Examples]
  2. Your investigation of XXX batches which failed XXXX is incomplete. These lots were rejected and your firm suspended production XXXX in March 2007. Your investigations are incomplete in that they did not identify a root cause for the failure and did not include an evaluation of the cleaning processes and procedures for product contacting equipment to determine if equipment cleaning is effective in preventing cross contamination of the inactivated batches.


  1. Appropriate validation studies have not been conducted for critical
    processes. For example:
  2. SOP, the cleaning procedure for XXX was revised April 1, 2005 to remove the requirement for…. Additionally, the cleaning procedure for XXXX was revised April 15, 2006 to… These new cleaning procedures were not validated to establish the impact of the changes on the cleaning process.

[More Examples]

This is the ‘body’ of the warning letter. The observations are all numerically arranged but interspersed with the title of the area that is relevant to these observations. The classifications are important to both you and the FDA. For example, when the FDA list findings under ‘Production and Process Controls’, that whole area is suspected to have deviations, the specific observations are actual examples that the FDA is citing. Again, it is important to fix the specific issues, but whole area of ‘Production and Process Controls’ should be addressed. Often times, the company is expected to evaluate the entire quality system including the SOPs, records, practices that are not even mentioned in the Warning Letter.

It is akin to finding a small termite nest on one side of the house, the whole
house needs to be examined and treated. Notice the language here too ‘sterility is not assured’, ‘process is not validated’, ‘you failed to follow procedures’, ‘investigation is incomplete’, ‘you failed to include other batches’, ‘did not address the reason or root cause’. All these phrases are meant to underscore a broken system. You must address these warning carefully on a point by point base and on a systemic basis.

PART V – WARNING – This is not all, you must to something, promptly…. Or else

(a) The deficiencies described in this letter are indicative of your quality control unit not fulfilling its responsibility to assure the identity, strength, quality, and purity of your components/in-process materials. Please describe in detail how YOUR COMPANY will attain CGMP compliance with regard to these observations. Please include in
that description how YOUR COMPANY will use all of the relevant
information to conduct thorough investigations to ensure that adequate
steps are taken to evaluate whether deviations impact
product, and to implement effective corrective and preventive actions.

(b) We acknowledge receipt of your written responses dated XXXX, and XXXX which address the inspectional observations on the Form FDA 483 issued at the close of the inspection. Corrective actions addressed in your letter may be referenced in your response to this letter. Your response appears to address the individual FDA Form 483 items. However, we note that your response addresses these issues individually and not as part of a comprehensive corrective action plan.

(c) Neither this letter nor the list of inspectional observations (Form
FDA 483) is meant to be an all-inclusive list of deficiencies that may
exist at your facility. It is your responsibility as management to
assure that your establishment is in compliance with the provisions of
the FD&C Act, PHS Act, and applicable federal regulations. Federal
agencies are advised of the issuance of all Warning Letters about
drugs so that they may take this information into account when
considering the award of contracts.

(d) You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in FDA initiating regulatory action without further notice. Such action may include license suspension and/or revocation.

(e) Pleasenotify us in writing, within 15 working days of receipt of this letter, of any additional steps you have taken or will take to correct the noted violations and to prevent their recurrence. Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections
will be completed.

(f) Your reply should be sent to me at the U.S. Food and Drug Administration,


(g) If you have any questions regarding this letter, please contact XXXX,
Director at XXXX agency [Phone No.]

This is the Warning section.

Section (a) tells you that your company has failed to meet the regulations and you must do something. FDA wants to know what you will do and specifically, how you intend to do get back in compliance. It is also hinting here that the there is impact on the product and although it does not clearly mention the product in the field, it is implied.

Section (b) acknowledges your initial response but it is also saying that it was inadequate
in that it does not address the overall Quality System, rather the individual observations.

Section (c) is essentially stating that what they found is not ‘all’ that is wrong with
your quality system, rather these are the symptoms. The word facility is used for deviations, but then the statement reminds you of your responsibility of getting your establishment into compliance (notice the broader scope).

It also warns you of the fact that other federal agencies are advised of your non-compliance and if you have any supply agreements or contracts in place,
these could be impacted.

Section (d) is the meat of the warning asking you to take action and telling you that you
could be hit with a ton of bricks (figuratively).

Section (e) is giving you 15 days to respond with specific corrective actions along with
the evidence of corrective actions. It is also providing you flexibility to take longer than 15 day to take the action but you should explain why. Take this opportunity. It is our experience that no company can develop and implement a corrective and preventive action plan in 15 days. FDA recognizes these limitations. You response should be very thorough, well articulated, and specific. We will deal with a sample response in a separate post.

Section (f) is just giving you the address of your response. Please use Certified Mail and
keep all records, time-stamps and proof. Consider faxing your respond as a back-up.

Section (g) gives you the name of the person you should contact if you have questions. Take this opportunity to talk with that person. Make appointments, if necessary, to
have a face to face discussion as you want to make sure that you and the FDA
are on the right page.

Part VI- Who wrote the letter and who else is copied on it



Office of Compliance

c: Vice President Quality Operations

This section identifies the person who signed the letter for the FDA. You may have never met that person, but as a part of your follow-up or clarification meetings, you might want to request his/her presence. Note who else is copied on the letter and ensure that response to the FDA comes from the main addressee and not from the person copied. This is to impress upon the FDA that the Senior Management is the one taking the responsibility of responding to the FDA communications.

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