EU, FDA and WHO Regulations Part Two, FDA Regulatory Requirements and Inspection Tips

For many pharmaceutical organizations, receiving a U.S. FDA GMP inspection has always been perceived as a nerve-wracking experience. While an inspection/audit by any government or client can be considered as a stressful moment, the FDA has always held a special place in our hearts and minds. The “guilty until proven otherwise” approach the FDA is infamous for has become slightly milder over the years, nonetheless we will provide you with some valuable information in this article. It explores why the FDA gained its infamous status and how its inspections are structured, how you can prepare and how the FDA organizes its (c)GMP inspections.

Introduction - the U.S. FDA

We’ve introduced the FDA and its history in our previous article which you can read here. To summarize; The FDA is the federal agency responsible for ensuring that foods are safe, wholesome and sanitary; human and veterinary drugs, biological products, and medical devices are safe and effective; cosmetics are safe; and electronic products that emit radiation are safe. The FDA also ensures that these products are honestly, accurately and informatively represented to the public.

The FDA has a number of district offices where staff are posted in strategic locations, for example in; China, India, Latin America and Europe. These local inspectors are the eyes and ears of the FDA and the general public.

When the FDA has established that a company does not adhere to the CFR (Code of Federal Regulations) or other laws that might require the FDA to act the following measures can be taken by the FDA:

  • Warning Letters
     

    Warning letters are an opportunity for individuals and firms to take voluntary and prompt corrective action. These warning letters are made public by the FDA, with the omission of certain names and production related information (such as the substances used). When the FDA issues a warning letter, it expects a response. If the response is inadequate or if there is no response whatsoever, the FDA may decide to employ other means of enforcement.

  • Recall
     

    When unforeseen problems have occurred, it can sometimes lead to the recall of a product. Recalls basically remove the product from the market which can sometimes be the most effective corrective action to protect public health.

  • Seizure

    The FDA will take possession of the products. This may involve multiple types or batches of products. Subsequently the FDA will recondition, relabel or dispose of the products. The costs for these actions will be charged to the defendant.

  • Injunction

    An injunction is a civil judicial process initiated to stop or prevent violation of the law, such as to halt the flow of violative products in interstate commerce, and to correct the conditions that caused the violation to occur. If a firm has a history of violations, and has promised correction in the past, but has not made the corrections, the injunction is more likely to succeed. However, the freshness of the evidence is critical. When the defendant is in contempt of the injunction, the FDA will consider a civil or criminal contempt of court or other regulatory action.

  • Administrative Detention, Money Penalties and/or Prosecution

    Administrative detention gives FDA the authority to implement administrative detention with respect to drugs intended for human or animal use. This authority is intended to protect the public by preventing distribution or subsequent use of drugs encountered during inspections that are believed to be adulterated or misbranded, until FDA has had time to consider what action it should take concerning the drugs, and to initiate legal action, if appropriate.

    When a company or individual violates to Food, Drug and Cosmetics act the FDA may choose to impose misdemeanor fines which may reach $ 500,000 (USD) under some circumstances. The fines below are applicable for certain offences;

    • Up to $100,000 for a misdemeanor by an individual that does not result in death.
    • Up to $200,000 for a misdemeanor by a corporation that does not result in death.
    • Up to $250,000 for a misdemeanor by an individual that results in death, or a felony.
    • Up to $500,000 for a misdemeanor by a corporation that results in death, or a felony.

    Prosecution can come in many forms for a multitude of offences and is conducted by the Food and Drug Administration Office of Criminal Investigations, a few examples of prosecution following a (GMP) violation include; the New England Compounding Company (NECC), Gallant Pharma and Ozay Pharmaceuticals.

FDA GMP Inspections 

The FDA conducts GMP inspections both domestically and abroad. These inspections of manufacturers of pharmaceutical products are usually conducted by two to three inspectors, with one lead inspector amongst them. Each inspection team is assembled by expertise. The duration of FDA inspections varies between a few days and up to three weeks.

The inspectors are civil servants with a strong belief in purpose. Specialized training is provided to the inspectors on subjects such as human psychology and deception. Unlike investigators from the EU/WHO, the FDA inspectors have no vested interest in the inspected organization’s success.

During inspections, investigators can request the assistance of expert investigators, analysts and microbiologists (amongst others).

Before an inspection the FDA inspectors will usually review the district files to become familiar with the operation and compliance history, this includes warning letters and company responses. Other information considered during the preparation includes the correspondence from the organization on any changes since the last inspection.

During the district file review, the FDA investigator will examine which profile class to cover (i.e. liquids, tablets, capsules, parenterals, etc.). With pre-approval program receiving priority, some profile classes may not have been covered for a while. Nonetheless, all profile classes should receive inspectional coverage.

The focus of the district file review is to determine weaknesses in the organization’s operations. Because of the increased complexity associated with the production and control of drugs, in-depth inspection of all manufacturing and control operations is usually not feasible or practical. As such an audit approach is generally undertaken by the FDA in which therapeutically significant drugs, drugs difficult to manufacture and low sales volume drugs are covered in greater detail.     

When the preparation has been concluded, the FDA inspection team will visit the organization at a (usually) predetermined date and time. FDA officials are not required to notify domestic facilities prior to inspection, whereas they’ll always provide notice to foreign suppliers prior to inspection.

Preparing for FDA GMP Inspections 

When the FDA is at your doorstep you have only one chance to make a good first impression. People form opinions within the first few seconds of an encounter, the first encounter will paint the future of the relationship which can be either positive or negative. We’re not just talking about your dress code; body language is extremely important. You appear nervous or defensive if you cross your arms in front of your body, not looking a person in the eyes can be seen as a sign of dishonesty and standing up straight shows confidence. Remember this when receiving your next inspection, what is your body language? And perhaps equally important, what is the body language of the inspector, is he confident or defensive?

Meeting the FDA Inspectors 

To make sure you make a good impression here are a few tips for receiving FDA inspectors;

  • Make sure designated company personnel has been notified of the investigator’ arrival,
  • Inform the receptionist how to handle arriving investigators (don’t make them wait!),
  • Review the credentials of the investigator,
  • Receive form FD-483, notice of inspection,
  • Take the investigators to the meeting room straight away,
  • Ensure investigators remain escorted at all times,
  • Assemble the reception committee. 

When everybody’s assembled in the meeting room it’s time for a round of introductions, allow the investigators (inspectors) to introduce themselves first. If they don’t; kindly invite them to do so. Introduce your own key personnel briefly. Stick to the essentials, don’t introduce inconsistencies in function versus responsibilities already.

Establishing the Purpose of the Visit 

After the round of introductions, you’ll want to establish the purpose of the visit. Allow the FDA inspectors to explain why they’re there and go through the agenda. Make sure you find out WHY they’re visiting you;

  • Follow-up,
  • Post-approval,
  • Problems,
  • Pre-approval,
  • Combination of all of the above (!),
  • First visit,
  • Establish products to be covered. 

Now you know why the FDA is in your factory, it’s time for you to explain what it is you do exactly. Explain your manufacturing process in a comprehensive manner;

  • Show the product(s),
  • Describe the manufacturing method(s),
  • Describe the manufacturing premises,
  • Show who is responsible for what steps,
  • Allow inspectors to ask questions. 

To explain the points above, use a formal presentation with slides.

Finally, you’ll want to establish what each inspector’s “field of interest” will be. Find out what their program is (for each individual inspector), what issues they want to see, when they want to start and stop, lunch, dinner and travel arrangements and finally what office support requirements they have.

The Factory Tour 

During the factory tour each investigator should be allocated a personal escort for the duration of the visit, inspectors should never be left alone.

The DUTIES of the escort include:

  • To provide the investigator with all basic information,
  • Ensure smooth running of program,
  • Ensure right personnel are available to answer questions,
  • Maintain inventory of all paperwork given out,
  • Keep a detailed record of the inspection,
  • Be aware of any potential "483" issues,
  • Report to the Inspection Committee every night,
  • Take care of any travel or hotel problems for the investigators. 

Escorts should be efficient, knowledgeable and friendly. Escorts are USUALLY from the QC/QA organization. 

Good Inspection Practices 

Below we'll share a number of Good Inspection Practices which will help you prepare for an FDA/WHO/EMA inspection. These practices can also be applied to client audits.

Good Inspection Practices - Premises & Equipment 

When receiving the inspection, you want it to proceed as smooth as possible. This will not only make the inspectors feel at ease but will also speed up the process significantly. As much as we advocate proper and thorough supervision of pharmaceutical organizations, the sooner everything that has to be seen has been seen, the sooner you can return to your day to day business.

As such, you’ll need to check a few things, most notably;

  • Is all my paperwork in order and can I present it promptly?
  • Are my premises accessible and do they meet the FDA’s requirements for being clean, state-of-the-art and adequately maintained?
  • The same applies to your equipment (and associated SOP’s). 

Additionally, make sure that all the personnel involved in the inspection have been properly trained. Your inspection team must be highly organized and trained themselves. But most important; BE PREPARED for all eventualities, so that there are no surprises during the inspection.

Good Inspection Practices - Organization & Questions 

  • Develop a strategy for who will deal with which inspection-related issues,
  • Develop the “war room” concept for managing paperwork needed during the inspection,
  • Plan the inspection down to the smallest detail,
  • Attempt to keep to the agreed programme wherever possible,
  • Keep inspection within the original terms of reference - do not allow it to go "off limits",
  • Keep the inspection group as small as possible,
  • Organise internal daily wrap-up sessions to reassess strategy and to address potential “483” issues,
  • Where possible, correct “483” issues before the final wrap-up.

Whether or not the inspector is satisfied does not only depend on the factual correctness of your answer. It’s how you respond to these questions that will determine whether an inspector is fully satisfied with the answer or not.

During an inspection, questions will be asked. And whether or not the inspector is satisfied does not only depend on the factual correctness of your answer. It’s how you respond to these questions that will determine whether an inspector is fully satisfied with the answer or not. Think of an investigator’s line of questioning as if you’re the suspect of a crime. Once you start talking, it's hard for you to stop. When a police officer tells you your fingerprints were found on the inside doorknob of a home that was robbed two days ago, you get nervous, even if you wore gloves the whole time you were inside. With this in mind, make sure you have a good Q&A strategy.

A good Q&A strategy revolves around;

  • Understanding all the questions fully, seek clarification,
  • Do not feel compelled to answer quickly
  • Answer clearly, concisely and honestly
  • Do not answer questions about issues which are not your responsibility
  • Do not be afraid to say: I DON'T KNOW ! 

A bad Q&A strategy is evidenced by;

  • Longwinded, complicated explanations,
  • Offering opinions and beliefs instead of facts
  • Argumentative or dismissive behaviour
  • Underestimation of the inspector’s knowledge 

Good Inspection Practices - Presenting Data 

Besides the answers you provide whilst talking to the investigators they will undoubtedly want to see some documents. As we have said before, make sure that you have those documents ready. Making an inspector wait will surely result in an observation on your ability to provide documentation in a timely manner.

  • Only show data which is requested
  • Do not present overviews, reports, lists etc.
  • Do not present "Draft" documents, unless it is absolutely clear they are not official
  • Take a few seconds to review any documents before presentation (via War room)
  • Do not present unofficial documentation
  • Do not present documentation which is "off limits", i.e. not part of the inspection brief 

Good Inspection Practices - Other Tips 

  • Do not argue for the sake of arguing
  • Be aware of any major "483" issues and consider response for wrap-up
  • Be prepared to accept a few "483" citations - it is not necessary to have a clean sheet
  • Be prepared for inflexibility
  • Be aware of language difficulties
  • Be prepared to be mistrusted
  • Be prepared for detailed questions
  • Keep unnecessary conversation to a minimum
  • Never lie or misrepresent information
  • Don’t antagonize inspectors
  • Listen carefully to questions; request clarification if unsure
  • Keep answers succinct
  • Correct all errors/ miscommunications as soon as possible
  • Avoid language using typically, normally, generally and usually
  • Don’t guess – defer the question if unsure

Providing Paperwork 

Inspectors are allowed to take any paperwork (except that relating to commercial activities) which may help them in their evaluation. It is important to know that all paperwork given to inspectors can under certain circumstances be available to competitors under FOI, as such always make sure you have a record of all documents given out and stamp each document (each page) CONFIDENTIAL". Don't give the paperwork immediately - provide it at the end of the day or at the end of the inspection. This give time to consider implications and to check paperwork first. All documents should be issued through a designated person only.

Finishing an FDA GMP Inspection 

When the inspectors have seen it all it becomes time to wrap up the inspection. The inspectors will usually need some time to prepare for this wrap up meeting. The primary purpose of this meeting is to notify the company of all deficiencies, the company can use the meeting to clarify any misunderstandings in those deficiencies. But most importantly, show that you care! Make firm commitments to the inspectors.

Before the inspectors leave make sure that all deficiencies have been agreed upon in writing. Don’t hold back on trying to clarify issues. The inspectors should allow the company as much time as needed to clarify any issues. When you’ve corrected any problems during the inspection you must bring this to the attention of the inspectors immediately.

After the inspectors have left they will work out their report. If they feel that certain objectionable conditions exist, an FDA Form 483 will be issued to the company’s management. Remember that the 483 constitutes an opinion; not a violation. Companies are encouraged to respond to the FDA Form 483 in writing with their corrective action plan and then implement that corrective action plan expeditiously. The 483 lists observations and deficiencies, the most significant are listed first. It’s important to remember it’s not the number of observations that’s important but the type of observations.

Conclusion 

The FDA regulates the U.S. industry, it is required by law to periodically conduct site inspections to assess compliance with the regulations. As evidenced in this article; Inspections are serious business and not to be taken lightly. The preparations before and conduct during the inspection can influence the outcome. Everyone in a pharmaceutical organization undergoing an FDA GMP inspection has a role and can make a contribution. If you need help preparing for a U.S. FDA GMP inspection or if you have been inspected and are looking for the correct response to a 483, click here.