Preparing for GMP inspections, particularly pre-approval inspections, can be a challenge when resources are limited and staff may have little expertise in these important activities. This becomes especially complex for start-up companies that are virtual, or essentially virtual, and rely on contract manufacturers and contract laboratories. Virtual firms are responsible for the content of the submission, release of product to the clinic or for commercial distribution and post approval safety reporting even though they may not manufacture API or dosage form. The following are some suggestions for these firms to ensure a successful inspection outcome when they have limited experience in this activity and limited resources:
Forms 483 Addressing Sterility Assurance and Cross-Contamination
Along with data integrity, deficiencies in sterility assurance and the potential for product or API contamination identified during FDA inspections often lead to warning letters. Also many product recalls are based on lack of sterility assurance or less frequently on potential cross contamination. Here we take a look at six forms 483 that include observations associated with sterility assurance and potential cross contamination. These are certainly not meant to provide an all-inclusive view of the topic, but rather represent recent inspection observations in these areas to demonstrate the broad scope of the topic. FDA’s flurry of inspections and enforcement actions against compounding pharmacies and outsourcing facilities focuses heavily of requirements associated with expectations regarding aseptic manufacture of sterile drug products. These sites are often also cited for the potential for cross contamination. Lack of sterility assurance and the potential for cross contamination, particularly by high potency compounds or sensitizing agents both have potentially serious consequences for patient safety. Many compounding pharmacies and outsourcing facilities have recalled large numbers of products due to concerns about sterility assurance. We include one example of this type of facility in the collection presented below. Failure to complete adequate cleaning validation for multi-product equipment is often another source of potential cross contamination even when products do not include high potency compounds or sensitizing agents.
A consent decree agreement is an agreement filed in the US courts formalizing a voluntary agreement between two parties. Here we will address consent decree agreements between FDA and several pharmaceutical companies based on repeated failures to adequately address CGMP deficiencies. It is not an action taken on the basis of a single form 483, or a single warning letter. Generally, a series of events play out over time when critical inspection observations are not addressed and are identified in subsequent inspections. Frequently one or more warning letters are involved. Consent decree agreements often include fines, with the option for additional financial penalties if conditions to which the firm agrees are not met. Often these firms are required to use a 3rd party consultants to perform lot release. Firms operating under a consent decree agreement have largely lost their independence in GMP activities. Unlike Corporate Integrity Agreement which have a defined duration, firms must petition to have the consent decree agreement condition rescinded.
If you haven’t been to FDAzilla.com in a while, then you’ve come to the right place. If any part of your job involves preparing your company for FDA GMP inspections, let me take you on a quick tour of some tools and resources that you might find useful! Take 4 minutes and check out these 4 things:
“Forget about actual warning letters. The cost of us receiving a moderately bad 483 is roughly $250,000.”
I heard this from a reputable Head of Manufacturing of one of the largest biopharma companies in the world. While most pharma and med device companies seems to learn quickly from everyone else’s mistakes, companies still occasionally get a “moderately bad” 483. And then what happens after that? Continue reading →
FDA and the EU have taken serious enforcement actions against several firms in the others geographic jurisdiction in calendar year 2016. Perhaps this flurry of my-inspectors-are-more-rigorous-than-yours type represents an unofficial test of sorts as these two agencies move to rely more on each other’s inspections. These inspections may test the limits and validity of the underlying assumption that would permit this mutual recognition. Also interesting is that the European inspections specifically evaluate investigational product manufacture, something FDA does not generally do except on a for-cause basis. Below we cover the three EU reports of GMP non-compliance issued regarding sites in the US and three FDA warning letters, one FDA import alert, and one untitled letter issued regarding sites in the EU.
Due to popular demand, we have decided to add EIRs into our store. Establishment Inspection Reports (EIRs) are an important tool in your tool belt of inspection preparation and intelligence. If you aren’t familiar with them, read our recent post on the 5 Things to Look for in an EIR. Continue reading →
Benjamin Franklin said, “By failing to prepare, you are preparing to fail.” Prepare for your FDA inspections with Establish Inspection Reports (EIR). An EIR is the full report of an FDA inspection written by the investigators. Among the features identified in the report are:
I asked Barb Unger a difficult question, “If you could just pick 6 483s to understand this Data Integrity problem, which 6 would you pick? And why?” Here is her response.
As we continue to follow the data integrity story, let’s take a look at six (6) forms 483 associated with data integrity that had broad impact throughout the industry or resulted in serious enforcement actions including consent decree agreements. You will see that they are not limited to a single country and many of the observations are similar or exactly the same over a decade. Continue reading →
Warning letters are the FDA’s second level of enforcement actions after issuance of a form 483. The FDA determined that either the firm’s response to the form 483 was inadequate or the observations were serious enough to support issuance of a warning letter. Often it is possible to determine the corrective actions necessary and the impact that the warning letter will have on the business. To determine a letter’s impact on the business, I ask these questions:
A form-483 is the document that FDA issues at the close of an inspection where they identify observations made during the inspection. If no observations have been made, no form 483 is issued. Based on the response submitted by the firm, FDA classifies the inspection as: No Action Indicated (NAI) when no form 483 is issued, Voluntary Action Indicated (VAI) or Official Action Indicated (OAI). In general, where FDA issues a form-483 with observations and the firm’s response is satisfactory, the inspection is classified VAI.
The FR announced availability of the long awaited 10-page FDA draft Guidanceon Data Integrity and Compliance with CGMP for comment. I include links to the MHRA guidance HERE and the draft WHO guidance HERE for comparison. The guidance is structured in a Q&A format with a total of 18 questions. This guidance focuses heavily on identifying and citing the predicate rules as they apply to electronic records and data integrity, and for this it is an excellent reference. In my opinion, though, the excessive citation of regulations detracts from the content and provides little insight into FDA’s intent and actual expectations in this area.