Quality and Laboratory System

In my earlier post, I described the techniques and approaches that are currently being used to inspect international firms who are importing products to USA or Europe.

Continuing with my original format I will try to compare the different methodologies used by FDA and EU inspectors to conduct Quality and Laboratory systems inspections.

Laboratory System

The laboratory system is a key area of focus for almost all the inspections. This off-course is due to the level of importance that testing results are to the outcome of the lot of material being manufactured. This also a key Achilles heel to most of the companies and base on recent warning letter is fertile ground for data integrity and manipulation of results. If you look through the warning letters that have been issued in the last 5 years you will find that inadequate laboratory controls, make up more than 70% of the citation.

As we compare the methodologies US and European inspectors evaluate the laboratory.

US and EU  laboratory are inspected using a traditional approaches. The inspectors will conduct a full walk-through of the labs. They will look at each equipment to make sure they are clean, calibrated and qualified. The inspectors will pick instruments that are used to test critical attributes for each product and will make request for method validation, test results for last 5-10 lots, any out of specification or deviations. The inspectors will complete the tour and then will sit with appropriate subject matter expert to evaluate the method validation, its performance, trends and if any investigations that may have impacted quality of the product. The inspector may also look at any test that were used to reply to a customer complaint and review the stability program for their level of completeness and adherence.

For international firms the inspection will be conducted with a very different perspective. The laboratory walk-through is the first chance for the inspectors to see if there are any activities that may not be in alignment with their experience. The laboratory walk-through make take a few days and expect each of the rooms, refrigerators, closet, cold storage and printers to be inspected for their appropriate usage. The inspector will focus on the instruments and computer system that are attached to it. They will evaluate any opportunity for data integrity opportunities which may be avail to the analyst. The inspectors will focus on data recording sheets to ensure that they can’t be duplicated and that an analyst does not have any opportunity for fraud. Be prepare for the inspectors to sit down in each of the instruments and conduct a full file search to ensure there is not duplication of test results.

The data integrity checks will be conducted with heighten sense of suspicion and every word that an analyst speaks will be evaluated with an FBI like level precision. The inspectors will spend a significant amount of time at desk of critical equipment and will evaluate any possible opportunities for files to be hidden or deleted. The inspectors will use their knowledge of computer file structures to analyze how and where files are stored and any opportunity for deletion.

The laboratory walk-through will continue daily and be prepare for further deep dive assessment for all critical instruments. For biologics and biosimilars be prepare to defend HPLC and Bioassay methods and all the data analysis that comes with it. The inspectors will request audit trail print outs which they will review with fine tooth comb. Be prepare to explain any temporary files that may remain on the local computers and how those files got there and how are they used. The inspectors will also review all configurations on computers that are used to acquire CGMP data to ensure there is no possibility of hiding data.

The laboratory walk-through will also test your cleaning procedures they will pay special attention to hoods and filters. The neatness of the laboratory will be also tested by a full review of how each of the data is controlled. Loose paper left at an analyst desk without proper controls will lead to a stern look and very likely an observation. The inspectors will pay close attention to laboratory records that are in progress, those that are completed and anyone that is waiting for supervisory actions. The genealogy of the paper documentation will be challenged and the inspectors will expect that there is full accountability of the documents from issuance through its final archival step.

Training of each of staff members will be an area of focus. In addition, the inspectors will be looking for any sign of management controls that may impact the judgement of the analyst. In some instances an analyst maybe called to private meeting where the inspectors are accessing their level of honesty and most important managements influence on the final test results. As the laboratory tour continues be prepared for inspectors to walk into the office spaces and review any records that being reviewed.

The inspectors come with a full charge mentality and the firm must show that there is no opportunity for anyone in the laboratory to alter test results. This will also be tested by their intense and thorough review of the computerized systems that collect data. Finally, the inspectors will also be looking at the management team during the inspections to ensure there is no negative pressure on the analyst. The demeanor of the head of quality and the subject matter experts is very important and they must note that they are also being inspected through very subtle techniques during the walk-through or through the long pregnant pause.

Quality System

Quality Systems are reviewed in every inspection. Elements of the Quality System inspection will likely involve a full review of  change control, deviation, investigation, corrective and preventative actions, training, management oversight, complaints, stability, annual product reviews and management of recalls.

US and EU inspection of the Quality System will involve a full review of 1-3 of the elements outlined above. Typically, the inspectors will look at how the company manages change and how they react to events in their deviation and investigation process. The inspectors will request a list of all the deviations, change controls, CAPA and the last quality review documents. They will look at any trends and may pick a few deviations that were classified as high risk. The inspector will them have a subject matter expert explain the event and the companies’ response through their investigational process. The inspector may follow the deviation through the CAPA and if it has led to change will look at how the change(s) was evaluated and implemented. The inspectors will continue through this process until they have felt satisfied that the system and company response are in alignment with the observe event. This part of the inspection may take one day and then the inspectors moves on to the next system.

For international firm the inspection looks very different and focus in more on the integrity of the decision making and how that is documented in the paper trail. The elements mentioned above will looked at one by one. The inspectors will start with reviewing the historical performance of every Quality System element. They will review all trends and analyze any item that through their experience may constitute product quality risk. They will challenge the internal quality risk assessments and leveling while scrutinizing the decision making that is evidenced in the documentation.

In the case of deviations and investigations, be prepare to discuss the root cause and when a root cause was not identified why did company stop there. They will be looking for impact assessment on lots with statistically based rationale for the number of lots included in the retrospective assessment. The scientific rigor and decision making will come into question and your subject matter experts will be tested by seemingly set of dull questions that are designed to test their understanding.

Quality Management reviews are expected to identify trends and CAPA(s) are expected to be opened for new discovered patterns. The change control system and CAPA system will be question with a focus on effectiveness checks and how they ensure deviation or events do not occurred again. The number of deviations and investigations that result in human error with a training as corrective action will be challenged and expect an observation if the training outcome do not proof to be effective. The curriculum and training programs will be also come into question and everyone is expected to be recertified at a pre-established frequency. Once a year cGMP training will be expected and everyone I mean 100% of people working in the facility will need to go through this basic training. This include all external contractors and temporary workforce.

There is definite difference in how international inspections are conducted vs those that are done in the US and Europe. The inspectors are laser focused on ensuring that the data created and product reflect the appropriate quality level. The inspector ultimate responsibility is to ensure that product being distributed to the US and European markets are safe. Most importantly they are looking for the company to have their own internal quality process that has the product quality and patient safety in mind. The observations that are finally documented reflect the inspectors understanding of areas for improvement.

Time to Panic

Be aware that the most critical observations that can be made by an inspector is the lack of management oversight and controls that may cause product to be “Adulterated” which is defined in the federal register.

As always I welcome your comments and most important any additional color that you may add to this post. If you like some additional detail please connect with me [email protected]