FDA-483 Observations – Implementing A Preventative Approach

By Christian Fortunel, vice president, LZ Lifescience Inc.

The US Food and Drug Administration (FDA) is responsible for issuing 483 observations to life sciences companies if routine audits find violations, production or quality issues which raise concerns to the safety of the general public. With news stories regularly documenting that an increasing number of organizations are being issued with FDA-483s, often with serious outcomes, avoiding these warnings is a priority and necessitates an understanding of industry requirements, the use of appropriate tools and conducting comprehensive audits.

Christian Fortunel, vice president at LZ Lifescience, explores some of the most common inspection observations and key reasons for receiving FDA-483s and subsequent Warning Letters, as well as how they should be handled with an appropriate response. The role of manufacturing execution system (MES) technology in providing a preventative approach is discussed.

The FDA-483

The FDA’s Office of Regulatory Affairs (ORA) is the lead office for all inspections and enforcement. During an inspection of a manufacturing facility, ORA investigators may observe conditions or practices that they deem to be in violation of the Federal Food, Drug and Cosmetic Act.¹ Any warning signs that indicate a food, drug, cosmetic, medical device or biologic may have been adulterated or rendered injurious to health, will be listed.

What is the FDA looking for?

Typically, FDA audits are looking for proof of compliance with current Good Manufacturing Practices (GMP). In the case of pharmaceuticals, this will relate to the 21 Code of Federal Regulations (CFR) Parts 210 and 211.²

Investigators will assess process validations and the quality of management systems used by a pharmaceutical manufacturer. This can involve looking at whether thorough responses are made in the incidence of atypical events, which might include deviations, specific failures, rejections and complaints. Prevention of the reoccurrence of these events will also be reviewed. Here, investigators will be checking that issues are dealt with appropriately. For example, if a company initiates corrective actions which are effective, a drop should be seen in the number of incidents relating to that problem. However, if the issue persists, or occurrences increase, the corrective action may not be appropriate and further action is necessary.

Investigators will look at the suitability of manufacturing processes, whether they are robust and consistent, and whether complaints or failures in the market could indicate that a process might be questionable. Real-time monitoring and the use of quality systems to provide a snapshot of what is happening within a process, will also be evaluated. To meet requirements, manufacturers must demonstrate that they have a system in place that will monitor the quality of a product in real-time, and which enables them to respond to issues quickly. Finally, the investigator will be looking to establish trust in a manufacturer’s data integrity, particularly the validity and transparency of laboratory data.

What is a Warning Letter?

After a Form-483 is issued and the inspector has completed an Establishment Inspection Report, the agency may issue a Warning Letter. A Warning Letter indicates that higher FDA officials have reviewed the observations and that a serious violation may exist. The letter makes clear that the company must correct the problem and provides directions and a timeframe for the organization to inform the FDA of its plans for correction.

FDA-483 and Warning Letter triggers

In addition to the aforementioned process validation and data integrity issues, an FDA-483 or Warning Letter may be triggered due to:

• Inadequate executive oversight or quality assurance
• Recurring problems – poor corrective and preventative actions
• Inadequate training of personnel
• Poor investigation of atypical events
• Deviations or investigations that remain undocumented
• Significant backlogs
• Untimely reporting
• Failure to meet agreed course of action

Most organizations take FDA-483s and subsequent Warning Letters seriously, however, in some cases the agency may have to advise that it is considering enforcement action due to continued violations. There are several actions that the agency has at its disposal, including seizure and injunction, as well as prosecution. Generally, these can be averted by a well thought out and committed remediation plan.

Handling FDA-483s and Warning Letters

A formal written response demonstrates good practice, opens up the channels of communication and will help to establish a working partnership with the agency. Organizations should respond promptly within 15 days, after this time the agency is not obliged to consider the response in its decisions for subsequent action. If more time is needed to establish a thorough plan, it is best to get in touch with the district office directly. In the majority of cases, they will allow additional time if necessary.

It is advisable that once an organization has put together a comprehensive response, it requests a review from a third-party that can offer objective feedback prior to submission. Although responding can seem like a very complicated process it can be broken down into demonstrating four key steps:

1. Show that those at the very top of the organization understand and acknowledge the objectionable conditions
2. Indicate how root causes have been identified
3. If necessary, demonstrate how outside expertise will be used
4. Provide an indication of how progress will be monitored, evaluated and presented

Working through each of these with urgency will demonstrate an organization’s commitment to rectifying problems.

Responding with action

Organizations are responsible for taking corrective actions internally to address the cited objectionable concerns and any related non-cited objectionable concerns that might exist. Understanding why an issue has occurred and using this as a driver to identify other similar problems, is advisable. For example, if the FDA-483 and Warning Letter has been triggered by a piece of instrumentation being incorrectly calibrated, take this as an opportunity to check the state of other instrumentation that might also be susceptible.

While is it important to acknowledge the severity and significance of the situation and communicate this to an organization’s workforce, it is important that the situation remains calm. Once staff understand that the management team is committed and in control, they are highly likely to remain with the business and contribute to remediation. Inform each member of the team about what needs to be done, who is going to be responsible for what, appropriate timelines and how everyone will be kept informed of progress.

The agency should also be kept informed of the progress being made via monthly or quarterly updates, depending on what frequency is agreed with investigators. One point to consider is that organizations should be wary of over-promising, keep commitments reasonable to what can be done in the agreed timeframe to correct problems. Commitments should also be tracked with staff assigned to ensuring that actions are completed correctly and each observation is responded to.

Finally, it is all too easy for an organization to let its guard down once a particular problem has been eradicated. Measures should be put in place that stop a company from reverting back and creating further issues during subsequent inspections.

Prevention is better than cure

All organizations have some issues and receiving an FDA-483 largely depends on the individual investigator, the nature of the issue and the severity of its implications. In many cases, organizations are oblivious to the problems and surprised when they are identified. A robust and objective internal audit program can help identify problems early and enable corrective actions to be taken before they escalate.

Organizations should ensure that the quality systems they implement speak to each other. Fragmented systems create challenges, therefore, complaint, corrective action and deviation systems all need to work together to gain a big picture of what is going on. Frequent compliance reviews to discuss issues are vital and should include top management and executives to build understanding across the company.

Real-time monitoring using process capability metrics can trend and track processes and enable companies to establish if certain thresholds are about to be reached and require action. Again, having somebody outside the organization undertake a periodic third party review of processes under a confidentiality agreement, can bring valuable insight into what is happening within a facility.

The role of MES technology in prevention

Another way to prevent observations that instigate FDA-483s is through the implementation of MES technology which can automate many aspects of production. The wide-ranging functions typically include the ability to schedule activity, deliver training and instructions to operators, synchronize manual activities with automated processes and integrate with manufacturing computer systems. This allows manufacturing organizations to ensure quality control, deviation management and effective planning, as well as enabling users to document floor activities for monitoring and reporting purposes.

These systems provide real-time instructions to operators to enforce GMP practices. They serve as a GMP system of record providing electronic device history records (EDHRs) and electronic batch records (EBRs) documentation that can be accessed in real-time by all users, helping to simplify compliance and improve transparency throughout manufacturing processes. As a result, this type of system can help manufacturers achieve compliance improvements, performance improvements and real-time visibility of data.

MES and frequent observations

MES provides an answer to many of the frequent reasons for FDA-483s. By far the most common, and easiest to avoid, is the failure to establish and follow appropriate written procedures. MES allows organizations to define electronic workflow instructions and present them to operators. This enables the information in paper batch records, as well as paper-documented standard operating procedures (SOPs), to be turned into an interactive electronic format. The level of control assigned to operators during execution can then be designed, including workflow sequencing and how deviations are handled, e.g. whether a signature is required from a manager once a deviation has occurred. With MES, operators can be put in a position where it is very hard to deviate from defined practices. 

A second common observation is that records do not include the signature of a second person. When MES is deployed, any data entry, check or verification is automatically attached to an operator name and timestamp. By default, the system acts as a second signature, eliminating this problem entirely.

Organizations failing to properly review and approve all drug product production and control records is another observation frequently cited. Moving to an MES system can define the exact specifications of how procedures should be executed. The system will require operators to acknowledge any deviations before an EDHR or EBR is closed, for example a skipped process step or an out-of-range value. This ensures that all production steps were executed properly, and that deviations are reviewed and approved before closing a production batch.

The absence of written procedures can also cause significant problems. Using MES, organizations are able to document procedures and electronic work instructions using a library approach. This forces them to have processes in place for anything that happens on the production floor. The library aspect also means that these can be reused across products or product families, thereby eliminating time spent maintaining paper records. 

When using manual programs, other procedures which can easily be performed incorrectly include the routine calibration, inspection and checking of equipment. Here, MES can support equipment maintenance and ensure that at the point of use, it is clean, calibrated and available.

Although much less frequent, the absence of expiration dates, missing components, or drug product containers or closures not being appropriately identified, can be deemed as serious observations. Again, this is an area where an MES system is used to check that a container is in the right state, the expiry date of the batch has not been violated and the product is available in the right quantity, all in real-time at the “point of use”.

Finally, the incorrect documentation of actual versus theoretical yields can be a further source of error. By using actual parameters of the production floor, MES can undertake the necessary calculations to determine these values. This minimizes the likelihood of errors by ensuring calculations are automatic, correct and require no need for subsequent checks.

Conclusion

With regulations increasing in complexity, the use of robust internal audit programs in combination with real-time monitoring of processes and problems, is vital in preventing FDA-483s.

MES technology allows paper-documentation to be replaced with computerized records which can be accessed in real-time by all users. Essential functions such as EBRs, EDHRs and equipment management, focus attention where it is needed by preventing issues from occurring in the first place.

The technology is now being adopted at a faster rate in the life sciences space than any other manufacturing sector. Despite this, the fact remains that all too often operations managers find the prospect of implementing new processes daunting. The benefits might be clear, but there is a perception that MES systems are expensive and complicated to implement. While this may have once been the case, cloud-based systems have made cost-effective solutions accessible, putting the opportunity to improve quality and increase compliance firmly within the reach of organizations of all sizes.

References

1. http://www.fda.gov/ICECI/Inspections/ucm250720.htm
2. http://www.gmp-compliance.org/guidemgr/files/1-1-1.PDF

Author Biography

Christian Fortunel is vice president at LZ Lifescience Inc. (USA). He is responsible for operations management and the successful financial running of the US business, as well as bringing a wealth of MES deployment expertise to his role.

With an MSc in computer science, Christian began his career as a software engineer at Columbia University. Since then he has progressed to executive level positions within the MES industry.

Christian has over 20 years’ experience developing, managing and deploying MES solutions, having worked with many of the top 30 pharmaceutical and biotechnology companies across the world to manage large scale MES implementations.

He uses his strong technical, business and management experience to successfully lead software development teams, build business units and advise executives on operational issues, software selection, risk management and process improvements.