Beating FDA to the punch

Aug. 10, 2023
A proactive approach to risk mitigation can help weed out quality issues before they become citations

The pharma industry is one of the single most regulated industries in the world: From adherence to Good Manufacturing Practices (GMP) to FDA oversight and auditing, there are quality rules that can make or break successful commercialization of critical drugs.

Yet, despite the most careful oversight, sometimes the simplest mistakes can have life-threatening ramifications and can cost pharma companies millions of dollars in revenue and staff time. For this reason, ensuring optimal product quality is paramount across the full drug development life cycle.

From 2021 to 2022 alone, the FDA issued citations within Form 483s to hundreds of companies for failure to focus on quality. These citations and findings covered numerous areas including failure to properly separate storage areas to prevent material and product mix-ups, failure to verify the identity of raw materials prior to manufacturing, cross contamination and waste flow issues, and out-of-spec (OOS) test results.

Often, pharma companies can weed out these quality issues on their own, before they involve an FDA citation. While still costly in terms of expenses and resources, issues first discovered by companies are less damaging than external fines, penalties and setbacks that can also harm a company’s corporate reputation. But whether identified by a company on its own or by the FDA, the best way to address quality issues is to avoid them in the first place by taking a proactive approach to mitigating the risk.

Five common mistakes

There are several mistakes made regularly by pharma companies — all of which are preventable with proper processes, oversight and automation.

1. Noncompliance with safety procedures

This is one area that even experienced lab workers have a habit of ignoring, but failure to follow standard operating procedures (SOPs) contained in safety data sheets can result in serious consequences. 

For example, handling volatile chemicals without understanding or complying with established rules can lead to accidents, fire or explosions. Because of a lack of training, employees can fail to dispose of chemicals properly, creating risk for people, products and the environment.

Per FDA regulations, SOPs are an important part of the primary documentation requirements under GMPs, and they must be in place to successfully navigate an FDA inspection. Safety documents are required with the initial shipment of all hazardous chemicals including drugs and pharmaceutical products, except for drugs as defined by the Federal Food, Drug and Cosmetic Act which are in solid final form for direct administration to the patient (i.e., tablets, pills, etc.).

The most effective way to reduce risks is to ensure employees both read and use the safety data sheets prior to chemical use, and then confirm that they have done so. This can be achieved by providing easy access to SOP documents in a centralized database. It’s also important to make proven hazard communication training a requirement before enabling laboratory or chemicals access, as well as having a system to track and manage training and certification completion.

2. Improper chemical storage

A lack of proper or clearly defined chemical storage procedures can be a major issue that can impact the structure or quality of the chemical, cause toxic byproducts or, in large-quantity batches, block a fire exit — all of which can be a prime reason for a lab failing an audit. Companies that don’t have adequate chemical storage facilities are leaving themselves open to not only preventable accidents but also a failure to comply with federal or state regulations.

Companies can reduce improper chemical storage in facilities by firstly ordering just enough chemicals, eliminating the need to store or dispose of extra supplies. This can be done by integrating inventory tracking systems with supplier management tools. Companies should also tighten their audit storage procedures, making chemical storage a focus point in internal audits.

3. Equipment issues

Some of the costliest pharma safety mistakes involve equipment. These can be the result of lack of proper training, poor maintenance records or other things such as a lack of basic surge protectors for expensive equipment. If equipment fails, millions of dollars could be accrued in losses that could have been avoided with a relatively inexpensive fix.

Most of these issues are easily mitigated with common sense procedures and a robust environmental, health and safety (EHS) process. Something as basic as an agitator that needs a new part and maintenance records that are out-of-date could cause an unknowing employee to use the device without realizing that it isn’t operating at full capacity.

4. Runaway reactions

Scaling up chemical reactions can cause unpredictable problems for a variety of reasons. While a controlled reaction may not have an impact in a two-liter vessel, that same byproduct can become explosive when scaled up to 50 liters. This is an issue that will become more prevalent as organizations transition from batch to continuous process manufacturing, but it remains something that companies should be aware of from day one.

In order to reduce the risks associated with scale up, companies can employ an engineering testing lab to better understand how the chemical should be handled. Whether they use an outside lab or test on their own, companies should screen for potential hazards, evaluate the main reactions and conduct a what-if scenario, and then plan accordingly. It is important that each identified potential risk is documented with associated preventative mitigation(s) to help keep the runaway reaction from occuring, as well as immediate corrective action mitigation(s) which can be deployed if preventive mitigation measures don’t work.

5. Unexpected QC results

Often, when a chemical doesn’t perform as expected or contains too many impurities, it is beyond the control of even the most experienced scientist. Yet, there are some ways to improve the odds. These may include more properly vetting suppliers of raw materials, changing scale-up methodologies or developing a small batch in a kilo lab before ramping up manufacturing.

In any event, unexpected lab results require further investigation, which can help define if there is a need to generate a nonconformance or a corrective and preventative action (CAPA). Today, automated tools are available that can automate the documentation process for out-of-specification (OOS) and out-of-trend (OOT) lab test results, determine the root cause, resample or retest the results and issue a nonconformance or CAPA.

Identifying risk

Those examples are just a few of the issues that cause risk to pharma companies. The key is to look for risks, assess those risks, and then take action. But looking for risk can be difficult. The components usually manifest themselves as either ‘hazards’ or ‘harms.’ Hazards represent the potential source of a harmful event, or its cause. Harm is the resulting damage to chemicals, people or the environment.

To quantify hazards and harms, many pharma manufacturers look at their severity and frequency and, with these two components, can develop a scale in which to measure. This type of risk assessment can help guide the processes, procedures and best practices to mitigate risk. But while a risk matrix can hold the key to unlocking quantitative risk-based processes, ultimately people are the drivers to bringing about change that will mitigate risk. So how can an effective hazard (or risk) analysis plan be implemented? Consider the following best practices:

  • Identify critical control points: In pharma processes, there are always stages when specific controls can be applied to ensure risk is reduced to acceptable levels. A hazards analysis can help to uncover those stages and set risk limits on those critical control points (CCPs).
  • Establish the critical limits: Each process will have its own limits based on predefined quality standards and regulatory requirements.
  • Monitor CCPs: Once CCPs are established, it’s important to regularly monitor them to uncover changing requirements or protocols.
  • Take corrective action: Taking corrective action on risk events enables a company to have a systematic way to mitigate risk and enable continuous improvement.
  • Ensure solid documentation: Sound record-keeping is key to internal risk mitigation, but it’s also a GMP and FDA requirement. This documentation identifies issues and how they were addressed, proves that CCPs are being effectively monitored and that everyone in the company is following proper training protocols and procedures.

Any number of things can go wrong in the lab or pharmaceutical manufacturing environment — many not predictable nor avoidable. Yet, it is surprising how many things are within a company’s control. By taking a proactive approach to risk mitigation it is possible to avoid expensive mistakes that can do more than just set projects back, but that can cause real harm to the patients that rely on safe and effective drugs and treatments. 

About the Author

Justin Evert | Product Manager, ETQ