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In the Chaos of COVID-19 Pandemic, What is “Current” in cGMP?

The COVID-19 pandemic has disrupted almost every aspect of our daily lives. We applaud everyone in the life sciences industry who has worked tirelessly to ensure an uninterrupted supply of pharmaceuticals and medical devices to maintain the public’s health and save lives. 

This is an unfamiliar experience to most of us, and it reminds us to rely on our education, training, or experience (as in 21 C.F.R. § 211.25) to remain “good” practitioners in what we do. As emergency demand for these drugs, devices and other supplies continues to surge, dramatic action is required. These measures are not new. For instance, when the 3 Mile Island incident occurred in March 1979, the Food and Drug Administration (FDA) created a New Drug Application (NDA) for potassium iodide and had companies manufacturing it, practically overnight, to provide protection against possible thyroid cancer due to radiation exposure. The American public needed an emergency supply and the FDA responded with a common sense approach to regulate production of the oral tablet and address the emergency.

We face a similar situation today, and common sense must prevail in determining what the current standards should be. A good practice is: documented, repeatable compliance with calibrated and reproducible procedures. People and companies are leaping into the fray, but one issue that is almost universally overlooked is the logistics of production and delivery. The military has an adage that “tactics are for amateurs; logistics are for professionals.” Promising millions of tablets to address the crisis is a great aspiration. Producing quality product in a reasonable timeframe requires extensive work and logistics.  

The term, current good manufacturing practices (cGMPs), was not part of the original 1938 Federal Food, Drug, and Cosmetic Act (FFDCA). The language was added in 1953 along with other provisions to improve FDA’s ability to regulate the quality of pharmaceuticals and devices through inspection authority, records review, etc.

Those four simple words – current good manufacturing practices – have evolved over the decades through case law, rulemaking, and informal advice (the “Motise notes” and then “FDA notes”). They are considered technology forcing in the sense that as technology evolves, the requirements evolve. And, as contrary to due process as this concept seems, the courts have routinely upheld it. Various districts had various standards. FDA has tried to normalize the standards by consolidating the field district operations into regional centers. One can speculate that the “current” approach is to bring a semblance of repeatability and reproducibility of consistent results into the regulatory process.

Human nature must also be considered. People are nervous and afraid of the unknown. They will adjust to protect themselves and their families. One of the tenets of cGMPs that remains one of the primary citations in Form’s 483 and Warning Letters involves recording your actions and following them. In times of disruption with shortages of materials and personnel, this principal remains paramount.

Here are five tips to help your company stay in cGMP compliance:

  1. If you do something new or make adjustments in these times of trial, write it down. If you write it down, explain your rationale and make sure to follow it. Focus on broader platform activities that are more robust. Minutiae should be avoided. They are harder to reproduce and are more likely to be ignored.
  2. Continuing education and updating your staff are essential to cGMP compliance. In particular, clearly educating staff about the issues we face concerning COVID-19 especially communicable disease precautions. Documenting the training is also important.
  3. Review FDA’s basic cGMP regulations and your Standard Operating Procedures. This accomplishes several things. It refreshes your memory about the basics, which are often lost in the mundanity of conventional manufacturing. The review will also ensure you are complying with your already written requirements. For instance, normally sick employees are limited in access to production and receipt of products. Should these requirements be expanded? Or is a more robust broader standard better?
  4. Review your facilities and equipment requirements through the filter of COVID-19 and how you want your company and products protected from the virus and other future viruses. Are new sanitation and cleanliness standards required or are the existing standards adequate? The same applies to equipment cleaning. Will you need to do new cleaning validation studies or are the existing standards adequate? Documenting your examination can be invaluable in the future should questions arise.
  5. After you feel that you have prepped your people, facilities, and equipment, remember that components, products, and process controls need to be reviewed in this new context. Are new cleaning and training modules necessary? Are new acceptance standards or additional quarantine times necessary for component, packaging, labeling, etc.?

Remember that your personnel are people. They will tire, and they will get bored especially if you are required to run extra shifts to meet increased demands. One of the world’s foremost experts on Pharmaceutical Quality by Design, Dr. Ajaz Hussain, has written extensively about procedures for minimizing human error caused by monotonous actions. He also recognizes the role that stress plays in these times of crisis. Pressure to ramp up quickly to deal with product shortages will expose people to great stress. Common sense and the points addressed above will be helpful in surviving the current crisis.

People under extreme stress may take extreme measures. FDA has identified a series of issues to watch for such as multiple users of a computer with the same log in name, tampering with the results of High Performance Liquid Chromatography along with other results, etc. In times of crisis, FDA has tolerance for errors, if written and explained. It will have ZERO tolerance for fraud. The Agency will come at people with a vengeance.

What is good practice? It is documented, repeatable compliance with calibrated and reproducible procedures. Procedures calibrated and demonstrated to be reproducible in a given context are repeatable when performed by qualified staff and their supervisors. In the COVID-19 pandemic, the context has changed in many ways. Senior management must recognize that calibrations and reproducibility of their current procedures may need to be reevaluated in the context of pandemic-induced uncertainty, such as uncertainty in their supply of raw materials and human resources. They must step up to take responsibility to ensure repeatability and provide adequate time, resources and written records of their actions to lay the groundwork for good practice and common sense.

Outside Contributor: Ajaz S. Hussain, PhD, President, The National Institute for Pharmaceutical Technology & Education