To pharmaceutical manufacturers, it may seem that quality has always been a key pillar of pharmaceutical development and manufacturing. Sometimes it is spoken of as a monolithic, unchanging factor that the industry must manage around.
But quality is actually quite flexible, mutable, and in a state of flux. The drug industry’s quality expectations and concerns are always evolving. Processes, techniques or outcomes that might have raised worries a few short decades ago are no longer sources of anxiety. Concerns at one time unknown – think nitrosamines – have become big priorities in drug manufacturing quality.
The FDA recognizes that our understanding of quality – and our capabilities to ensure it – are constantly evolving. In fact, they’ve embraced it, and encourage industry’s use of innovative technology and processes to facilitate the implementation of effective quality management. In 2014, the agency developed an Emerging Technology Program that promotes the FDA’s collaboration with technology-developing companies to help improve pharmaceutical quality and cultivate recommendations for technological support and implementation.
The top quality challenges facing drug manufacturers can often be discerned by understanding what the FDA and other regulatory bodies see as causes of concern. When quality requirements aren’t met by industry, the FDA serves companies a 483 observation. No company wants to receive a warning letter as it becomes a black mark on your regulatory record. But 483s are often easily remedied.
Common FDA 483 Observations
What were the most common FDA 483 observation causes in 2021?
- Failure to follow procedures
- Investigative failures
- Lack of adequate written procedures
- Data integrity problems
- Lack of environmental monitoring
- Insufficient cleaning, sanitizing, and maintenance
Many of these 483s suggest the process of documenting quality wasn’t adequately emphasized, such as data integrity problems or procedure-related failures.
Top Pharmaceutical Manufacturing Quality Challenges
Given the FDA’s emphasis on the documentation of quality, some of the top pharmaceutical manufacturing quality challenges companies face are:
- Supply Chain Deficiencies
In 2022, as with the last two years, quality assurance has been laser focused on supply chain deficiencies. As the COVID-19 pandemic began to recede, pharma was left facing the aftermath: continuing late deliveries, staffing challenges, unavailable APIs or capacity, and long lead times on consumables.
The trend in quality is to scrutinize the entire supply chain, rather than a specific process component. Quality information is shared from the site of manufacturing, which is often in a different nation, through the distribution of the drug product. Since supply chain disruptions at the distributor level are fairly common, distributing organizations – including LGM – have a great deal of responsibility to customers.
- Manufacturer Quality
Another area of mounting concern is the qualifying process of active pharmaceutical ingredient (API) manufacturers. API suppliers should undergo a screening process to ensure that they meet the regulatory requirements of the country of distribution – a process that many companies shortchanged during COVID in the frantic race to secure supplies.
There are some very important questions to be answered prior to finalizing a supply partnership with a pharmaceutical ingredient manufacturer:
- Has the facility been screened for GMP compliance?
- What is the organization’s quality assurance process?
- Has the facility been in noncompliance with a regulatory agency in the past?
- Is there a record of import alerts or warning letters associated with the company?
If a manufacturer has multiple compliance offenses (see the FDA 483 section above), these should disqualify them from potential partnerships – leaving you searching for new suppliers.
- Distribution Quality
The quality of a drug product that is deemed ready for distribution can also present a challenge. The product, regardless of its nation of origin, should be considered suitable based on U.S. regulatory standards. This consideration is especially applicable to the compounding side of the industry.
- Data Integrity
Data integrity continues to be a major source of FDA 483 observations and is one of the factors driving the industry’s embrace of digital transformation. Internal reviews depend heavily on the quality of the investigative process and the integrity of the data generated and shared.
Data integrity ensures proper documentation detailing the chain of custody is available. Some of the areas which are causing data quality challenges include:
- Are approved written procedures being followed precisely?
- Is the equipment used compliant with CFR Part 11 regulations?
- Are passwords properly protected?
- Is there a backup system for access to archived data?
- Are there regular internal audits performed to confirm compliance?
- Are customer complaints and audit findings being properly investigated?
- Are corrective actions and preventive actions (CAPA) being constructed to eliminate the cause of deficiencies?
According to our Quality team at LGM Pharma: “While our understanding of what constitutes quality continually evolves, we are always looking at potential new regulations and guidance to ensure we’re ready for future regulatory developments.”
What’s on the Horizon for Drug Quality?
What’s on the FDA’s radar in 2023? Here are two issues for which draft guidance has been issued:
- Changes to Quality Metrics
Draft guidance has also been created addressing the quality metrics. The draft requests that manufacturers regularly submit their metrics to ensure that they align with regulatory expectations. The document includes a list of quality metrics to be submitted at specific intervals or included in the annual report. The FDA will no longer have to request data during onsite audits; it will already have the information on hand. For affected companies, resource allocation will be necessary to ensure that data is adequately compiled, reviewed, and promptly submitted.
- Guidance for Animal Drugs and Compounding
Additional guidance has been created for animal drugs and compounding. Veterinary Medicine guidance through CVM GFI Number 256 regulates the compounding of animal medications from bulk pharmaceutical substances. The direction, which covers the use of compounded drugs for animals that do not produce food, requires the drugs to be in compliance with the FD&C Act’s approval for animal drugs. Additionally, current good manufacturing practices (cGMP) must be used in the manufacturing process.
Responding to the Changes in Quality
As an industry leader, LGM Pharma remains quality centric. We have identified key performance indicators (KPIs) and maximized the utilization of our quality management system in the weekly and monthly monitoring of our performance. The indicators drive our continuous improvement process, allowing us to implement timely corrective actions and process improvements.
Our quality assurance includes the monitoring of lot acceptance rates, invalidated OS rates, and product quality complaints allowing us to address quality insufficiencies quickly and proactively. We don’t believe in waiting for regulatory mandates to improve our quality systems and often monitor data that is not required. This ensures we are ready for future regulatory developments while enabling us to measure and achieve higher standards today.
Learn more about Quality at LGM Pharma:
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LGM Pharma provides analytical and microbiological testing services for drug substances and products.