Regulatory Update: A Perfect Storm of Poor Quality

Can FDA Disperse the Perfect Storm Forming Around Poor Pharmaceutical Quality?

BY Lynne Ensor, Vice President, Technical,Parexel - 10.4.19

Certain areas of the global biopharmaceutical market continue to struggle with poor product quality, which has impacted the U.S. market and its patients.  This is a result of a perfect storm forming since before the beginning of the millennium around questionable pharmaceutical practices impacting quality, and its eye has stalled mostly over generic drugs. 

Several factors feeding this storm include varying global quality culture practices, lacking oversight of supply chain suppliers by the drug product manufacturer (especially with manufacturing occurring at multiple sites), political pressure to provide affordable medications to patients, global movement for testing and production of pharmaceuticals (predominantly driven by corporate revenue), and limited regulatory agency staff and contemporary facility inspection tools to adequately assess manufacturing quality practices (especially abroad).

Recent drug contamination events have only heightened FDA’s concerns regarding pharmaceutical quality and global supply chain integrity.  Over the past year there have been multiple contaminated drug products.  Most recently those contaminated with the probable human carcinogen N-Nitrosodimethylamine (NDMA), including several Angiotensin II Receptor Blockers (Valsartan, Losartan, and Irbesartan) and Ranitidine, have been highly publicized recalls. 

Questionable pharmaceutical quality contamination events led former FDA Commissioner, Dr. Scott Gottlieb, to make numerous public statements over the past year referencing the need to improve pharmaceutical quality to prevent recalls, adverse events, and drug shortages.  The FDA has committed to provide information to assist companies in establishing and maintaining a quality culture and has mentioned dedicated initiatives towards that goal.

One of these initiatives spearheaded by the former Commissioner is updating the current good manufacturing practice (CGMP) regulations.  It is anticipated that these updates will likely address increased monitoring and accountability for the manufacturing supply chain, as this oversight is desperately needed to address varying global quality cultures and drug product manufacturers with numerous production facilities and/or contract manufacturers spanning the globe.   

The FDA may likely follow the lead of the EU when it comes to updating its CGMP regulations including enhancement of supply chain integrity.  This assumption is based on the more mature European regulatory requirements around increased accountability of supply chain integrity, as highlighted in the Good Distribution Practice for APIs for medicinal products for human use and the EU GMP Guide, Part II. 

Anticipating that the FDA may follow suit on enhancing supply chain accountability in their revisions to the CGMP regulations and to ensure integrity over the manufacturing supply chain, it may benefit companies in the U.S. market to develop a risk assessment model, including both initial and ongoing assessment, of suppliers for drug product components.  Recommendations for this model include:

  • A risk assessment of all components, containers, and closures used in the drug product to comply with CFR 211.80.
     
  • Attributes of the component (e.g., its role in formulation, amount in the drug product, its function, etc.) and drug product (e.g., the final dosage form, route of administration and intended patient population, etc.) can be included in the initial risk assessment.
     
  • Elements of the ongoing risk assessment can include evaluation of audit results, periodic verification of the product’s critical quality attributes, ongoing communication with the supplier, the quality agreement with the supplier, and monitoring of the components either intended for use or those used in production lots.
     
  • There are elements which can be included in both the initial and ongoing component risk assessment, such as the source of the component and how it is used, attributes of the component important to product quality or performance, risk of intentional substitution, supply chain complexity, and any regulatory actions associated with the component or its supplier.

The knowledge and data gained from both the initial and ongoing supplier risk assessments should be leveraged during initial and ongoing supplier qualification activities.

Biosimilars, “generic versions” of large molecule biologics, comprise another area seeming to struggle from quality issues and feeding into a similar perfect storm.  There are several factors contributing to this.  To begin with, there are rather few biosimilar applications submitted to the agency and recently several of these applications have been refused to file by FDA due to lacking quality and/or completeness.  Also, these products tend to have higher risk manufacturing associated with them because they are predominantly sterile products and are derived from living systems, by definition, which are inherently more difficult to maintain quality control over. 

Foreign manufacture of these also poses a large challenge for FDA to maintain appropriate regulatory oversight of, including suitable expertise for their assessment and inspection.  The potential for the formation of this perfect storm situation which needs to be mitigated to ensure biosimilar treatment options.  Availability of quality biosimilars would be hugely beneficial to patients if they could obtain access to safe, effective, and inexpensive versions of these medicines, since many of these are oncology products, and biologics appear to be potential or the only candidates for treatment options.

In addition to ending these perfect storms from forming due to poor drug quality, the pharmaceutical industry can reap several benefits for investing in a quality culture for drug manufacturing and exerting control over its manufacturing supply chain suppliers.  These benefits can include patient safety, product effectiveness, safety of manufacturing facility operators, positive corporate and product reputation, and improved interfacing with global regulatory agencies potentially resulting in faster and more drug product approvals. 

Developing a corporate quality culture can lead to enterprising approaches for quality oversight throughout a product’s lifecycle, from product development through post-approval.  This will drive towards the marketing of safe and effective drugs with patient-centric development, robust quality metrics, compliant operations through the product’s lifecycle ensuring that all critical quality attributes for the product are consistently achieve, which benefits both the pharmaceutical industry and patients.  Until both industry and the FDA focus on developing and appropriately regulating quality pharmaceuticals, storms resulting from poor product quality may always be looming on the horizon.

 


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