HealthJanuary 20, 2016

Concerns over sterility assurance spur sterile compounding recalls

The compounding industry continuously sees recalls and safety alerts issued based on sterility assurance concerns expressed by the US Food and Drug Administration (FDA). For compounding pharmacies, the heightened activity drives home importance of sterility issues and proper documentation.The most recent safety alerts involve compounding pharmacies in Alabama, Arkansas, California, Oklahoma and Texas.1 The FDA recommended that one pharmacy cease the production of sterile products and that another facility issue a recall. Those requests were rebuffed by the companies involved, prompting the FDA to issue safety alerts warning clinicians and patients not to use drug products intended to be sterile made and distributed by these pharmacies. Four additional sterile compounding facilities issued voluntary recalls and two have ceased compounding operations entirely.

The Form 483 reports associated with these safety alerts indicate that these pharmacies, like many others that received less serious warning letters, have faced challenges in complying with significant portions of USP Chapter 797. In these specific instances, inspectors expressed concern about unsanitary or unsterile conditions, which prompted the recalls or closure of the operations. The inspection reports also provide insight into the less obvious procedural and documentary violations that ultimately compromise sterility and concern regulators.

Chief among those concerns are consistent, documented monitoring of environmental conditions. This includes certification of laminar flow hoods, buffer rooms and ante rooms performed under dynamic conditions as well as written, scientific specifications for the classified rooms, such as air exchange rates, particle counts and pressure differential. Documentation of activity monitoring of personnel and the environment must also be done every day sterile products are made.

The FDA also clearly expects that any company that registered as an outsourcing facility under section 503B of the Food and Drug Cosmetic Act (FDCA) will comply with current good manufacturing practices (CGMP) for finished drug products, just like a pharmaceutical manufacturer. These requirements differ substantially from those imposed on non-outsourcing compounding pharmacies and include validated and/or stability-indicating analytical methods, robust quality control systems and documented compliance to more rigorous standards.

In addition, the FDA requires proper follow up on alerts and action limits for environmental and personnel monitoring excursions. Compounders should maintain documentation of each investigation, identify isolates, determine the root cause of the excursion, and resolve them. Policies and procedures should include when and how often monitoring is performed, how to respond to out of range results, when to cease production, and how to record follow up as well as checklist forms that ensure all required tests and documentation occur.

According to Lachman Associates, the 10 most common adverse observations cited by the FDA for outsourcing compounding pharmacies all affect sterility assurance and are noted in more than 60% of inspections.1

They include:

  1. Inadequate facilities design and controls and inadequate smoke studies
  2. Insufficient environmental monitoring of facility and people
  3. Inadequate laboratory procedures and controls including a uniform definition of a "batch," sampling and testing controls
  4. Lack of standard operating procedures to prevent microbial contamination
  5. Inadequate deviation/variance controls and lack of adequate investigation
  6. Stability program nonexistent or does not support beyond use dating
  7. Inadequate validation of final sterilization (filter or terminal) or poor media fill design
  8. Inadequate cleaning and disinfection programs
  9. Inappropriate batch release (most done at risk or with no testing for sterility, potency, identity and pyrogens)
  10. Inadequate calibration program or preventive maintenance for equipment

Even traditional compounding pharmacies should pay attention to these areas of concern. The Food and Drug Administration has issued Warning Letters to more than 40% of compounding pharmacies inspected this year and has made critical observations via Form 483 or other means for nearly 100% of compounders visited.None of the Warning Letters has been lifted and quite a number of compounders that received Form 483 or Warning Letters last year or earlier this year have had repeat visits more recently. Other areas frequently cited include:

  • Lack of validated analytical methods for stability and potency testing
  • Lack of analytical methods for determining impurities and extraneous peaks in chromatography
  • Inadequate personnel qualifications and insufficient training and assessment of GMPS skills
  • Inadequate standard operating procedures
  • Labeling issues
  • Poor documentation
  • Insufficient separation of operations

Many of these issues may be mitigated by the implementation of a sophisticated web-based quality management system that stays current as the regulations for compounding pharmacies evolve. These systems can help pharmacists identify and address their ongoing and emerging risks, document preventive and corrective actions, provide standard operating procedures and essential forms, and facilitate and document training and personnel assessments.


1. 2015 Safety Alerts for Human Medical Products. US FDA. 

2. Sturgeon R. FDA Is Diving Deeper in GMP Compliance for Compounding Pharmacies--A Follow-up. Lachman Associates. September 14, 2015.

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