Recent Regulatory Actions: Focus on Quality in Compounding

Posted on August 6, 2014

by Craig A. Boyce , RPh

Over the past month, a number of regulatory changes have occurred surrounding aseptic and sterile compounding.  Some of the significant regulatory actions include:

  •  FDA release of the cGMP Interim Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act (7-1-2014)
  •  Massachusetts passage and signing of H.R. 4235 amending the Massachusetts General Laws governing pharmacy (7-10-2014)


Examination of these regulatory actions finds that assurance of quality is a recurring theme.   Pharmaceutical quality measures must ensure that the finished product meets the specifications for identity (is the product what the label states?), strength (is the active ingredient within the allowable tolerances for the entire in-use period?), and purity (is the product free of contaminants?)  End product testing is the most commonly used method to ensure quality, but is inherently flawed since testing only proves the quality of the item tested.  It is difficult, if not impossible, to ensure quality through just end product testing.  This is especially true for human manual compounding since identical execution of each step in the compounding is necessary.  Humans are simply not capable of flawless performance 100% of the time, so end-product testing of a representative sample may not be indicative of the quality in an entire batch.

Quality by Design (QbD) is a high-reliability method to ensure quality and uniformity for the production of sterile pharmacy products.  QbD should be used by everyone, not just FDA-regulated finished drug product manufacturers.  The central tenet for QbD is that quality is built into every finished product through a thorough assessment and understanding of each element involved in the compounding processes.  These processes are a complex interaction of personnel, environment, raw materials, consumables, and aseptic manipulations, each contributing unique risks to the quality of the finished product.  Quality by Design works to eliminate risks at the point when they occur, which prevents out-of-specification results in the process.

Underlined statements in the following regulatory action excerpts illustrate QbD principles for designing quality into a process and monitoring to ensure conformity with performance measures.

FDA Interim Guidance for Human Drug Compounding Outsourcing Facilities

  • Process flow should be designed in a manner to prevent the influx of contamination from adjacent areas and rooms of lower air quality, and to avoid any disruption of HEPA unidirectional flow
  • Monitoring for pressure differentials, humidity, and temperatures should occur during production, and prompt action should be taken to correct inappropriate conditions. If a problem cannot be immediately corrected, production should stop until corrected.
  • Environmental monitoring should consist of a well-defined program that evaluates the potential routes of microbial contamination of the human drug that could arise from the air, surfaces, process, operation, and personnel practices. The program should contain an appropriate detection component to verify state of control of the environment.
  • Each lot of equipment, containers, and closures must be examined to verify identity and tested to ensure conformity with appropriate specifications before use
  • Equipment must be qualified as capable of performing its intended functions or operations before first use
  • Personnel, material, and process flow should be optimized to prevent unnecessary activities that could increase the potential for introducing contaminants to exposed product, container-closures, or the surrounding environment.
  • Media fill studies should closely simulate aseptic manufacturing operations incorporating, as  appropriate, worst-case activities and conditions that provide a challenge to aseptic operations
  • The quality control unit must periodically review records of compounding operations to evaluate the quality standards for each drug product to determine the need for changes in specifications or control procedures. As part of this review, the quality control unit should identify trends and evaluate quality indicators

Massachusetts Amendments

  • Expert in patient safety and quality improvement added to Board of Registration in Pharmacy
  • Inspection agents shall be trained in USP Chapters <795> and <797>
  • Pharmacists engaged in sterile compounding must have 5 hours of annual continuing education in area of sterile compounding
  • New definition added: “Quality assurance”, a set of activities used to ensure that compounding processes lead, with a high degree of assurance and certainty, to finished drug preparations meeting pre-determined specifications and standards of quality.
  • Sterile compounding pharmacy employee must be trained in lean concepts – “tools that assist in the identification and steady elimination of waste and promote continuous improvement in quality and efficiency.”
  • Law directs Board to establish regulations for 11 different quality-related standards for ensuring quality and sterility
  • Establishes advisory committee to the Board with specific expertise in both USP and cGMP for aseptic processing

Sterile compounding requires safety and precision to be built into every dose that is prepared.  Quality by Design is a method that allows us to examine both the overall and minute processes to ensure that risks in each step are either eliminated or mitigated to the lowest possible level.  The promulgation of new guidelines, standards, laws, rules, and regulations are beginning to roll out and contain many quality by design principles, but we should not wait on regulations to force us into making decisions on implementing high-quality processes.   Quality by Design must become our new sterile compounding standard of practice to protect those who depend upon us for the best care we can provide.



Craig Boyce is a pharmacist on staff at Intelligent Hospital Systems, designer and manufacturer of RIVA a Fully Automated IV Compounding System

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