Applying Quality by Design to Sterile Manufacturing Processes - Pharmaceutical Technology

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Applying Quality by Design to Sterile Manufacturing Processes
The author reviews the draft guidance on process validation, its QbD applications, and its potential impact on sterile manufacturing operations.

Pharmaceutical Technology

Environmental testing and validation

Environmental testing is designed to check facility, process, personnel and environmental cleaning methods to determine: (A) that after being in a state of shutdown that includes relaxed gowning, the facility and equipment can be cleaned, sanitized, and in a state of microbial control appropriate for pharmaceutical operations; and (B) that the facility can maintain a level of environmental control during normal processing operations.

Critical testing required before startup include: high-efficiency particulate air (HEPA) filter testing, room differential verifications (e.g., air flows, alarms), cleanroom smoke studies, and environmental mapping during static and dynamic conditions (i.e., nonoperational and operational conditions). Note that any physical change(s) made in aseptic processing (e.g., facilities, equipment, layout) when adding a new process requires revalidation.

Aseptic processing

Aseptic processing includes sterile manufacturing, aseptic filling, lyophilization, stoppering, sealing, and spray-drying. Examples of facility and processing-type CQAs that enhance overall process control from outside influence are outlined below.

  • Aseptic operations should be protected from potential leaks (e.g., roof leaks and process leaks, including condensation from heat, ventilation, and air conditioning [HVAC] systems). Some processing equipment (e.g., restricted access barrier systems [RABS]) may also contain HVAC or refrigeration that create moisture issues.
  • Critical operations should be visible without environmental impact. The objective is to keep personnel out of the critical processing areas while still being able to view operations for documentation and training.
  • Gowning areas, including barriers such as the step-over for applying booties, are typically dirty due to employee activity. Consider airflow turns higher than normally recommended (at least 80 air turns is preferred).
  • Cleanroom airlocks should be designed at the same classification as the area they support. Consider having sweeping airflow from the clean side to the dirty side with the return close to the dirty side's entry door.
  • Cleanrooms should be designed to take up just one classification level, thereby eliminating confusion (e.g., no Class A (ISO 5] and Class B [ISO 6] in the same room).
  • Filling lines and critical processes should be physically separated from operators. Equipment within isolators or RABS can help to significantly control contamination.
  • When using isolators with VHP (H2O2), consider the location of HVAC room inlets and returns to avoid potential cooling impact on the sterilization process.
  • Cleanroom access should be limited to those personnel essential to the operation, including quality assurance personnel. It is amazing to see how the industry has added nonessential personnel to critical areas in the guise of quality when people are the number one environment problem.
  • Each processing area should have its own separate gowning area and exit, without overlapping pathways.
  • Environmental-monitoring (EM) data control should be automated. Software systems are available that effectively track and manage all environmental data based on the latest regulatory guidelines.
  • Design equipment to limit product exposure to personnel and the environment, including any environmental monitoring.
  • Include capability to clean-in-place and sterilize-in-place (CIP/SIP).
  • Consider 100% check weighing.
  • Check preventative maintenance operations capability from outside the aseptic area. Determine whether there is a need for process-piping temperature control from the manufacturing process through filling. Does the piping travel through noncontrolled environments?
  • Determine whether there is a maximum time for filled product to be removed from cold storage. These operations should be considered as automation of process.
  • Use of disposables and presterilized items can be positive, but transfers into Class-A areas without a verifiable method of sterilizing the bagged sterile items can be troublesome. Use VHP or CLO2 to mitigate this concern.


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