Assurance of Sterility for Sensitive Combination Products and Materials: New Paradigms to Bring Innovative Healthcare Products to Patients

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Assurance of Sterility for Sensitive Combination Products and Materials
Copyright
Contributors
Foreword
1
Introduction: Sterilization or aseptic processing of single use combination products
	Introduction
	Sterility assurance terminology
2
Sensitive combination products: Devices, pharmaceuticals, and biologics
	Introduction to combination products
	Considerations for sterilization of combination products
		Drug-enhanced devices
		Drug delivery systems: Traditional and novel
		Regenerative medical devices with biologics
		Electronics, bioabsorbables, and other novel materials and the future of combination product development
	References
3
Terminal sterilization
	The history of sterilization
		History of radiation sterilization
		History of EO sterilization
		History of dry and moist heat sterilization
	Sterile validation of current methods
		Product qualification
		Equipment qualification
		Sterilization validation approaches
			Bioburden-based approach
			Bioburden and BI-based approach
			BI approach
		Validation overview
	Future approaches to sterilization
	Conclusion
	References
	Further reading
4
Aseptic processing
	Aseptic processing of sterile combination products
	Drug product sterility
	Aseptic processing
	Aseptic process design
	Sterility by design
	Line of sight [9]
	Defining aseptic process requirements
	Basis of design
	User requirement specification (URS)
	Aseptic practices
	Interventions and activities in the aseptic processing critical area
	First air principles
	Environmental monitoring
	Personnel monitoring
	Clean room design
	Airflow or air profile visualization (smoke) studies
	Isolators, RABS, BFS, and other advanced aseptic barrier systems
	Critical utilities
	Aseptic process qualification and validation
	Aseptic process simulation design
	Microbial contamination case study
	Aseptic process simulation study design
	When should aseptic process simulations be performed?
	What process steps should be included in the aseptic process simulation?
	How many aseptic process simulations should be run for the simulation study?
	How should the “worst-case” parameters or conditions be included in the study?
	How long should the aseptic process simulation be?
	What are the aseptic process simulation acceptance criteria?
	The future of aseptic processing
	Conclusion: Quality risk management and risk-based critical thinking
	References
5
Package/container closures
	History of sterile packaging
	Technologies
		Introduction
		Packaging functions
		Differences between requirements of medical device and pharmaceutical packaging
		Container types/definitions/dosage form
		Considerations for plastic selection-pharmaceutical and medical device packaging
		Stability issues related to packaging
		Challenges for packaging combination products
	Validation principles
		Validation and patient safety
		Package integrity and the limitations of sterility testing
		Test methods
			Integrity test methods
			Integrity testing—Conclusions
			Microbial barrier test methods
			Seal strength test methods
			Validation of test methods
		Design validation
			Material qualifications, chemical, and biological compatibility
			Microbial barrier properties
			Biological compatibility and toxicological attributes
			Extractables and leachables
			Performance qualification
				Defining the distribution and storage environment
				Clinical use: Aseptic technique and usability aspects
			Stability studies
		Forming, sealing (closure) and assembly process validation
			Process design
			Installation, operational, and performance qualifications
			Process control and monitoring (continuous process verification)
		Packaging and device families
		Managing changes and revalidation
		Examples of validation approaches
	Power and sample size considerations for medical and pharmaceutical device packaging
		A conceptual overview of power and sample size
		A power and sample size example for packaging
		Power and sample calculations in practice for significance testing
		An overview of equivalence testing
		Power and sample size considerations for equivalence testing
		Sample size for process capability in process validation
		Concluding remarks for power and sample size
	New developments
	References
6
Review of current practice in preventing health care associated infections
	Introduction
	Background in HAIs
	Assessment of risk
		Identifying HAIs
		Assessing the burden/impact of HAIs
	Causes of HAIs
		Patient-related factors
			Source of microorganisms
			Susceptible host
			Means of transmission
		Procedural-related characteristics
			Risks based on the procedure
				HAI classification
			Non-device-associated infections
			Device-associated infections
				Industrial single-use devices
				Reusable devices
				Surgical site infections
	Preventing HAIs
		WHO safe surgery saves lives initiative
			CDC SSI guideline 1999
		Behavior
			Isolation precautions
			Standard precautions
		Transmission-based isolation precautions
			Surgical hand scrub
			Health-care personnel attire
			Nonsurgical setting attire
			Surgical setting attire
		Procedural interventions
		Engineering solutions—HCFs
			Suite/room design
				Airflow and ventilation
				Traffic patterns
				Protection and barriers
					Facial protection
					Hoods, caps, and shoe covers
					Gloves
					Gowns and drapes
				Cleaning
					Cleaning validation
					Disinfection
				Sterilization at the HCF
					Steam under pressure
					Terminal sterilization
					Immediate use steam sterilization
					EO sterilization
					Hydrogen peroxide
					Hydrogen peroxide/ozone
					Peracetic acid
	Conclusion
	References
7
Risk to the patient—Quantifying assurance of sterility
	Risk concepts applied to sterility assurance
	Statistical concepts applied to sterility assurance
		Point estimates
		Confidence interval example
		Confidence bounds
		Statistical analysis types
			Nonparametric analysis
			Parametric analysis
	Statistical analysis of risk associated with packaging and sterilization
		Introduction to scenarios analyzed
		Point estimates and confidence bounds—Packaging
		Point estimates and confidence bounds—Aseptic processing
			Conclusion—Point estimates and confidence bounds—Aseptic processing
		Point estimates and confidence bounds—Terminal sterilization; bioburden-based approach
			Section A
			Section B
			Conclusion—Point estimates and confidence bounds—Terminal sterilization; bioburden-based approach
		Point estimates and confidence bounds—Terminal sterilization; overkill method
			Section A
			Section B
			Conclusion—Point estimates and confidence bounds—Terminal sterilization; overkill method
		Summary of statistical analysis
	Relative patient risks from various industry sectors compared to real-world infection rates
		Estimates of infection probabilities
			Probability of P1
			Probability of P2
			Probability of P3
			Probability of P4
		Other factors influencing the assurance of sterility
			Patient’s immuno-compromised status and ability to treat the infection
			Bioburden control in the manufacturing environment
			Sterilization validation methodology
		Comparison to real-world infection rates
	Risk acceptability—Bringing it all together, the real risk to the patients
	Conclusion
	References
8
Developing new products
	Background
	Sterilize at 10 − 6 SAL
	Aseptic processing
	Alternative SAL
		Improving device compatibility
		Reducing exposure time
		Reducing bioburden
		Other SAL options
			Identifying the risks
			Identifying the benefits
	Conclusion
	References
9
Regulatory pathway for labeling combination products as sterile
	Labeling products as sterile
		Communicating with regulatory authorities
	Seeking FDA feedback
		Additional points to consider
	EU submission process
		Regulatory classification
		Marketing authorization as a medical product
		CE-marking for a medical device
	FDA guidance on labeling devices as sterile
		Methods of sterilization
		Content recommendations for 510(k)s
	Documents pertaining to terminal sterilization and SAL
		Guidance from the Association for the Advancement of Medical Instrumentation
		European standards for terminal sterilization
		New guidance from ISO
		Documents pertaining to aseptic processing and assurance of sterility
		ISO 13408 series
		EN 556-2
		Evaluation of medicinal products
	Summary
	Further reading
10
Path forward
	What is next with combination products?
	Sterility assurance landscape in the 2020s
	Pan-industry sterility assurance risk framework
		Sterility assurance risks in health-care facilities
		Sterility assurance risks related to single-use products
	What is next for sterility assurance professionals?
		End-to-end sterility assurance
		Bringing it all together in a risk management framework
	What is next for the patient?
	References
Index
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