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How Design Controls Affect Sterilization Process Development and Validation

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI October 1997 Column


Design control demands that all factors affecting a product's performance be considered before production. For sterile medical devices, that means the sterilization process should be addressed during each phase of the design control process.

By this time, everyone within the medical device community knows that the new quality system regulation mandates design controls for many medical devices. Many in industry, however, may not fully understand how to incorporate manufacturing processes into the act of complying with design controls. This may well result from the fact that most manufacturers have long since subjected their manufacturing processes to process validation, as required by the now-superseded good manufacturing practices regulation. What's new is that under design controls, manufacturers are now required to undertake and document process development and validation early in the design phase for each and every applicable medical device.

The extent to which design control concepts are applicable to process development and validation depends on the nature of the process in question. The sterilization process, of course, is a critically important step in the manufacture of sterile medical devices. For that reason, it is subject to the design control requirements as outlined in section 820.30 of the quality system regulation.


The multifunctional design control process must involve many departments to be effective. This is especially true with sterilization. Sterilization cycles cannot be designed without input from the R&D and manufacturing functions, and conversely, designers cannot develop a safe and effective device without input from the sterilization function. Management with executive responsibility must play an active role in the design process by creating an environment where the concept of interdepartment communication and cooperation will flourish.

The effectiveness of a sterilization process for a specific medical device derives from the relationship between the robustness and the capability of the two proceses. Process robustness is the ability of the process to withstand product variations while maintaining its quality attributes­in this case a minimum, validated sterility assurance level. The process capability, by contrast, is a measure of the ability of the process to reproducibly manufacture product. In the case of sterilization, this means that the process for a specific device must be designed to be able to effectively sterilize a product or product family within the expected range of acceptable product variation.

The primary objective of design controls in the sterilization process is to ensure that an effective, reproducible cycle is routinely used to process a particular device or device family. Because of the importance of consumer safety in sterilized medical devices, risk management associated with sterilization cycle development is directed toward the ultimate safety of the processed device. Risk can be considered the probability of occurrence of a hazard causing harm; safety, the freedom from unacceptable risk. A 10­6 sterility assurance level (SAL; the probability of one nonsterile unit out of one million units processed) is generally considered an acceptable risk of nonsterility and is therefore used as a basis of sterilization cycle design.

The design control features of the new quality system regulation are outlined in section 820.30 and encompass the following elements:

  • Design and development planning.
  • Design input.
  • Design output.
  • Design review.
  • Design verification and validation.
  • Design transfer.
  • Design changes.
  • Design history file.

Many organizations have historically conducted sterilization validation studies under defined, preapproved protocols that used worst-case challenge conditions encompassing many of the concepts outlined in 820.30. Following the current domestic standards for sterilization validation­i.e., ANSI/AAMI/ISO 11135 for ethylene oxide, 11137 for radiation, and 11134 for steam­ensures that many of the elements of design control are addressed. However, the application of each section of the design control requirements may not be immediately obvious. The following discussion is intended to help clarify these requirements.

Design and Development Planning. This section of the regulation outlines the need for the design to be addressed in a plan prepared before starting the development process. For sterile devices, a sterilization master plan is often prepared that meets this objective. This plan usually addresses the equipment to be validated, defines in general terms the methodology and schedule to be used, outlines the responsible departments, and defines milestones where management reviews are required. The master plan is a dynamic document that should be updated throughout the product development life cycle. Copies of the plan and its updates must be placed in the design history file.

Design Input. FDA recognizes the design input stage, sometimes referred to as the requirements stage, as the basis of a successful sterilization validation program. The developers must match the product and packaging specifications to the sterilization process capabilities, taking into account such factors as gas access, material compatibility, safety, manufacturing process requirements, bioburden, and exposure. If requirements are not defined in this phase, the sterilization validation will be inadequate.

After being converted to specifications, the requirements of the design input stage should be testable. In the development of a sterilization process, these requirements are that the product have a defined SAL (10­6) and that both the product and packaging remain functional after sterilization. Since these requirements involve different aspects of product development, the input to a sterilization development program and its review are multidisciplinary, requiring the participation of R&D personnel, sterilization scientists, and packaging engineers.

Design Output. The design output stage supports specification development and results in establishing essentially all of the product specifications. Design output includes a description of the complete specifications and provides the basis for the development of the remainder of the device master record. In the case of sterilization, this should include a description of any restrictions on product or packaging temperature, moisture, or vacuum, as well as all the quality checks required for sterilization cycle control and monitoring. It should culminate in a description of the final sterilization cycle parameters.

Design Review. This stage occurs after each step in the design plan. The final cycle documentation must be reviewed and approved by the appropriate individuals, who should include as a minimum a sterilization engineer, a packaging engineer, an R&D engineer, and someone from quality control or regulatory affairs. A regulatory affairs specialist is especially pertinent if the intent or claim of the sterilization cycle validation program is to conform to a specific domestic or international standard.

Loaded cobalt 60 rods will provide gamma radiation sterilization.

Design Verification and Validation. It is common industry practice to validate all sterilization processes. This is commonly done under a comprehensive, preapproved protocol that clearly defines the acceptance criteria of the sterilization validation study and references a particular standard or guideline. The validation is performed under limit conditions or worst-case operating conditions and conducted with multiple lots or batches to demonstrate reproducibility.

The results of the sterilization validation must be detailed in a final report that is reviewed, approved, and signed. The final report and associated protocols should be permanently archived in the validation file, which should be a part of, or referenced, in the product's design history file.

Design Transfer and Changes. After the validation is completed, the specifications are transferred to a manufacturing function. This functional group is typically responsible for assuring that the validated sterilization cycle parameters are accurately incorporated into approved specifications.

Any subsequent design changes must be controlled through a formal change-control process. Any changes to the product-process specification must be subjected to the same level of controls and reviews as the initial development effort. That is, changes must be made under the design control requirements and reviewed and approved by individuals in the same functions and departments as those who approved the original design documentation. Changes to documents, such as correcting text or graphic errors or adding procedural text, must be made under the document controls section of the quality system regulation (820.40).


To effectively integrate sterilization process development and validation into a design controls program, medical device manufacturers may need to structure their procedures to integrate the additional review and approval steps at the appropriate intervals as defined in the regulation. While at first the necessity of these numerous review and approval steps may seem overly burdensome, redundant, and unnecessary, in the long run this comprehensive review process should lead to a reduction of errors and deviations. Adherence to these concepts will provide assurance that the sterilization cycle will be effective and will meet all quality requirements­which is, after all, the primary goal of all manufacturers.

Robert R. Reich is president of Pharmaceutical Systems, Inc. (Mundelein, IL).

Illustrations by Brad Hamann

Copyright ©1997 Medical Device & Diagnostic Industry
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