Packaging Operations Technical Subcommittee

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2 and Sterile About the Presenter John Derek Thompson Lead Sterile Engineer, DePuy Synthes Certified Professional with the IOPP Member of the Medical Device Technical Committee Chairman of the Member of the Institute of Environmental Sciences and Technology

3 and Sterile Introduction Medical Device Manufacturing is a heavily regulated industry. Important is the awareness of the regulations and standards that speak to compliance in facilities and environmental control. Combination medical devices add an additional consideration where pharmaceutical regulations also apply. Seeing your controlled environment facilities as an integral part of your Sterile process helps to assure the success of your process development project and ongoing compliance.

4 and Sterile Standards and Regulations at a Glance ISO Hygiene has become increasingly important in many areas of modern society. In such areas, hygiene or biocontamination control methods are, or will be, used to create safe and stable products. International trade in hygiene-sensitive products has greatly increased. At the same time, the use of antimicrobial agents has been reduced or forbidden, creating a need for increased biocontamination control. many factors besides cleanliness must be considered in the design, specification, operation and control of cleanrooms and associated controlled environments.

5 and Sterile Standards and Regulations at a Glance CFR 21; Subchapter H; Part 820; Subpart G - Buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent mix-ups and assure orderly handling. ISO (Part 2) The sterile barrier system shall be assembled under appropriate environmental conditions to minimize the risk posed by contaminants to the medical device. ISO If work environment conditions can have an adverse effect on product quality, the organization shall establish documented requirements for the work environment conditions and documented procedures or work instructions to monitor and control these work environment conditions.

6 and Sterile Standards and Regulations at a Glance CFR 21; Chapter I; Subchapter C; Part 211 Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations. GUI-0001; C Premises layout is designed to avoid mix-ups and generally optimize the flow of personnel and materials.

7 and Sterile Process Layout and Controlled Environment Design Key Points to Consider: How much space is needed for the process? Design the environment around the process and not the other way around. Lean tools can optimize process flows and minimize waste of space. Space design should account for strategic capacity growth. Remember to consider airflow requirements, critical points of product exposure and potentials for turbulence.

8 and Sterile Risk Management in Controlled Environment Design Guidance/requirements examples ISO (Part 2) The sterile barrier system shall be assembled under appropriate environmental conditions to minimize the risk posed by contaminants to the medical device. Potential failure modes and action levels having the greatest impact on the process should be identified and addressed (failure mode and effects analysis, cause and effect analysis).

9 and Sterile Risk Management in Controlled Environment Design Guidance/requirements examples (continued) EudraLex - Volume 4 (Chapter 3) [Premises] Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products. Both the European Commission GMP and Health Canada speak to the environment that, when considered together with measures to protect the manufacturing processes, presents minimal risk of causing contamination of materials or products.

10 and Sterile Risk Management in Controlled Environment Design A risk based approach should be taken in the design of the controlled environment. Risk analysis should be a collaborative effort acquiring input from Subject Matter Expert groups including (but not limited to) Product Development, Engineering, Sterility Assurance, Manufacturing and Facilities. Risk analysis serves to determine where process controls are required in order to mitigate risk. For medical device, non-conformances are classified based on patient risk. The controlled environment design and function should serve to mitigate the risks associated with the potential for product contamination.

11 and Sterile Facilities Capability Assessment Key Questions to Answer: What utilities are needed to support the room and operate the equipment within it? Controlled environment support equipment requirements must match facility support capabilities unless facility additions or modifications are possible. Are there special environmental support requirements? Depending on the product requirements and the lead-in process, environmental requirements can be from unclassified controlled areas to much more controlled (even aseptic) levels. Will an existing space be converted or is new construction required?

12 and Sterile User Requirements Specification (Primarily based on guidance from ISO ) Must be developed and agreed upon. Well developed URS serves as the controlled environment project plan. Should be developed with the relative Subject Matter Expert groups including (but not limited to) Product Development, Engineering, Sterility Assurance, Manufacturing and Facilities. Defines the requirements of the product, process and controlled environment. Sets the scope of the controlled environment project and serves as reference guide for design review.

13 and Sterile User Requirements Specification (Primarily based on guidance from ISO ) Defines the purpose of the room. Identifies the segregation control concept to be employed for the controlled environment and clean zones within it. Defines key regulatory elements the design must conform to such as building, environmental and safety, and good manufacturing practice guidelines. Includes (at a minimum): If new or revision/upgrade Intended use

14 and Sterile User Requirements Specification (Primarily based on guidance from ISO ) Includes (at a minimum): Process description and flow Equipment list with equipment description, intended process use, utility requirements, heat generation, etc... Construction type Clean zone description, number of zones and ISO class requirements per zone Air Change Rate Air Handling Unit specification

15 and Sterile User Requirements Specification (Primarily based on guidance from ISO ) Includes (at a minimum): Filter specification (% efficiency rating and sizes) Parametric requirements of the segregation concept chosen Environmental monitoring requirements and planned methods Materials of construction The completed project plan shall be reviewed and agreed upon.

16 and Sterile Key Terms (Per ISO ) Occupancy States As-Built - Condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel present. At-Rest - Condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present. Operational - Condition where the installation is functioning in the specified manner, with the specified number of personnel present and working in the manner agreed upon.

17 and Sterile Commissioning Per ISO : Planned and documented series of inspections, adjustments and tests carried out systematically to set the installation into correct technical operation as specified. Carried out in the As-Built state. Assures installation is ready for qualification. No, not that one Testing required depends on the intended use of the room, ISO classification and design layout.

18 and Sterile Certification Certify [Merriam-Webster] To say officially that something or someone has met certain standards or requirements. In cleanrooms, certification is documenting that the room and/or clean zone meets the acceptance criteria that demonstrates meeting a given ISO classification. This also includes (as applicable): airflow, filter, temperature, humidity, lighting, noise and segregation concept related testing.

19 and Sterile Validation CFR 21; Subchapter H; Part 820; Subpart G Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented.

20 and Sterile Validation For cleanrooms validations, we consider the total aspect of intended performance under specified conditions, not just the particle counts that serve to meet a given ISO classification. Ensures the controlled environment is designed per specifications, is functioning as intended, and can consistently meet the intended use of the area. Validation testing is performed in each of the occupancy states to demonstrate proper function and ability to maintain the environment under that given condition.

21 and Sterile Considerations in Standard Operating Procedures Procedures that govern operation of and within the controlled environment must be established. Procedures cover: Maintenance and cleaning Personnel gowning, conduct and hygiene Environmental monitoring requirements Non-conformance handling and remediation (including disaster recovery)

22 and Sterile Considerations in Standard Operating Procedures Procedures cover: Record requirements to document compliance to procedures, regulations and standards (includes requirements for record retention). Change Control. Requirements for training and certification.

23 and Sterile Considerations in Personnel ISO The organization shall establish documented requirements for health, cleanliness and clothing of personnel if contact between such personnel and the product or work environment could adversely affect the quality of the product. The organization shall ensure that all personnel who are required to work temporarily under special environmental conditions within the work environment are appropriately trained or supervised by a trained person.

24 and Sterile Considerations in Personnel ISO Personnel shall be instructed in hygiene-related issues that will prepare them for properly working in the cleanroom environment. A policy concerning jewelry, cosmetics and similar materials that can cause contamination problems shall be determined. Cleanroom personnel shall be trained to conduct themselves in a manner that minimizes generation of contamination which can be transferred or deposited on or into the product.

25 and Sterile Ongoing Maintenance CFR 21; Subchapter H; Part 820; Subpart G - Each manufacturer shall establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities, including the date and individual(s) performing the maintenance activities, shall be documented.

26 and Sterile Ongoing Maintenance Maintenance activities must be designed to limit or prevent negative impact to environmental control. This not only includes maintenance on the room itself, but on the process equipment within it and the support utilities as well. Downtime expectations (where applicable) should be established and planned for as well as standard restoration activities such as cleaning and testing following completion of scheduled maintenance. Maintenance and repairs must be well documented and consider where re-validation may be required following certain repairs.

27 and Sterile Ongoing Monitoring ISO Continued compliance with air cleanliness (ISO class) requirements specified for the installation is verified by performing specified tests and by documenting the results. Monitoring data is used as an indication of installation status and may determine the frequency with which tests are carried out. ISO The user of a cleanroom or controlled environment shall set microbiological alert and action levels. These levels shall be appropriate to the field of application, to the classification of the risk zones and to what is achievable using current technology. ISO Detection and monitoring of biocontamination in risk zones shall be carried out by sampling and enumerating viable units with appropriate methods in accordance with a sampling plan.

28 and Sterile Ongoing Monitoring (Primarily based on guidance from ISO ) Good monitoring program Is not just based on measuring non-viable particles to meet ISO Must be established, implemented, trained to, and maintained. Is an integral part of the quality system. Is based on an appropriate risk assessment. Has established alert and action limits and established corrective actions. Has established documentation and document retention requirements. Has limits set based on sampling at a given occupancy state.

29 and Sterile Ongoing Monitoring (Primarily based on guidance from ISO ) Good monitoring program Is conducted using a sampling device appropriate for the sample to be collected and the area being monitored. Has established frequency and sampling location requirements. Has procedure for storing, transporting and processing of samples and evaluations of results. Includes trending to identify patterns in results. Must not itself present a contamination risk by its execution.

30 and Sterile Audit Preparation Some thoughts from the codes: ISO 11607, Part 2 - Periodic revalidation or reviews should be considered since multiple minor changes could cumulatively affect the validation status of the process. CFR 21; Subchapter H; Part 820; Subpart G Each manufacturer shall establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system.

31 and Sterile Audit Preparation Know the relative regulations and standards and have a system for notification of updates. Conduct frequent self audits. Consider a DMAIC approach continuously improve, optimize and re-stabilize the controlled environment design and operations. Know the relative regulations and standards and have a system for notification of updates. (Yes I wrote it twice).

32 and Sterile Final Thoughts ISO Many factors besides airborne particulate cleanliness should be considered in the design, specification, operation and control of cleanrooms and other controlled environments. In some circumstances, relevant regulatory agencies may impose supplementary policies or restrictions. In such situations, appropriate adaptations of the standard testing procedures may be required.

33 and Sterile Conclusion In the Sterile Pack of medical devices, combination medical devices and pharmaceuticals, the sterile pack controlled environment, design, people and operations are integral parts of the packaging process control. Considering them as such better assures the success of your sterile packaging process development project and ongoing compliance.

34 and Sterile Questions?

35 Learn more about membership and support of the Task Group of the Medical Device Technical Committee at the Institute of Professionals webpage at or contact John Derek Thompson at