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Regulatory Considerations for Environmental Monitoring

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Regulatory Considerations for Environmental Monitoring

  1. 1. Regulatory Considerations for Environmental Monitoring FDA Compliance for Sterile and Non-sterile Products
  2. 2. Defining Environmental Requirements for Sterile and Nonsterile Production <ul><li>The regulators require environmental monitoring for sterile production, but why do I need an environmental monitoring program for nonsterile production? </li></ul><ul><ul><li>EM is a basic requirement across multiple regulated industries; food, cosmetics, nutriceuticals, drugs and devices. </li></ul></ul><ul><ul><li>It is a measure of cleanliness of a utility, and therefore the biological safety of the product being manufactured; manufacturing is after all a people process and people are the primary contributors of microorganisms in any manufacturing industry. </li></ul></ul><ul><ul><li>Extent of maintaining environmental control to prevent contamination depends on the type of product, the route of administration and the health of the person consuming that product. </li></ul></ul>
  3. 3. People are part of the process!!!!! Defining Environmental Requirements for Sterile and Nonsterile Production
  4. 4. Defining Environmental Requirements for Sterile and Nonsterile Production <ul><li>What FDA states on contamination control and its impact on non sterile products: </li></ul><ul><ul><li>In both Pharmaceuticals and Medical Devices the FDA evaluates the process against the: </li></ul></ul><ul><ul><ul><li>The laws in the Code of Federal Regulations applicable to the product and the manufacturer </li></ul></ul></ul><ul><ul><ul><li>The pharmaceutical NDA/ANDA or device application claim of product sterile packaging or non sterile packaging </li></ul></ul></ul><ul><ul><ul><li>Potential for the product to promote or harbor pathogenic microorganisms </li></ul></ul></ul><ul><ul><ul><ul><li>Impact on the patient </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Impact on the product </li></ul></ul></ul></ul>
  5. 5. Defining Environmental Requirements for Sterile and Nonsterile Production <ul><li>The CFR, USP/NF, EU Volume 4 Annex 1, ISO 14644 & 14698 and how they relate to environmental monitoring requirements. </li></ul><ul><ul><li>The nature of your environmental monitoring program will depend on a number of issues: </li></ul></ul><ul><ul><ul><li>Industry: pharmaceutical, medical device, nutriceutical </li></ul></ul></ul><ul><ul><ul><li>Product claim: sterile, non-sterile, microbiologically controlled </li></ul></ul></ul><ul><ul><ul><li>Regulatory body governing point of sale to consumer </li></ul></ul></ul><ul><ul><ul><li>Route of delivery of the product </li></ul></ul></ul><ul><ul><li>The CFR, USP/NF, EU Vol. 4, Annex 1, ISO 14644 & 14698 all contain valuable information on establishing, controlling your EM Program in relation to the product. </li></ul></ul>
  6. 6. The Core Requirements, HVAC, Cleaning and Facility Design <ul><li>What Are the Core Requirements? </li></ul><ul><ul><li>Products Sold as Sterile </li></ul></ul><ul><ul><ul><li>HVAC requirements, room construction & particulate monitoring as defined by the ISO 14644 documents </li></ul></ul></ul><ul><ul><ul><li>Micro requirements defined by FDA or EMEA depending on point of sale of sterile product </li></ul></ul></ul><ul><ul><ul><ul><li>Both Non-viable and Viable particles must be controlled </li></ul></ul></ul></ul><ul><ul><li>Products Sold as Non-Sterile </li></ul></ul><ul><ul><ul><li>HVAC requirements and room design defined by engineering design for the room/facility </li></ul></ul></ul><ul><ul><ul><li>Typically no particulate requirements, but maybe product specification requirement </li></ul></ul></ul><ul><ul><ul><li>Micro requirements defined by company policy and product micro susceptibility </li></ul></ul></ul>
  7. 7. The Core Requirements, HVAC, Cleaning and Facility Design <ul><li>The role of effective cleaning in controlling microorganisms </li></ul><ul><ul><li>Cleaning agents must be antimicrobial (USA need EPA registration claims, EU has EU registration claims) </li></ul></ul><ul><ul><li>Cleaning agents must be effective against the organisms in the environment used </li></ul></ul><ul><ul><li>Whether a sterile product or non sterile product, you want to follow clean room cleaning regimes </li></ul></ul><ul><ul><li>Need dedicated qualified clean room cleaners </li></ul></ul>
  8. 8. The Core Requirements, HVAC, Cleaning and Facility Design <ul><li>How to pick good cleaning and disinfection agents </li></ul><ul><ul><li>Need at least two and at least one of the cleaning agents should be sporicidal </li></ul></ul><ul><ul><li>Compatible with clean room surfaces and with other cleaning agents; not leave a sensory residual </li></ul></ul><ul><ul><li>Effective against microorganisms in the room </li></ul></ul><ul><ul><li>Nontoxic to personnel </li></ul></ul><ul><ul><li>Readily obtainable </li></ul></ul><ul><ul><li>Comes with good technical support </li></ul></ul>
  9. 9. The Core Requirements, HVAC, Cleaning and Facility Design <ul><li>HVAC basics for effective contamination control </li></ul><ul><ul><li>Adequate pressure differentials </li></ul></ul><ul><ul><li>Sufficient air changes, air changes for aseptic are governed by ISO 14644 </li></ul></ul><ul><ul><ul><li>ISO 14644 is a general clean room standard that is applied in aseptic processes. </li></ul></ul></ul><ul><ul><li>HVAC System needs to be properly maintained and serviced </li></ul></ul><ul><ul><li>Defined temperature and or humidity (if required); ranges with alerts and alarms </li></ul></ul>
  10. 10. The Core Requirements, HVAC, Cleaning and Facility Design <ul><li>Facility design and construction, good ideas to implement and bad practices to avoid </li></ul><ul><ul><li>Need to provide architect/engineering planner with critical user requirements for the facility based on the product being manufactured (sterile or non-sterile) </li></ul></ul><ul><ul><li>Why would you want to build a aseptic facility for a non-sterile product? </li></ul></ul><ul><ul><li>In the USA, it is a good idea to consult with the local FDA office, they are eager to assist you. Help now can prevent trouble later </li></ul></ul><ul><ul><li>Payment to contractors should be incomplete until the facility meets the environmental requirements in the design documents </li></ul></ul>
  11. 11. Precursor Activities <ul><li>Validation, what you need to know and do </li></ul><ul><ul><li>Requirements are defined by whether you make a sterile product or a non-sterile product </li></ul></ul><ul><ul><li>Should do good engineering studies prior to starting validation, allows you to tweak the facility before starting validation. </li></ul></ul><ul><ul><li>Validation activities </li></ul></ul><ul><ul><ul><li>Defined by validation master plan, VMP </li></ul></ul></ul><ul><ul><ul><li>Cleaning agent qualification </li></ul></ul></ul><ul><ul><ul><li>HVAC Controls </li></ul></ul></ul><ul><ul><ul><li>Cleaning to remove soils from the room/facility </li></ul></ul></ul><ul><ul><ul><ul><li>Semi-annual, routine, and following actions and alerts according to approved SOPs </li></ul></ul></ul></ul>
  12. 12. Precursor Activities <ul><li>Writing SOPs </li></ul><ul><ul><li>SOPs need to complete, detailed and approved prior to validation </li></ul></ul><ul><ul><li>SOPs that are method related, such as cleaning, should be effectively demonstrated prior to approval and validation </li></ul></ul><ul><ul><li>SOPs need multiple approvals, facilities, manufacturing, microbiology as well as any other stake holders </li></ul></ul>
  13. 13. Precursor Activities <ul><li>Writing good PQs </li></ul><ul><ul><li>The PQ is a demonstration of the room to meets its user requirements </li></ul></ul><ul><ul><li>PQs should be done under static and dynamic conditions. Effective demonstrations of room requirements under static conditions must be demonstrated before dynamic conditions. </li></ul></ul><ul><ul><li>PQs are used to establish routine testing (monitoring, HVAC maintenance, cleaning) and to establish action and alert limits </li></ul></ul>
  14. 14. Method Selection and Data Collection <ul><li>Selecting sample methods, don’t make it harder then it has to be </li></ul><ul><ul><li>Sample for the type of product (sterile/non-sterile) in the room </li></ul></ul><ul><ul><li>Select appropriate equipment recognized by industry to perform sampling </li></ul></ul><ul><ul><ul><li>When bringing up a new facility, it’s is best not to be the guinea pig for new technology </li></ul></ul></ul><ul><ul><li>Establish any incubation requirements prior to PQs </li></ul></ul><ul><ul><li>There are difference between continuous particle monitoring systems, and point of testing particulate sampling </li></ul></ul>
  15. 15. Site Selection and Data Collection <ul><li>The logic of picking air and surface sites to prove effective cleaning </li></ul><ul><ul><li>Need to visit the room/facility to select sample sites </li></ul></ul><ul><ul><li>Select areas to test where people and equipment come in contact </li></ul></ul><ul><ul><li>Select critical sites that can alter product integrity if compromised </li></ul></ul><ul><ul><li>Select areas that could have dead air </li></ul></ul>
  16. 16. Common Mistakes <ul><li>A cross section of FDA citations, 483 and Warning Letters from poor EM programs: </li></ul><ul><ul><li>483s </li></ul></ul><ul><ul><li>Warning Letters </li></ul></ul>
  17. 17. Common Mistakes <ul><li>Excerpts from warning letters.doc </li></ul>
  18. 18. Common Mistakes <ul><li>For Pharmaceutical Companies </li></ul><ul><ul><li>Citation i.e: CGMP for Finished Pharmaceutical / Adulterated </li></ul></ul><ul><li>For Medical Device Companies: </li></ul><ul><ul><li>Citation i.e: CGMP/QSR/Medical Devices/Adulterated </li></ul></ul>
  19. 19. Referenced Material <ul><li>The CFR </li></ul><ul><ul><li>United States C ode of F ederal R egulations. </li></ul></ul><ul><ul><ul><li>Specifically Title 21. </li></ul></ul></ul>
  20. 20. Referenced Material <ul><li>FDA </li></ul><ul><ul><li>US Food and Drug Administration Compliance Policy Manual # 7382.845, Inspection of Medical Device Manufacturers , June 15, 2006 </li></ul></ul><ul><ul><li>US Food and Drug Administration FDA 97-4179, Medical Device Quality Systems Manual: A Small Entity Compliance Guide, First Edition (Supersedes the Medical Device Good Manufacturing Practices Manual), December 1996 </li></ul></ul><ul><ul><li>US Food and Drug Administration, Guide to the Inspections of Pharmaceutical Quality Control Laboratories , July 1993 </li></ul></ul><ul><ul><li>US Food and Drug Administration, Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories , July 1993 </li></ul></ul>
  21. 21. Referenced Material <ul><li>FDA </li></ul><ul><ul><li>ICH Q2A International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline Text on Validation of Analytical Procedures , October 27, 1994 (ICH Q2A) </li></ul></ul><ul><ul><li>ICH Q2A International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Harmonised Tripartite Guideline Text on Validation of Analytical Procedures: Methodology , November 6, 1996 (ICH Q2B) </li></ul></ul>
  22. 22. Referenced Material <ul><li>USP/NF </li></ul><ul><ul><li>U nited S tates P harmacopeia/ N ational F ormulary, </li></ul></ul><ul><ul><ul><li>Chapter <1116>, Microbiological Evaluation of Cleanrooms and Other Controlled Environments </li></ul></ul></ul><ul><li>EU Annex 1 </li></ul><ul><ul><li>E uropean U nion Volume 4 </li></ul></ul><ul><ul><ul><li>The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use Annex 1 Manufacture of Sterile Medicinal Products, 14 February 2008 </li></ul></ul></ul>
  23. 23. Referenced Material <ul><li>ISO </li></ul><ul><ul><li>I nternational O rganization for S tandardization. Several documents: </li></ul></ul><ul><ul><ul><li>ISO 13465:2003, Medical devices — Quality management systems - Requirements for regulatory purposes </li></ul></ul></ul><ul><ul><ul><li>ISO 14644-1, Cleanrooms and associated controlled environments Part 1: Classification of air cleanliness, 05/01/1999 </li></ul></ul></ul><ul><ul><ul><li>ISO 14644-2, Cleanrooms and associated controlled environments Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1, 09/15/2000 </li></ul></ul></ul><ul><ul><ul><li>ISO 14644-3, Cleanrooms and associated controlled environments Part 3: Test Methods, 12/15/2005 </li></ul></ul></ul>
  24. 24. Referenced Material <ul><li>ISO </li></ul><ul><ul><li>I nternational O rganization for S tandardization. Several documents: </li></ul></ul><ul><ul><ul><li>ISO 14644-5, Cleanrooms and associated controlled environments Part 5: Operations, 12/06/2001 </li></ul></ul></ul><ul><ul><ul><li>ISO 14644-6, Cleanrooms and associated controlled environments Part 6: Vocabulary, 2007 </li></ul></ul></ul><ul><ul><ul><li>ISO 14644-7, Cleanrooms and associated controlled environments Part 7: Separative enclosures (clean air hoods, gloveboxes, isolators, mini-environments), 07/22/2001 </li></ul></ul></ul><ul><ul><ul><li>ISO 14644-8, Cleanrooms and associated controlled environments Part 8: Classification of air cleanliness, 08/15/2006 </li></ul></ul></ul>
  25. 25. Referenced Material <ul><li>ISO </li></ul><ul><ul><li>I nternational O rganization for S tandardization. Several documents: </li></ul></ul><ul><ul><ul><li>ISO 14698-1, Cleanrooms and associated controlled environments – Biocontamination Control- Part 1: General principles and methods, 09/01/2003 </li></ul></ul></ul><ul><ul><ul><li>ISO 14698-2, Cleanrooms and associated controlled environments – Biocontamination Control- Part 2: Evaluation and interpretation of biocontamination data, 11/01/2004 </li></ul></ul></ul>
  26. 26. Citations <ul><li>The Code of Federal Regulations: </li></ul><ul><ul><li>§21 CFR211.67 (a) Equipment cleaning and maintenance </li></ul></ul><ul><ul><ul><li>(a) Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements. </li></ul></ul></ul><ul><ul><li>§ 211.84 (c) (1) Testing and approval or rejection of components, drug product containers, and closures </li></ul></ul><ul><ul><ul><li>(c) (1) The containers of components selected shall be cleaned when necessary in a manner to prevent introduction of contaminants into the component. </li></ul></ul></ul>
  27. 27. Citations <ul><li>The Code of Federal Regulations: </li></ul><ul><ul><li>§ 211.84 (d) (6) Testing and approval or rejection of components, drug product containers, and closures </li></ul></ul><ul><ul><ul><li>(d) (6) Each lot of a component, drug product container, or closure with potential for microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use. </li></ul></ul></ul><ul><ul><li>§ 211.113 (b) Control of microbiological contamination </li></ul></ul><ul><ul><ul><li>(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. </li></ul></ul></ul><ul><ul><ul><li>Such procedures shall include validation of all aseptic and sterilization processes. </li></ul></ul></ul>
  28. 28. Citations <ul><li>The Code of Federal Regulations: </li></ul><ul><ul><li>§ 820.70 (c), (d), (e) Production and process controls </li></ul></ul><ul><ul><ul><li>(c) Environmental control. </li></ul></ul></ul><ul><ul><ul><ul><li>Where environmental conditions could reasonably be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental conditions. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Environmental control system(s) shall be periodically inspected to verify that the system, including necessary equipment, is adequate and functioning properly. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>These activities shall be documented and reviewed. </li></ul></ul></ul></ul>
  29. 29. Citations <ul><li>The Code of Federal Regulations: </li></ul><ul><ul><li>§ 820.70 (c), (d), (e) Production and process controls </li></ul></ul><ul><ul><ul><li>(d) Personnel </li></ul></ul></ul><ul><ul><ul><ul><li>Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>The manufacturer shall ensure that maintenance and other personnel who are required to work temporarily under special environmental conditions are appropriately trained or supervised by a trained individual. </li></ul></ul></ul></ul>
  30. 30. Citations <ul><li>The Code of Federal Regulations: </li></ul><ul><ul><li>§ 820.70 (c), (d), (e) Production and process controls </li></ul></ul><ul><ul><ul><li>(e) Contamination control. </li></ul></ul></ul><ul><ul><ul><ul><li>Each manufacturer shall establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality. </li></ul></ul></ul></ul>

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