What Regulations Apply to Me and Why? What is “Cold Chain” and Why it Matters Putting the Whole Package/Process together within Your Industry

Pharmaceuticals and The Regulated Environment WE Live In

Electronic Signatures and Records 21 CFR 11 cGMPs For Manufacturing, Processing, Packing, or Holding Drugs 21 CFR 210 cGMPs For Finished Pharmaceuticals 21 CFR 211 Biological Products 21 CFR 600 cGMPs For Blood and Blood Components 21 CFR 606 Medical Devices 21 CFR 800

Data Distribution Equipment Facilities Data Distribution Equipment Facilities Personnel Utilities Warehousing Etc… Personnel Utilities Warehousing Etc…

Safety and Efficacy of the Product What are the goals of all of these regulations? State of Control How does one meet these goals?

The management of documents within an organization promoting continuity of lifecycle. Accomplished through the use of a standardized quality system. Document Control The documentation of procedures to ensure repeatability and audit ability. Formalization of Processes

Document Format Approval Process Documentation Standards TrainingDeviations Corrective/ Preventative Actions Auditing

Standard Operating Procedure (SOP) document format should be determined PRIOR to implementing the document control program.

The Approval Process for any controlled document should be routed through the individuals that are most appropriate for the document. The review/approval process should involve an appropriate number of individuals to put a critical eye to the process.

Must be complete No empty fields Must be free of obliterations, erasures, and correction fluid Corrections must be done in GMP format Initial, date of correction, single line through incorrect information Signatures should be dated when they are made

Basic cGMP TrainingOverall Job OrientationSOP Specific TrainingTraining RecordsRe-TrainingMeasurement

Documentation of instances that SOP’s were not followed. Deviations Plans to correct a situation causing a deviation or to proactively address a situation that may cause a deviation in the future. CAPAs

Internal Auditing Ensuring Compliance With Existing Procedures Vendor Qualification Ensuring Vendors Meet The Regulatory Needs External Audits Investigations Into Your Existing Quality System By Regulatory Organization or Potential Customers/Partners

Helps Maintain Validated State of Equipment Manages Change Through Documentation and Evaluation Changes should be proposed before being made. Proposed changes should be evaluated by an experienced person/panel. Evaluation should include a conclusive argument as to the re-validation of the equipment. Once signed off, documents should be filed with validation lifecycle documents.

SOPs should fit your operation The SOPs should be developed using a risk based approach. What are your critical processes? Electronic means should augment your paper based system 21 CFR Part 11 should be followed for critical systems

Processes that have a direct impact on the product should all be formalized. Receipt Shipping Storage Maintenance Pest Control Security Calibration Validation

SOPs Need to Cover Not Only the Process, But Also All of the Critical Pieces of Equipment/Processes Used Within and Outside the Process. Gaps in Integration Create Chances to Adulterate Product Are You Willing To Take Them? Formalization of Processes Need to Address All Aspects of the Mission

Improve Them as They Evolve Audit ALL of the Processes Formalize the Processes Decide Which Are Critical to Your Mission Take Risk Based Approach Toward Your Equipment/Processes Develop Quality System Design Document Control System

“Cold Chain” Management in the Pharmaceutical Industry

Starts Upon Acceptance and Ends When Product Administered or Destroyed Not Always “Cold” Label Approved via the FDA Label is Benchmark of Proper Stewardship Data Can Ensure the Safe Use of Product After Excursion Law Puts Responsibility on Possessor Responsible for Safety and Efficacy of Product WHO Study - 50% of Products Compromised Ensure Product Via Proactive Use of Materials Management Tools and Data Generated Data is Essential to Proving Compliance Proving Compliance with Standards and Regulations is Challenge Starts Upon Acceptance and Ends When Product Administered or Destroyed Not Always “Cold” Label Approved via the FDA Label is Benchmark of Proper Stewardship Data Can Ensure the Safe Use of Product After Excursion Law Puts Responsibility on Possessor Responsible for Safety and Efficacy of Product WHO Study - 50% of Products Compromised Ensure Product Via Proactive Use of Materials Management Tools and Data Generated Data is Essential to Proving Compliance Proving Compliance with Standards and Regulations is Challenge

Equipment Multiple Sites and Building Many Brands and Generations Various Equipment Validation Preventive Maintenance Equipment Files Calibration Product Efficacy Label Requirements Data Records Liability / Risk management Patient is more educated than before Regulatory Compliance FDA / JCAHO Birth to Death records Guilty until proven otherwise QC /QA Eliminate moving target – define your system Subcontractor Meets Standards? Real Time Management Alarm notification Data retention / vaults Reporting Support team

Process and Practices Highly FragmentedIn Most Cases Employs Low-Tech SolutionsLow Quality ControlsSignificant Failure Rates “ An estimated 17% to 37% of providers expose vaccines to improper storage temperatures. Refrigerator temperatures are more commonly kept too cold than too warm. Out-of-range temperature readings require IMMEDIATE action. It is estimated that more than $100 million worth of vaccine is exposed to freezing temperatures each year in the United States”.

Is Automated Better Than Manual or Does it Matter? Can I Meet the Requirements Without A System or Process? What Do the Regulators Say Medication Refrigerator Temperature Logs Q: Are we required to maintain temperature logs for medication storage refrigerators and freezers? A: Joint Commission does not specifically require temperature logs for refrigerators and freezers used for medication storage. Standard MM.2.20 requires that medications be stored under necessary conditions to ensure stability. EC.6.10 additionally requires that you describe and implement processes to maintain and monitor equipment performance. If your organization chooses to use temperature monitoring to achieve this, the monitoring method must track temperature in an ongoing fashion to indicate whether or not internal temperature has deviated from the required ranges for all drugs stored. In addition, the organization should have a defined process outlining disposition of medication from a refrigerator or freezer which has deviated from the recommended temperature range Is Automated Better Than Manual or Does it Matter? Can I Meet the Requirements Without A System or Process? What Do the Regulators Say Medication Refrigerator Temperature Logs Q: Are we required to maintain temperature logs for medication storage refrigerators and freezers? A: Joint Commission does not specifically require temperature logs for refrigerators and freezers used for medication storage. Standard MM.2.20 requires that medications be stored under necessary conditions to ensure stability. EC.6.10 additionally requires that you describe and implement processes to maintain and monitor equipment performance. If your organization chooses to use temperature monitoring to achieve this, the monitoring method must track temperature in an ongoing fashion to indicate whether or not internal temperature has deviated from the required ranges for all drugs stored. In addition, the organization should have a defined process outlining disposition of medication from a refrigerator or freezer which has deviated from the recommended temperature range

“The United States Pharmacopoeia (USP) is an official compendium which defines various terms relative to the proper management of time, temperature, sensitive medications and prescription products. Although the USP is not “the law” it is used by the Food and Drug Administration, state authorities and the courts to establish standards of practice.” Freezer A place in which the temperature is maintained thermostatically between -20C and -10C (-4F and 14F). Cold Any temperature not exceeding 8C (46F). A refrigerator is a cold place in which the temperature is maintained thermostatically between 2C and 8C (36F and 46F). Cool Any temperature between 8C and 15C (46F and 59F). An article for which storage in a cool place is directed may, alternatively, be stored in a refrigerator, unless otherwise specified by the individual monograph. Room Temperature The temperature prevailing in a work area. Controlled Room Temperature A temperature maintained thermostatically that encompasses the usual and customary working environment of 20C to 25C (68F to 77F); that results in a mean kinetic temperature calculated to be not more than 25C; and that allows for excursions between 15C and 30C (59F and 86F) that are experienced in pharmacies, hospitals and warehouses. An article for which storage at Controlled Room Temperature is directed may, alternatively be stored in a Cool Place, unless otherwise specified in the individual monograph or on the label.

System Should Have Real Time Product Support, Oversight and Data Management Provide Continuous Monitoring of Critical Alarm Parameters Established Contact Procedures for Designated Emergency Contacts Powerful & Economical System Based Cold Chain Management Tool Continuous Witness Providing 24/7 Oversight of Your Critical Systems Monitoring Possibilities 90% of Applications are Temperature Computers, Flood, Power Outage, Open Doors Application Should be Continuously Upgraded and Applied Process Improvements Implemented 100% Scalable to Customer Needs System Should Have Real Time Product Support, Oversight and Data Management Provide Continuous Monitoring of Critical Alarm Parameters Established Contact Procedures for Designated Emergency Contacts Powerful & Economical System Based Cold Chain Management Tool Continuous Witness Providing 24/7 Oversight of Your Critical Systems Monitoring Possibilities 90% of Applications are Temperature Computers, Flood, Power Outage, Open Doors Application Should be Continuously Upgraded and Applied Process Improvements Implemented 100% Scalable to Customer Needs