Role of FDA FDA was designed to promote and protect the public’s health Food and Drug Cosmetic Act first passed in 1906 to prevent the sale of unacceptable food and drugs

Role of FDA Minimum requirement for release of a drug is that it has to safe and effective There are always risks and side effects The FDA has to determine when the benefits out weigh the risks Vaccines and life threatening diseases Clinical trials: when is enough enough? Thalidomide incident

Center for Drug Evaluation & Research CDER Group which assures the safety and effectiveness of drugs available in the U.S. Monitors for adulterated or contaminated drugs Adulterated: drug or food produced by methods which do not conform to cGMP

Center for Biologics Evaluation and Research CBER Reviews applications for new biologics produced from microbes and viruses Examples: vaccines, allergens, monoclonal antibodies Regulates all aspects of the process from mfg. to QC, to labeling and advertising

Center for Devices & Radiologic Health CDRH Regulates medical devices and some in vitro diagnostic kits Examples of devices: Pace maker, ultrasonic cleaners for cleaning medical instruments, insulin monitors, thermometers Examples of in vitro diagnostic kits CK-MB kits

Center for Food Safety & Applied Nutrition Protects and promotes health & economic interests by ensuring that foods are safe, nutritious, and honestly labeled Also oversees cosmetics

FDA Actions Facility Inspections 483: inspector’s note documenting a deficiency Not following procedure Incomplete records Warning letter: written letter citing cGMP violations. Requires a written response of corrective actions to be implemented.

FDA Actions If a company does not comply with FDA requests the FDA can do any and all of the following: Take the product(s) off of the market Sue and or arrest executives Detain imports / exports FDA cannot do nothing when they know there are issues at a company

Product Development: Ideas to Market Computer Modeling In vitro studies Pre-clinical Animal studies Investigation New Drug Application Clinical studies New Drug Application and Approval Manufacturing Marketing and Sales

GLP Good Laboratory Practices Prescribes practices for conducting non clinical lab studies that support or are intended to support applications for research or marketing of regulated products. Required for research applications to be submitted to the FDA Intended to assure the quality and integrity of safety data filed Does not include human studies or clinical studies

Examples of what’s included Good lab practices Labeling reagent bottles w/ proper info. Reagent name, date, initials or name of who prepared it Equipment monitoring Calibrated, cleaned and verification logs Written procedures Filled out, reviewed by QA, and maintained Personnel should be qualified or at least knowledgeable

Standard Operating Procedures: SOPs Procedures for the following: Manufacture the product Test and release the product Train personnel Label and packaging the product How to handle non conforming product How to design new products

Standard Operating Procedures Good SOPs contain the following: Purpose or scope Materials Procedure Must be written in proper order Must include sufficient detail for operator to follow Should include “checkers” for calculations Must include initials and signature of operator Must have Supervisors review and sign off\ Should be reviewed and updated as needed

Clinical Investigation Definition: any experiment that involves a test article and one or more human subjects and that is either subject to requirements for submission to FDA or is not subject for submission but results are intended to be submitted later.

Phases of Clinical Trials Phase 1: small number of patients, (10-20) Can take 9-18 months to complete May continue with animal studies for long term data Phase 2: continues to test safety and evaluates how well the new drug is working. More patients enrolled (100-300) May take 1-2 years to complete Phase 3: most extensive study,1-3 years Fully assess safety and effectiveness of drug 100-1000 patients involved, diverse group, multiple sites May compare old and new drug treatments Evaluating side effects Phase 4: long term side effects and effectiveness

Single and Double Blinded Study Single-Blind study: clinical trial study in which the human subjects do not know if they are receiving the active product or a placebo. Double-Blind study: study in which neither the subject nor the investigator knows the treatment assigned. (usually subjects, investigators, monitors and data analysts are unaware)

Participants in clinical trials Investigator Sponsor Sponsor Investigator Human Subject Institution Institution Review Board

Clinical Trial Data Analysis Data analyzed by Statistics or Biostatistics group Use well defined, accepted and pre-determined data analysis formulas and methods. Looking for levels of significance 99% still means 1% error possible of 1/100 (0.01). Is that good enough? How do you balance the data with the delay in releasing a product? Outlier: data point outside of the average range and is usually larger or smaller than the rest of the points

Clinical Trial Data Analysis INCLUSION/EXCLUSION CRITERIA: The medical or social standards determining whether a person may or may not be allowed to enter a clinical trial. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. It is important to note that inclusion and exclusion criteria are not used to reject people personally, but rather to identify appropriate participants and keep them safe.

Institutional Review Board Definition: any board, committee or group formally designated by an institution to review biomedical research involving human subjects IRB approval MUST be obtained before an investigator can begin a study

Institutional Review Board Usually comprised of medical and lay persons (at least 5 members, no conflict of interest) Established to protect the human subjects and ensure fair enrollment Review and Approve Informed Consent Conduct periodic reviews to ensure integrity of the study

What are cGMP’s Designed To Do? Protect consumers from adulterated product Protect consumers from products that do not contain what is claimed on the label Provide consistent industry-wide requirements Ensure quality of product not safety or efficacy of dietary ingredients

Operations responsibilities This is where cGMP comes into play

General Provisions cGMP should apply to activities associated with manufacturing packaging holding distributing Manufacturer would need to comply with requirements applicable to operations performed

Components of a cGMP Personnel Physical plant internal environment Equipment and utensils Production and process controls Records and Recordkeeping

QSR QSR: Quality System Regulations Standard produced by the FDA which companies MUST follow Include standards such as training, document control, process control, design control cGMP and QSR are essentially the same Mandated by FDA; only in US

ISO Similar to QSR International standard Voluntary Provides marketing edge and is well received by customers Risks: failure or loss of certification, add’tl expense ISO 9001

Batch Records FDA Requirement cGMP requirement QSR requirement ISO requirement Failing to do so can get you into a heap of trouble! Used to ensure consistent product

Batch Record: Record Keeping What are some record keeping requirements? Black ink No white out Single line, date, initial No blanks, N/A any lines which do not apply Legible

Label Approval and Control Regulatory, Quality Assurance and Marketing are the groups who “approve” the final label Materials, QA, QC, and Mfg. “control” the label from receipt, through inspection to application to product, through finished product inspection.

Labeling and Packaging Control Why would this be an area to be audited? Label text: pre-approved and inspected Label adhesion: pre-approved and inspected Label accountability: verified at every step Package insert content: pre-approved and inspected Package insert accountability: verified at every step CONTROLLED TO PREVENT MIXUPS

Label Text Fixed Text Variable Text Text that does not change with each lot Company name, address, Product Name, storage temp, ingredients Variable Text Text that does change with each lot Lot number and or serial number Expiration Date Concentration or Potency

Marketing Information Labels and Package inserts are highly controlled Marketing information such as product informational flyer Approved by Regulatory and Marketing Marketing distributes w/out control

Audits The evaluation of the company, the process, and the product to assure quality and reliability Management Responsibility Auditing (internal and external) Design Control Document Control Purchasing Control Identification and Traceability

Process of Auditing Meeting to review process and timing Tour of company Ask for records Review records Ask for interviewees if necessary Write preliminary report Review prelim report w/mgmt