Feldman 20 February Pilot Plant through Scale-Up Manufacturing Martha A. Feldman, RAC Drug & Device Development Co., Inc. P.O. Box 3515 Redmond, WA USA FAX:

Feldman 20 February Pilot Plant Needed to make supplies for –bench studies, product characterization, purity –animal studies toxicology pharmacokinetics, ADME efficacy –clinical studies

Feldman 20 February Regulations Code of Federal Regulations Title 21 –Part 210 and Good Manufacturing Practices for Drugs –Part Processing of Biological materials –Part Quality System Regulations for Medical Devices Subpart C: Design Controls

Feldman 20 February Initial Manufacturing Stages Goals: –increasing compliance with regulations as product moves through testing and evaluation –increasing knowledge about the product –increasing knowledge about the possible problems, snags, pitfalls with manufacturing, processing, packing, storing (and installing) the product

Feldman 20 February Drugs and Biologics

Feldman 20 February Clinical Trials Supplies for Drugs and Biologics -1 Prior to phase I: need product safety testing and basic characterization information, cell bank characterization Phase I/II: requires completed safety profile and further characterization of the product (stress testing), process controls, assay descriptions, beginning specifications or limits

Feldman 20 February Clinical Trials Supplies for Drugs and Biologics -2 Phase III requires full characterization: –Impurities profiles –Specifications: Identity, Potency, Purity, Safety –Raw materials testing –Stability testingProcess Validation –Container/closureAnalytical Validation –Process controlsEquipment Validation –Batch recordsFacility Validation –Yield expectations

Feldman 20 February Good Manufacturing Practices 1 Part 210 –Current GMPs in manufacturing, processing, packing or holding of drugs Part 211 –Current GMPs for finished pharmaceuticals –Ten major areas

Feldman 20 February Good Manufacturing Practices 2 Organization and Personnel Buildings and Facilities Equipment Control of components and drug product containers and closures Production and process controls Packaging and labeling control Holding and distribution Laboratory Controls Records and reports Returned and salvaged drug products

Feldman 20 February Good Manufacturing Practices 3 When regulations in Parts (biologics) are in conflict with these regulations, the ones most closely pertaining to the drug product will supersede. This regulation may not be applicable to OTC products that are ordinarily marketed and consumed as human food.

Feldman 20 February Biologics Manufacturing (21 CFR Parts ) Current GMPs for blood and blood components General biological products standards General requirements for blood, blood components and blood derivatives Additional standards for human blood and blood products Additional standards for diagnostic substances for laboratory tests Additional standards for miscellaneous products

Feldman 20 February Medical Devices

Feldman 20 February Initial Development - 1 Must follow Design Controls from the outset (Design Controls for Medical Device Manufacturers [Mar 1997] Must develop or use validated tests to determine –operating conditions, e.g., temperature, humidity, altitude limits –reliability –durability; robustness –stability; shelf life –biocompatibility –ergonomics, e.g., ease of use

Feldman 20 February Initial Development - 2 –sterility –electromagnetic compatibility –radio frequency interference –electromagnetic compatibility –radio frequency interference –electrical leakage –power output –material strength, flexibility, durability, etc.

Feldman 20 February Initial Development - 3 Must develop vendor qualifications If using contract manufacturer, should obtain prior Inspection Reports (483s), do an independent audit Must develop training program for others, e.g., receptionist (regarding calls on complaints, visits by FDA inspectors), customer service (re: complaints), etc.

Feldman 20 February Clinical Trial Supplies for Medical Devices -1 Device must meet Design Controls –Design input and output –Design review –Verification and validation If changes occur during clinical study –Simple modifications: Clarify Instructions For Use Annual Report ( ) 5-Day Notice (812.35)

Feldman 20 February Clinical Trial Supplies for Medical Devices - 2 –Significant changes Modification to study design or device material IDE Supplement requiring approval (812.35) Who decides what to submit? –Decision on which type of submission is manufacturer’s responsibility –Decision is based on Range of minor to significant Type of device Type of modification

Feldman 20 February Clinical Trial Supplies for Medical Devices - 3 Credible information (812.35) –Used to support developmental changes in the device (including manufacturing changes) –Includes data generated under design control procedures preclinical/animal testing FDA-issued testing (e.g., guidance) peer reviewed published literature other reliable information (e.g., clinical data)

Feldman 20 February Quality System Regulation 1 (21 CFR Part 820) QS Requirements - management responsibility Design Controls Document Controls Identification and Traceability Production and Process Controls Acceptance Activities Nonconforming Product

Feldman 20 February Quality System Regulation 2 Corrective and Preventive Action Labeling and Packaging Control Handling, Storage, Distribution and Installation Records Servicing Statistical Techniques

Feldman 20 February Software-driven Medical Devices Software verification, validation and testing required Must look at integration as features or modules are added Guidance documents: –General principles of software validation, Guidance for Industry and FDA (Jan 11, 2002) –Off-the-Shelf Software use in medical devices (Sep 9, 1999) –Content of Premarket Submissions for software contained in medical devices (May 28, 1999)

Feldman 20 February In Vitro Diagnostic Devices

Feldman 20 February Clinical Trial Supplies for IVDs May need to consider both GMP and QSR regulation Design controls apply for device aspects Depending on components, may follow parts of 21 CFR and 820 New office in CDRH for IVDs; led by Dr. Steven Gutman

Feldman 20 February References Guideline for the manufacture of in vitro diagnostic products (Jan 10, 1994)

Feldman 20 February FDA Inspections of Manufacturing Facilities

Feldman 20 February FDA Inspections Medical Device Quality Systems Manual, A Small Entity Compliance Guide, (Apr 14, 1999) an.html

Feldman 20 February QSIT Approach Quality System Inspection Technique –7 major systems –do CAPA and one other Guide to Inspections of Quality Systems Handbook (Aug 1999) guide.htm

Feldman 20 February References 21 CFR Parts 210, 211, , 820 Guidance documents –Guide to Inspection of Quality Systems guide.htm –Inspection of Medical Device Manufacturers, Final Guidance for Industry and FDA

Feldman 20 February More References Center for Drug Evaluation and Research, List of Guidance Documents (Jan 6, 2003) –General Principles of Process Validation –Drug Master Files –Sterilization Process Validation –SUPAC (Scale-Up and Post-Approval Changes) - several documents –etc.