Pilot Plant through Scale-Up Manufacturing

Presentation Transcript

Martha A. Feldman, RAC

Drug & Device Development Co., Inc.

P.O. Box 3515 Redmond, WA 98073-3515 USA

1-425-861-8262 FAX: 1-425-869-5854

mfeldman@druganddevice.com

Feldman 20 February 2003

Pilot Plant

Needed to make supplies for

bench studies,

product characterization, purity

animal studies

toxicology
pharmacokinetics, ADME
efficacy

clinical studies

Regulations

Code of Federal Regulations Title 21

Part 210 and 211 - Good Manufacturing Practices for Drugs
Part 600 - 680 Processing of Biological materials
Part 820 - Quality System Regulations for Medical Devices

Subpart C: Design Controls

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

Drugs and Biologics

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

Clinical Trials Supplies for Drugs and Biologics -2

Phase III requires full characterization:

Impurities profiles
Specifications: Identity, Potency, Purity, Safety
Raw materials testing
Stability testing Process Validation
Container/closure Analytical Validation
Process controls Equipment Validation
Batch records Facility Validation
Yield expectations

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

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

When regulations in Parts 600-680 (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.

Biologics Manufacturing (21 CFR Parts 600-680)

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

Medical Devices

Initial Development - 1

Must follow Design Controls from the outset (Design Controls for Medical Device Manufacturers [Mar 1997] http://www.fda.gov/cdrh/comp/designgd.html
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

sterility
electromagnetic compatibility
radio frequency interference
electromagnetic compatibility
radio frequency interference
electrical leakage
power output
material strength, flexibility, durability, etc.

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.

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 (812.150)
5-Day Notice (812.35)

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

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)

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

Quality System Regulation 2

Corrective and Preventive Action
Labeling and Packaging Control
Handling, Storage, Distribution and Installation
Records
Servicing
Statistical Techniques

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 http://www.fda.gov/cdrh/comp/guidance/938.html (Jan 11, 2002)
Off-the-Shelf Software use in medical devices http://www.fda.gov/cdrh/ode/guidance/585.html (Sep 9, 1999)
Content of Premarket Submissions for software contained in medical devices http://www.fda.gov/cdrh/ode/57.html (May 28, 1999)

In Vitro Diagnostic Devices

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 600-680 and 820
New office in CDRH for IVDs; led by Dr. Steven Gutman

References

Guideline for the manufacture of in vitro diagnostic products (Jan 10, 1994) http://www.fda.gov/cdrh/comp/918.pdf

FDA Inspections of Manufacturing Facilities

FDA Inspections

Medical Device Quality Systems Manual, A Small Entity Compliance Guide, (Apr 14, 1999) http://www.fda.gov/cdrh/dsma/gmp_man.html

QSIT Approach

Quality System Inspection Technique

7 major systems
do CAPA and one other

Guide to Inspections of Quality Systems Handbook (Aug 1999) http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm

References

21 CFR Parts 210, 211, 600 - 680, 820
Guidance documents

Guide to Inspection of Quality Systems http://www.fda.gov/ora/inspect_ref/igs/qsit/qsitguide.htm
Inspection of Medical Device Manufacturers, Final Guidance for Industry and FDA http://www.fda.gov/cdrh/comp/7382.845.html