Expectations for Facilities & Expectations for Facilities & cGMPscGMPs

Biological Response Modifiers Advisory Committee Meeting

October 9, 2003

Nicholas Obiri, Ph.D.

CBER

ScopeScope

Regulatory Authority Facility Design Principles Environmental and Process Control Aseptic Processing

Regulatory AuthorityRegulatory Authority

Public Health Service Act Section 351Authority for licensing biological

products when certain conditions are met

Regulatory Authority contd.Regulatory Authority contd.

Title 21 CFR Section 601.2(d)Approval of an application shall constitute a

determination that the establishment(s) and product meet applicable requirements to ensure the continued safety, purity and potency of such products.

The requirements include the applicable regulations (21 CFR 210-211; 600s; 800s).

A QUALITY PRODUCT

VALIDATION/QUALIFICATIONROUTINE MONITORING

QA/QC

ENVIRONMENT

EQUIPMENT

RAW MATERIALS

COMPONENTSPROCESS

Broad overview of facility Broad overview of facility and control issuesand control issues

Appropriate facility design A controlled environment Equipment qualification Adequate measures to control cross

contamination Adequate measures to control mix-up of

patient materials

Broad overview of facility Broad overview of facility and control issuesand control issues

Control of incoming raw materials Independent Quality Assurance/Quality

Control staff Records and documentation

Facility Design PrinciplesFacility Design Principles

Influenced by the nature of the source material Tissue derived vs Cell culture Single vs multiproduct operations

Critical manufacturing areas designed for aseptic processing

Facility Design Principles Facility Design Principles contd.contd.

Process Flow:Designed to control the manufacturing

environment (personnel and process)Adequate and separate areas for various

activities (receipt of materials, testing, manufacturing)

Material Mix-upMaterial and personnel flows designed to

maximize efficiency and minimize product mix-ups

Environmental ControlEnvironmental Control

Air Quality HEPA-filtered air in manufacturing

areas; higher level of control for critical manufacturing steps

Use pressure cascade to protect the productHigh pressure to low pressure Pressure sink to protect other

manufacturing areas and personnel

Environmental ControlEnvironmental Control

Need to qualify the HVAC system to confirm that the equipment, its control and circulation systems meet expected performance or quality standards(Monitored under static and dynamic conditions)

Pharmaceutical grade reagents and supplies (Water, Process Air, Utility Gasses)

Process controlProcess control

Validation Process (demonstrate manufacturing

consistency, aseptic processing) Equipment Demonstrate concurrent control over

other facility systems (e.g. HVAC)

Qualified personnel

Quality SystemQuality System

Vendor auditMaterial qualificationOversight of processChange controlPersonnel trainingInvestigation of deviations, recalls, product

complaints, Medwatch program

A QUALITY PRODUCT

VALIDATION/QUALIFICATIONROUTINE MONITORING

QA/QC

ENVIRONMENT

EQUIPMENT

RAW MATERIALS

COMPONENTSPROCESS

Aseptic ProcessingAseptic Processing

A processing approach in which product manufacture occurs under environmental and processing conditions that assure minimal opportunity for contamination from the environment or personnel.

Aseptic ProcessingAseptic Processing

Since terminal sterilization is not a feasible option for islets, the final product has to be assembled by introducing the aseptically processed final formulation into a sterilized container and sealed with a sterilized closure system in a high-quality environment

Aseptic ProcessingAseptic Processing

Required for all open manipulations and connections involving product

Involves trained and qualified personnel Must be validated (media challenge)

Aseptic ProcessingAseptic Processing

Typically occurs in class 100 environment under laminar air flow (BSC) with appropriate environmental monitoring e.g. viable and non-viable airborne particulate monitoring

May also occur in “Closed” systems (Requires validation)

SummarySummary

Design compliance into the facility plans. Advisable to seek CBER input prior to construction.

Establish a thorough qualification/validation program

Maintain an effective QA/QC unit to assure maintenance of quality standards and regulatory compliance

Summary contd.Summary contd.

Maintain aggressive approach to compliance with aseptic processing requirements

ResourcesResourcesFor questions on facilities and manufacturing operations, including arrangements for pre-approval inspection:

DirectorDivision of Manufacturing and Product QualityFDA, CBER1401 Rockville Pike, 200S, HFM-670Rockville, MD 20852-1448Ph.: (301) 827-3031

 

AcknowledgementAcknowledgement

1. John A. Eltermann, M.S, R.Ph., Director, DMPQ

2. John Finkbohner, Ph.D., Deputy Director, DMPQ

3. DMPQ Review Staff