Transcript Selling an Idea or a Product - American Society of Gene

QC/QA
Mary Malarkey
Director, Division of Case Management
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
March 21, 2001
QC/QA = CGMP
Preparation of products for administration
to humans, including clinical trials
 GLPs are not GMPs
 CGMPs cover manufacturing, controls,
testing and documentation
 Difference between Quality Assurance and
Quality Control not addressed

Quality Control Unit
21 CFR 211.22
Approve/reject all components,
intermediates, products
 Approve/reject procedures/specifications
 Review records; ensure investigations are
conducted
 Adequate laboratory facilities for testing
 Responsibilities and procedures in writing
 (Should be independent from production)

QC vs. QA
proposed revision to 211
Some confusion over QC vs. QA
(names, functions, requirements)
 QC - generally testing activities to assure
that specifications adhered to
 QA- oversight responsibilities
(“the QC of QC”) - auditing methods,
results, systems and processes; trending

Other Regulations

Good Laboratory Practices
 21
CFR 58.35 “Quality Assurance
Unit…..shall be responsible for monitoring
each study to assure management that the
facilities, equipment, personnel, methods,
practices, records and controls are in
conformance with the regulations in this
part….shall be entirely separate from and
independent of the personnel engaged in the
direction and conduct of the study.”
Other Regulations

Good Tissue Practices (proposed rule)
CFR 1271.3(oo) - “Quality Program…This
program includes preventing, detecting and
correcting deficiencies that may lead to
circumstances that increase the risk of
introduction, transmission, or spread of
communicable disease.”
 21
QC and QA
Dear Sponsor Letter 3/6/2000

Summary of QC/QA programs. Brief
description of system for preventing,
detecting and correcting deficiencies that
may:
 compromise
product integrity or function
 lead to possible transmission of adventitious
infectious agents
QC and QA:
Dear Sponsor Letter
Identify each individual who has authority
over the QC/QA program(s)
 Provide date of last QC/QA audit of:

 your
operations
 contract manufacturers, vendors and other
partners
QC and QA:
Dear Sponsor Letter
 Unique
considerations for these
products:
 QC
and/or QA may be one individual
 most “QC”, that is testing, may be contracted
out;
 most validation/qualification activities
contracted out;
 many vendors involved, e.g. water, media
 facility may be used by multiple sponsors
General Considerations

DOCUMENTATION - approval/review
 Batch
Production Records (211.188 & 211.192)
 Equipment - cleaning and use (211.182)
 Laboratory Records (211.194)
 Standard Operating Procedures (211.100)
 “Distribution” Records (211.196)
 Complaint Files (211.198)

SHOULD ALLOW TRACEABILITY
Prevent Deficiencies - 1

Testing of all cell and viral banks
 review

of SOPs, protocols, results from test lab
Testing, or certification, of components
 example;
media -> animal derived materials
BSE free countries (1/6/98 FR notice)

Screening of patients or use of universal
precautions
Prevent Deficiencies - 2

Facility
 adequately
designed, validated
 equipment calibrated, qualified, certified
 maintenance and monitoring procedures
 requalification procedures in place
 cleaning procedures in place for equipment and
facility (variety of cleaning agents)
 segregation procedure in place
Prevent Deficiencies - 3

Manufacturing process (vector and product)
 controls
developing
 validation of aseptic processes
 operator training and qualification
 procedures for deviations from process or other
deviations associated with production
 testing of product; review of all records
associated with lot - > release
Detection Considerations

Monitoring
 facility
 personnel

Testing
 components
 in-process
 final

product
Trending
Correction Considerations
Importance of traceability
 Procedures for investigations (211.192)
should extend to other lots of product
 Procedures for corrective actions
 Procedures for handling of complaints or
AEs that may be associated with
manufacturing
 Procedures for notification

Examples -1

Sterility test failure
 perform
identification
 review records on components
 review records on equipment cleaning and use
 review environmental and personnel
monitoring records
Examples - 1
Isolate identified as S. epidermidis
 Personnel monitoring result - same
organism
 Retrain and requalify operator
 Increase routine monitoring of operator

Examples - 2 (actual)

Mold contamination of in-process cells
 investigation

inconclusive
Mold contamination of in-process cells
 trace
both flasks to shelf in incubator
 monitor incubator
 isolate same mold

Corrective action - addition of fungicidal
agent (was using only IPA)
Description of Program
Should hit on points previously described
which should ensure prevention, detection
and correction of deficiencies that may
compromise product.
 Distinguish between testing (QC) and
oversight (QA) activities

Identification of Authority
Should be separate from “production”
which is sometimes the sponsor
 Should have ultimate authority to
release/reject, i.e. shouldn’t be producing,
testing, reviewing, releasing
 Ideal - separate unit with ultimate reporting
to sponsor, but authority, i.e, sponsor should
accept decision

QC/QA Audits
Date of last audits for the following should
be provided…….
 Later paragraph suggests that a plan for
audits should be in place: what needs to be
audited, how audited, frequency of audits

QC/QA Audits

Manufacturing operations (211.180)
 annual
 representative
number of batches
 all associated records and deviations,
complaints
 responsible individual must be notified of
results
QC/QA Audits

Vendors (211.84)
 could
be quite an undertaking given number of
components; audit may entail testing of certain
lots of components to ensure C of A accurate.
Certification by vendors.

Contract Manufacturers
 most
likely testing - cell and viral banks, final
product; should be reviewing and approving
SOPs, validation protocols used
QC/QA Audits

Contract Validation Activities
 should
be involved in plans and implementation
 should “pick up ball,” that is, maintain
validated state through proper monitoring and
maintenance activities
 revalidation/requalification/recertification
programs
Conclusion
Sponsors should be in compliance with
CGMPs with respect to QC/QA functions
 Problem areas:

 Lack
of documentation
 Lack of traceability
 No separation between QC/QA and other
operations
Mary Malarkey
OCBQ/DCM
301-827-6201