PRODUCT REVIEW
Biacore® C: compliant concentration
analysis of biopharmaceuticals
Fredrik Sundberg, Biacore AB, Uppsala Sweden
Biacore® C is the world’s first automated surface plasmon resonance (SPR)-based
system specifically designed for GxP (GCP, GLP, GMP) applications. The validated system is optimized for regulated concentration analysis of biopharmaceuticals.
C
omputerized analytical instruments
operating in a regulated environment
must comply with the requirements of
Good Clinical Practice (GCP), Good Laboratory Practice (GLP) and Good Manufacturing
Practice (GMP). The end user is ultimately
responsible for ensuring compliance with
current regulations. Due to the high degree of
automation and the complex systems used in
today’s laboratory, technology and validation
support are needed from specialized vendors.
The on-going qualification processes in the
GxP laboratory.
PQ
OQ
IQ
VENDOR QUALIFICATIONS AND ON-SITE AUDITS
PM
Qualification
Approval
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DEFINITION OF VALIDATION AND CRITICAL POINTS FOR REGULATORY COMPLIANCE
One of the most important ways of maintaining
the safety and effectiveness of a drug or pharmaceutical product is to maintain control over the
instrumentation used in analysis. Validation is a
necessary exercise for product approval and
should provide evidence of control. According
to the US Food and Drug Administration
(FDA), the definition of process validation is:
“Establishing documented evidence which provides a high degree of assurance that a specific
process will consistently produce a product
meeting the predetermined specifications and
quality attributes” (1).
A company producing therapeutic drugs is
expected to validate software programs and
analytical instruments used in drug development and manufacturing quality control (QC)
or in-process control (IPC).
PM PM
PM
Preventive Maintenance (PM) & Re-Qualification
A validation plan should include a vendor
audit program to select the preferred vendor.
The preferred vendor should be:
• Technically competent
• Commercially qualified to supply and support
the proposed system
• Experienced and have knowledge of current
validation requirements
Qualifications of selected vendors should be
verified through on-site evaluations, focusing on
the vendor’s quality system. For software-based
Biacore Journal – Number 2 2002
PRODUCT REVIEW
Modifications to sample evaluations are tracked in Biacore® C software with computer generated, time-stamped audit trails.
systems, the Software Quality Assurance System
(SQAS) should be a major factor in evaluating
the capability of the vendor.
SYSTEM DEVELOPMENT LIFE CYCLE AND SOFTWARE VALIDATION
For successful validation and maintenance of
computerized systems the software programs
controlling the instrument should be developed to
support the GxP regulated working process. To
build in quality, effectiveness and functions
meeting with current regulations, validation
should be considered part of the complete life
cycle of a computer system, including all stages
of planning, specification, programming, testing,
commissioning, documentation, operation, monitoring and modification (2). A System Development
Life Cycle (SDLC) approach can be applied to
software used to control analytical instruments.
This model facilitates effective software development
of safe products and ensures adequate validation of
software being developed. Truly validated software
programs are verified in-house by the vendor to conform with, and function according to specification,
with documented evidence of testing available on
request. It is usually not realistic for the user to
perform this type of structural testing of software,
as testing for source code accuracy can be timeconsuming. However, regardless of how and
when the testing is performed, the user must be
responsible for understanding and evaluating
these tests.
MEETING 21 CFR PART 11 REQUIREMENTS IN THE GXP LABORATORY
Appropriate security and backup measures must be
designed into computerized systems. For example,
both physical and logical access should be controlled
and restricted to authorized personnel only (3).
Biacore Journal – Number 2 2002
Every significant modification to validated systems
should be carefully evaluated and documented
according to defined procedures. Systems not
meeting U.S. FDA guidelines for 21 CFR Part
11 (Electronic Records; Electronic Signatures)
must be brought into compliance, or replaced
with new, compliant systems. During recent
years, FDA has put more emphasis on enforcing
the regulation and is increasingly issuing warnings.
The industry is now faced with the administrative and technical burden of applying the
rule to legacy systems without totally shutting
down today’s operations.
EQUIPMENT QUALIFICATION
Regulatory authorities expect that a company
producing therapeutics will qualify their
analytical instruments prior to use in the
laboratory. Equipment qualification is the process by which it is ensured that a system is
appropriate for its intended use. Equipment
qualification is commonly broken down into
design, installation, operational, and performance
qualification. Design qualification (DQ) relates
to all procedures prior to installation of the system
in its selected operating environment. Installation qualification (IQ) involves verifying complete arrival of the system as purchased, with a
list of components, instruments, and required specifications to be checked and signed off. Operational
qualification (OQ) includes procedures for
testing the system in its selected environment.
Performance qualification (PQ) is documented
verification that a method works for a specific
system according to its routine usage. The pharmaceutical producer usually carries out this phase
and ongoing performance tests to ensure that
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PRODUCT REVIEW
the system is maintained in a validated state.
The ongoing qualification process is supported
by periodic preventive maintenance (PM) visits,
calibrations and re-qualifications that keep the
system in a validated state. Modifications to
validated systems do not always require a fullblown re-qualification. Instead after initial risk
analysis, modifications can be managed with
change control procedures. Change control
needs to be in-place for all stages in the life
cycle of the system.
Points to consider for compliance when
qualifying equipment include:
• On-site performance of IQ/OQ/PQ to take
environmental factors into consideration
(temperature, voltage, operating procedures,
etc.)
• Use calibrated instruments for the qualification
exercise
• Work with GMP-trained personnel
• Document everything – while doing it!
The qualification protocols generated should
be stored in a safe location and be easily retrieved.
The end user is responsible for providing documentation when the system is inspected.
the initial IQ/OQ, continuous follow-up with
preventive maintenance and re-qualifications are
included in the service. The system is thus suitable
to be applied across a broad range of assays in
pre-clinical and clinical trials and manufacturing
QC and IPC.
FULLY AUTOMATED CONCENTRATION ANALYSIS USING BIACORE® C
Increasing speed and quality of concentration
analysis, while still meeting stringent regulatory
requirements is essential for ensuring success in
regulated manufacturing QC and IPC. Key
advantages are:
• 21 CFR Part 11 compliance for electronic
records and enhanced data security
• Label-free, real-time sample analysis and
minimal usage of limiting reagents
• Validation support & services meeting
worldwide regulatory expectations
• Cost-efficient active concentration detection
To maintain systems in a validated state,
Biacore also offers a maintenance re-qualification
service (PM GxP). PM GxP is preventive maintenance adapted for a regulated environment,
with fully documented and extended system
functionality tests included.
TTM FOR THERAPEUTIC DRUGS AND OUTSOURCING VALIDATION
The first product that is released for a particular
indication often gains most of the market share.
Time to Market (TTM) can be shortened by:
• Working with a vendor with knowledge of
validation requirements
• Assembling and developing the proper
documentation in a shorter time frame
• Using experienced and GMP-trained personnel.
Vendors are usually the most qualified party
to assemble an installation and operational qualification protocols. Costs can be cut if validation
documents are assembled quickly by personnel
specifically trained in GMP.
LEADING-EDGE TECHNOLOGY IN DRUG DEVELOPMENT AND MANUFACTURING
Biacore® C software is designed to support the
GxP-regulated working processes in the laboratory. The user-friendly software interface guides
the user through assay development as well as
daily routine analysis. Regulatory demands on
data security, traceability and 21 CFR Part 11
are also supported in the software. Authorized
users can be defined into three different access
levels in the system. As support for the overall
system validation process, Biacore provides
access to design-validation documentation from
system development and Equipment Qualification
services meeting worldwide regulatory expectations. This service includes Installation Qualification (IQ) and Operational Qualification (OQ)
performed by qualified Service Engineers. After
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CONCLUSION
• A validation life cycle applied to a computerized
system will keep the system in a state-of-control
during the entire product life cycle, until its
retirement.
• Analytical systems must be brought into
compliance with 21 CFR Part 11, or be
replaced with new, compliant systems.
• Working with vendors providing validated
systems and outsourcing the equipment qualification effort can drastically cut the Time-toStart-up for instruments and process equipment, accelerating TTM for new therapeutics.
• Biacore® C has been designed for GxP
regulated areas of drug development and
manufacturing processes, geared to accelerating
QC and IPC of biopharmaceuticals.
References
1. General guidelines for process validation,
U.S. FDA (1987).
2. Good manufacturing practices, Medicinal
products for human and veterinary use,
European Commission, Directorate General
III - Industry, Pharmaceutical and cosmetics.
Computerised systems, Annex 11, Vol. 4
(1998).
3. 21 Code of Federal Regulations Part 11,
Subpart B - Electronic records, Section 11.10
Controls for closed systems, U.S. FDA.
Biacore Journal – Number 2 2002