Application of Quality Risk

Management Principles during

Review and Facility Inspections
Patricia F. Hughes, Ph.D.
Team Leader
Biotech Manufacturing Team
Division of Manufacturing and Product Quality
Office of Compliance
FDA-CDER
July 28, 2009
WCBP CMC Strategy Forum, CASSS

Quality Risk Management (QRM)

Definition as described in ICH Q9:
A systematic process for the assessment, control,
communication, and review of risks to the quality of
the drug product across the product lifecycle.
Risk is the combination of probability of occurrence of
harm and the severity of that harm.

ICH Q9

QRM
Risk associated with quality must be managed to protect
patients from harms.
Quality must be maintained throughout product
lifecycle
Quality attributes must remain consistent with those
used in clinical studies
QRM involves the identification and control of
potential quality issues during development and
manufacturing

ICH Q9

QRM
Two primary principles:
The evaluation of the risk to quality should be based
on scientific knowledge and ultimately link to the
protection of the patient; and
The level of effort, formality, and documentation of the
QRM process should be commensurate with the level
of risk

ICH Q9

Goal in Manufacturing
To establish commercially successful processes that are
capable of producing consistently a high quality product
with a high degree of assurance (low or no failures).
Regulatory oversight is intended to ensure product
quality and is managed through
Application approval process
Establishment inspections (pre-approval and
CGMP)

QRM: During Review

Reviewers use QRM principles to determine if the
applicant has:
Identified potential risks to product quality attributes or
process consistency
Ensured appropriate controls are in place
Demonstrated the effectiveness of the controls
through process validation at scale

Role of the Biotech Manufacturing Team in the

review of submissions and in pre-approval
inspections
BMT reviewers in OC/DMPQ conduct reviews of BLAs
and supplements and lead pre-approval inspections.
Submissions are assessed from the following
perspectives:
Microbial control strategy during drug substance
manufacturing
Sterility assurance for sterile drug product
manufacturing
Microbial Product Quality Attributes
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Purpose of Pre-approval Inspections

Assess the CGMP compliance status of manufacturing
facilities during the pre-license or pre-approval
inspections
Systems based approach
Assess that the products manufactured comply with the
standards established in the BLA
Verify information and data in the submission (BLA or
PAS) to the FDA (data integrity)
Evaluate the capabilities of the manufacturing processes
to consistently produce products that are safe, pure and
potent as established in the license application
Assess in process controls

QRM and Inspections

Degree of oversight on inspection depends on the
several risk factors
Overall compliance status and history of the company
or facility
Results or previous audits/inspections
Complexity and novelty of the site, manufacturing
process, product and its therapeutic significance
Previous recalls, product defects or manufacturing
problems
Major changes of building, equipment, processes, key
personnel
Experience with manufacturing of a product
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Microbial Control in Biotech Product

Manufacturing: Risks
Biotech processes are susceptible to microbial
contamination because of the type of buffers, column
resins, cell culture raw materials, cell culture
/fermentation conditions, etc.
Cell culture processes are susceptible to adventitious
viruses that can lead to cell death
Bioburden resulting from microbial proliferation can
cause protein degradation, loss of potency,
immunogenicity, protein heterogeneity, change impurity
profiles and lead to inconsistent processes.
Bioburden can increase endotoxin levels
Bioburden must be controlled in the pre-sterile filtration
step and not compromise the sterility assurance of the
final drug product manufactured using in aseptic
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processing.

Benefits of Risk Management of Microbial

Control
Better control of the process and product quality
Fewer batch deviations/investigations and possible
failures
Better management of change control
Regulatory relief

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Sources of Microorganisms

Raw Materials
Cell culture and cell banking
Complex raw materials (serum, peptones)
Purification
Reusable resins
Reusable filters
Cell substrates
Microbial contamination
Manufacturing Environment
Water
Air
Personnel
Equipment
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Mitigating Microbial Contamination Risks

Reduce opportunities for the ingress of microbial
contaminants
Eliminate contaminants at critical step in the process
Validate critical manufacturing steps to eliminate and
prevent ingress of adventitious agents.

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Examples of Purification Review Issues

No microbial monitoring or inadequate monitoring during
manufacturing
Unknown risks to the quality attributes of the product
Root cause failures in product stability cannot be
assessed adequately
No established microbial limits during purification
Microbial intermediates reported to contain high levels
of bioburden
Risks to protein through microbial degradation
Presence of uncontrolled impurities due to different
microorganisms that can effect the validated
purification process
Effect on the stability of the product due to the
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presence of degradative microbial enzymes

Examples of Purification Review Issues

Inadequate control of hold conditions for process
intermediates
Risks:
Increases in bioburden during hold time
Unsupported hold conditions may lead to process
and intermediate quality variability

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Examples of Review Issues during Drug

Product Manufacturing

Sterility Assurance of Drug Product

Sterilization of components, containers and closures
Inadequate evidence sterility assurance
Aseptic Processing
Three media fills not completed
Inadequate bracketing
worst-case not assessed
Stability
Container closure integrity not adequately validated
Lack of controls
Sensitivity of test method
worst-case not simulated

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Facility: Key Control Elements

Design
Environmental control
Disinfection

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Raw Materials: Key Control Elements

Segregation, testing and pre-treatment of at-risk raw
materials
Cell bank characterization, handling and storage

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Raw Materials
Raw materials from natural sources (peptones,
soytones, yeast extracts, etc.) may be a source of
bioburden, including viruses and mycoplasma
May need to be handled in segregated/dedicated
areas and treated before use in manufacturing
Culture media and media components should be
evaluated before use for the presence or absence of
endogenous or adventitious agents.
Consideration should be given to pre-use treatment
to reduce possibility of facility and process
contamination (e.g., inactivation procedures such as
sterilization, pasteurization, 0.1micron filtration,
irradiation, etc.)
These materials should be kept to a minimum and have
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satisfactory documentation on the origin of material

Equipment: Key Control Elements

Use of specialized equipment and surface finishes
smooth and polished
Cleaning studies and validation to prevent carryover
Sterilization/sanitization and inactivation of microbial
contaminants

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Process: Key Control Elements

Microbial and mammalian derived products

Closed and open operations
Segregation of pre-viral and post-viral operations
Effectiveness of Cleaning, Sterilization, Sanitization, and
Inactivation steps

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Risks associated with products derived

from different expression systems

Mammalian cell lines

Carriers of viruses
Expansion of viruses can occur in cell culture
Cross contamination with viruses from different cell lines
inadequate inactivation, cleaning, sterilization, change
over procedures, etc.
Susceptibility of many cell lines to contamination from
adventitious agents
Cross contamination from raw materials, facility, equipment,
personnel
Viral inactivation methods are specific for each process and are
used where terminal sterilization is not feasible
Based on known and potential viral contaminants and load

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Risks associated with different expression

systems
Microbial
Endotoxins and other specific microbial derived
impurities may be of concern in multi-product
manufacturing
The impurities are biochemical in nature
Addressed with process design and cleaning
validation studies
Mammalian viruses are not known to expand in
microbial cells.
Risk of cross contamination of microbial cells with
mammalian viruses is not likely
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Viral Risks to Cell Culture Processes

Contamination of cell cultures processes by adventitious
agents continues to be a major risk to the industry
Firms will typically inform and meet with the FDA
when an establishment experiences a contamination
by an adventitious virus
Events are devastating and can lead to drug
shortages
Prolonged shut down of the facilities for
decontamination
Important actions include
Quality risk management
Risk assessment, control, communication,
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review

Multi-product Manufacturing: Risk

Assessment
Consider the ability of microorganisms to:
Ingress into a process through raw materials, facility,
personnel, equipment, process
Survive and proliferate
Produce microbial toxins/degradative enzymes
(proteases, etc.)
Cross contaminate and carryover to other processes

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Recent 483 Observations

Inadequate QRM for the production process:
Multiple lots of drug substance were released which
had unacceptably high levels of bioburden during the
final purification steps.
In addition, bioburden limits have not been
established for each step in the purification
process.
Risks:
Effect of impurities on the validated process
Effect of microorganisms on the product
Effects of microbial by products on the stability
of the product

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Recent 483 Observations

Inadequate QRM for the production process:
Fermentation lots [xxxxx] contained two morphotypes
in the fermentation harvest cultures instead of a
monoculture.
The root cause investigation for the appearance of
the two morphotypes was inadequate.
Risks:
Instability of the expression system may affect
process consistency
Appearance of contaminating microorganisms
must be ruled out
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Recent 483 Observations

Inadequate QRM of the production process:
Hold times for four column eluates [column steps x, y,
z] have not been adequately validated
microbiologically.
No microbial limits are established
Results show high bioburden levels (>1000
cfu/mL)
Risks:
Effect of impurities on the validated process
Effect of microorganisms on the product
Effects of microbial by products on the stability
of the product
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Recent 483 Observations

There is no assurance that adequate microbial controls
are in place during [drug substance] manufacturing. For
example,
During the harvest of the unprocessed bulk, sublots of
Lot xxxx (H9, H10, H11, H12, H13, H14) and Lot
yyyyy (H7) exceeded the established action limits for
bioburden.

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Risk Management of Microbial Control

during Review and Inspections
Microbial control is fundamental to the manufacture of a
quality product.
Product quality can only be assured if appropriate
microbial risk management measures are in place:
quality is built in the design of the facilities,
equipment, processes manufacturing and cleaning
processes
raw materials are appropriately screened and
selected based on microbial quality characteristics
appropriate analytical methods are in place to monitor
and control and adjust a process.
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