FDA's Perspectives on Cross-

Contamination in CMO
Facilities, Considering High
Risk Products
Bo Chi, Ph.D.
Biotech Manufacturing Assessment Branch
DGMPA/OMPQ/OC/CDER
1
 Outline
• Regulatory framework

• Regulatory expectations for cross-

contamination control

• Case studies

2
 Unique challenges of CMOs
• Multiple and diverse products
• High risk biotech products
(antibody-drug-conjugates, toxins,
etc.)
• Risks of cross-contamination

3
 Risk and science based
manufacturing
• Examples of regulations and guidance
intend to encourage risk and science
based manufacturing:
– ICH Q8, Q9, Q10
– 21 CFR 211.42(c)
– ICH Q7 4.4
– 21 CFR 600.11(e)

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 Regulation and guidance
• 21CFR211.42(c)

“…There shall be separate or defined areas or

such other control systems for the firm’s
operations as are necessary to prevent
contamination or mix-ups during the course of
the following procedures…”

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 Regulation and guidance
• 21CFR211.42(d)

“Operations relating to the manufacture,

processing, and packing of penicillin shall be
performed in facilities separate from those
used for other drug products for human use.”

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 Regulation and guidance
• ICH Q7 4.4 Containment
“Dedicated production areas…should be
employed in the production of highly
sensitizing materials, such as penicillins or
cephalosporins.”

“Dedicated production areas should also be

considered when material of an infectious
nature or high pharmacological activity or
toxicity is involved… unless validated
inactivation and/or cleaning procedures are
established and maintained.” 7
 Regulation and guidance
• 21CFR600.11(e)(3) Work with spore-
forming microorganisms
“Manufacturing processes using spore-
forming microorganisms conducted in multi-
product manufacturing site must be
performed under appropriate controls to
prevent contamination of other products and
areas within the site.
Prevention of spore contamination can be
achieved by a separate dedicated building or
by using process containment if
manufacturing is conducted in a multi-
product manufacturing building.”
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 Regulation and guidance
• 21CFR600.11(e)(4) Live vaccine processing
(i)(A) “Using a dedicated manufacturing
area….”

(ii) “If manufacturing is conducted in a multi-

product manufacturing building or area, using
procedural controls, and where necessary,
process containment”.
“Process containment is deemed to be
necessary unless procedural controls are
sufficient to prevent cross contamination of
other products and other manufacturing
areas within the building”.
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 FDA expectations for facilities
manufacture high risk products
• The decision to manufacture high risk
products in dedicated or shared facilities
should be approached holistically and factors
considered should be documented in a risk
management plan.

• Risk management plan is evaluated during the

inspection and/or submission review
processes.
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 Risk Management
• ICH Q9, “Quality Risk Management”
• Risk assessment for cross-contamination
– Identify, analyze, and evaluate the risks
• Risk control and mitigation to acceptable level
for cross-contamination
– Determine facility, procedure, and process
controls necessary to minimize risks of cross-
contamination
• Use dedicated facility or areas if risks cannot
be mitigated to acceptable level
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 Cross-contamination routes (1)
• Mix-up
– Accidental use of wrong materials or
contaminated equipment
Overlapping process flows and transit routes, common
storage areas
• Mitigations: facility design, procedures (e.g., adequate
changeover procedures, labeling) and controls

• Retention
– Product residue carryover
Inadequate equipment cleaning
• Mitigations: adequate cleaning validation, cleaning
verification of shared equipment between campaigns

ISPE Volume 7, “Risk-based manufacture of pharmaceutical products”, 2010 12

 Cross-contamination routes(2)
• Mechanical transfer
– Contaminant residue moving from one process or
area to another
• Mitigations: procedure (e.g., gown control, equipment
wipe down), closed process, and facility control (e.g.,
adequate flow of equipment and personnel)

• Airborne transfer
– Powder available in air and contacts product and
equipment
• Mitigations: containment, closed process, segregated
areas, and facility control (e.g., adequate pressure
differential and airlocks)
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ISPE Volume 7, “Risk-based manufacture of pharmaceutical products”, 2010
Regulatory expectations for Cross-
contamination control

• Facility Design
• Process containment
• Equipment
• Procedure controls

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 Facility design
• Facility layout designed to allow for adequate
material, personnel, product, equipment flow
to minimize potential cross-contamination
through crossover points.

• Segregation
– Spatial segregation for different operations
– Separate air handling units (AHU) to control
mixing of air from different areas
– Use airlocks and pressure differential for product
protection and process containment
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 Process containment
• Use closed systems whenever possible
– Closed product transfer
– Closed sampling

• Contain high risk open operations (e.g.,

in an isolator)
– Spore-forming production microorganisms
– Toxin purification process
– Weighing and dissolving the drug
component of antibody-drug-conjugates
(ADCs) 16
 Equipment
• Equipment
– Dedicated or disposable equipment
– Shared product contact equipment
• Process equipment
– Shared non-product contact
equipment
• Isolator (weighing and dissolving drug)
• CIP and COP systems

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 Equipment decontamination
• Decontaminate spores and
neutralize/inactivate/solubilize
hazardous compounds on equipment
using validated method prior to
equipment cleaning
– More effective cleaning
– Reduces risk of cross-contamination
through shared glass washers and CIP
systems
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 Equipment cleaning validation
• Cleaning validation acceptance criteria for
product residues should be scientifically
determined for adequate cross-contamination
control
• 1/1000th of the lowest clinical dose or 10 ppm
may not be appropriate for potent/toxic
products
• Acceptable Daily Exposure (ADE) considered
– Toxicologically derived
– A dose that is unlikely to cause an adverse effect if
an individual is exposed, by any route, at or below this
dose every day for a lifetime.
(ISPE Vol 7, 2010)

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 Equipment Cleaning Validation
• Analytical method for product
residue
• Sensitivity
• Dedicated or disposable equipment
should be used if the cleaning
acceptance criteria cannot be met
• We recommend dedicating
equipment for carcinogenic/
mutagenic products
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 Procedure controls
• Campaign-based manufacturing
• Adequate flow of equipment, products,
raw materials, and waste to prevent
cross-contamination through product
crossover points
• Procedure controls to prevent mix-ups
• Gowning and flow of personnel
• Personnel training
• Spill control procedures
• Effective facility cleaning and
disinfection
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 Changeover
• Dedicated equipment, raw
materials, consumables, product,
waste, and documents for the
previous product are removed

• Cleaning verification of shared

product-contact equipment during
changeover
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 Changeover (Continued)
• Verification of no residual spore-
forming production microorganisms in
shared equipment during changeover (if
equipment is not sterilized)
• Effective decontamination of the
shared area
• Environmental monitoring specific for
the spore-forming production organisms
is performed for the shared area
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Case studies

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 Case Study #1
• Contract drug substance manufacture
site for antibody-drug conjugates
• Multi-product facility
• Campaign-based manufacturing
• Conjugates highly potent small molecule
drugs to monoclonal antibodies

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 Case Study #1 (Continued)
• No documented risk management plan
available
• The highly potent small molecule drugs
(powder) are weighed and dissolved in an
isolator.
The facility could not provide
justifications for the cleaning validation
acceptance criteria for the small
molecule drug residue for the isolator. 26
 483 Observation
The risk assessment to justify the
containment strategy and controls that are
necessary to prevent cross-contamination of -
- bulk drug substance by another potent
product is inadequate. Specifically,
a. there was no written risk assessment evaluating
the cross-contamination of Product X by the highly
potent small molecule intermediate … and the
potent bulk drug substance of another product
manufactured at the same area.
b. the acceptance criteria for cleaning validation of
shared non-product contact surfaces for highly
potent small molecule intermediates are not
justified……..The isolator is used to weigh and
dissolve small molecule intermediate for Product X
during its bulk drug substance campaign. 27
 Case Study #2
• Contract manufacturer for aseptically
filled drug products
• Multiproduct filling line for
toxic/potent products
• The product of interest (Product A)
shares a product-contact hold tank with
a carcinogenic/mutagenic product
(Product B)
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 Case Study #2 (Continued)
Shared sterile hold tank:
– Cleaning validation acceptance criteria for
product residue limits were determined
based on 1/1000th of the lowest clinical
dose
– No cleaning verification conducted during
product changeover
– No cleaning verification conducted after
the initial validation three years ago
– Concern of safety and purity of some
clinical and market launch lots of Product A29
 Resolving of potential cross-
contamination issues
• FDA OND Pharmacology/Toxicology team was
consulted for the evaluation of ADE for
Product B
• Cleaning validation acceptance criteria
established based on the ADE were agreed
• Multiple information requests and
teleconferences with the contract facility
• CMO was requested by FDA to inform the
sponsor of the submission
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 Resolving of issues (Continued)
• Cleaning verification of Product B was
conducted with three runs and results
met the agreed product residue limits
• The initial cleaning validation data met
the new product residue limits
• Short-term remedy: cleaning
verification after changeover
• Long-term remedy: dedicate a hold tank
to Product A
• The submission was approved 31
 Lessons learned
• The sponsor should have reviewed
CMO’s risk management plan for cross-
contamination control
• Risk mitigation strategies for cross-
contamination should have been
adequately implemented
• Practice should have been improved
when introducing a new product
• Better communication between the
sponsor and the CMO 32
 Case Study #3

• Contract drug product manufacture site

• Submission for introducing a potent

toxin to a filling line approved for a
monoclonal antibody

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 Case Study #3 (Continued)
• Quality risk management plan
• Follows ICH Q9
• Evaluated risks from mix-up, retention,
mechanical transfer, and airborne
transfer (ISPE Risk-MaPP Baseline
Guide Volume 7)

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 Case Study #3 (Continued)
• Drug substance pre-formulated

• Extremely diluted toxin

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 Case Study #3 (Continued)
• Process containment
– Facility
• High air exchange rate
• Dedicated return air system
• Use of airlocks

– Closed operations whenever possible

• Closed sampling and transfer process of
the bulk
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 Case Study #3 (Continued)
• Equipment
– Dedicated or disposable product-
contact equipment
– Toxin is inactivated by the cleaning
agent
– Equipment is autoclaved prior to use

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 Case Study #3 (Continued)
Procedure controls
• Campaign dedicated suites
• Gowning Controls and disposable gowning
• Redundant procedure controls to
prevent mix-ups
• Operator training
• Spill control procedures
• Rooms are decontaminated and sanitized
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 Summary
• Multiproduct CMOs for high risk
products are expected to identify
cross-contamination risks and implement
controls necessary to minimize these
risks
• FDA reviews the risk management plans
during inspections and/or submission
reviews

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 Summary
• Adequate quality agreement should be in
place between the CMO and sponsor
• Oversight of the CMO is the
responsibility of the sponsor
• Both the CMO and sponsor are
responsible in ensuring that the
manufacturing process in place has
adequate cross-contamination control
Guidance for Industry, “Contract Manufacturing Arrangements for Drugs: Quality
Agreements” , 2013 draft guidance
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 Acknowledgements
• Patricia Hughes, Ph.D.
• Reyes Candauchacon, Ph.D.
• Lakshmi Narasimhan, Ph.D.
• Kalavati Suvarna, Ph.D.

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