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 firms
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 areasshould 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
CMOs 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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