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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

Outline

• Regulatory framework • Regulatory expectations for cross-

contamination control

• Case studies

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Unique challenges of CMOs

• Multiple and diverse products • High risk biotech products

(antibody-drug-conjugates, toxins, etc.)

• Risks of cross-contamination

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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.”

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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. 10

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)

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

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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)

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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 21

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

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.

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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.

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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 A

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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

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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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