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 crosscontamination 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) 4
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 5
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. 6
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 sporeforming microorganisms Manufacturing processes using sporeforming microorganisms conducted in multiproduct 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 multiproduct manufacturing building. 8
Regulation and guidance 21CFR600.11(e)(4) Live vaccine processing (i)(a) Using a dedicated manufacturing area. (ii) If manufacturing is conducted in a multiproduct 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. 9
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 crosscontamination Use dedicated facility or areas if risks cannot be mitigated to acceptable level 11
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 13
Regulatory expectations for Crosscontamination control Facility Design Process containment Equipment Procedure controls 14
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 15
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 17
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 18
Equipment cleaning validation Cleaning validation acceptance criteria for product residues should be scientifically determined for adequate cross-contamination control 1/1000 th 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) 19
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 20
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 22
Changeover (Continued) Verification of no residual sporeforming 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 23
Case studies 24
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 25
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) 28
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 29
Resolving of potential crosscontamination 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 30
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 crosscontamination control Risk mitigation strategies for crosscontamination 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 33
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) 34
Case Study #3 (Continued) Drug substance pre-formulated Extremely diluted toxin 35
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 36
Case Study #3 (Continued) Equipment Dedicated or disposable productcontact equipment Toxin is inactivated by the cleaning agent Equipment is autoclaved prior to use 37
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 38
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 39
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 40
Acknowledgements Patricia Hughes, Ph.D. Reyes Candauchacon, Ph.D. Lakshmi Narasimhan, Ph.D. Kalavati Suvarna, Ph.D. 41