Article Figures & Data
Figures
- Figure 1
Direct and indirect risks that may result in pharmaceutical drug shortages.
Tables
Type of Surface Virusa Inoculum (Viral Titer) Persistence (Temperature) Steel MERS-CoVHCoV 105103 48 h (20°C)8–24 h (30°C)5 d (21°C) Aluminum HCoV 103 2–8 h (21°C) Wood SARS-CoV-1 105 4 d (RT)b Paper SARS-CoV-1 106105104 24 h3 h<5 min (All at RT) Glass SARS-CoV-1HCoV 105103 4 d (RT)5 d (21°C) Plastic SARS-CoV-1MERS-CoVSARS-CoV-1HCoV 105105107105107 ≤5 d (22--25°C)48 h (20°C)6--9 d (RT)4 d (RT)2--6 d (RT) Polyvinylchloride HCoV 103 5 d (21°C) Silicon Rubber HCoV 103 5 d (21°C) Surgical Glove (Latex) HCoV 5 × 103 ≤5 d (21°C) Disposable Gown SARS-CoV-1 106105104 2 d24 h≤8 h (All at RT) Ceramic HCoV 103 5 d (21°C) Teflon HCoV 103 5 d (21°C) - TABLE II
Antivirus Activity of Representative Commonly Used Disinfectants and Sporicidal Agents in the Pharmaceutical Industry (34)
Active Ingredient Product Name Company Contact Time (Minutes) Formulation Type Emerging Antiviral Claim Hydrogen Peroxide Accel (Concentrate) Virox Technology 5 Dilutable Yes Phenolic LpH Steris 10 Dilutable Yes Phenolic Vesphene II se Steris 10 Dilutable Yes Sodium Hypochlorite CloroxPro™ Clorox® Germicidal Bleach Clorox ProfessionalProduct Co. 5 Dilutable Yes Isopropyl alcohol DECON-AHOL WFI® Formula 70% Veltek Associates NA RTU No Hydrogen Peroxide and Peracetic Acid DECON-SPORE 200® Plus Veltek Associates NA RTU No Quaternary Ammonium;Ethanol Lysol® Disinfectant Spray ReckittBenckiser LLC 5 RTU Yes Hydrogen Peroxide Oxy-1 Wipes Vorox Technology 0.5 Wipes Yes Ethanol PURELL ProfessionalDisinfectant Wipes GOJO Industries 5 Wipes Yes Sodium Hypochlorite Clorox Healthcare®Bleach Germicidal Wipes Clorox ProfessionalProducts Co. 3 Wipes Yes Class of Clean room Airflow Type Average Velocity (Ft./Min.) Air Changes/hr. ISO 8 (Class 100,000) N/M 1–8 5–48 ISO 7 (class 10,000) N/M 10–15 60–90 ISO 6 (Class 1,000) N/M 25–40 150–240 ISO 5 (Class 100) U/N/M 40–80 240–480 N is Non-unidirectional; M is Mixed Airflow; U is Unidirectional. Note: 10 ft/min equals 3.048 m/min.
- TABLE IV
Appropriate Personal Protective Equipment for Routine Pharmaceutical Manufacturing (40)
Protective Clothing Non-Sterile Manufacturing Areas Sterile Manufacturing Areas Plant uniform or plant uniform with overalls for high-risk product and environment Yes Yes Hair/beard coverings Yes Yes Safety glasses Yes Yes Dedicated shoes or shoe coverings Yes Yes Gloves Yes (if in direct product contact) Yes Face masks Yes (if in direct product contact) Yes Enclosed respirators Only if manufacturing high-potency, toxic drugs or infectious biological agents Only if manufacturing high-potency, toxic drugs or infectious biological agents Sterile clean room uniforms (coveralls), hoods, sleeves, goggles, face masks, and gloves No Yes, if in critical aseptic processing area Cell Line Cell Line Origin SARS-CoV Replicationa References CHO Chinese Hamster Ovary Incompatible (Kreil, 2020 Personal Communication) HEK293 Human Embryonic Cells Incompatible (Kreil, 2020 Personal Communication) HT1080 Human fibrosarcoma Incompatible (Kreil, 2020 Personal Communication) A549 Human Adenocarcinoma Cells Incompatible 50 HUH Human Liver Cells Moderate 50 HEK293T Human Embryonic Cells Moderate 50 VERO African Green Monkey Kidney Cells High 50 ↵a Incompatible is no growth, no cytopathic effect (CPE); Moderate is growth but no CPE; High is growth and CPE.
Activity Risk Identification Risk Rating Risk Mitigation/Critical Process Controls Recruitment of new staff Local; Regional; National; International Low to Moderate Remote interviews; Limit domestic and international travel; 14-day quarantine prior to starting work Training new hires and existing employees Lack of information;Issues not addressed in corporate policies and procedures Moderate to High GMP compliance; Coronavirus awareness training;Symptoms identification Deployment of employees Domestic; International Moderate to High Staff functions conducted from home; Restrictions on nonessential domestic and international travel; deferment of large staff meetings Management and Supervision of Employees Staff and line functions Moderate to High Illness recognition; Monitoring with thermal sensors; Universal wearing of non-medical face masks on the job Employee Attendance Employees working sick; Loss of human resources; Inability to commute Low Flexibility in working hours;Stress importance of staying home when ill; Provide sickness benefits; Add company sponsored transportation when public transportation is unavailable Materials Risk Identification Risk Rating Risk Mitigation/Critical Process Controls Pharmaceutical Excipients Excipients derived from plant, animal, or mineral origin; Excipients of synthetic or semisynthetic origin Low Supplier awareness of potential COVID-19 risk; Standard duration of transit and hold times Drug Substances Drug substance of synthetic or semisynthetic origin Low Standard duration of transit and hold times Packaging Components Glass vials, stoppers and seals (Sterile products)Plastic container, heat induction seals and caps (non-sterile products) Low Standard duration of transit and hold times; automation of component handling; washing, depyrogenation and sterilization (sterile products) Labeling Materials Labels and package inserts Low Reduce handling during label identification and reconciliation Incoming Potable Water Ground or surface water Low Communication with local water authority - TABLE S-III
Risk Assessment—Testing of Incoming Pharmaceutical Ingredients, Packaging Components, Intermediates, and Finished Products during COVID-19 Pandemic
Materials—Sampling and Testing Risk Identification Risk Rating Risk Mitigation/Critical Process Controls Sampling of incoming materials Human intervention; Limited environmental controls in warehouses Moderate Personal protective equipment; sampling booths; labeling sampled containers Transportation to the testing area Transition through the facility Low Disinfection of the surface of containers, drums, shrink-wrap, and pallets Sample testing Personnel handling Low Personal protective equipment; limited access to testing area; environmental controls Sample disposition Disposal Low Controlled destruction of samples Materials— Plant Utilities Risk Identification Risk Rating Risk Mitigation/Critical Process Controls Pharmaceutical-grade water Incoming potable water Low Maintain existing microbial monitoring program Pharmaceutical-grade plant air Distribution lines and delivery nozzles Low Assure sanitary design Compressed gases None Low Maintain existing microbial monitoring program HVAC system Poor temperature, humidity, and air exchange; Recirculation and lack of segregation Low to Moderate Reduced recirculation in more critical areas; Higher air change rates; High room ultraviolet germicidal irradiation Domestic and clean steam None Low None Vacuum Discharge Low Review vacuum discharge Washing facilities Poor design and opportunities for cross-contamination Low to Moderate Access to detergents, hot water, and hand sanitizing agents;Segregation of clean and dirty materials Waste and sewage disposal Poor separation Moderate Backflow elimination;Segregation of clean and dirty materials - TABLE S-V
Risk Assessment—Representative Non-Sterile Drug Product (Compressed Tablet) during COVID-19 Pandemic
Manufacturing Process Risk Identification Risk Rating Risk Mitigation/Critical Process Controls Incoming material sampling and testing Sampling is an invasive process Moderate Sampling booths; Personal protective equipment (PPE) Warehousing Limited environmental control Low Improved environmental control Ingredient weighing Weighing is an invasive process Low to Moderate Evaluate weighing booths and PPE Excipient size reduction Equipment cleaning Low Upgrade COP and CIP operations Blending Equipment cleaning Low Upgrade COP and CIP operations Granulation— Dry Granulation—Wet Equipment cleaning Low Upgrade COP and CIP operations Compression Equipment cleaning Low Upgrade COP and CIP operations Bulk Tablet Storage None Low None Packaging and labeling Packaging operations are labor intensive Low to Moderate Evaluate HVAC Systems; Automation of component handling; PPE Finished goods warehousing Poor environmental control Low Improved environmental control Shipping Lack of chain of custody Low Dedicated carriers Clean Out-of-Place (COP) and Clean In-Place (CIP).
- TABLE S-VI
Risk Assessment—Representative Sterile Drug Products (Liquid-filled Stoppered Glass Vials) during COVID-19 Pandemic
Manufacturing Process Risk Identification Risk Rating Risk Mitigation/Critical Process Controls Incoming material sampling and testing Sampling is an invasive process in a warehouse Moderate Sampling booths and personal protective equipment (PPE) Warehousing Limited environmental control Low Improved environmental control (IEC) Ingredient weighing Weighing is a labor-intensive process Low to Moderate Evaluate weighing booths and PPE Bulk solution preparation Solution preparation is a potentially invasive process Low to Moderate Use of Restricted Access Barrier Systems (RABS) and isolators Packaging component preparation Component loading and unloading is a potentially invasive process Low Automation of component handling; Depyrogenation and sterilization of vials and stoppers Sterile filtration and aseptic filling and Sealing Aseptic processing is a potentially invasive process Low Use of RABS and isolators Visual inspection Inspection is an invasive process Low Handling automation; IEC; PPE Packaging and labeling Packaging is an invasive process Low Handling automation;IEC; PPE
