Enhancements to Cardinal Health NPS Lab to USP-787 Standards

Jose A. Figueroa Rodriguez Master of Engineering in Rafael Salgado Mangual, Ph.D. Polytechnic University of Puerto Rico

Abstract⎯ As the world develops and populations PROBLEM STATEMENT expand, new diseases arise at an exponential rate. The pharmaceutical industry is evolving every This research is based on employing new day with new advancements and technology modifications to NPS (Nuclear Pharmacy Services) development. The current process requires rigorous Laboratory at Cardinal Health, Inc. (Guaynabo, supervision to control cleanliness and standards Puerto Rico) in order to provide facilities with the procedures in order to comply with federal necessary enhancements to comply and provide regulations. In Figure 1, Cardinal Health 120, Inc. quality products to clients and patients in the is a manufacturer & distributor of medical devices island. The primary purpose of this project is to industry located in Guaynabo, Puerto Rico. The increase the facilities capabilities in management purpose of this research is to include all of radioactive materials used for patient’s medical information required to integrate necessary solutions, increasing the compliance modifications to facilities in order to comply with under federal regulations, reducing costs in the new USP-787 requirements. Total budget allocated process and provide a high-quality product without for this project is $150,936.77 which is expected to compromising safety. Current federal regulations return investment in 12 months period time. require pharmaceutical and biopharmaceutical manufacturers to follow a specific quantity of particles in their cleanroom process stated as ISO 7 or 8 cleanroom standards. The actual project development plan is to bring this facility into these standards no later than December, 1st 2019. KeyTerms⎯ Nuclear pharmacy services, Figure 1 federal regulations, radioactive materials. Cardinal Health, Inc. Facilities Location

BACKGROUND LITERATURE REVIEW

A Nuclear Pharmacy is involved in the A Nuclear lab, also called in the core as a preparation and handling of medical products based radiopharmacy, consists in the management and on radioactive materials a principal component to creation of radioactive medical solutions for treat specific diseases (i.e. Alzheimer's disease, treating diseases or conditions that require a etc.). There are two types of nuclear pharmacy specific treatment: hyperthyroidism, thyroid cancer, environments: Institutional which works directly lymphomas and some types of targeted cancer. The with hospital/medical center elaboration in site. The majority of these products are in the form of second is a centralized commercial pharmacy which capsules, injections, aerosols, etc. At this time in prepares products and delivers them to distinct Puerto Rico, there are only two nuclear pharmacies medical institutions (i.e Cardinal Health, Inc.). This that support patients around the island: Cardinal institution which intends to bring new products for Health PR 120, Inc. (Guaynabo, P.R.) and Lantheus fabrication and distribution around the world will Mi Radiopharmaceuticals, Inc. (San Juan, P.R.). be a center for new technology and innovation in Cardinal Health PR 120, Inc. was established at Puerto Rico. Guaynabo, Puerto Rico in 1951. Currently from that date, it has consistently served over 1,500 which are engineered as an ISO 7 or ISO 8 room customers including hospitals, pharmacies, standards conditional on the product created in the physicians, and other healthcare providers with cleanroom. The buffer zone or clean room which is over 20,000 products from over 1,000 supply positive pressurized room must be in an effective sources. [1] pressure cascade to assure a clean environment. The Food and Drug Administration (FDA) and Figure 2, shows timeline execution following the United States Nuclear Regulatory Commission implementations at CAH-PR NPHS laboratory (U.S.NRC) regulates the nuclear pharmacy industry facilities: in order to satisfy regulations and ensure proper • Maintain the CFM/ACH Values As ISO 7 handling of hazardous materials such as radioactive (30 < x < 60) materials. To fulfill supply demands and new • 4 Clean Air Pass Thru product compliance, physical modifications had • Fixed Window Vision Panel been designed under CAR (Capital Acquisition • Double Vestibule Door (Ante Room) * Request) to facilities in order to comply with ISO 7 • Air Diffusor Unit, Filter Units (2”X4”) or 8 and USP-787 Standards. • Air Diffuser Relocation The USP-787 standard is a regulatory process • New Return Air at 1’-0” to the Finish established by the United States Pharmacopeial Floor Convention (USP) for Subvisible Matter in • New BMS connection to site temperature Therapeutic Protein Injections, which became Relative monitoring and alarms. official on August 1, 2014 [2] and is based • New Interlock for ante to Buffer Room and fundamentally in the number of particles present in Weight room. the final manufactured product. The USP-787 chapter allows principally for two scenarios: the presence of insoluble protein particles as intrinsic parts of therapies, which are called inherent particles (no hazard) and particle populations below

10μm has to be monitored to reflect the reliability of the final drug product. [3]

In order to fulfill federal regulations and requirements, nuclear pharmacies must have a controlled environment, free of contaminants and pollutants, which is called a cleanroom. The aim of the clean room is to remove pollution by particulate Figure 2 matter, some of which may possibly include Project Timeline(Gantt Chart) microorganisms and biotoxins in order to provide a These modifications to current infrastructure controlled physical environment with a close will allow the facilities to achieve ISO 7 and USP- monitoring of temperature, pressure and humidity. 787 industry standard regulations. Temperature is measured by a digital sensor with multiple ranges, high-accuracy static pressure METHODOLOGY differential gage (Magnahelic sensors) and relative Controlled environments consist in a specific humidity sensor [4]. are divided with group of variables to be monitored in order to several rooms, which are suited with different ensure product quality and federal regulations purposes before entering the clean area, these are compliance. However, in order to establish a divided by: WBC, Ante & Buffer Room. The process that is well documented and simple to anteroom is an area close next to the cleanroom follow, Figure 3 shows a DMAIC diagram performed to illustrate the data gathering, analysis and process implementation. Figure 4 Actual HVAC Layout (NHPS) Area

HVAC Design is based on basic

and principles which

are been develop for the past century and are still

been used on modern engineering innovations. In a

closed loop system (HVAC system) a basic equation is used to state the amount of energy Figure 3 needed or dissipated on a system, called: Sensible DMAIC Project Chart Heat Equation [5]:

On December 1st, 2019 project execution will 푩푻푼 = (ퟏ. ퟎퟖ ∗ 푪푭푴 푿 ∆푻) + (ퟎ. ퟔퟖ 풙 푪푭푴 푿 ∆푾 )(1) 풉풓 품풓 be developed with current regulations and process 푪푭푴 = 풄풖풃풊풄 풇풆풆풕 풑풆풓 풎풊풏풖풕풆 (풂풊풓) agreed under project CAR: CAH-PR NPHS. In ∆푾푮풓 order to satisfy these requirements, parameters will = 풄풉풂풏품풆 풊풏 풉풖풎풊풅풊풕풚 풓풂풕풊퐨 (풑풔풚풄풉풓풐풎풆풕풓풊풄 풄풉풂풓풕) be monitored such as (i.e. , static ∆풕 = 풕풆풎풑풆풓풂풕풖풓풆 풄풉풂풏품풆 Room Dimension Calculations: pressure differential across rooms, humidity, 푹풐풐풎 = 푹풐풐풎 풙 푹풐풐풎 (2) particle size, etc. 푨풓풆풂 푾풊풅풕풉 푳풆풏품풕풉 2 푅표표푚1 = 8.83 푓푡.∗ 11.33 푓푡. = 100 푓푡 Current system arrangement does not comply 2 푅표표푚2 = 13.5 푓푡 ∗ 12.63 푓푡. = 170.5 푓푡 with laboratory criteria. Therefore, agreed by 2 푅표표푚3 = 26.92 푓푡. 12.58 푓푡. = 338. 푓푡 project CAR, all existent ductwork must be ퟐ ퟐ 푹풐풐풎푽풐풍풖풎풆 = 푹풐풐풎푨풓풆풂(풇풕 ) ∗ 푯풆풊품풉풕 (풇풕 )(3) removed and existent machinery applicable will be 2 3 푅표표푚1 = 100 푓푡 ∗ 9.5푓푡 = 950푓푡 re-routed to comply with agreed scope of work. 2 3 푅표표푚2 = 170.5푓푡 ∗ 9.5 푓푡 = 1620푓푡 2 3 푅표표푚3 = 338.7푓푡 ∗ 9.5푓푡 = 3217푓푡 RESULTS AND DISCUSSION Codes for ISO7 or ISO8 quality standards In order to successfully create a HVAC system required a quantity of ACH (Changes in Air Per that satisfies an ISO7 or ISO8 nuclear lab federal Hour) in a clean room [3]. Calculations is as regulation requirement, the following criteria or follow: methodology was implemented. For the purpose of Assumptions: this project, some of the equipment and structure Per project requirements, was re-utilized according to CAR and requirements • BUFFER & ANTE Room = 45 > ACH permitted. • WBC = 40 > ACH ISO 7 Particle Size Requirements: Volume of Room∗ACH Required CFM = (4) • ≥ 0.5µm = 352,000 60 minutes (950) ∗ (40.00) • ≥ 1 µm = 83,200 푅푒푞푢푖푟푒푑 퐶퐹푀 = = 634 퐶퐹푀 푅표표푚1 60 • ≥ 5µm = 2,930 (1620) ∗ (45.00) 푅푒푞푢푖푟푒푑 퐶퐹푀푅표표푚2 = To calculate load requirements, the volume of 60 = 1215 퐶퐹푀 area to be supplied has to be calculated in Figure 4, (3217) ∗ (45.00) which is as follows: 푅푒푞푢푖푟푒푑 퐶퐹푀 = 푅표표푚3 60 = 2413 퐶퐹푀 Required CFM = 4320 CFM An additional Outside Fresh Air Supply is An Airflow Diagram (Figure 5) represent a provided to the system = 75 CFM in order to basic visual layout on overall air supply maintain a proper air/moisture ratio percentage. distribution. As a rule of thumb, 1 ton equals 460 CFM, therefore the requirement load for complying to the system is 10 ton.

In Table 1, to provide consistent supply across all rooms, the following formula was used for pipe sizing requirements:

Table 1

Piping Size, Length and CFM Balance Figure 5 CFM Width Duct Height (in.) Airflow Diagram Balance (in.)

A 2500 18 16

B 2100 16 16 C 1750 14 14 C 1400 14 14 D 1050 10 14 E 700 6 14 E 350 6 14 F 260 14 11 Figure 6 G 260 14 14 Final Proposed Concept H 260 16 12 I 260 18 14 Figure 6 shows final layout of the nuclear J 260 18 18 pharmacy and current setup. At this time, nuclear K 260 18 18 pharmacy lab acoustic ceiling, as it is, does not Total 4320 - - comply with ISO 7 standards established by the Supply Food & Drug Administration (FDA). Therefore, to Total 4275 + 75 - - Return (Outside Air completely seal the system NPS Dow Caulking 732 0 (Balanced Non-flowable white silicone caulking will be used Σ System) in all grids in direct contact with the panels, light fixtures, edges, etc. Air supply into the rooms will be controlled To successfully assure project execution, NPS with a HEPA (High Efficiency Particle Air) FFU Cardinal Health Nuclear Pharmacy must record and (Fan Filter Unit) which traps high level of particles test the following items to be in agreement with For a properly contained system, a (BDD) design intent: Back Draft would be installed on ducts • Test and adjust each blower RPM to design return air to Room#2 and Room#3 (i.e. similar to requirements. Ruskin CBD2). A back draft damper acts as a one- ▪ Test and record each motor full load ducts way flow valve allowing contaminated air to come and obtain design cfm at fans. out of the system but not allowing to return into the ▪ Measure coil face velocities. closed room system. Below is the proposed concept ▪ Test and record system static pressure; i.e. HVAC System ISO7 compliant. filter "clean and dirty", cooling and Balancing dampers also will be incorporated as heating coils, fan suction and discharge, essential pieces of the system which actuates as a air flow measuring stations, etc. regulator of air passing by the duct which reduces ▪ Test and adjust system for design pressures imbalances (ie. Random drafts or air, recirculated air, cfm. randomly slams of doors, etc.) ▪ Test and adjust system for design outside RECOMMENDATIONS OR FUTURE NEXT air, cfm. STEPS ▪ Test and record entering air temperatures. (D.B. cooling). In the process of developing the project, new ▪ Test and record entering air temperatures. potential improvements emerged to increase (W.B. cooling). efficiency and ensure consistent and continuously ▪ Test and record leaving air temperatures. 100% clean environment. (D.B. cooling). • All light switches and receptacles when ▪ Test and record leaving air temperatures. possible, be oriented vertically instead of (W.B. cooling). horizontally to reduce the accumulation of ▪ Adjust all main supply and return air ducts foreign or contaminants materials on the to proper design cfm. surfaces exposed. ▪ Adjust all zones to proper design cfm, • Monthly (potentially bi-weekly) recurrence supply and return. pressure gauges constant pressure validation. ▪ Test and adjust each diffuser, , and • Constant compliance of 6S criteria in nuclear register to within percent of design pharmacy laboratory requirements to assure requirements for system. top efficiency and cero waste processes. ▪ Identify each grille, diffuser, and register as to location and area. CONCLUSIONS ▪ Identify and list size, type, and Cardinal Health, Inc. as one of two facilities in manufacturer of diffusers, , the island that provides services for radioactive registers, and all tested equipment. Use materials in the pharmaceutical controlled manufacturer's ratings on all equipment to environment, which this project has expanded its make required. capacity and provided a new market that could ▪ In rooms requiring pressure or flow reach new products to elevate company market cap differentials between rooms, test and and support local economy. As a process record the values obtained. verification, HVAC system reached desired ▪ Include required velocity and test velocity, specifications required. and required volume and test volume after adjustments of diffusers, grilles and REFERENCES registers. ▪ In cooperation with the control [1] “Historia”. 2020, Oct. 25. Retrieved, from https://cardinalhealth.pr/includes/abt_we_are.aspx?LN=ES manufacturer's representative set adjustments of automatically operated [2] “USP 787”. 2020, Oct. 25. Becman Coulter Life Sciences. Retrieved, from https://www.beckman.com/ dampers to operate as specified, indicated resources/industry-standards/usp-787 and/or noted. [3] “Cleanroom Requirements for Liquid Particle Testing”. ▪ Adjust all diffusers, grilles and registers to Becman Coulter Life Sciences. 2020, Oct. 25. Retrieved, minimize drafts in all areas. from https://www.beckman.com/resources/industry- ▪ Test duct systems for "dirty" filter standards/usp-787/cleanroom-requirements-for-liquid- condition by providing temporary particle-testing resistance in ductwork, and then for [4] “Monitoring Positive Pressure in Clean Rooms”. 2016, "clean" filter condition. Nov. 3. PROdataloggers. Retrieved on 2020 Oct. 25, from https://www.prodataloggers.com/monitor-pressure- temperature-rh-cleanrooms/

[5] 2015 ASHRAE handbook: heating, ventilating, and air- conditioning applications, Inch, Pound Ed. American Society of Heating, Atlanta, GA. 2015. Retrieve from: https://www.worldcat.org/title/2015-ashrae-handbook- heating-ventilating-and-air-conditioning-applications-inch- pound-edition/oclc/921242601#borrow