RE: MHA and MSHP and Joint Comments Proposed 247 CMR Sterile Compounding Regulations

Transcription

1 November 10, 2017 David Sencabaugh, R.Ph. Executive Director Board of Registration in Pharmacy 239 Causeway Street, 5th Floor, Ste. 500 Boston, MA RE: MHA and MSHP and Joint Comments Proposed 247 CMR Sterile Compounding Regulations On behalf of our respective members, the Massachusetts Society of Health-Systems Pharmacists (MHSP) and the Massachusetts Health & Hospital Association (MHA) appreciates the opportunity to submit comments regarding the proposed changes to 247 CMR outlining pharmacy s requirements for conducting sterile compounding. We also appreciate the time and efforts by the Board to meet with our members throughout the past period as the Board staff were developing these proposed regulations. While there is a statutory requirement for the development of these regulations, we are very concerned that the proposed regulations are not aligned with evidence based practices and nationally recognized industry standards for sterile compounding. In particular, we strongly feel that many provisions of the proposed regulation exceed the standards of practice within USP 797 without any supporting evidence showing they will lead to additional improvements to patient care. Many of these proposed changes will result in increased costs and operational disruptions to patient care, two of the very issues that healthcare providers have been working with EOHHS to address in the changes to the healthcare delivery system. Our comments supporting these concerns around costs and disruptions to patient care are primarily related to four key areas; (1) the pharmacy s physical structure, (2) environmental monitoring, (3) personnel expansion and training, and (4) increased reporting requirements. Many of the changes associated with these four areas include exorbitant investments, for some hospitals in the millions of dollars, just to meet compliance in facility structure and the hiring of additional staff to comply with monitoring and reporting requirements that will not improve sterile compounding practices. In addition, many of these changes pose extensive risks of operational shut downs on pharmaceutical compounding and preparations that will only result in delays to accessing critical and urgent care, increase poor patient outcomes, and increase operational costs for providers to buy supplies and drugs from external retail pharmacies. We hope that the board will seriously consider our comments and recommendations and help support our ongoing efforts to ensure continued access to timely, evidence based, and appropriate pharmaceutical interventions for all patients within our institutions. Sincerely, Anuj K. Goel, Esq. Vice President Legal & Regulatory Affairs Massachusetts Health & Hospital Association David Seaver Legislative Committee Chair Massachusetts Society of Health-System Pharmacists Attachment

2 MSHP/MHA Joint Comments and Recommendations for amending the Proposed 247 CMR Regulations - Sterile Compounding Pages Priority Areas of Concern Section Draft Recommendation Evidence Impact/Notes General 247 CMR 17 does not have a definition section Include a definition section. The definitions should include but not be limited to biological material, stock solutions, equipment, etc. CMR A definition section is necessary to provide clarifications to the chapter for the end user (2) A pharmacy may not pool or prepare stock solutions utilizing single dose vials to extend a beyond use date (BUD) beyond 6 hours after puncture within ISO Class 5 Use current USP Standards for a Medium Risk Product in the absence of sterility testing: BUD = 30 hours RT or 9 days Refrigerated OR use draft version of the 2015 USP for a Category 2 product in the absence of sterility testing, no preservative added, prepared from sterile starting components BUD = 6 days RT or 9 days refrigerated USP 2

3 Section Draft Recommendation Evidence Impact/Notes A licensee shall prepare a non-hazardous, nonradiopharmaceutical, low risk level CSP with a 12 hour BUD at room temperature or 24 hour BUD refrigerated in an ISO Class 7 buffer room or an ISO Class 8 dedicated compounding room ( DCR ) equipped with a commercially manufactured PEC such as a LAFW or BSC and shall comply with all other provisions of 247 CMR 17.00, unless otherwise provided Use current USP Standards for a Low Risk Product in the absence of sterility testing BUD = 48 hours RT or 14 days Refrigerated OR Use draft version of the 2015 USP for a Category 2 product in the absence of sterility testing, no preservative added, prepared from sterile starting components BUD = 6 days RT or 9 days refrigerated OR if products used have preservative added BUD = 28 days RT or 42 days refrigerated. OR Retain the 12hour BUD restriction but remove in an ISO Class 7 buffer room or an ISO Class 8 dedicated compounding room ( DCR ) and replace with in a segregated compounding area, per USP 797 standards., USP If left as written, pharmacy satellites will not be able to prepare ambulatory compounded sterile products such as allergens and anticipatory medications for infusion services, or anticipatory medications in procedural areas such as the OR or ED. A 12-hour BUD will inhibit allergy ambulatory clinics from giving their patients appropriate allergen therapy. See impact comments for In USP 797, the use of a 12hr BUD for low-risk CSPs applies to medications compounded in a segregated compounding area. This 12hr BUD restriction is necessary because in an SCA, CSPs are compounded in a PEC, but there are not sufficient secondary engineering controls required to maintain ISO 8 or better air in the room. This is a suitable rule for satellite pharmacy areas that employ a hood for just in time compounding, such as in EDs and ORs. If left as written, pharmacy satellites will not be able to prepare medications for patients and will need to revert to have the medications prepared by nursing or physician staff, this is a major step backwards in medication safety. The massive costly renovations needed to convert satellites built as SCA into the new DCR definition are not only cost prohibitive and will cause significant downtimes for pharmacy operations, in many cases, the engineering changes are not possible to achieve within the hospital building (5) A pharmacy may not compound a component of a CSP from API when a version of that component is commercially available. Add the following verbiage "unless products are on the national drug shortage list". FDA Drug Shortage Database Considerations must be made for national drug shortage crisis where hospital pharmacies should be allowed to compound from API if critically necessary and for immediate use. As drafted, patient care is in jeopardy if hospital pharmacies are unable to provide lifesaving medications to their patients who are currently receiving care or have been scheduled for a service/procedure in the event of a national shortage. 3

4 Section Draft Recommendation Evidence Impact/Notes A BUD must be calculated from the time of compounding and shall include the time a drug will reside inside an implantable infusion pump reservoir (2) The procedures for compounding CSPs using bloodderived or other biological material shall require compounding to be separate from routine materialhandling procedures and must describe cleaning of PEC and other equipment used in CSP preparation to avoid cross-contamination (1) A Licensee may not conduct sterile compounding in a segregated compounding area that is not ISO classified Use current USP prior to administration When CSPs are likely to be exposed to warmer than 30 for more than 1 hour during their administration to patients, the maintenance of their sterility and stability should be confirmed from either relevant and reliable sources or direct testing. Use current USP definition of a Beyond-Use Date (BUD): The date after which a compounded preparation shall not be used; determined from the date the preparation is compounded. Remove and shall include the time a drug will reside inside an implantable infusion pump reservoir Include definitions differentiating blood-derived and other biological material so substances such as insulin (biologically derived from animals) are not misinterpreted as being a biological material. Use 2015 draft USP : Segregated Compounding Areas: In some situations, a PEC may be located within an unclassified area, without a buffer or ante-area. This type of design is called a segregated compounding area. Category 2 CSPs must never be compounded in segregated compounding areas; only Category 1 CSPs can be compounded in facilities with such designs. CDC, Product Package Insert CDC, Product Package Insert USP It is not the industry standard to include the time the drug is inside the reservoir in the calculation of a beyond use date. This section could result in labeling that can easily be misinterpreted by the end user. If the end user is familiar with the standard BUD definition, they could think the drug is good for much longer than it is, leading to a significant risk for patient harm, including death from serious infection. In addition, this creates unnecessary extra steps, time and effort that could impact patient care for products that do not need to be treated any differently than any other sterile compounded product. If left as written, a hospital pharmacy could have to follow extra steps, time and effort that could impact patient care for products that should not be treated any differently than any other sterile compounded product. If left as written, hospital pharmacies will not be able to continue providing service to many ambulatory clinics and procedural areas. See impact comments for It is critical to maintain the designation of segregated compounding areas in order to maintain safe medication practices currently provided by the ED and OR satellites in our facility. The alternative is to perform immediate usecompounding on a countertop with a 1 hour BUD. Clearly this is inferior to compounding the CSP inside a PEC. If left as written, hospitals are prohibited from using PECs anywhere outside of an ISO 8 or better room, even if they want to use it in a setting of immediate use compounding. 4

5 Section Draft Recommendation Evidence Impact/Notes (3) The air changes shall come from the HEPA filtered air. HEPA filtered air shall be introduced at the ceiling. Any air exchanges supplied to buffer room from the PEC must be in addition to the 30 ACPH (4) A pharmacy may not utilize any ISO classified area for both sterile and non-sterile compounding. Adjust to allow for the addition of PEC air in the calculation to be in line with USP 797 and current CETA guidelines Adjust to a best practice with wording such as, Should not routinely utilize ISO Class 5 areas for both sterile and non-sterile compounding without thoroughly cleaning between compounding sessions. Current USP ASHP Sterile Compounding Guidelines. CAG Current and the proposed USP allows for the addition of PEC air in the calculation. If left as written, satellite pharmacies that are built as DCRs, especially pediatric satellites, will be prohibited from compounding the non-sterile medications routinely needed for patients because they also compound CSPs in that room. In the setting of hazardous non-sterile compounding, such as hydroxyurea suspensions, the negative pressure classified area is the only alternative negative pressure area available to perform the non-sterile compounding. This will leave pharmacies with no options to provide medications to patients and meet NIOSH standards to keep employees safe (9d) Beginning January 1, 2018, a pass-through shall: (a) be constructed of a nonporous, smooth, nonshedding, impermeable material such as acrylic, polycarbonate or similar fiberglass-reinforced plastic, glass, or stainless steel; (b) have a double interlocking door design; (c) not have an opening larger than 4 square feet; (d) be located between: 1. ISO Class 7 buffer room and ISO Class 8 area or better; 2. ISO Class 8 area to unclassified space or better; or 3. ISO Class 7 ante room to unclassified space or better; (e) not be a refrigerator unit. Adjust to May be located between, allowing pharmacies the ability to design a cleanroom environment that fits the needs and space of their organization, OR remove requirement of 1. ISO Class 7 buffer room and ISO Class 8 area or better Requiring a pass-through between all classified spaces is unnecessary depending on the workflow and design of a pharmacy. Pass-throughs require a large amount of unusable space. In our facility, the workflow is such that a pharmacist moves between the classified areas to check the work of the technicians. This traffic pattern will not change with the addition of a pass-through. If left as written, the unnecessary required addition of a pass-through will encroach on valuable square footage in a space-constrained footprint. 5

6 Section Draft Recommendation Evidence Impact/Notes (12) A pharmacy shall validate at least once per year, with direct testing, the recovery time of each primary and secondary engineering controls for particle count, temperature, and humidity, following activities including personnel entering and exiting, gowning, staging, material transfer, compounding, labeling, cleaning, and testing (14) A pharmacy may not locate a refrigerator, dishwasher, incubator, or other appliance in an ISO Classified area (1) A pharmacy shall locate an ISO Class 5 PEC for nonhazardous drug compounding within a positive pressure ISO Class 7 buffer room or ISO Class 8 DCR (5) A pharmacy shall prepare CSPs in a commercially manufactured ISO Class 5 PEC. A pharmacy may not prepare CSPs in a vertically integrated ISO Class 5 workbench or ISO Class 5 open buffer room design. Remove this from the regulation and instead make this a Best Practice or policy issued by the Board so that routine changes based on national standards can be adopted in a timelier manner outside the regulatory process. Change to any appliances that use running water (i.e. dishwasher) or used to promote microbial growth (i.e. incubator). Include, or segregated compounding area. Or use USP 2015 language A PEC used for compounding may be placed in an unclassified, segregated compounding area if only Category 1 CSPs are compounded in the PEC. Remove section entirely, or adjust to include USP 2015 definition of a LAFS (Laminar airflow system). LAFS: Provides an ISO Class 5 or better environment for sterile compounding. A LAFS provides smooth, unidirectional HEPA-filtered airflow that is designed to prevent contamination of a sterile compounding environment. The LAFS can consist of either a LAFW or a HEPA filter alone creating an ISO Class 5 zone within an ISO Class 7 room, as long as unidirectional airflow is maintained. FDA:GMP Standards ISO USP USP USP Semi-annual recertification of the PEC is used to determine the maintenance of functionality of the PEC. The functional recovery time of a PEC is almost immediate based on the hood volume and airflow, typically less than 1 minute. Recovery time of a SEC, though longer than a PEC, can be noted within the room recertification under dynamic operating conditions. A standard 30 minutes as stated in these regulations along with a 1 hour standard for SEC coupled with cleaning and disinfection procedures handled on a local policy level provides substantial safety for continuation of compounding. The addition of a continuity of care plan as stated in these regulations provides an outline for managing situations directly related to planned or unplanned interruptions of airflow. If left as written, this would be restricting innovation in pharmacy operations. Consideration has to be made for new technology and future needs: i.e. pass- throughs that are carousels (both refrigerated and non-refrigerated), robotics with cooling systems. If left as written, hospital pharmacies will not be able to continue providing service to many ambulatory clinics and procedural areas, such as ORs and EDs. See impact comments for and (1). If left as written, organizations with this design will be prohibited from operating, forcing them to undergo significant and costly renovations, causing major interruptions in patient care. New expensive renovations recently opened in 2017 employs a LAFS open buffer room design and will be prohibited. 6

7 Section Draft Recommendation Evidence Impact/Notes (1a) Buffer Room (a) A buffer room shall be at least 144 square feet (2d) Ante Room (d) An ante room shall be at least 100 square feet (3f, g) (f) A buffer space in a DCR shall include 40% of the square footage in the DCR. (g) An ante space in a DCR shall: 1. include 60% of the square footage in the DCR; (1) 17.17: Sterile Compounding Facility; Laminar Air Flow Workbench ( LAFW ) (1) A pharmacy may not locate a LAFW outside of an ISO Class 7 buffer room, unless: (a) the LAFW is located in a DCR; (b) the pharmacy holds an institutional sterile compounding pharmacy license issued under M.G.L. c 112, 39I; and (c) the CSPs are prepared for on-site administration. Remove entirely the square footage requirement of 144 square feet or make substantial adjustments to a more practical minimum square foot standard like linear feet of hood space or removing entirely (e.g. 64 square feet + 8 square feet for every linear foot of hood over 8 feet). Remove the requirements for specific square footage space requirement. Remove entirely the square footage requirement of or make substantial adjustments to a more practical minimum square foot standard like linear feet of hood space + amount of reasonable space that a human body needs to work (e.g. Square footage occupied by the hood + 8 square feet for every linear foot). This section is redundant with section : Sterile Compounding Facility; ISO Class 5 Primary Engineering Controls and should be combined into that section. Current USP ASHP Sterile Compounding Guidelines. Current USP ASHP Sterile Compounding Guidelines. Current USP ASHP Sterile Compounding Guidelines. Current USP ASHP Sterile Compounding Guidelines. There is currently no standard for the size of a buffer room. The state of control is regulated by the HVAC, SEC and PEC, which are fined tuned to the size of the room built. The room should be built to the size needed to perform the necessary operations, and not be dependent on a fixed number. For example, one 3 hood in a room this size vs five 4 hoods and carts and staff and the supplies needed to support this implied volume of work. It is not evidence based to assume a pharmacy cannot demonstrate a state of control in a room of 130 square feet without an additional 14 square feet. There is currently no standard for the size of an ante room. The size of the room should be dependent on the work occurring within and the available space to implement a buffer room or cleanroom suite operation of a given size. There is currently no standard for the size of a buffer or ante room. The size of the room should be dependent on the work occurring within and the available space to implement a buffer room or cleanroom suite. This section was newly incorporated into this draft, as an attempt to respond to previous comments about square footage. See impact comments for sections (1a and 2d). This section is redundant with section LAFW should be permitted for use in a segregated compounding area for low risk medication. If left as written, hospital pharmacies will not be able to continue providing service to many ambulatory clinics and procedural areas, such as ORs and EDs. See impact comments for and (1),

8 Section Draft Recommendation Evidence Impact/Notes (7) A pharmacy shall operate and monitor the HVAC systems that supply conditioned air to the nonclassified areas of the pharmacy 24 hours per day, seven days per week. Include an exemption for hospital pharmacies, provided that the facility is able to demonstrate that they have a process through their engineering or other departments to monitor such systems. USP Hospital pharmacies do not operate the HVAC system in a hospital setting. This is typically the engineering department. A reasonable exception must be made for hospital pharmacies or consideration for partnerships with the Facility Management team to monitor the HVAC systems. If left as written, hospital pharmacy departments will need to request additional FTE's and training to perform this function. This adds to the increase in overall healthcare cost for a hospital stay (8) A pharmacy shall operate and monitor the HVAC systems that supply HEPA filtered air to ISO classified areas 24 hours per day, seven days per week (10) Each secondary engineering control shall have ducted air returns mounted low on the wall in order to create a general top-down dilution of room air with HEPAfiltered make-up air (11) Relief air vents shall be mounted low on the wall and designed to prevent the ingress of less clean air or contaminants from adjacent ISO classified space or ambient air. Include an exemption for hospital pharmacies. USP The "pharmacy" does not operate the HVAC system in a hospital setting. This is typically the engineering department. A reasonable exception must be made for hospital pharmacies. If left as written, hospital pharmacy departments will need to request additional FTE's to perform and training to perform this function. This adds to the increase in overall healthcare cost for a hospital stay. Remove this from the regulation and instead make this a Best Practice or policy issued by the Board so that routine changes based current and proposed USP 797 so changes can be adopted in a timelier manner outside the regulatory process. Remove this from the regulation and instead make this a Best Practice or policy issued by the Board so that routine changes based current and proposed USP 797 so changes can be adopted in a timelier manner outside the regulatory process. Current USP ASHP Sterile Compounding Guidelines. Current USP ASHP Sterile Compounding Guidelines. The overall ISO classification is determinant on particulate count regardless of return locations. This verbiage should be captured as a "should" not a "must". The overall ISO classification is determinant on particulate count regardless of return locations. This verbiage should be captured as a "should" not a "must". 8

9 Section Draft Recommendation Evidence Impact/Notes (3) A pharmacy shall measure the differential pressure between each ISO-classified area with a gauge and shall document the differential pressure at each location 24 hours per day, seven days per week, by a continuous recording device (5) A pharmacy shall review differential pressure logs and continuous monitoring device reports daily and shall document the review and response to any out of range pressure. Remove this from the regulation and instead make this a best practice or policy issued by the board. At a minimum, the requirement should be daily documentation of pressure differentials. Current USP ASHP Sterile Compounding Guidelines. Current USP 797, proposed USP 797 and the ASHP guidelines only require documentation of pressure differential daily Remove Pharmacy from this section. USP Consideration should be made to new technology and continuous monitoring devices and altering for out of specification results. This eliminates the need to have someone manually document reviews daily. If left as written, hospital pharmacy departments will need to request additional FTE's to perform this manual monitoring. This adds to the increase in overall healthcare cost for a hospital stay (2) The certification testing shall be completed in its entirety within a 24 hour time period. Certification testing includes: (a) airflow and velocity test; (b) airflow smoke pattern test; (c) room pressurization test; (d) air flow displacement test, as applicable; (e) HEPA filter leak test; (f) induction leak and back streaming test; (g) airborne non-viable particle counting, conducted under dynamic operating conditions; and (h) Temperature and humidity test. Remove the temperature and humidity test. CETA There is no evidence showing that this requirement is necessary and is an optional test within the CETA requirements. 9

10 Section Draft Recommendation Evidence Impact/Notes (1 & 2) (1) A pharmacy shall conduct a smoke study of primary and secondary engineering controls: (2) A pharmacy shall conduct a smoke study: (a) AND (b) 7.24 (17) A pharmacy shall incubate environmental monitoring samples at the following temperatures: Remove section entirely. Pharmacies should incubate environmental monitoring samples based on manufacturer instructions for sampling kits that may be used. FDA Guidance - Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturin g Practice. Current USP No evidence that this improves quality and secondary engineering control smoke tests are not required by FDA or CETA. No mention of SEC smoke tests in current USP 797 or proposed USP 797. Environmental monitoring of samples should be based on the instructions supplied by the manufacturing instructions and should align with current evidence based standards found in the proposed USP (20) A pharmacy shall utilize a two-plate method for collection of viable air and surface samples. One plate shall be a general growth medium and the other plate shall be a medium that specifically supports the growth of fungus (4) Viable Air Sample Action levels ISO 5,7,8 and Highly Pathogenic Organisms Provide an exemption for the incubation of one media at two temperatures or the utilization of two types of media. For example, an FDA approved validated and marketed kit to conduct surface sampling with one method will not be allowed under these regs. Remove the "greater than or equal to" sign and change to "greater than" sign. 797 USP 797 and current evidence supports the use of one general media incubated at 2 temperatures. The "equal to" is allowing for zero counts in an ISO classified areas as well as highly pathogenic organisms. This is unrealistic and will increase unnecessary reporting to the Board. USP does NOT use the "greater than or equal to" sign. If left as written, pharmacies will have to report all growth (even 1CU). In addition, most commonly found bacteria and fungi due to normal human contaminates are considered highly pathogenic. This will result in unnecessary and burdensome reporting for hospitals and unnecessary additional work for the Board. 10

11 Section Draft Recommendation Evidence Impact/Notes (5) Surface Sample Action levels ISO 5,7,8 and Highly Pathogenic Organisms Remove the "greater than or equal to" sign and change to "greater than" sign. USP The "equal to" is allowing for zero counts in an ISO classified areas as well as highly pathogenic organisms. This is unrealistic and will increase unnecessary reporting to the Bop. USP does NOT use the "greater than or equal to" sign (4) Prior to entering an ante room, compounding personnel shall don scrubs and dedicated shoes Add "or shoe covers" to align with (3). USP (1) BUD for Low, Medium and High Risk Align with new draft of USP Category 1 and 2 BUD. A Category 2 product in the absence of sterility testing, no preservative added, prepared from sterile starting components BUD = 6 days RT or 9 days refrigerated OR if products used have preservative added BUD = 28 days RT or 42 days refrigerated (2) A pharmacy shall validate each master formulation record to ensure CSPs compounded pursuant to that master formulation record are stable and sterile and have the correct potency. A pharmacy shall conduct the validation: (a) upon the first use of the master formulation record; (b) at least annually for low and medium risk CSPs; (c) at least quarterly for high risk CSPs; and Allow an exception for low/med anticipatory compounding when BUDs will not be extended. USP Current and If left as written, hospitals would have an increased amount of medication waste and would not be able to store controlled substance per DEA requirements in an automated dispensing machine. If BUDs will not be extended (batch or otherwise) then sterility testing once or repeated is not needed. This has been scientifically proven, validated and supported throughout the literature and guidance documents. Take the example of two sets of 10 vancomycin bags (one gram each in 250mL of NS) mixed at the same time, one per 10 patient specific orders and the other in advance of orders. The same exact technical process will be used to make each set of 10 vanco bags and while both sets will be identical in every way (stability, sterility, etc.) these regs treat them differently. Agree completely that a MF record is needed for any batching but MF should not always mean you need to conduct potency and sterility testing (i.e. when not extending BUDs). 11

12 MSHP/MHA Joint Comments and Recommendations for amending the Proposed 247 CMR Regulations - Sterile Compounding Pages 12through 20 - Additional Comments/Considerations Section Draft Notes Provided (1) (1) A pharmacy licensed by the Board shall comply with 21 U.S.C. 353a, M.G.L. c. 94C, 17 & 22, and M.G.L. c. 112, 39F. A pharmacy may not dispense a compounded sterile preparation ( CSP ) prior to receipt of a patient-specific prescription (2) A pharmacy may not pool or prepare stock solutions utilizing single dose vials to extend a BUD beyond 6 hours after puncture within ISO Class 5 Clarification Requested: This section appears to preclude the preparation of office use only medications. Most hospital systems rely on the ability to dispense compounded preparations to ADMs and clinic areas for use. This does not specify requirements for medication orders seen in the institutional environments vs commercial areas that are based on a prescription. Clarification Requested: 1. As drafted this statement appears to imply that there is a specific practice of pooling SDV with the intent to extend a BUD. It is reasonable and well within to draw up two 1G SDVs of vanco into one syringe (i.e. pooled) and inject into a bag. Is the intent of this requirement to eliminate this type of compounding? A licensee shall prepare a non-hazardous, non-radiopharmaceutical, low risk level CSP with a 12 hour BUD at room temperature or 24 hour BUD refrigerated in an ISO Class 7 buffer room or an ISO Class 8 dedicated compounding room ( DCR ) equipped with a commercially manufactured Primary Engineering Control ( PEC ) such as a laminar air flow workbench ( LAFW ) or biological safety cabinet ( BSC ) and shall comply with all other provisions of 247 CMR 17.00, unless otherwise provided. 2. Is the intent to make it crystal clear that pooling SDVs does not alter the 6 hour BUD requirement assigned to puncture SDV in an ISO5 space? In other words, pooling of SDV to make a single dose or multiple doses is a necessity of practice however, that pooled solution only has a 6 hour BUD? Clarification Requested: 1. Why would a PEC located in an ISO Class 7 buffer room be required to meet the Low Risk Level 12-hour Room Temperature or 24-hour Refrigerated BUD? 2. A PEC is defined as a device or zone that provides an ISO Class 5 environment for sterile compounding. Therefore, a CAI or CACI would fit the definition of a PEC. It is our interpretation that the 12-hour room temperature/24-hour refrigerated BUD language in could also apply to a CAI or CACI located in a DCR. Is this correct or would a CAI/CACI located in a DCR have the BUD listed in 17.16, namely, 36 hours room temperature or 9 days refrigerated? 3. Massachusetts pharmacies are preparing to meet requirements for both the draft 247 CMR regulations and the draft revised USP Chapter. In the draft revised, the term RABS (Restricted Access Barrier System) refers to CAIs and CACIs. Under Section 4.2 (Facility Design and Environmental Controls) subtitle RABS of the draft revised it states: If used to prepare Category 2 CSPs, the area surrounding the RABS must meet ISO Class 7 or better air quality. It is our interpretation that a CAI/CACI could be placed in a DCR meeting an ISO Class 7 air quality. Our position is further based on 247 CMR Section (3) (Dedicated Compounding Room ( DCR )) which states that A DCR shall: Be ISO Class 8 or better. Therefore, a CAI/CACI placed in an ISO Class 7 DCR would allow the pharmacy to meet the criteria for compounding Category 2 CSPs per the draft revised USP. Why would this interpretation not be correct? 12

13 Section Draft Notes Provided 17.07(1) A BUD must be calculated from the time of compounding and shall include the time a drug will reside inside an implantable infusion pump reservoir. Further Review Requested: The maximum allowed BUD indicated by the BOP is 14 days (for refrigerated CSP s) or 48 hrs (room temperature CSP). If a patient must receive an implantable pump reservoir over the course of 30 days (at room temperature) - including dwell time, this regulation will become a major issue. A patient will be required to change the pump more frequently and thus, increasing the risk of infection/contamination for each refill made and administered. Also, consider that these implantable pumps may include CII medications in solution and per state law prescriptions for implantable infusion pumps consisting of Schedule II or Schedule III controlled substances may be filled for a maximum of 90 days. Recommendation: altering this to address the core issue rather than the relatively rare instance of an implantable pump. BUD is indeed calculated from the date/time it was prepared, after which the product should not be administered (per section 17.41). The practical issue that is being addressed in this requirement is that practitioners need to make sure they take this into account before AND during administration of the CSP. In other words, the infusion time should not extend beyond the BUD of the prep, regardless if it is via an implantable pump or the variety of external devices that are used to infuse medications. The current working definition of BUD/exp date is that as long as one starts to use the prep with the BUD we are okay. The BORP should also consider that the pharmacy will assign the BUD as appropriate, for example 30 hours; the clinic staff will start a 3 day infusion within those 30 hours. The pharmacy in which the above prep was compounded may not be able to impact the administration so if this requirement is to dictate the administration criteria it should be adjusted as needed to meet this goal CSPs made with a patient s Blood-Derived or Biological Material Recommendation: remove this section entirely or change this entire section to be specific to biohazard material only. This should not apply to sterile albumin and/or Intravenous Immune Globulin. The policies and procedures should be no different from any other CSP Clarification requested: as written is specific to using blood derived or biologic material from a single patient ( a patient s ).Statements in this section, if read alone may be confusing as they do not reiterate the single patient piece. IVIG is a marketed FDA approved product and the active ingredient is derived from human plasma (blood). This requirement should not apply in the case of IVIG and under the heading of it would not. Recommend clarifying sub-points in this section to make it clear. 13

14 Section Draft Notes Provided 17.13(7) Beginning January 1, 2018, the doors to ante rooms and buffer rooms shall be constructed with an interlocking design to prevent the ante room door and buffer room door from opening at the same time 17.13(9) Beginning January 1, 2018, a pass-through shall: (a) be constructed of a nonporous, smooth, non-shedding, impermeable material such as acrylic, polycarbonate or similar fiberglass-reinforced plastic, glass, or stainless steel; (b) have a double interlocking door design; (c) not have an opening larger than 4 square feet; (d) be located between: 1. ISO Class 7 buffer room and ISO Class 8 area or better; 2. ISO Class 8 area to unclassified space or better; or 3. ISO Class 7 ante room to unclassified space or better; (e) not be a refrigerator unit. Clarification requested: Replacing doors using an interlocking design is extremely costly, will the board consider alternatives such as the use of an alarm system to allow one door opened at a time instead? Clarification requested: 1. Also, due to the layout of some pharmacies the installation of a new pass-through in one of the above locations would be considerably less functional and increase the traffic into and out of the buffer and/or clean rooms. 2. if the pass-through is designed as an ISO class 5 HEPA filtered device with a 1-minute air purge, could it be located between ISO class 7 buffer room and an unclassified space? This could decrease the amount of traffic/activity between ante and buffer rooms. 3. How does a double interlocking door compare to the interlocking design required in point 7 in this section? The goal is the same in that only one door should open, recommend removing double (12) (12) A pharmacy shall determine the recovery time of each primary and secondary engineering controls for particle count, temperature, and humidity, following activities including personnel entering and exiting, gowning, staging, material transfer, compounding, labeling, cleaning, and testing (18) An ISO classified area constructed or renovated after January 1, 2017 may not contain dust-collecting overhangs or ledges Clarification requested: Will the BOP consider adding this requirement as part of the certification process performed by a third party? Or is it required to be performed by pharmacy personnel? Please clarify. Is there a standard for the evaluation of recovery time? Recommendation: Adjust to Best Practice. One 4 hood provides x more dust collecting ledge area than a 0.25 ledge around a window or door in the clean room. Regularly cleaning would be sufficient. Request for clarification to be made on the word may. Handling at policy level for regular cleaning and disinfection is more than adequate (19) A pharmacy shall utilize cleanroom grade lights in all classified areas. Clarification requested: Further explanation on cleanroom grade lighting is warranted (2) A pharmacy may only use compounding equipment in a PEC with vertical laminar airflow (6) A pharmacy may not locate computer screens, keyboards, computer mouse, or printer within an ISO Class 5 area unless it is essential to compounding. Recommendation: Adjust to a best practice. As drafted, clarification is needed on the word may. Certification of the PEC with required compounding equipment in place can be used to show airflow dynamics within normal limits and minimize turbulent airflow. Implementation of policies and procedures for cleaning and disinfection are effective in managing equipment as well as consistent oversight and surveillance. Recommendation: Reword this section to better address the intent as Workflow Management systems that utilize computerized mechanisms (camera) for visual aid and gravimetric readings are critical to reducing errors. Is the goal here to prevent items that can generate particulates or possible be impossible to clean (key board)? There are screens that are cleanable and do not create dust. 14

15 Section Draft Notes Provided 17.15(3) Dedicated Compounding Room ( DCR ) (a) A pharmacy may only prepare CSPs in a DCR if it holds an institutional sterile compounding pharmacy license, issued under M.G.L. c. 112, 39I and the CSPs are administered on-site. Clarification requested: What is the rationale for the on-site requirement; provide guidance on intent and process if this impacts operations and ability to provide compounding if facility meets other general safety and operational requirements (3) A pharmacy may not assign a BUD to any CSP prepared in a CAI located outside of an ISO Class 7 buffer room that exceeds 36 hours at room temperature or 9 days Refrigerated. A pharmacy may not freeze a CSP prepared in a CAI dedicated compounding room (2) A pharmacy shall maintain a detailed HVAC design plan that includes air flow diagrams (3) A pharmacy shall utilize a closed loop ducted system, a sealed plenum system, or other similar contamination control system approved by the Executive Director or his/her designee for HVAC systems supplying HEPA-filtered air to ISO-classified spaces (6) A pharmacy shall conduct engineering control performance verification in accordance with USP in the event of a planned or unplanned interruption of HVAC operations (7) A pharmacy shall operate and monitor the HVAC systems that supply conditioned air to the non-classified areas of the pharmacy 24 hours per day, seven days per week (9) A pharmacy shall immediately assess the impact on the classified environment for any HVAC failure and implement a CAPA (2) Each HEPA filter shall be leak tested using the most penetrating particle size according to the most current Controlled Environment Testing Association ( CETA ) guidelines at the factory, then leak tested again in situ after installation as part of initial certification and recertification (every 6 months) and any time a HEPA filter is repaired or replaced. Clarification requested: The BUDs for medium risk level CSPs are 30 hours at room temperature and 9 days refrigerated. Was the 36 hours room temperature stated in meant to be 30 hours in order to be in agreement with Section (Storage and Beyond-Use-Dating ( BUD ))? Recommendation: Partnerships with Facility Management teams to store and also decipher these drawings are essential. Added clarification into the line would be beneficial to the end-user. Clarification Requested: Clarification on Executive Director is warranted. As the major importance for both air supply and air conditioning is the supply entering at the ceiling, a properly developed maintenance and preventative action plan is as effective. The implementation of policies and procedures managed at the local level is most appropriate and extremely important. Recommendation: Include consideration for downtime procedures to be implemented in place of a performance verification plan. Room recovery is a mathematical calculation that can be determined in place of a validation test. Development of polices and procedure regarding planned and/or unplanned interruptions in HVAC operations can provide the same benefit and safety as performance verification. A continuity of care plan as stated in these draft regulation can be utilized to manage these situations. Recommendation: Include consideration for partnerships with the Facility Management team to monitor the HVAC systems. Monitoring of pressurization within the classified room is the most important aspect of daily operation. Safeguards such as audible alarms can provide the same benefit. Further review requested: The development of a CAPA program is vitally important to the overall quality management program. As stated above regarding the dedicated AHU and HVAC systems for Pharmacies, the implementation of an appropriate CAPA and risk management program coupled with a solid remediation plan is as effective as the addition of a dedicated air handling unit. Clarification requested: This appears to say that the room would need to be recertified after a HEPA filter is replaced even if the room passed certification with the defective filter. Is this the intention? What is the intent for the visual inspection? The HEPA filters in our PECs are protected behind metal filter guards and, therefore, cannot be visibly inspected without removing this guard which would significantly disrupt the environment and the daily workflow. 15

16 Section Draft Notes Provided 17.19(5) A licensee shall visually inspect the external portion of PEC filters at least daily Clarification requested: Does this require written documentation of visual inspection? Please clarify. All of them? How is this done? A leak would often not be visually recognized. Is there evidence of the value of this? (4) Beginning January 1, 2017, a pharmacy shall mount all pressure differential gauges for secondary engineering controls in the non-classified area adjacent to the classified areas (1&2) (1) All ISO Classified areas shall maintain a temperature of 68 degrees or less. (2) All ISO Classified areas shall maintain a relative humidity of 65% or less. Clarification requested on the extent of visual inspection. Knowing that even a pinhead sized hole in the filter can cause a leak to develop, the human eye is unable to easily distinguish the difference. To include this as a requirement rather than within the overall aseptic process provides no benefit or value. Emphasis on aseptic work practices and a regular maintenance program to manage these inspections is beneficial. Recommendation: Adjust this to be a Best Practice. Although it would be nice to have a state-of-the-art facility, interior monitors can be recorded by properly garbed compounding staff members and prevent negative effects on the environment. Properly alarmed devices will provide awareness to staff on issue with pressurization to stem investigation. Clarification requested: Does monitoring take into account seasonal fluctuations in temperature and humidity? Current plant unable to maintain low humidity without increasing temperature above 68 deg F during the summer months. New HVAC would be of significant cost to the institution given the vertical structure in which the pharmacy resides. Recommendation: Consideration to harmonize humidity levels for both the classified and non-classified space to 65%. As temperature goes down, humidity will increase causing fluctuations in humidity %. 65% is a more achievable level. A regular cleaning and disinfection program implemented is effective in managing contamination. 16

17 Section Draft Notes Provided 17.22(3) In the event a primary or secondary engineering control requires major repair or major servicing, a pharmacy shall stop compounding and may not resume compounding until: (a) the repair or service is complete; (b) the affected engineering control has been certified; and (c) Environmental monitoring results in the affected engineering control within USP action levels are obtained. Recommendation: Instead of stopping compounding completely, put a 12 hour time frame (commonly used in practice today), to prevent pharmacies from having to shut down any action level. It has been proven that you are bound to and should get positive results by having ISO 7 negative pressure adjacent anteroom and a sink. Clarification requested: 1. It can take up to 7 days before the viable results of the environmental monitoring are available. Many hospitals would not be able to function for a full week without operating clean rooms. 2. If a facility followed the repair with an intensive cleaning and disinfecting of the area and an environmental testing, is it necessary to wait the 7 days before compounding can resume? The re-test could immediately confirm that the HEPA filters and PECs are working properly and the particle counts are within range for the room ISO classification(s). 3. In the event of an unscheduled down time, it could take many days before it is possible to arrange for a testing company to arrive on site. This delay could push out the ability to use the clean room to up to 2 weeks. In the event that one of the ISO 5 SEC needed to be repaired, would the entire room need to be shut down or can compounding continue in other ISO 5 SECs? (6) A pharmacy shall validate the maximum number of compounding personnel simultaneously capable of working in a buffer room or buffer space without disrupting ISO classification at least once per year. The validation shall include non-viable air, viable air, and surface sampling (7) A pharmacy shall conduct environmental monitoring of each primary and secondary engineering control: (j) In response to a sudden or significant change in staffing or workload. Recommendation: Removing this section entirely and using regular certification process already delineated in 17. Dynamic conditions per current national standards are the conditions any certification should be conducted under. Clarification requested: Please define significant change in staffing or workload 17

18 Section Draft Notes Provided 17.24(8) At minimum, a pharmacy shall conduct routine environmental monitoring of each primary and secondary engineering control at the following intervals: (d) high risk level CSPs with extended BUDs, and high risk level intermediate or stock solutions: Recommendation: Remove this requirement. This requirement does not appear to be evidence-based and is not required by 797. Non-viable and viable air sampling monthly poses as a significant financial burden especially for smaller operations. The financial burden is already high with meeting overall compliance. This requirement does not appear to be evidence-based and not required by 797 and should be reconsidered. Potential Unforeseen Impact: Due to 3-4 high risk compounded ophthalmic preparations that serve a critical patient need, the institution will be required to conduct extensive environmental monitoring. An additional FTE will be required to satisfy these conditions. Additionally, technicians with the skillset to conduct this level of monitoring are very difficult to find in the greater Boston area. The institution will be forced to invest in additional monitoring equipment and will incur significant monitoring costs. Costs to the patient will be increased to account for the increased overhead (10) Personnel that perform environmental monitoring shall be qualified and shall demonstrate competency and proficiency in all sampling techniques including media selection, media preparation, sample collection, incubation protocols, identification of positive results, proper handling of samples for contracted lab distribution, and proper disposal of sampling plates (10) Conditions for Resuming Sterile Compounding following an above action level environmental monitoring result: (a) ISO 5 Classified Area (b) ISO 7 Buffer Room: (c) ISO 7 Ante room and ISO 8 Classified Area(s) (10a) ISO 5 Classified Area 1. A pharmacy may not resume compounding in an ISO Class 5 PEC following an above action level environmental monitoring result until remediation is completed and proven by microbiology reports of repeat environmental monitoring demonstrating results within acceptable levels Recommendation: Include considerations for hospitals that routinely use microbiologists to incubate, identify positive results and dispose of plates. The regulations need to reflect and take into consideration if facilities are already employing staff that provides these services so we are not adding to the overall costs to operate a pharmacy. Recommendation: Exclude prescriptions affecting patient care. There should be consideration for the impact of ceasing high risk compounding of certain drugs (like ophthalmic preparations), which will have a detrimental effect on patient care. The board should make differentiation between drugs such as ophthalmic topical preparations and other sterile dosage forms. Further review requested: This requirement would overall increase public risk and harm to patients in institutions with only one hood at the time these regs go into effect. The regulations should take into consideration options to add redundancy but those take time. Patient care must be maintained in any bridge scenario and if the hood cannot be used the compounding would be pushed to the point of care outside of the pharmacy operation as immediate use compounding. 18