Submitted at Reg.Testimony@state.ma.us

November 29, 2017 David Sencabaugh, R.Ph. Executive Director Board of Registration in Pharmacy 239 Causeway Street, 5th Floor, Ste. 500 Boston, MA 02114 RE: IACP Comments – MA Proposed 247 CMR 17.00 Sterile Compounding Regulations Dear Mr. Sencabaugh,

Thank you for the opportunity to submit our comments on proposed changes to 247 CMR 17.00 outlining pharmacy’s requirements for sterile compounding. As the Board considers proposed 247 CMR 17.00 sterile compounding regulations, the International Academy of Compounding Pharmacists (IACP) appreciates the opportunity to share our comments and concerns and to work with the Board in the future on this very important issue. IACP is an association representing more than 4000 pharmacists, technicians, students, and members of the compounding community who focus on the specialty practice of pharmacy compounding. Compounding pharmacists work directly with prescribers including physicians, nurse practitioners and veterinarians to create customized medication solutions for patients and animals whose health care needs cannot be met by manufactured medications.

IACP understands and supports the need to protect public health. However, patient access is a patient safety issue and as such, it is essential that patient access is preserved to vital, and often life-saving, compounded medications. It is also essential that the physician-patient-pharmacist triad and the right of a provider, when working with the patient, to choose the best medication for the patient’s well-being be preserved.

While there is a statutory requirement for the development of these regulations, IACP is 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 current USP 797 without any supporting evidence showing the proposed provisions will lead to additional improvements to patient care. To the contrary, many of these proposed changes will result in increased costs and operational disruptions to patient care and thus decreasing patient access to vital compounded medications.

As proposed, these regulations would result in a significant decrease in the availability of sterile compounded medications for MA patients as a result of the exorbitant costs associated with meeting these requirements. Decreased patient access means decreased patient safety and well-being. In addition, the proposed regulations appear to have been drafted from a strictly academic perspective, and there appears to have been no opportunity for other stakeholders, particularly those in daily practice helping patients, to provide a practical perspective and make certain the voice of patients was represented. There is also little scientific basis for many areas of the proposed regulations that exceed USP <797> standards. In other areas, the proposed regulations actually contradict USP standards and scientifically supported sterile compounding practices. Any requirements that exceed or vary from USP <797> should be carefully considered for their impact on patient safety. The increased level of inspectional and reporting requirements will add an extraordinary burden to the Board, both from a liability standpoint and from a resource standpoint, with no added improvement in patient safety.

IACP urges the Board to utilize IACP as a resource for future revisions. We appreciate your consideration of our comments and welcome the opportunity to work together to preserve patient access to vital compounded medications.

Sincerely,

Cynthia Blankenship, Esq. Executive Vice PresidentInternational Academy of Compounding Pharmacists4638 Riverstone Blvd.

Page 1 of 17

Missouri City, TX 77459

Page 2 of 17

International Academy of Compounding Pharmacists recommendations for amending the Proposed 247 CMR 17.00 Regulations - Sterile Compounding

Draft Recommendation Impact/NotesA pharmacy shall train its employees annually in lean concepts, in accordance with M.G.L. c. 112, section 39G. Lean

concepts are tools that assist in the identification and steady elimination of waste and promote continuous improvement in quality and efficiency.

“Lean concepts” is an extremely broad term encompassing countless methods and tools for process improvement. This proposed regulation does not specify which lean concept tools are required, making it difficult to understand both the expectations for compliance and the overall benefit to public health.

A pharmacy may not engage in high risk level sterile compounding until and unless the pharmacy receives notification from the Board stating the pharmacy achieved a satisfactory Board inspection specifically pertaining to high risk level sterile compounding. All costs associated with inspections of non-resident sterile compounding pharmacies shall be paid by the non-resident pharmacy or applicant.

Indicate a date for which this requirement becomes effective; indicate who is authorized to conduct non-resident pharmacy inspections; establish an upper limit to the costs paid by non-resident pharmacies for this inspection.

As written, this proposed regulation would require pharmacies to discontinue high risk sterile compounding on the date the regulation is promulgated, and not be permitted to resume sterile compounding until inspection is complete and the pharmacy has received the satisfactory inspection report, thereby causing a major disruption to patient access. Additionally, it is not clear who will be conducting non-resident pharmacy inspections, and if/how they will be trained and qualified to conduct such inspections.

A pharmacy may not prepare high risk level CSPs in suspension, emulsion, pellet, metered dose inhaler, or depot form

This is very limiting. Suggestion would be to update language to reflect that these dosage forms may not be dispensed without successful completion of process and sterilization validation procedures and evidence of stability throughout the duration of the assigned BUD

This proposed regulation does not take into consideration potential drug shortages/ backorders and lack of patient access, resulting in an interruption to active therapy.

A pharmacy may not compound a component of a CSP from Active Pharmaceutical Ingredient (“API”) when a version of that component is commercially available.

This does not take into consideration that commercial products may be on backorder, that final concentrations of compounded preparations may not be achievable using only commercially available products or that commercially available products may have excipients and other ingredients that are intolerable to the intended patient.

Page 1 of 17

Draft Recommendation Impact/NotesA pharmacy shall sterilize the final preparation of a high risk level CSP. A pharmacy shall ensure the sterility of the

final preparation of a high risk level CSP in accordance with USP 71

Modify to read “A pharmacy shall sterilize the final preparation of a high risk level CSP. A pharmacy shall perform sterility testing on high risk level CSPs in accordance with USP <797> Requirements. Sterility testing shall be performed in accordance with USP <71>.

As written, registrants would be required to perform USP <71> sterility testing on all high risk level preparations. This is not practical based on USP <797> and proposed chapter 17beyong-use dating. High risk preparations stored at room temp are given a 24 hour BUD, 3 days refrigerated, and 45 days frozen.

USP <71> sterility testing requires a minimum of 14 days incubation (many times it takes 18 days). If pharmacies are required to perform USP <71> sterility testing, preparations stored at room temp and refrigerated medications would exceed their BUD before being able to be dispensed.

17.06(8)A pharmacy may not dispense a high risk level CSP without preservatives unless the CSP is dispensed in a single use container and labeled as “single use only.”

Strike this requirement or modify to permit multiple doses of a preservative free preparation to be dispensed in a single container so long as the container is verified to prevent contamination of preservative-free formulations

This does not allow for advancement in device technology. Devices are currently available on the market to allow for multi-use applications of preservative formulations.

Example: eye dropper bottles that utilized a 0.2 micron filter to filter air coming into the bottle prior to expelling the drop of the medication.

17.08(1)A pharmacy that prepares intermediate or stock solutions from commercially available sterile components, excluding the pooling of commercially available single dose vials, may not assign a BUD that is longer than a medium risk BUD in accordance with 247 CMR 17.41, to each intermediate or stock solution.

If preparing a low risk-level intermediate solution, low risk dating should be applicable and acceptable.

USP <797> allows for extended dating for all risk levels, so long as a sterility and stability program has been established for that specific preparation.

If sterility testing in accordance with USP <71> has occurred and there is evidence to support stability beyond USP <797>, what is the justification to limiting dating to medium risk?

Page 2 of 17

17.13(2)An ISO Class 8 room shall maintain a minimum of 20 air changes per hour. The origin of 20 air changes per hour in an ISO 8 room is unclear. USP General Chapter <797> does not have an air change requirement for an ISO 8 environment.

Draft Recommendation Impact/Notes17.13(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 the buffer room from the PEC must be in addition to the 30 air changes per hour (“ACPH”).

the air exchanges supplied by the PEC to count toward the 30 ACPH.It is unclear what evidence was used to exclude the PEC air exchanges from the buffer room’s 30 ACPH in the proposed regulation. USP General Chapter <797> allows the air exchanges supplied by the PEC within the buffer room to count toward the required 30 ACPH.

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.

Clarify: Does this apply to all sterile compounding labs (institution & community)? Existing labs currently in operation or those built after the compliance date? If so, change date to one further in the future.

Note: Change all dates in the chapter to future dates, at least 18 months post publication to allow organizations the time necessary to comply.

extremely costly and may not be possible in all sterile compounding labs without extensive reconstruction of the space.

an alarm system to allow one door opened at a time instead?

Beginning January 1, 2018, a pass-through shall 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;

or3. ISO Class 7 ante room to unclassified space or

better.

Page 3 of 17

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.

this a “Best Practice” recommendation.

changes based on national standards can be adopted in a timelier manner outside the regulatory process.

determine the maintenance of functionality of the PEC and SECs. The functional recovery time of a PEC is almost immediate based on the hood volume and airflow, typically less than 1 minute.

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.

Page 4 of 17

Section Draft Recommendation Evidence Impact/Notes17.13 (14) A pharmacy may not locate a refrigerator, dishwasher,

incubator, or other appliance in an ISO Classified areaChange to “any appliances that use running water (i.e. dishwasher) or used to promote microbial growth (i.e. incubator” or something similar).

USP <797> If left as written, this may be interpreted to include “appliances” such as autoclaves and depyrogenation ovens required in all sterile compounding operations. This may also restrict access to innovations 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, etc.

17.13(18) An ISO classified area constructed or renovated after January 1, 2017 may not contain dust-collecting overhangs or ledges.

Change date to reflect a future date, suggesting 18 months post publication.

Change verbiage to “An ISO classified area constructed or renovated after Month Day, Year shall be constructed to minimize dust-collecting unnecessary overhangs or ledges

Adjust to “Best Practice”. One 4’ hood provides much more dust collecting “ledge” area than a 0.25” ledge around a door in the clean room.

Pass-throughs need to have a wide enough deck/ base for material to be set down onto it during transfer between rooms. Walls between the anteroom and the adjacent space and between the anteroom and buffer room(s) would need be 24" + thick to remove all "dust collecting overhangs".

17.13(23) Beginning January 1, 2018, sprinkler heads in all ISO classified areas shall be specifically designed for clean rooms and installed in such a manner to withstand weight-bearing loads on the ceiling

Simplify to “sprinkler heads in all ISO classified areas shall be specifically designed for clean rooms”.

Clarify: what is the importance of having the sprinkler heads being load-bearing? This will be very confusing and difficult to construct and adhere to.

Page 5 of 17

Section Draft Recommendation Evidence Impact/Notes17.15 (1a) Buffer Room

(a) A buffer room shall be at least 144 square feet.Remove entirely the square footage requirement of 144 square feet.

Current USP<797>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.

17.15 (2d) Ante Room(d) An ante room shall be at least 100 square feet.

Remove the requirements for specific square footage space requirement.

Current USP<797>ASHP Sterile Compounding Guidelines.

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.

17.18 (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.

Remove the requirement or add language “where prescription medications are handled and stored”.

USP <797> The purpose and scope of these proposed regulations, as stated in 17.01, “…is to establish minimum professional standards for sterile compounding in order to safeguard the public health and welfare.” Establishing HVAC requirements for pharmacy personnel offices, customer waiting areas, rest rooms, conference rooms, office supply storage areas, and non-sterile compounding areas fall outside the scope of these proposed regulations.

Page 6 of 17

Section Draft Recommendation Evidence Impact/Notes17.19(5) A licensee shall visually inspect the external

portion of PEC filters at least dailyRemove this requirement or clarify What is the “external portion of the PEC filters”? Ease of

access to the visible portions of PEC filters varies based on manufacturer. Accessing filters on a daily basis is likely to cause unnecessary and unanticipated damage to filters that could be avoided if this were stricken from the requirements.

If this becomes regulation, does this require written documentation of visual inspection? If so, how is this done? A leak would often not be visually recognized. Is there evidence of the value of this?

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 provides no benefit or value.

17.20 (2) ISO Class 5 PEC shall include a pressure differential gauge and/or a low flow device displaying the positive pressure differential between the upstream and downstream air flow in accordance with manufacturer specifications. The pressure shall be logged daily prior to compounding. Should the PEC display a loss of pressure exceeding 10% of the last reading, compounding in the PEC shall be suspended until remediated.

Strike the last sentence of this requirement, or change to read “Should the PEC display a pressure differential below the minimum standard required by the manufacturer, compounding in the PEC shall be suspended until remediated.”

It’s unclear how a 10% drop in pressure differential was determined to be significant enough to shut down sterile compounding operations within an ISO 5 PEC even if that 10% drop results in a new pressure differential that is still above minimum requirements.

17.20 (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.

Strike this requirement or modify language to require that the pharmacy respond and document any UNEXPECTED out of range result

USP <797> While it agreeable that unexpected or egregious out of range results should be documented and responded to, there are instances in which differential pressures may be out of range that do not require response. Every time a door opens between labs, pressure differentials drop. The way this requirement is currently written, pharmacies would be required to keep a log of every time the pressure drops due to a door opening.

Page 7 of 17

Section Draft Recommendation Evidence Impact/Notes17.21(1) All ISO Classified areas shall maintain a temperature of

68 degrees or less.Change language to read: All ISO Classified areas shall maintain a temperature in accordance with current USP standards

USP NF 33 According to USP NF 33, appropriate temperature range for drug storage (rx products are commonly stored within ISO classified spaces) is 68-77oF however, USP recognizes that lower temperatures may be more contusive to a compounding environment and allows for broad temperature range of 59-86oF so long as the mean kinetic range does not exceed 77oF.

This range requires appropriate drug storage and operating temperatures while permitting fluctuations that occur in ISO Classified areas.

17.21(2) All ISO Classified areas shall maintain a relative humidity of 65% or less.

Change “shall” to “should” or permit planned excursions, such as those experienced during daily and monthly cleaning activities, where the introduction of a large volume of liquid cleansers results in RH higher than 65%.

If this language were to become regulation, pharmacies would be in violation every time they perform daily or monthly cleaning activities. Introducing a large volume of cleaning agents often causes an increase in humidity above 65% RH.

It is unclear what evidence was used to determine this relative humidity limit and how that evidence is applicable to all ISO Classified areas.

17.22(1)(c) (1) Primary and secondary engineering controls shall be certified at least:

(c) whenever the room is altered; and

Remove “altered” or define This language is too vague. What is considered altered?

17.22(2) The certification testing shall be completed in its entirety within a 72 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 “airflow smoke pattern test” or make this a best practice recommendation.

CETA There is no evidence showing that this requirement is necessary and is an optional test within the CETA requirements.

Page 8 of 17

Section Draft Recommendation Evidence Impact/Notes17.22(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 <797> action levels are obtained.

Change “shall” to “should” Clarification requested:1. It can take up to 7 days before the viable results of

the environmental monitoring are available. Many organizations 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 17.22(6) A pharmacy shall verify 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 verification procedures shall include non-viable air, viable air, and surface sampling.

Strike or provide guidance as a best practice recommendation

CETA does not provide guidelines for this. Certification occurs based on the people, activities and conditions of the room at the time of certification. In the past, when asked, CNBT certifiers have stated they cannot provide a maximum number of people to us because it depends on the materials and activities going on in the room.

It will be very difficult for pharmacies to comply with this regulation, which required cooperation of the CNBT certifiers.

Page 9 of 17

Section Draft Recommendation Evidence Impact/Notes17.23 All language Remove section entirely.

.

FDA Guidance- Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice. USP 797

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 USP General Chapter <797>.

17.24(7)(g)(h)(j)

A pharmacy shall conduct environmental monitoring of each primary and secondary engineering control:(g) in response to identified problems with staff technique;(h)in response to actual or suspected defect or contaminant of a CSP or potential patient infection;(j) in response to a sudden or significant change in staffing or workload.

Remove and replace with “as required to determine the root cause of a contaminated CSP”.

The language used in (g), (h), and (j) is extremely vague and subjective, thereby providing no clarity of both the expectations for compliance and the overall benefit to public health. The recommended language would require environmental monitoring to be conducted in order to determine or rule out the controlled environment as a possible cause of CSP contamination.

Page 10 of 22

Section Draft Recommendation Evidence Impact/Notes

Page 11 of 22

17.24(8) All language Frequency of environmental monitoring shall occur in compliance with USP <797> environmental monitoring requirements.

USP <797> The frequency provided in the proposed chapter 17 will require some pharmacies to perform environmental monitoring on a daily basis. This will greatly interfere with hospital and pharmacy operations, significantly decrease the amount of time and resources spent preparing patient medications and result in operating costs that far exceed what any company could afford, effectively eliminating outpatient sterile compounding.

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: high risk compounded ophthalmic preparations that serve a critical patient need, 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.

Page 12 of 22

Section Draft Recommendation Evidence Impact/Notes17.24(13)(16) (13) If a pharmacy has a water purification system,

the pharmacy shall also test source water and water at point of use for microorganisms quarterly or in accordance with manufacturer specifications.(16) A pharmacy engaged in high risk level compounding shall have a water purification system for water supplied to the sink used for handwashing.

Remove the requirements of (16) entirely; edit the requirements of (13) to indicate acceptable levels and test methods.

It is not clear what evidence was used to determine that the proposed requirements of (16) are adding any value to prevent microbial contamination, or why the requirements of (16) should only be applicable to the handwashing water used by personnel conducting high risk level sterile compounding versus other sterile compounding risk levels.

The proposed requirement of (13) requires microbial testing, but does not indicate an acceptable test method nor acceptable microbial limits for the tested water.

17.24 (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.

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 regulations.

Current evidence supports the use of one general media incubated at 2 temperatures.

17.24(21) A pharmacy that has qualified internal personnel collect environmental monitoring samples shall validate sampling procedures at least once every six months through a qualified third-party vendor.

Clarify what is meant by “validate sampling procedures” and what a “qualified third-party vendor” is.

Extremely subjective regarding what is sufficient evidence that a pharmacy has qualified a third-party vendor. It’s also extremely unclear what is needed by that vendor to validate the pharmacy’s sampling procedure.

17.24(22) A pharmacy shall obtain a “Growth Promotion Certificate” for environmental monitoring plates to validate that the media is able to support microbial growth

Change to a, ‘“Growth Promotion Certificate” or similar”

This language is too restricting. Not all media manufacturers provide a “Growth Promotion Certificate”. For example, Remel provides a “Certificate of Quality”.

17.24(23) A pharmacy shall utilize plates intended for environmental monitoring and may not utilize plates intended for research only.

Remove the requirement, or change language to specify the requirements for environmental monitoring plates.

As written this proposed regulation would require pharmacies to somehow obtain plates labeled “For environmental monitoring”. If there is a concern about specific differences in environmental monitoring plates versus research plates, those specifications should be described.

17.25(1) A pharmacy shall collect air samples under dynamic conditions.

Clarify when this requirement is applicable, as it conflicts with the non-viable air sampling requirements in 17.24 (8) which specify “prior to compounding”, which would indicate static conditions.

Page 13 of 22

Section Draft Recommendation Evidence Impact/Notes17.27(3) Non-Viable Air Sample Action Levels Change requirements to match USP <797> standards Current USP

<797>Currently, USP states that an out of range result is > that value provided, not greater than or equal to.

17.27 (4) Viable Air Sample Action levels ISO 5,7,8 and Highly Pathogenic Organisms

Change requirements to match USP <797> standards USP <797> 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 1 CFU). This will result in unnecessary and burdensome reporting for pharmacies and unnecessary additional work for the Board.

17.27 (5) Surface Sample Action levels ISO 5,7,8 and Highly Pathogenic Organisms

Change requirements to match USP <797> standards USP <797> 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.

17.28 All language Indicate whether or not some or all of this section applies to non-viable and viable environmental sampling results.

Indicate whether or not Board approval of a remediation plan is required prior to a pharmacy implementing such plan. If Board approval is required, indicate the time frame within which the Board must respond to pharmacy with their approval/denial.

While outlining expected pharmacy activities in response to environmental results that have exceeded action levels, this proposed regulation is extremely unclear as to purpose, role, and benefit of the Board’s involvement. The reporting requirements of 17.28(2) and (3) would seem to impose additional liability risk to the Board unless acted upon within a specified time frame.

Page 14 of 22

Section Draft Recommendation Evidence Impact/Notes17.28(10) (b) (2)(A)

The environmental monitoring data does not indicate 2 or more consecutive sampling reports with above action level results; and

Add “within the last 6 months” As written, there is no time frame for how far back registrants must look for 2 or more consecutive sampling reports with out of specification results. As is it written now, the time frame is indefinite and will cause confusion. Pharmacies may not be able to compound for test results from several years prior.

17.28(10) (b)(3), (5)

A pharmacy resuming compounding of CSPs during remediation of ISO 7 buffer room above action level results shall limit the BUDs for CSPs to 24 hours room temperature, 3 days refrigerated or a timeframe agreed upon by the Executive Director or his or her designee until the repeat environmental monitoring reports demonstrate results within acceptable levels

(5) A pharmacy may not freeze any CSP upon receipt of an above action level environmental monitoring result in ISO 7 buffer room until repeat monitoring reports demonstrate results within acceptable levels unless otherwise approved by the Executive Director or his or her designee

Change requirement to read:(3) A pharmacy resuming compounding of CSPs during remediation of ISO 7 buffer room above action level results shall limit the BUDs for CSPs prepared in that buffer room to shorter than or equal to USP <797> BUDs.

(5) strike this statement

Current USP <797>

24 room temperature and 3 days refrigerated is much more stringent that USP requirements for low and medium risk level CSPs.

USP 797 allows for the preparation of CSPs that are stored in frozen storage conditions. There are compounded medications that require frozen storage for stability assurance. This requirement will limit patient access to these medications and will result in a gap in patient therapy.

17.28(10) (c)(2)

All language See comments above for 17.28(10)(b)(2)(A), 17.28(10)(b)(3) and 17.28(b)(5).

Current USP <797>

See comments above for 17.28(10)(b)(2)(A), 17.28(10)(b)(3) and 17.28(b)(5).

Page 15 of 22

17.29(7) A licensee shall allow sterile 70% isopropyl alcohol (“IPA”) to remain in contact with surfaces to be disinfected for 30 seconds before compounding activities are started

Clarify that sterile IPA is to be used inside the ISO Class 5 PEC and/ or immediately prior to transferring materials into the ISO 5 PEC. Non-Sterile IPA is permitted on surface outside of the ISO 5 PEC in the ISO 7 buffer room (such as stainless steel tables were staging occurs).

This regulation is confusing and gives the impression that only sterile 70% IPA is permitted for used in sterile compounding (including outside of the ISO 5 PEC). Non-sterile IPA is traditionally acceptable when disinfecting items outside of the PEC (surfaces, staging materials, etc.)

Section Draft Recommendation Evidence Impact/Notes17.29(13) A pharmacy shall not engage in compounding during daily

or monthly cleaning activities.A pharmacy shall not engage in sterile compounding during daily or monthly cleaning activities in the ISO Classified Buffer room where cleaning is occurring.

Recommend clarifying “in the specific area being cleaned”. In other words if daily cleaning is being performed on the floor in the first buffer room does that mean someone can’t use the second room to compound? Consideration should also be given to STAT patient medication orders.

17.30(6)(c) don:1. A non-shedding disposable coverall for low and

medium risk level compounding; or2. A non-shedding sterile disposable coverall for high

risk level compounding

Remove “disposable” from requirements of #2. If non-sterile coverall is used, it is appropriate to require that coverall to be disposable, however if a sterile coverall is used, it seems unnecessary to require that sterile coverall to be disposed after use; many sterile coveralls are reusable in that they are laundered, sealed, and re-sterilized by an outside company prior to being sent back to the pharmacy.

17.30(10) A compounding individual shall perform antiseptic hand cleansing using a waterless alcohol based surgical hand scrub and shall don new sterile gloves prior to reentering the buffer room if he/she exited the buffer room but did not cross the line of demarcation

Change “A compounding individual” to “Prior to performing aseptic compounding, an individual…”

Sterile compounding personnel are permitted to move between the buffer room and the “clean” side of the anteroom without donning new sterile gloves when participating in cleaning activities, environmental monitoring activities, staging compounding materials in the buffer room, etc. The way this regulation is written, it can be interpreted that this would not be permitted

17.33(12) In the event a compounding individual fails a gloved fingertip/thumb sample or media fill sample, the pharmacy shall evaluate the CSPs prepared by that individual to detect potential contamination of the CSP.

Strike this requirement Gloved fingertip/thumb samples provide retrospective data and the requirement to review compounding records and patient infection data provides only supplemental data with little to no benefit.

Page 16 of 22

17.34(6) All Language Align state regulations with USP <797> requirements Current USP <797>

Frequency of personnel monitoring should be aligned with USP requirements. The gloved fingertip testing regime proposed is very cumbersome and time consuming, reducing the time that can be spent serving patients. This will require, for some facilities daily gloved fingertip testing which far exceeds USP <797> testing requirements. Testing at this frequency will require pharmacies to hire additional staff to perform and monitor gloved fingertip test media, an additional cost to Massachusetts patients. Daily testing is unprecedented and will provide minimal benefit.

Section Draft Recommendation Evidence Impact/Notes17.34(7) A pharmacy that prepares high risk level CSPs or low and

medium risk level CSPs with extended BUDs shall utilize both a general growth media and a fungal specific growth media for all gloved fingertip/thumb sampling.

Strike this requirement or revise to include incubating a general growth media (TSA) at two temperature ranges; 30-35oC for 24-48 hours, then 20-25oC for 5-7 days to promote growth of both bacterial and fungal organisms

Current USP <797>

TSA is a general growth media that is capable of growing both bacterial and fungal CFUs when incubated at appropriate temperatures. Requiring the use of two different media will result in unnecessary testing fees and an increase to the overall cost of healthcare.

17.35 Sterile Compounding Personnel Training; Media Fill Challenge Testing

Update language to reflect USP <797> media fill requirements

Current USP <797>

Align media fill testing with USP <797> for the reasons described in notes to 17.34(6

17.36(7) A pharmacy shall record temperatures of incubators daily. Add “on business days when in use” to draft regulation.

As written the proposed regulation would require daily temperature recording, including weekends or holidays, of incubators even if there are no samples being stored/incubated on that day.

17.38(3) A pharmacy that performs high risk level sterile compounding shall confirm that APIs meet the requirements of the federal Food, Drug & Cosmetic Act, section 503a(b)(1)(B).

Add the word “human” prior to the word “high” in the proposed regulation.

Section 503a of the FDCA is applicable to human patients only. As written, this proposed regulation would unnecessarily impose 503a requirements onto animal patients.

Page 17 of 22

17.39(1) A pharmacy may not utilize ethylene oxide gas or irradiation to sterilize components, equipment, ingredients, or CSPs.

Remove this requirement There is no known basis for this prohibition, other than to potentially support the proposed prohibition on the dosage forms found in 17.06(2). Components purchased by pharmacies pre-sterilized, such as sterile filters, sterile tubing, sterile syringes, etc. are normally sterilized via one of these sterilization methods. This proposed regulation would prevent a pharmacy from utilizing those components.

In addition, a pharmacy that utilizes these sterilization methods according to a validated sterilization process, including stability testing of the finished preparation, should be permitted to continue to do so.

Section Draft Recommendation Evidence Impact/Notes17.39(2) A pharmacy may not utilize steam sterilization or dry heat

sterilization if the CSP can be sterilized using filtrationStrike this requirement USP <797> This proposed regulation appears to be in direct conflict

with USP <797>, is in direct conflict with all principals of contamination control related to sterile medications, and if promulgated, will actually increase risk to the public.

Steam sterilization and dry heat sterilization are typically performed to terminally sterilize the CSP in its final container. The fact that these sterilizations methods do not require manipulation of the CSP after sterilization make them significantly less risky than filtration sterilization, which requires the manipulation of the CSP after it has been sterilized.

17.39(4) A pharmacy shall depyrogenate all glassware and containers, able to withstand dry heat, utilized for sterile compounding with dry heat

Start this statement with, “Unless utilizing sealed, unopened, commercially depyrogenated glassware and containers, …”

Many pharmacies purchase sterile, depyrogenated vials for use in compounding. Opening and depyrogenating sealed, sterile and pyrogen free vials is a gross misuse of employee time and resources.

17.39(5)(c) A pharmacy shall utilize sterile filters that are intended for human-use applications in sterilizing CSPs and suitable for the intended use.

Change “intended for human-use” to “pharmaceutical grade”.

Most filters are labeled “Pharmaceutical Grade” not “intended for human-use” and most pharmaceutical manufacturers are hesitant to state that the filters are suitable for human use. Changing this verbiage to “pharmaceutical grade” will eliminate the use of “for research only filters”, if that is the intent of the regulation.

Page 18 of 22

17.39(6)(b) A pharmacy shall pass CSPs through a filter with a nominal pore size not larger than 1.2um immediately prior to filling containers that will undergo terminal dry heat sterilization or steam sterilization.

Edit to specify CSPs that are solutions. Ophthalmic ointments or gels that will be terminally sterilized via dry heat or autoclave cannot pass through a filter.

17.39(6)(c) Prior to steam sterilization, a pharmacy shall tightly wrap plastic and glass in low particle shedding paper or sealed in envelopes that prevent post sterilization microbial penetration.

Clarify to indicate this is only applicable to components.

There is no value in wrapping glass vials full of finished CSPs in envelops to prevent post sterilization contamination.

17.40(6) A pharmacy shall conduct bacterial endotoxin assay testing according to USP 85 on the following types of CSPs:

Change to: “A pharmacy shall conduct bacterial endotoxin assay testing according to USP 85 on the following types of CSPs intended for parenteral or intrathecal routes of administration”:

USP <797>USP <85>

USP <797> does not require USP <85> endotoxin testing on compounded preparations not intended for parenteral or intrathecal routes of administration, such as ophthalmic preparations.

Section Draft Recommendation Evidence Impact/Notes17.41 Storage and Beyond-Use-Dating: Align entire section with USP <797> BUD standards Current

USP <797>Maximum BUDs are determined by USP expert counsel. The state of Massachusetts should align Chapter 17 requirements with the requirements of USP <797>. This is more consistent with what the rest of the country is doing.

There is no scientific basis for these proposed BUD standards, and these artificial limitations will greatly reduce patient access to CSPs.

17.43 (2) A pharmacy shall verify 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 verification:(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

Revise to read:“A pharmacy shall create each master formulation record to ensure preparations compounded pursuant to that master formulation record would result in CSP with the correct potency, sterility, and stability for the BUD period assigned to that CSP.”

Within the proposed regulation, it is unclear what would constitute “verification” of the master formulation record, particularly what would be acceptable verification of stability.

Assuming potency and stability have been established initially through some scientifically acceptable means, and sterility testing is occurring on each batch, there appears to be no benefit to public safety to conduct quarterly or annual potency, stability, or sterility testing on that formulation.

Page 19 of 22

17.43(4)(l) (l) Endotoxin Limit, as applicable. Remove this requirement USP <85> Endotoxin limits are in part, based on the average patient’s weight and the volume of preparation to be administered.

Endotoxin limit calculations are typically performed by the professionals performing the endotoxin tests and are provided to the pharmacy with the test results. It does not make sense to include this information on the MFR as it may change based on patient weight and max volume to be administered.

This would also require that some pharmacies retroactively modify their MFR’s post compounding.

Page 20 of 22