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1 Comment Submission Template for: General Chapter <797> Pharmaceutical Compounding Sterile Preparations Revision proposed in Pharmacopeial Forum 41(6) Nov/Dec 2015 Send completed template to by January 31, 2016 Commenter s Name: International Academy of Compounding Pharmacists Position: Full Contact Details: General Comments: The International Academy of Compounding Pharmacists (IACP) appreciates the opportunity to provide comments regarding USP s proposed revision to General Chapter <797> Pharmaceutical Compounding Sterile Preparations. IACP represents nearly 4,000 pharmacists, technicians, students, and members of the compounding community who focus upon 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 supports practices and quality standards for preparing compounded sterile human and animal drugs. However, IACP has strong concerns with several of the proposed revisions that would place an undue burden upon pharmacists and result in decreasing time spent with patients as well as patient access to vital compounded medications. At a time when patients are already facing decreased access to compounded medications due to skyrocketing drug shortages and new burdensome regulations, the Revised Chapter <797> will result in further decreasing patient access to these vital compounded medications. The burden that these revisions place on pharmacists will result in many pharmacists foregoing sterile compounding altogether resulting in further reducing patient access to medications. The sections within the Revised Chapter <797> that will burden pharmacists the most and have the greatest impact on decreasing patient access are the sections related to air quality monitoring, establishing beyond-use dates, and in-use times are of greatest concern. IACP shares the concerns of many other organizations that the current revisions provide very few citations in support of the specific proposed requirements. As the burden that is being placed on pharmacists is so high by these revisions as to lead to drastically reducing patient access to medications, IACP strongly encourages that any revisions proposed be based on data, studies, and specific information. Therefore, while IACP appreciates USP s work on this issue, IACP has strong concerns as to the unintended consequences of the proposed revisions on patient access to medications. IACP urges USP to consider patient access to compounded medications and revise the proposed revisions as detailed below.

2 Specific Comments: Section(s) Line Number(s) Existing text: (Provide the proposed text.) N/A N/A Allergenic Extracts as CSPs Docking of the proprietary bag and vial systems The risks to the sterility associated with a particular CSP depends on a number of factors, including the following: Batch size Ultimately, the risk to the population of patients is lower if the compounding is done for an individual patient as compared to when the compounding is done in a batch for multiple patients. Suggested change: (Provide the revised suggestion to replace the existing text.) Addition of Allergenic Extract direction Remove Batch Size or change to Batch size if not terminally sterilized Remove Comment Will there be any direction as to what compounding pharmacies will do who compound allergenic extracts? What are the storage requirements for these CSPs and will they still not be subject to the personnel, environmental, and storage requirements for (now Category 1 and 2 CSPs) when certain criteria are met? Please clarify: Is the implication that such docking must be performed in a PEC? Implies that larger batch size automatically equals higher potential for contamination. Implies sterile compounding should be done on a patient-specific basis to reduce risk; implies anticipatory compounding is risky. Rationale / Scientific Evidence There has been much evidence of 0.4%Phenol/0.9% NormalSaline being the diluent of allergenic extracts that maintain stability much longer than the BUDs described in section 12. For terminally sterilized CSPs, batch size should have no scientific effect on the risk of contamination to any units prepared in that batch. This statement is scientifically incorrect, because as written, it is claiming that for a population of say 20 patients, each receiving a single vial of an injectable CSP, the scientific probability of one or more of those vials being contaminated is higher if all 20 vials were made in a

3 Urgent-Use CSPs It should explicitly be noted that the BUD clock begins at the moment of compounding, not dispensing All personnel involved in the preparation and handling of CSPs must be trained and qualified and must undergo annual refresher training and requalification in appropriate sterile compounding standards and practices Annual Refresher for compounders Each fingertip/thumb a fter, full hand Remove and handling Perhaps change refresher to something more definite. What constitutes enough refreshing for each compounding facility? Ex: 5 hours of in house documented sterile operation education NA It s not clear what the definition of handling is and whether this training requirement would apply to a pharmacy employee whose only interaction with the CSPs within that pharmacy is to apply a label to the finished CSP or place a finished CSP into a box for shipment. There needs to be more definition so it is not left up to interpretation for inspectors to see only their point of view on this matter in this chapter Is this sampling in addition to the fingertip/thumb sampling after the media fill? Recommend requiring single batch (compounded by a single individual and sterilized via a single autoclave cycle or single sterilization filter) versus each vial being compounded individually on 20 different occasions (compounded by potentially multiple individuals, sterilized via 20 different autoclave cycles or 20 different sterilization filters). There is no value in requiring aseptic compounding training and requalification of aseptic technique for employees who only stock/label/transport containers of finished CSPs. See comments

4 hygiene and garbing procedures competent personnel Without applying sterile alcohol or any other agent NA Clarify that disinfectants can be used during media fill process as indicated in procedure in Box days incubation Previously, 797 suggested hours. Why the example of 5 days at that broad range of temperature Fourth bullet of the table states that time should be documented. NA Non-existing text For large batch media fill procedures, is there any direction as to how to discard of media fill vials (or other containers or other media plates for that matter)? 2.2, 5.3 & , 765 & 815 Sixth bullet of table providing incubation times. Recommended incubation schedule is not in conformance with USP <1116>: Incubating at the lower temperature first may compromise the recovery of Gram-positive cocci that are important because they are often associated with humans. fingertip/thumb sampling after media fill as it appears in the current version <797>. Text is currently unclear. Please define competent. As a potential regulatory document, this term should be well defined. Need more clarification Need more definition to the conducive time period. Will 48-72hours at Celsius still work? What is the purpose of documenting the time? Date should be sufficient. Or recommend documenting time of day and not specific time. See Comment Please provide rationale for incubating at lower temperatures first or invert the current recommendation start with higher temperature range first, then lower to conform to other USP Chapters. Media fills should mimic compounding process, so this needs to be defined that you can use sterile alcohol on your hands during the media fill Microbial growth is evident on TSA with lecithin and poly 80 at 48-72hrs at degrees Celsius. There should be proper direction as to what to do with media fill supplies upon completion. Improper handling/dumping could lead to contamination of other supplies if contaminated media were exposed.

5 Eighth bullet of the table states making media in-house Persons who fail written tests; visual observation of hand hygiene, garbing, and aseptic technique; gloved fingertip/thumb sampling; or media-fill tests must undergo immediate requalification through additional training by competent compounding personnel Personnel who fail 3 Personal Hygiene and Personal Protective Equipment NA Remove through additional training by competent compounding personnel from this sentence. This bullet should be removed as pharmacy staff are typically not been trained in preparing microbial growth media. There s no description of what qualifies the individual providing training to be competent, leaving this to be determined by the regulator inspecting the pharmacy. Pharmacists who employ only a small number of compounders will potentially be unable to compound for an extended period whereby the failure may be due to some factor other than compounder competency. Recommend retaining existing 797 language in section Action Levels, Documentation, and Data Evaluation The useful Appendices III, IV, and V found in the current version are not included in new version. These appendices have been useful resources In order to perform growth promotion the user has to use viable microorganisms in the facility. We feel by doing so, increases the risk of contamination of the facility.

6 Dry hands and forearms with either Topping off of soap dispensers Washing hands up to elbows th bullet Immediately prior to donning sterile gloves Suggest this being a possibility if soap has antimicrobial properties? Need more definition is this a unidirectional washing of hands? How to interpret up to elbows? Immediately prior to donning sterile or non-sterile gloves Suggest adding Dedicated, cleanable shoes As noted previously, put on shoe covers, head As noted previously, put on shoe covers, head and facial hair covers, and face masks, before and we request they be revised appropriately and included in revised version. By not being mentioned, we are assuming air dryers are no longer allowed. Please clarify if this is the case and offer explanation. See suggested change Inspectors could misinterpret the proper way to be washing our hands and arms. Request allowance for use of sterile or non-sterile gloves The gown should be put on after hand washing Antimicrobial soap properties would rid of the potential bacterial contamination while topping off See Comment The preparation work will be done before sterilization occurs. Things should be kept as clean as possible but there is no reason or possibility for a sterile process to occur while preparing/weighing ingredients or handling equipment that has been decontaminated but not sterilized. Sterile gloves should be donned after the prep work is completed. Shoes disinfected and kept in the classified environment reduce risk compared to adding shoe covers every time to shoes not stored in the classified environment. Recommend to don gown after hand cleaning procedures, not before, to

7 and facial hair covers, face masks, and gown, before If sterile gowns are used, put on sterile gloves and gowns after hand cleansing and 346 procedures Coveralls and sterile gowns must not The room Which room does this section refer to in the compounding facility? Ante Room or Buffer Room or Prep Area or all? Temperature and humidity must be controlled through an efficient heating, ventilation, and air conditioning (HVAC) system rather than through use of humidifiers and dehumidifiers, which can contain standing water that can contribute to microbial contamination. NA Re-write to read: Temperature and humidity must be controlled through an efficient heating, ventilation, and air conditioning (HVAC) system and humidifiers and dehumidifiers that do not utilize or produce standing water that can contribute to microbial contamination. This section should stipulate that if sterile coveralls or bunny-suits are used, coveralls are to be donned prior to gloving The requirement for disposable gowns is not supported with evidence or rationale, and ignores the successful use of reusable gowns, especially if now used in conjunction with sterile sleeves. We request a change to daily use for sterile gowns. Allowance should be provided for hanging in sterile area and reuse the same day. Very appreciative of the values given but just need to know where this is applicable Existing text implies that no humidifiers or dehumidifiers can be used, even if they don t produce standing water or are incorporated into the building s HVAC system To prevent the Please clarify. The implication is a minimize contamination of the gown and for ease of cleaning hands and lower arms. This process will help to ensure sterile gloves are not contaminated during the full coverall garbing procedure See Comment

8 flow of poorer quality air from one area to another area of higher air quality classification The results must be reviewed and documented on a log they must be sealed Floors must be overlaid with wide sheet vinyl flooring Before being brought into buffer area Before a facility is used to compound either Category 1 or Category 2 CSPs, it must be certified by an independent, qualified individual as meeting its design and air quality specifications (see Table 3). Perhaps suggest an optional panel in facilities to stay unsealed to allow for HEPA filter integrity testing provided that a thorough cleaning of the room be done using a sporicidal agent just as for monthly cleanings Or poured epoxy floors What if the buffer area is the same ISO classification as the Ante room? Would staging still be necessary? Remove qualified or keep but add/define what credentials the certifier must have. In addition, provide what standards are to be followed during this certification process (i.e. CETA standards) need for two pressure differentials of 0.02 (between buffer ante and ante unclassified) or does there need to be only one differential of 0.02 between buffer and unclassified areas? As long as a continuous recording device system is used to monitor pressure differential, organizations should be exempt from the required daily monitoring as long as the device system is validated periodically. This can prove to be quite costly for a compounding facility owner to seal and unseal tiles during certifications and fire code inspections Epoxy is durable, free from cracks and crevices and easily cleanable. See Suggestions Multiple regulatory interpretations of what certified by an independent qualified individual actually means. If sufficient cleaning is done, there should be no problem with an optional tile being left unsealed, especially if pressure is maintained above inch water columns See Suggestions

9 Routine staff activity during compoundingrelated processes must be simulated during certification Smoke Studies for each PEC under full operational processing conditions to demonstrate unidirectional airflow and sweeping action over and away from the product(s) Sterile compounding facilities must be qualified initially The sampling program must be developed based on an understanding of risk factors, including but not limited to criticality of the environment sampled, number and types of activities conducted in the room being monitored, Replace routine with something more definitive or re-word completely to indicate most challenging processes must be simulated during certification Replace full operational processing conditions with most complex/challenging operational conditions Remove must and replace with should or may Regulators may not accept whatever the pharmacy considers routine activity as robust enough to demonstrate that the facility can pass certification under worse case/most challenging conditions. Similar to above, if a pharmacy is not conduction a smoke study under their most challenging process conditions, regulators may interpret as noncompliant. Please clarify what this means for pharmacies who are already compounding CSPs The word must means that in order for a pharmacy to demonstrate regulatory compliance that pharmacy would have to prove to a regulator s satisfaction that each one of these risk factors was scientifically studied and data from each of those studies was analyzed and incorporated into the sampling program. In addition, the term not limited to means that anything a regulator feels should have been studied but wasn t would be sufficient evidence that the pharmacy was not compliant.

10 maximum number of personnel that may be working in the room at one time, and how the CSPs will be exposed to the immediate environment during compounding DATA EVALUATION AND ACTION LEVELS If levels measured during the nonviable air sampling program exceed the criteria in Table 3 for the appropriate ISO classification levels of the area sampled when measured under typical operating conditions, an investigation of the cause must be conducted and corrective action must be taken to prevent future deviations. When nonviable air sampling results for an ISO Class 5 PEC exceed the Suggest dividing this paragraph into two separate paragraphs one to describe actions related to viable sampling results and one to describe actions related to nonviable sampling results. There also needs to be guidance/standards beyond just taking corrective actions, such as: When is it appropriate to resume/continue using the controlled area for sterile compounding? Is a recall required of all CSPs prepared in the environment since the last set of passing test results were taken? Is there an acceptable limit to how many times within a specified time period a controlled environment can exceed air quality action limits? Clearly the intent of this section is to require the compounder to do something in the event air quality testing indicates a problem, however without clarity around what action is expected, when environments/facilities can be put back into service, or how to handle CSPs compounded in a potentially compromised environment, all this section accomplishes is to allow regulators to determine that investigations were not sufficient, corrective actions not effective, and action taken by the compounder not appropriate. This is an area of huge opportunity for USP to provide concrete standards for quality practices. Requiring BUDs to be reduced to those for Category 1 CSPs does not require a pharmacy to actually correct whatever is causing excessive nonviable air particles. Requiring successful recertification of the environment after viable air particles exceed limits also does not require the pharmacy to actually correct the cause of the problem the pharmacy may simply just retest over and over until results are acceptable.

11 criteria in Table 3, all compounding activities must cease in that PEC and a corrective action plan must be implemented immediately. When nonviable air sampling results for ISO Class 7 or 8 areas exceed the criteria in Table 3, a corrective action plan must be implemented immediately. In such a case, if compounding is continued, the BUDs for any CSPs compounded must not exceed the BUDs for Category 1 CSPs until the area is successfully recertified. Some examples of corrective action include a procedural improvement, such as enhanced disinfection; a process or facility improvement; or HEPA filter replacement or repair. The extent

12 5.2 & & of the investigation should be consistent with the type of excursion, and should include an evaluation of trends. The extent of the investigation should be consistent with the type of excursion Active air sampling of all ISO-classified areas must be conducted during typical operating conditions at least monthly Monthly viable air monitoring NA Such sampling should be required no more frequently than every six months. More frequent sampling should only be required IF results of prior testing indicate a significant departure from prior findings. Perhaps every 2-3 months would develop a decent trend as well. If not, perhaps USP could contract with a company to have discounted air samplers for purchase before 797 comes into effect that compounders will inevitably have to buy. Please provide specific examples. Leaving this requirement open-ended as it is now will lead to confusion when inspections occur. Perhaps an appendix at the end of the chapter is warranted. Monthly air sampling is a major change that is not supported. There is no rationale for increasing the sampling frequency from every six months to monthly and in principle no additional information will be gained. This more frequent sampling will undoubtedly increase costs to pharmacists who provides sterile compounding services. This will lead to increased prices for sterile preparations as well as decreased access to these needed medications. Third party payors do not offer coverage for any of the tests. This is a big jump for compounding pharmacies and will likely require pharmacies to purchase this piece of equipment to keep up with the monitoring, which can cost upwards of $15,000 and additional training. Along those lines line 764 would employees be qualified as properly trained individuals to perform air sampling? See Comments

13 DATA EVALUATION AND ACTION LEVELS Evaluate counts against the action levels in Table 4, and examine counts in relation to previous data to identify adverse results or trends. If levels measured during the viable air sampling program reach or exceed the levels in Table 4, corrective actions must be taken, including repeat air sampling. If a CFU count is identified below the action levels in Table 4, primary screening and characterization must be performed (see Microbial Characterization, Identification, and Strain Typing 1113 ). Highly pathogenic microorganisms (e.g., gramnegative rods, coagulase positive staphylococcus, Similar to above, there needs to be text describing the expectation for effective corrective actions, when the environment is acceptable to resume compounding, if a recall should be conducted of CSPs made in the potentially compromised environment, etc. Same as above Same as above

14 molds and yeasts) are potentially fatal to patients receiving CSPs and must be immediately remedied through cleaning and disinfection, regardless of CFU count. If levels measured during viable air sampling exceed the levels in Table 4, the genus must be identified, and when possible, identify the species of any microorganism recovered, with the assistance of a credentialed microbiological laboratory CFU below action level Primary screening and characterization should be part of the process if CFU counts are above CFU limits for classified areas. What is the point in having action levels if there are potentially just as monetarily and opportunity-costly expensive consequences for not exceeding these levels? See Comments

15 primary screening and characterization must be performed Primary screening and characterization should be performed with the assistance of a credentialed microbiology laboratory 5.4 Table 5 Require the same (lower) action levels of viable samples for work surfaces and non-work surfaces within the ISO 7 and 8 environments. 6 Table 6 Site Minimum Frequency PEC (except for an isolator) At the beginning and end of each shift; before each batch; no longer than 30 minutes following the previous surface disinfection when Remove no longer than 30 minutes following previous surface disinfection when ongoing compounding activities are occurring If CFU counts are below action limits, mandatory screening and characterization should not be necessary; this should only be a requirement should CFU counts exceed action limits Please provide definition of credentialed. Lack of clarity around the difference between a work surface and a nonwork surface in these environments (eg could a cart used in an ISO 7 environment have both work and nonwork surfaces?) Implies that a CSP batch requiring more than 30 minutes of aseptic manipulation within the PEC is too large. While every step is made to control ISO classified environments, they are not sterile; occasional growth will occur as evidenced by USP s own defined action limits Whether or not a surface comes into direct contact with the materials used in compounding a CSP is only one factor. Surfaces touched by compounding personnel within an ISO 7 or 8 environment (chairs, control pad on a repeater pump, etc.) are also highpotential sources of viable contaminants to a CSP even though they don t come into direct contact with CSP materials. In instances where a single batch requires more than 30 minutes of work within the PEC, the operator working within the PEC would have to potentially stop in mid-batch, remove everything from the PEC, clean, then place all required items back into the PEC to resume working. This would create far more risk of

16 6 Table 6 and line848 ongoing compounding activities are occurring; after spills; and when surface contamination is known or suspected Walls Monthly Ceilings Monthly Storage shelving Monthly Cleaning and Disinfecting surfaces every 30 minutes Sporicidal agents used at least weekly Suggest cleaning walls and ceilings weekly. Also suggest adding equipment and surfaces in ISO 7 and 8 to table 6 at weekly intervals. Suggest requiring monthly sporicidal use. Suggestion to take this part out The interval is perfectly fine, but what parts of all ISO classified areas is the sporicidal used? Suggest in the place of the cleaning disinfectant agents used at the corresponding areas notated in Table 6, use the Line 848 requires weekly sporicidal on what seems to be the surfaces requiring daily cleaning, which means the sporicidal would be cleaned off/removed from these surfaces the very next day, preventing them from imparting their full effect. Interval between the cleaning of other surfaces is too long. It is certain that all sterile compounding employees clean their work area if it gets too cluttered or spills occur. Removing all equipment and supplies then staging them back into the hood after cleaning and disinfecting is very tedious and could potentially lead to more contamination of the products with coming in and out of the hood. Need more clarity to cleaning and disinfecting with the sporicidal rotation. Every pharmacy has been confused with interpreting the last 797 chapter and how/when to use a sporicidal. contaminating the batch compared to exceeding 30 minutes between cleaning. Since the viable limits for all work surfaces within the ISO 7 and 8 environments should be the same (see above comments related to Table 5) weekly cleaning will have a much higher level of assuring these surfaces stay within acceptable limits. This will increase the risk of contamination of product for batches that take longer than 30 minutes with taking equipment in and out of the ISO 5 area. Additionally, compounding employees may get careless with the frequency of cleaning during the production of the same batch See comments.

17 Sterile cleaning tools Appropriate amount of time All cleaning tools must be cleaned and re-sterilized after use. They must be discarded after an appropriate amount of time Floors in all ISOclassified and segregated compounding areas should be cleaned by mopping with a cleaning and disinfection agent once daily at a time when no aseptic sporicidal agent just make it every week for PECs, Isolators, Work Surfaces, and Floors with substituting the sporicidal with the cleaning and disinfecting agents monthly Recommend removing sterile in line Define appropriate amount of time perhaps recommending to discard no later than weekly or biweekly Cleaning tools are usually dedicated to the room they are stored in and should stay there at appropriate time intervals (which needs to be defined). ISO Classified rooms are not completely sterile, so why do all cleaning tools have to be sterile as long as they are being used and discarded in a correct, time-appropriate manner, respectively Need more clarification Please remove sterile Please clarify. The implication is that regardless if compounding is being performed the floors still need to be cleaned once daily. Our request is for mopping on in-use days only. See comments Some people will interpret this the wrong way and suggest that an appropriate maybe means annually and that the conditions of the material looks fine The classified areas are not sterile therefore there is no need for cleaning tools to be sterile

18 operations are Mopping must be performed by trained personnel using approved agents and procedures, which must be described in written SOPs no longer than 30 minutes following previous surface disinfection no longer than 30 minutes following previous surface disinfection No shipping or other external cartons are allowed into the buffer or ante-areas or segregated compounding areas The equipment also must be of suitable composition such that the Remove approved Are the agents listed in Appendix 2 USP approved, or does some other body approve the cleaning agents being used? Please remove the 30 minutes This could introduce more risk with having to remove everything from the PEC and bring back in after cleaning. NA Please remove the 30 minutes This could introduce more risk with having to remove everything from the PEC and bring back in after cleaning. For instance, completely removing a repeater pump & attached bags, tubing, etc. for TPN admixtures to disinfect the work surface underneath could increase the risk of Remove external and replace with cardboard or fiber Replace must with should Assumption seems to be that all external packaging is cardboard or fiber-based. Must would lead regulators to require evidence, even testing, to prove that the equipment and container-closure systems coming in contact with every CSP is not reactive, contamination. A plastic carton or outer wrapping can be sanitized appropriately to prevent contamination; cardboard cannot.

19 surfaces that contact components are not reactive, additive, or sorptive, and therefore, will not affect or alter the purity of the CSP Compounding personnel must keep a daily record of the accuracy measures and must review the results at least weekly to identify trends over time Compounding personnel must establish, maintain, and follow written procedures for the selection and inventory control of all CSP components, including all ingredients (i.e., bulk active pharmaceutical ingredients (APIs) and inactive ingredients), containers, and closures. These written procedures must be followed for all components, from receipt to Compounding personnel must keep a daily record that accuracy and calibration has been performed. Replace inventory control with environmental storage conditions additive, or sorptive, regardless of that CSPs assigned Beyond Use Date. Simply documenting that calibration has been performed and accuracy is confirmed for a given day should be sufficient to ensure accurate compounding procedures Inventory control implies maintaining accurate counts of components in inventory. Setting a firm date for review (ie. weekly) may not be useful for everyone. If the device is used once a week or every 2 weeks, a monthly review may provide more information than weekly. Consider using the word routinely instead of weekly. There seems little value to ensuring the quality of CSPs by requiring accurate inventory counts of components. There is value in requiring CSP components to be stored under proper temperature, humidity, and where necessary, ISO classified controlled environments.

20 consumption Compounders must use qualified vendors. A vendor is qualified Each API must be accompanied by a valid COA that includes the specifications and test results and shows that the API meets the monograph, if one exists, and any additional specifications required to appropriately compound the CSP When ingredients are obtained from an unregistered facility, the compounder must establish the identity, strength, purity, and quality of the ingredients obtained from that supplier by reasonable means. These means may include checking each lot of the component when received, or periodically Remove valid Re-write this section to include specific requirements. This language is vague and will be potentially difficult for pharmacies to document and/or meet this requirement. What constitutes a qualified vendor? Please clarify. Regulators will likely define a valid COA as meaning the pharmacy has performed testing of the incoming material to validate that the accompanying COA is accurate. See above comment Terms like reasonable means and listing vague examples of what these means may be has no value to the compounding pharmacist. Another area of great opportunity for USP to establish clear standards for quality practices. See above comment.

21 verifying quality by testing a sample of components obtained from that supplier to determine whether the COAs for ingredients sourced from that supplier accurately reflect the characteristics of the ingredients Each lot of commercially available sterile, depyrogenated containers and container- closure systems must be accompanied by a COA or other documentation showing conformance with established specifications Analytical results in the vendorsupplied COA for each lot of incoming ingredient must be inspected against the compounding facility s current specification sheet to ensure If there is a compendial monograph for any Remove conformance with established specifications and replace with sterilization and depyrogenation. Please remove It should be made clear that facilities are not required to perform their own analytical tests It s not known what established specifications are. Pharmacies do not have specification sheets for each chemical. This sentence, as it currently stands, could be misinterpreted by regulators to require facilities to perform their

22 ingredient received, facility personnel must verify that the COA for the ingredient demonstrates If the correct identity, purity, strength, and sterility of ingredients and other components intended for preparation of CSPs cannot be confirmed (e.g., containers of ingredients with incomplete labeling, unlabeled syringes, opened ampules, punctured vial stoppers, flexible intravenous bags), they must be promptly rejected, clearly labeled as rejected, and segregated to prevent their use before appropriate disposal Each CSP must be sterile and pyrogen-free before release. to verify conformance with compendial criteria. Replace entire sentence with If ingredients and components intended for use in preparing CSPs do not meet expected quality attributes, they must be promptly rejected, clearly labeled as rejected, and segregated to prevent their use before appropriate disposal. Each CSP must be sterile before release. own analytical testing to ensure the chemical received conforms with compendial monograph specifications. Similar to previous comments, without clear standards for how to confirm identity, purity, and strength of ingredients and components, there would be no consistent regulatory expectation for what should be rejected. While the term pyrogen-free is defined later in the chapter, we are concerned regulators will misinterpret this phrase and require facilities to produce pyrogen-free compounded sterile products. Please consider our All CSPs cannot be pyrogen-free.

23 8 1028, , 1173 Use of the word pyrogen free The sterilization method used must sterilize the CSP while maintaining its physical and chemical stability (i.e., appropriate strength, purity, quality), and the packaging integrity of the CSP Utensils and materials in direct contact with the components, the CSP, and the container closure system must be sterilized and depyrogenated using appropriate methods (see Sterilization of Compendial Articles 1229 ). Suggest maybe that the pyrogen load must not exceed that of which is indicated in the USP monograph for amount listed or the calculation based on a person s body weight. Or maybe pyrogen-limiting Replace while maintaining with without potentially degrading Remove entire sentence and replace with For CSPs prepared from non-sterile ingredients, utensils, mixing vessels, and other equipment in direct contact with the CSP during the mixing/blending of the non-sterile components must be depyrogenated using appropriate methods. Materials in direct contact with sterilized CSPs, must be sterilized and depyrogenated using appropriate methods. All final container-closure systems used for injectable CSPs must be sterilized and depyrogenated prior to being filled with either change or at least adding the definition of pyrogen-free in parenthesis after the phrase. Nothing can be pyrogen free, it can just be to a safe load Requiring that sterilization methods must maintain the CSP s physical and chemical stability would require that testing be performed or scientific data collected on each CSP to positively confirm that CSP s potency and purity are not altered by the sterilization method. As written, this would require that even the raw material supplier s containers holding the non-sterile API powder used in a CSP would need to be sterilized, as they are in direct contact with a component of the CSP. See comments some inspectors will read this for what it s worth and thing that pyrogen free must mean absolutely zero The only way to truly demonstrate compliance with this standard would be for pharmacies to conduct baseline (before sterilization) and poststerilization chemical testing on each CSP in order to confirm the sterilization method has not altered any physical or chemical properties of the CSP. Everything coming in contact with sterilized CSPs must be sterilized and depyrogenated. Final container-closure systems holding injectables, even if being filled with nonsterile CSP liquids prior to autoclaving/dry heat sterilization, should be sterilized and depyrogenated, as they could become a potential source of bacterial contamination of the finished CSP. Components, containers,

24 A description of the sterilization and depyrogenation process, including the temperature, pressure (if applicable), duration, and permissible load configuration for each cycle, must be included in the facility s written SOPs sterilized or non-sterilized CSP. A description of the sterilization and depyrogenation process, including the temperature, pressure (if applicable), duration, and permissible load configuration for each cycle must be included in the facility s documentation. This could also be stored in the master formula record and//or as a processed formula using compounding software Periodically Define periodically This could be up for misinterpretation during inspections manufacturer as suitable for pharmaceutical use The person responsible for selecting the sterilization method must utensils, etc. used to hold or mix the non-sterile portion of a CSP prior to sterilization should be depyrogenated, but there is little value in requiring these items to be sterilized, as they will be used to hold/mix non-sterile ingredients in an environment that is not designed to maintain sterility. Documentation of this information is important. Where the documentation physically resides is not. We would argue that this information should be required to be in the master formula record to ensure consistency from batch to batch. See comments NA Please remove Syringe filters are not certified by the manufacturers for pharmaceutical use. These do not exist. will make the choice of filter using available information sources to determine any incompatibilities with the CSP. Data does not always exist to ensure compatibility with every ingredient that may be used.

25 ascertain from appropriate information sources that the sterilizing-grade membrane filter selected is chemically and physically compatible with the specific formulation of the CSP The responsible person must ensure, directly or from appropriate documentation from the supplier, that the filters 1) are chemically and physically stable at the pressure and temperature conditions that will be used; 2) have enough capacity to filter the required volumes; and 3) will yield a sterile filtrate while maintaining prefiltration pharmaceutical quality, including strength of ingredients of the specific CSP completed without the need Remove 3) will yield a sterile filtrate while maintaining prefiltration pharmaceutical quality, including strength of ingredients of the specific CSP Essentially requires all CSP formulations sterilized by filtration to undergo some form of potency testing, regardless of whatever information has been found to support that the filter and CSP formula are compatible. The only way to ensure this is through direct chemical testing, pre and post filtration, of each CSP formulation. This may even require chemical/potency testing of each batch, because if a filter is going to hold-up active ingredient in a solution being passed through it, varying the volume of solution being passed through a single filter (varying the batch size) may alter the hold-up rate, causing an increasingly greater effect on the potency of the finished CSP. NA Please remove There are many formulations that will

26 for replacement of the filter during the process The sterilization cycle should be designed to achieve a SAL of NA Clean Water Define what clean means.. Purified? Distilled? Sterile Water? Perhaps put per 8.2 and and 1169 must undergo a depyrogenation process (e.g. dry heat or rinsing with pyrogen-free water) temperatures from approximately 170 o up to 400 o the testing must be performed in a manner consistent with <71>, The source of the contamination, if identified, must be manufactures specifications must undergo a depyrogenation process (e.g. dry heat) NA the testing must be performed in a manner consistent with <71> (or a method not described in the USP verification results demonstrate that the alternative is at least as effective and reliable as the USP Membrane Filtration method or the USP Direct Inoculation of the Culture Medium method where the Membrane Filtration method is not feasible.) Remove should and replace with must. Suggest adding language that prohibits continued Please provide a process to comply with this statement. People will most definitely put tap water in their steam autoclaves if given room to interpret this comment Please remove the rinsing statement. Please remove and keep the following line of 250 o for 30 mins. Not allowing for alternative testing, like laser scanning cytometry, decreases the ability for pharmacies to provide CSPs in a timely manner and greatly decreases the amount of time a CSP can be used once testing if completed and before the BUD. Existing text doesn t require the investigation to determine if other CSPs may have been compromised, if require the transfer or replacement of the filter. As long as all the filters are bubble point tested this should pose no extra risk. See comments Rinsing will help reduce but it does not render an item pyrogen-free

27 corrected, and the facility should determine whether the conditions causing the sterility failure affect other CSPS Name, address, and contact information of the compounder if the CSP is to be sent outside of the facility in which it was compounded The term expiration date is not appropriate for CSPs, because the types of full stability studies conducted by manufacturers to establish expiration dates for conventionally manufactured products are not typically performed for CSPs A containerclosure integrity test needs to be conducted A containerclosure integrity test needs to be conducted compounding of CSPs via processes, equipment, environment, etc. that may be involved in the source of contamination until corrective action is complete and those processes/equipment/environment, etc. have been re-certified. Remove compounder and replace with compounding facility Re-write to read The term expiration date is not applicable to CSPs since CSPs do not go through the new drug approval process required of conventionally manufactured drug products. NA NA a recall of other items is necessary. Also doesn t offer any standards around continued compounding (and potential further contamination of CSPs) during the time the investigation is being conducted/corrective action is being developed. It s not clear if the compounder is the individual(s) involved in preparing that particular CSP or if it s the facility dispensing the CSP. In trying to explain the somewhat insignificant difference in terms, the existing text not only makes an unfounded assumption that compounders don t conduct the necessary stability studies on CSPs to support assigned BUDs, but it also conveys a clear message that the sterility, strength, and purity of CSPs are likely to be lacking compared to conventionally manufactured products. Please provide a process to comply Question for the committee: can the container-closure integrity test be performed, published and the results utilized by others in the industry? For There s little value in including the name of the individual preparing the CSP on the label this information can quickly be obtained from compounding batch records. If the difference in the applicability of expiration date versus beyond use date is going to be defined, it should be based on the factual differences between the two terms, not based on assumptions.

28 and Table 8 The BUDs in Table 7 and Table 8 for CSPs are based on the risk of microbial contamination, not the physical or chemical stability of the CSP, and involve the following assumptions: 1. The CSP and its components can remain chemically and physically stable for the BUD period 2. None of the factors identified in 12.2 Critical Parameters to Be Considered in Establishing a BUD, would require a shorter BUD Revise the BUDs in Table 7 and Table 8 and/or provide the scientific basis for how these BUDs were determined. example, a university conducts a study of a frozen injectable product in three different fill volumes in two different types of container-closure systems. Can the published data be utilized by other facilities? The BUDs established in Table 8 do not appear to be established on the risk of microbial contamination. There appears to be no scientific basis for these BUDs, there s inconsistencies throughout the Table, and there s nothing in the existing text that references what studies, data, or scientifically accepted calculations were used as the basis for these BUDs. The purpose of these BUDs appears to be to limit a pharmacy to dispensing no more than a one month supply of a CSP unless the CSP is frozen. The BUDs established in Tables 7 and 8 do not appear to be established on the risk of microbial contamination, but rather on the number of days supply of a CSP the Committee feels is appropriate to be dispensed by a compounding pharmacy. For example, sterility testing itself has no impact on the risk of microbial contamination of the CSP, as described in previous comments. However, the BUDs for terminally sterilized CSPs in Table 8 that are stored at room temperature or do not contain a preservative are exactly 14 days longer if they are sterility tested compared to those that are not sterility tested. Given that the results of sterility testing take 14 days from the time of compounding to obtain, and assuming CSPs undergoing sterility testing are quarantined for those 14 days, it

29 becomes clear that these BUDs are established solely on the premise that a pharmacy should be able to dispense up to a 28 day supply of these CSPs. As described multiple times within Section 12 of this chapter, aseptically prepared CSPs have a higher potential for microbial contamination compared to terminally sterilized CSPs. However in Table 8 the BUDs for CSPs that undergo sterility testing are identical, regardless of whether the CSP was terminally sterilized or aseptically prepared. Based on this premise, the risk of microbial contamination of any CSP, regardless of how prepared or the effectiveness of the sterilization process, goes down as long as it undergoes sterility testing. Lastly, some sections of Table 8 indicate that refrigeration is just as effective at maintaining a CSPs sterility as a preservative, and in other areas refrigeration is not as effective. And there seems to be no additional assurance of maintaining

30 When the results of sterility testing are known before dispensing, a longer BUD is permitted in Table If a sterility test is performed and there is an urgent need to dispense the CSP before sterility test results become available, a CSP can be dispensed to a patient before the end of the sterility testing period if: The prescriber specifically requests dispensing before completion of the sterility test, and the request is documented of the testing period if: Remove Remove The prescriber specifically requests dispensing before completion of the sterility test, and the request is documented Suggest adding and or or - prescriber specifically requests Table 8 may allow for the assignment of longer BUDs for CSPs that are sterility tested, however if the pharmacy waits until the results of the sterility tests are known before dispensing (14 days), the amount of time left for the patient to use the CSP before reaching the BUD is not always longer than the amount of time the patient would have to use a non-tested CSP. See above comments sterility test results and/or prescribers requests, no matter how well documented, should not be the standards used for determining whether or not a CSP should be released and dispensed. This can be misinterpreted sterility by refrigerating a CSP that contains a preservative, unless the CSP is aseptically prepared, in which case refrigeration adds an extra 14 days of assurance on top of the preservative. Documented assurance that CSPs were prepared using verified processes, equipment, and personnel under controlled conditions should be the standards used to release and dispense CSPs. See comments