+-------------------------------------------+--------------------------+
| ## Baxter Healthcare Corporation          | **847.546-6311**         |
+-------------------------------------------+--------------------------+
| ## Route 120 & Wilson Road                |                          |
+-------------------------------------------+--------------------------+
| ![](media/image1.wmf){width="1.1in"       |                          |
| height="0.175in"}**Round Lake,**          |                          |
| **Illinois 60073-0490**                   |                          |
+-------------------------------------------+--------------------------+

Janet Woodcock, MD, Director CDER November 4, 2003

Food and Drug Administration

Rockville, MD 20852

Carol Lampe

Baxter Healthcare Corporation

Rt. 120 & Wilson Road

Round Lake, IL 60073

Re: Baxter Comments to the FDA Aseptic Processing Draft Guidance

Dear Dr. Woodcock:

Attached are Baxter's comments to the FDA's Draft "Guidance for
Industry, Sterile Drug Products Produced by Aseptic Processing --
Current Good Manufacturing Practice". Baxter wishes to recognize the
efforts made by the FDA to update these guidelines.

Respectfully,

Carol Lampe

Sr. Research Scientist

Baxter Comments to FDA Draft Guidance on Aseptic Processing

+-------+-----+--------------------------------------------------------+
| Ref.  | #   | # Comment                                              |
| Line  |  Cl |                                                        |
|       | ass |                                                        |
+-------+-----+--------------------------------------------------------+
| Ge    | T   | The use/meaning of "should" and "shall" is unclear.    |
| neral |     | Lines 40-41 it states, "The use of the word *should*   |
|       |     | in Agency guidances means that something is suggested  |
|       |     | or recommended, but not required." The document needs  |
|       |     | to be checked for use of these terms. For example,     |
|       |     | Lines 457-574, "Containers and closures should be      |
|       |     | rendered sterile and, for parenteral drug products,    |
|       |     | pyrogen free." This is clearly a requirement.          |
+-------+-----+--------------------------------------------------------+
| Ge    | E/T | General: the term \"microns\" should be replaced with  |
| neral |     | \"micrometers\", which is the appropriate SI           |
|       |     | measurement.                                           |
+-------+-----+--------------------------------------------------------+
| Ge    | E   | The document needs to be checked for spelling (e.g.,   |
| neral |     | Line 1825 "sterilyzed".                                |
+-------+-----+--------------------------------------------------------+
| Glo   | E/T | In general, definitions do not match existing ISO,     |
| ssary |     | IEST or other technically accepted definitions.        |
| Sec   |     |                                                        |
| tion- |     |                                                        |
| Lines |     |                                                        |
| 1928  |     |                                                        |
| -2059 |     |                                                        |
+-------+-----+--------------------------------------------------------+
| Line  | E   | "The terminally sterilized drug product, on the other  |
| 92-93 |     | hand, undergoes a single sterilization process in a    |
|       |     | sealed container, thus limiting the possibilities for  |
|       |     | error."                                                |
|       |     |                                                        |
|       |     | Some products are subjected to more than a single      |
|       |     | sterilization process. Remove the restrictive term     |
|       |     | "single" from the sentence.                            |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "It is a well-accepted principle that sterile drugs    |
| 11    |     | should be manufactured using aseptic processing only   |
| 0-115 |     | when terminal sterilization is infeasible. However,    |
|       |     | some final packaging may afford some unique and        |
|       |     | substantial advantage (e.g., some dual-chamber         |
|       |     | syringes) that would not be possible if terminal       |
|       |     | sterilization were employed. In such cases, a          |
|       |     | manufacturer can explore the option of adding adjunct  |
|       |     | processing steps to increase the level of sterility    |
|       |     | confidence."                                           |
|       |     |                                                        |
|       |     | These statements should be deleted. As stated in line  |
|       |     | 109, this guidance relates to CGMP issues and not how  |
|       |     | or why a product is developed. Discussions related to  |
|       |     | drug development should be left to the appropriate     |
|       |     | reviewing office.                                      |
+-------+-----+--------------------------------------------------------+
| Line  | T   | Alert and Action Levels                                |
| 14    |     |                                                        |
| 9-150 |     | "Table 1 footnote c- Values represent recommended      |
|       |     | levels of environmental quality. You may find it       |
| Line  |     | appropriate to establish alternate microbiological     |
| 21    |     | levels due to the nature of the operation."            |
| 4-215 |     |                                                        |
|       |     | "Air monitoring of critical areas should **normally**  |
| Lines |     | yield no microbiological contaminants. Contamination   |
| 11    |     | in this environment should receive investigative       |
| 82-83 |     | attention."                                            |
|       |     |                                                        |
|       |     | "In the absence of any adverse trend, a single result  |
|       |     | above an action level should trigger an evaluation and |
|       |     | a determination about whether remedial measures may be |
|       |     | appropriate."                                          |
|       |     |                                                        |
|       |     | It should be made clear that periodic excursions above |
|       |     | action levels are to be expected (especially in the    |
|       |     | class 5 areas where there is little tolerance) and may |
|       |     | not be cause for investigation and that procedures can |
|       |     | be written to tolerate these excursions provided they  |
|       |     | fall within or outside of a given frequency.           |
+-------+-----+--------------------------------------------------------+
| Line  | T   | "A velocity from 0.45 to 0.51 meters/second (90 to 100 |
| 200   |     | feet per minute) is generally established, with a      |
| Foo   |     | range of 20% around the setpoint. Higher               |
| tnote |     | velocities...."                                        |
| 4     |     |                                                        |
|       |     | Delete footnote and allow airflow velocity to be       |
|       |     | justified by the manufacturer as stated in line 199.   |
+-------+-----+--------------------------------------------------------+
| Line  | E   | However, even successfully qualified systems can be    |
| 21    |     | compromised by poor personnel, operational, or a       |
| 1-212 |     | maintenance practices.                                 |
|       |     |                                                        |
|       |     | This statement applies to all facets of an aseptic     |
|       |     | manufacturing operation, not just design. This         |
|       |     | sentence adds no value.                                |
+-------+-----+--------------------------------------------------------+
| Lines | T   | \"Active air monitoring of critical areas should       |
| 21    |     | normally yield no microbiological contaminants.        |
| 4-215 |     | Contamination in this environment should receive       |
|       |     | investigative attention.\"                             |
|       |     |                                                        |
|       |     | This paper implies that there is a limit of 0 in class |
|       |     | 100 areas for airborne monitoring. One organism in a   |
|       |     | class 100 area should not necessarily trigger an       |
|       |     | investigation, and does not mean that the area is out  |
|       |     | of control.                                            |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "For Class 100,000 (ISO 8) supporting rooms, airflow   |
| 247-9 |     | sufficient to achieve at lest 20 air changes would be  |
|       |     | typically acceptable."                                 |
|       |     |                                                        |
|       |     | A more flexible approach such as the language in Annex |
|       |     | 1, which states, \"In order to reach the B, C, and D   |
|       |     | air grades, the number of air changes should be        |
|       |     | related to the size of the room, and the equipment and |
|       |     | personnel present in the room." would be more          |
|       |     | appropriate. The goal is to maintain the particle      |
|       |     | limits and to ensure that a room can return to normal  |
|       |     | state in the event of a particle excursion. A smaller  |
|       |     | room with fewer air changes may be able to exhibit     |
|       |     | higher quality air and be able to clear out a particle |
|       |     | excursion due to less turbulent air mixing.            |
+-------+-----+--------------------------------------------------------+
| Line  | T   | A compressed gas should be of appropriate purity       |
| 262   |     | (e.g., free from oil and below water vapor) ..."       |
|       |     |                                                        |
|       |     | Compressed air lines are not actually free of water    |
|       |     | vapor. The gas is tested to assure that it is below a  |
|       |     | pre-determined acceptance limit.                       |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "Sterilized tanks or liquids should be held under      |
| 2     |     | continuous overpressure, *unless otherwise required by |
| 72-73 |     | the manufacturing process*, to prevent microbial       |
|       |     | contamination."                                        |
|       |     |                                                        |
|       |     | Some process incorporate vacuum dryers which are held  |
|       |     | at negative pressure. Other manufacturing processes    |
|       |     | employ receiving carboys, or tanks that are properly   |
|       |     | sealed but may not be amenable to constant             |
|       |     | overpressure. These vessels usually contain 0.2 μm     |
|       |     | vent filters. This should not be a requirement where   |
|       |     | practitioners have properly validated sterile holding  |
|       |     | systems via media fills.                               |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "These filters should be integrity tested upon         |
| 27    |     | installation, and periodically thereafter (e.g.,       |
| 9-281 |     | including end of use).                                 |
|       |     |                                                        |
|       |     | These filters are integrity tested prior to            |
|       |     | installation and upon removal from use -- they are not |
|       |     | removed for integrity testing once in use. While in    |
|       |     | use, they are regularly monitored for viable and       |
|       |     | non-viable counts. Any excursion in counts would       |
|       |     | prompt an investigation, which might include integrity |
|       |     | testing.                                               |
+-------+-----+--------------------------------------------------------+
| Lines | T   | Section IV.C.2. High-Efficiency Particulate Air        |
| 28    |     | (HEPA). General: We STRONGLY recommend that FDA        |
| 3-338 |     | reference Institute for Environmental Science and      |
|       |     | Technology (IEST) recommended practice IEST-RP-CC006.2 |
|       |     | for their HEPA filter section. This FDA draft section  |
|       |     | on HEPA filters contains outmoded and incorrect        |
|       |     | information that conflicts with standard industry      |
|       |     | practices, as outlined below.                          |
|       |     |                                                        |
|       |     | Lines 296 - 297: "Any aerosol used for challenging a   |
|       |     | HEPA filter should meet specifications for critical    |
|       |     | physiochemical attributes such as viscosity." The      |
|       |     | viscosity of the liquid challenge aerosol as a         |
|       |     | critical characteristic is not mentioned in IEST       |
|       |     | recommended practices. What is the source of           |
|       |     | information? I would recommend that FDA refer to       |
|       |     | Institute for Environmental Science and Technology     |
|       |     | (IEST) recommended practices for cleanroom             |
|       |     | certification or another industry recognized guideline |
|       |     | instead of trying to prescribe test methods that are   |
|       |     | outmoded and not consistent with current practices.    |
|       |     |                                                        |
|       |     | Lines 297-298: "Dioctylphthalate (DOP) and             |
|       |     | Poly-alpha-olefin (PAO) are examples of appropriate    |
|       |     | leak testing aerosols." DOP is an outdated method for  |
|       |     | testing and should not be referenced in this document. |
|       |     |                                                        |
|       |     | Lines 298 - 300: "Some alternative aerosols are        |
|       |     | problematic because they pose the risk of microbial    |
|       |     | contamination of the environment being tested." This   |
|       |     | comment seems to preclude using any challenge other    |
|       |     | than a PAO/photometer challenge. Again, if the agency  |
|       |     | feels it is important to include ULPA filters (IEST    |
|       |     | class F filters) in this document, an alternate        |
|       |     | challenge using polystyrene latex beads may be more    |
|       |     | appropriate, especially in environments such as        |
|       |     | isolators and laminar flow depyrogenation tunnels. It  |
|       |     | is the manufacturer\'s responsibility, however, to     |
|       |     | demonstrate that the alternative challenge aerosol is  |
|       |     | suitable. In general, FDA should reference IEST or ISO |
|       |     | recommended practices rather than giving such specific |
|       |     | directions in the Aseptic Processing Guidance. This    |
|       |     | will avoid tying the industry to outmoded practices as |
|       |     | technology improves.                                   |
|       |     |                                                        |
|       |     | Line 309-10: "...including a sufficient upstream       |
|       |     | challenge of 0.3 microns." The 0.3 micrometer particle |
|       |     | size recommendation may not be appropriate. For ULPA   |
|       |     | filters and some HEPA filters, the most penetrating    |
|       |     | particle size may be closer to 0.12 micrometers.       |
|       |     | Sticking with a mean particle size of 0.3 micrometers  |
|       |     | would preclude us from using hot PAO generators, which |
|       |     | generate an aerosol with a mean particle size of       |
|       |     | approximately 0.17 micrometers. As in the following    |
|       |     | comment, I would prefer that FDA refer to the IEST     |
|       |     | recommended practices, which are the standard for      |
|       |     | testing HEPA and ULPA filters.                         |
|       |     |                                                        |
|       |     | Line 312-13: " ...a DOP challenge should introduce the |
|       |     | aerosol upstream of the filter in a concentration      |
|       |     | ranging from approximately 25 to 100                   |
|       |     | micrograms/liter..." The recommended concentration     |
|       |     | conflicts with the Institute for Environmental Science |
|       |     | and Technology recommended practice IEST-RP-006.2,     |
|       |     | which recommends a challenge concentration of 10 - 20  |
|       |     | micrograms per liter. FDA should reference IEST        |
|       |     | guidelines or the upcoming ISO guideline (14644-3)     |
|       |     | that will replace IEST recommended practices. A larger |
|       |     | challenge concentration is unnecessary, does not set   |
|       |     | up the photometer properly for reading low level       |
|       |     | leaks, and may be difficult if not impossible to       |
|       |     | achieve in larger HVAC systems. Per IEST-RP-CC006.2, a |
|       |     | concentration of 10 micrograms/L is equivalent to 3 x  |
|       |     | 10\^10 droplets/cubic meter (10\^9 droplets/cubic      |
|       |     | foot).                                                 |
|       |     |                                                        |
|       |     | Lines 321 -- 324 "A single probe reading equivalent t  |
|       |     | 0.01 percent of the upstream challenge should be       |
|       |     | considered as indicative of a significant leak and     |
|       |     | should result in replacement of the HEPA filter or,    |
|       |     | when appropriate, repair in a limited area." This      |
|       |     | statement seems to indicate that replacement of the    |
|       |     | HEPA is the preferred method. This may not be true, as |
|       |     | repair of the HEPA is a preferable practice in many    |
|       |     | cases, due to the disruption in the cleanroom          |
|       |     | environment while removing and replacing the HEPA      |
|       |     | filter. IEST allows for repair of up to 3% of the      |
|       |     | filter face, as long as the shortest dimension of any  |
|       |     | repair is less than 3.8 cm (1.5 in).                   |
|       |     |                                                        |
|       |     | Lines 326-333: "HEPA filter leak testing alone is not  |
|       |     | sufficient to monitor filter performance. This testing |
|       |     | is usually done only on a semi-annual basis. It is     |
|       |     | important to conduct periodic monitoring of filter     |
|       |     | attributes such as uniformity of velocity across the   |
|       |     | filter (and relative to adjacent filters) *where       |
|       |     | possible*. Variations in velocity generally increase   |
|       |     | the possibility of contamination, as these changes     |
|       |     | (e.g., velocity reduction) can have an effect on       |
|       |     | unidirectional airflow. Airflow velocities are         |
|       |     | measured 6 inches from the filter face and at a        |
|       |     | defined distance proximal to the work surface for HEPA |
|       |     | filters in the critical area. Regular velocity         |
|       |     | monitoring can provide useful data on the clean area   |
|       |     | in which aseptic processing is performed." This        |
|       |     | verbiage implies that semi-annually monitoring the     |
|       |     | velocity across the filter is not frequent enough,     |
|       |     | when in fact it is standard industry practice to take  |
|       |     | this measurement when leak testing is performed on the |
|       |     | HEPAs. The modifier "where possible" should be added   |
|       |     | as shown. Some tunnels are of such construction that   |
|       |     | this measurement is not possible.                      |
+-------+-----+--------------------------------------------------------+
| Line  | T   | "Facility design should ensure that the ~~area~~       |
| 373   |     | *production path* between a filling line and the       |
|       |     | lyophilizer and the transport and loading procedures   |
|       |     | provide Class 100 (ISO 5) protection."                 |
|       |     |                                                        |
|       |     | This change allows for the use of HEPA filtered        |
|       |     | transport carts.                                       |
+-------+-----+--------------------------------------------------------+
| Lines | T   | " With rare exception, drains are not considered       |
| 403-5 |     | appropriate for rooms in class 100 and 1000            |
|       |     | ~~classified~~ areas of the aseptic processing         |
|       |     | facility."                                             |
|       |     |                                                        |
|       |     | Drains are needed and appropriate in class 10,000 and  |
|       |     | 100,000 areas in conjunction with washing, bulk        |
|       |     | dilution and compounding activities. Proper            |
|       |     | sanitization and monitoring can justify their          |
|       |     | inclusion in the class 10,000 and 100,000 areas.       |
+-------+-----+--------------------------------------------------------+
| Lines | T   | Personnel should not disrupt the path of laminar flow  |
| 4     |     | in the aseptic processing zone.                        |
| 59-60 |     |                                                        |
|       |     | This statement is not necessarily true for isolated    |
|       |     | processes.                                             |
+-------+-----+--------------------------------------------------------+
| Line  | E   | ".. several locations on a gown (e.g., glove fingers,  |
| 490   |     | facemask, forearm, chest~~,~~ ~~other~~ ~~sites~~)."   |
|       |     |                                                        |
|       |     | Delete "other sites"; it does not make sense in a "for |
|       |     | example" statement.                                    |
+-------+-----+--------------------------------------------------------+
| Line  | E   | Reference error -- reference should be to Section X.   |
| 527   |     | Laboratory Controls                                    |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "A container closure system that permits penetration   |
| 629   |     | of air... is unsuitable for a sterile product."        |
|       |     |                                                        |
|       |     | This is not necessarily true. Some bag containers may  |
|       |     | have very low air and water vapor transmission levels, |
|       |     | which over time (years) make the product unsuitable    |
|       |     | chemically, but have no negative impact on the         |
|       |     | microbiological quality of the product.                |
+-------+-----+--------------------------------------------------------+
| Line  | T   | "All personnel who enter the aseptic processing area,  |
| 75    |     | including technicians and maintenance personnel,       |
| 8-760 |     | should participate in a media fill at least once a     |
|       |     | year."                                                 |
|       |     |                                                        |
|       |     | The modifier "during manufacturing" should be added    |
|       |     | after "aseptic processing area". There are technicians |
|       |     | and maintenance people who may work in the room or on  |
|       |     | the equipment, that do so only after aseptic           |
|       |     | manufacturing as ceased and prior to cleaning. Their   |
|       |     | presence would not occur during production, so there   |
|       |     | is not need for it to occur during media fills.        |
+-------+-----+--------------------------------------------------------+
| Line  | E   | "For operations with production sizes under 5,000, the |
| 805 - |     | number of media filled units should be *at least*      |
| 807   |     | equal the maximum batch size made on the processing    |
|       |     | line (Ref. 8).                                         |
|       |     |                                                        |
|       |     | Clarified to agree with ISO verbiage.                  |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "The media fill program should adequately address the  |
| 8     |     | range of line speeds (e.g., by bracketing vial sizes   |
| 22-23 |     | and fill volumes) employed during production."         |
|       |     |                                                        |
|       |     | We agree that there may be a need to bracket unit      |
|       |     | sizes, but there should be no need to bracket fill     |
|       |     | volumes for any given size, so long as the volume      |
|       |     | filled into the container adequately contacts all      |
|       |     | internal surfaces of the unit.                         |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "Media fills should be adequately representative of    |
| 8     |     | the range of conditions under which actual             |
| 33-39 |     | manufacturing operations are conducted. An inaccurate  |
|       |     | assessment (making the process appear cleaner than it  |
|       |     | actually is) can result from conducting a media fill   |
|       |     | under extraordinary air and microbial quality, or      |
|       |     | under production controls and precautions taken in and |
|       |     | microbial quality, or under production controls and    |
|       |     | precautions taken in particulate and microbial         |
|       |     | quality, or under production controls and precautions  |
|       |     | taken in preparation for the media fill. To the extent |
|       |     | standard operating procedures permit stressful         |
|       |     | conditions, it is important that media fills include   |
|       |     | analogous challenges to support the validity of these  |
|       |     | studies."                                              |
|       |     |                                                        |
|       |     | It may be technically difficult to increase or         |
|       |     | decrease humidity in conjunction with increasing or    |
|       |     | decreasing temperature, whichever is "worst case" for  |
|       |     | a particular operation; and one must consider that     |
|       |     | after attempting to get a room to, or in excess of,    |
|       |     | its room operating parameters, one must then get it    |
|       |     | back to its "ideal" conditions. It is unclear how the  |
|       |     | agency anticipates achieving "worst case" viable and   |
|       |     | non-viable conditions. One assumes we are not expected |
|       |     | to purposefully contaminate a manufacturing area. A    |
|       |     | well constructed room should not vary widely and media |
|       |     | fills run twice a year should pick up these            |
|       |     | fluctuations. Add the work "only" to Line 836 as a     |
|       |     | point of clarification.                                |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "Media selected should be demonstrated to promote      |
| 84    |     | growth of USP \<71\> indicator microorganisms as well  |
| 5-848 |     | as isolates that have been identified by environmental |
|       |     | monitoring, personnel monitoring, and positive         |
|       |     | sterility test results."                               |
|       |     |                                                        |
|       |     | Inclusion of these isolates does not add value to the  |
|       |     | media fill program. Organisms referenced in USP \<71\> |
|       |     | reflect a broad spectrum of microorganisms.            |
|       |     | Environmental isolates are often difficult to work     |
|       |     | with in culture, die quickly, and do not represent     |
|       |     | true environmental conditions *in vitro*.              |
+-------+-----+--------------------------------------------------------+
| Lines |     | "Each media filled unit should be examined for         |
| 8     |     | contamination by personnel with appropriate education, |
| 77-78 |     | training and experience in microbiological techniques. |
|       |     | Each media-filled unit should be examined for          |
|       |     | contamination by personnel with appropriate education, |
|       |     | training, and experience in microbiological            |
|       |     | techniques."                                           |
|       |     |                                                        |
|       |     | This statement implies that formal education (i.e.,    |
|       |     | college degree) is required to examine media fill      |
|       |     | units. Any individual with appropriate visual acuity   |
|       |     | and training can accomplish this task. The word        |
|       |     | "education" should be removed from this statement.     |
+-------+-----+--------------------------------------------------------+
| Lines |     | "There should be direct quality control unit oversight |
| 87    |     | throughout any such examination."                      |
| 8-879 |     |                                                        |
|       |     | Direct quality control oversight could be interpreted  |
|       |     | to mean either a quality control unit approval by      |
|       |     | signature, or verified by (which would require quality |
|       |     | control check of all inspected vials). What is the     |
|       |     | expectation?                                           |
+-------+-----+--------------------------------------------------------+
| Lines | T   | \"After incubation is underway, any unit found to be   |
| 88    |     | damaged should be included in the data for the media   |
| 8-889 |     | fill batch, because the incubation of the units        |
|       |     | simulates release to the market.\"                     |
|       |     |                                                        |
|       |     | Media filled units may not be able to be processed     |
|       |     | with the same package integrity checks as the finished |
|       |     | products, therefore a damaged unit may go undetected   |
|       |     | unless growth occurs. This may not be representative   |
|       |     | of the finished product.                               |
+-------+-----+--------------------------------------------------------+
| Lines | T   | " Video recording of a media fill has been found to be |
| 9     |     | useful in identifying personnel practices that could   |
| 16-18 |     | negatively impact the aseptic process.                 |
|       |     |                                                        |
|       |     | Is this guidance or a requirement? The use of          |
|       |     | videotaping should be optional, and for those who      |
|       |     | chose to use it, it should not be treated as batch     |
|       |     | documentation or material which needs to comply to     |
|       |     | 21CFR Part 11. For those who chose to use it,          |
|       |     | videotapes should be treated as internal audit         |
|       |     | material to be reviewed, corrective actions taken as   |
|       |     | appropriate and them the tape destroyed. Additionally, |
|       |     | European and German law (protection of privacy) and/or |
|       |     | Unions might make it difficult if not impossible to    |
|       |     | obtain permission to tape such working sessions and to |
|       |     | keep the tapes on file.                                |
+-------+-----+--------------------------------------------------------+
| Line  | E   | " 2 contaminated units are considered cause for        |
| 940   |     | revalidation, ~~following~~ *as appropriate based on*  |
|       |     | investigation *results*."                              |
| Line  |     |                                                        |
| 944   |     | Clarify that the need to revalidate is based on the    |
|       |     | investigation results, not that revalidation occurs    |
|       |     | regardless of the investigation results.               |
+-------+-----+--------------------------------------------------------+
| Line  |     | "Normally, integrity testing of the filter is          |
| 10    |     | performed prior to processing, after the filter        |
| 20-21 |     | apparatus has already been assembled and sterilized"   |
|       |     |                                                        |
|       |     | It is not technically possible in many instances to    |
|       |     | perform integrity testing post sterilization and prior |
|       |     | to use without jeopardizing the sterility of the       |
|       |     | system. It is usually possible to perform integrity    |
|       |     | testing prior to sterilization. Propose change to      |
|       |     | read, "Normally, integrity testing of the filter is    |
|       |     | performed prior to and after processing."              |
+-------+-----+--------------------------------------------------------+
| Lines | E/T | Section IX.C Sterilization of Equipment and Container  |
| 1029  |     | Closures. Moist heat sterilization methods should be   |
| -1133 |     | referenced to documents dealing specifically with      |
|       |     | moist heat sterilization. As technology changes it is  |
|       |     | more likely that these documents will be updated more  |
|       |     | quickly and we could find ourselves with conflicting   |
|       |     | guidance.                                              |
+-------+-----+--------------------------------------------------------+
| Line  | E   | "[We]{.underline} recommend you consider use of        |
| 1027  |     | sterilizing-grade filters in series; this is a common  |
|       |     | practice."                                             |
|       |     |                                                        |
|       |     | This sentence appears to have been "stuck in" at the   |
|       |     | last minute and in the wrong location. Also the        |
|       |     | sentence structure is unusual in that it starts "We    |
|       |     | recommend..." which is language too informal for this  |
|       |     | type of document. This is an example of Compliance     |
|       |     | branch attempting to dictate process design that is    |
|       |     | provided to and agreed upon with the Review branch of  |
|       |     | the Agency. This statement should be removed from the  |
|       |     | document.                                              |
+-------+-----+--------------------------------------------------------+
| Line  | E   | "...these sites. Requalification and/o revalidation    |
| 1068  |     | ..."                                                   |
|       |     |                                                        |
|       |     | Insert a paragraph break between the sentences. The    |
|       |     | subject changes from initial qualification to          |
|       |     | requalification.                                       |
+-------+-----+--------------------------------------------------------+
| Lines | R   | "The formal program providing for regular (i.e.,       |
| 10    |     | semiannual, annual) revalidation should consider the   |
| 73-74 |     | age of the sterilizer and its past performance."       |
|       |     |                                                        |
|       |     | The age of a sterilizer should have nothing to do with |
|       |     | its acceptability. If the vessel is operating properly |
|       |     | and is covered under a routine maintenance program,    |
|       |     | then provided it passes revalidation that should be    |
|       |     | sufficient. The word "age" should be removed from the  |
|       |     | sentence.                                              |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "The microbial count and D-value of a biological       |
| 11    |     | indicator should be confirmed before a validation      |
| 17-18 |     | study."                                                |
|       |     |                                                        |
|       |     | ISO 11138-1: 1994 (E), United States Pharmacopeia      |
|       |     | (USP) \<55\>, USP \<1035\>, and USP \<1208\> all       |
|       |     | contain provision for accepting BI D-values from the   |
|       |     | manufacturer provided the supplier is an approved      |
|       |     | supplier.                                              |
|       |     |                                                        |
|       |     | If D-value is confirmed "in-house", this statement     |
|       |     | needs to be clarified as it is in the Glossary Section |
|       |     | (Lines 1960) that D-values are only required upon      |
|       |     | receipt and the D-value is good over the shelf-life.   |
|       |     | They do not need to be repeated before each validation |
|       |     | study. These two sections need to be corrected to meet |
|       |     | the requirements of the USP.                           |
+-------+-----+--------------------------------------------------------+
| Lines | T   | \"The monitoring program should cover all production   |
| 11    |     | shifts and include air, floors, walls, and equipment   |
| 52-54 |     | surfaces including the critical surfaces in contact    |
|       |     | with the product and container/closures.\" Critical    |
|       |     | surface monitoring is not necessary because sterility  |
|       |     | of these surfaces is demonstrated during media fills   |
|       |     | and validation of sterilizers. Monitoring of theses    |
|       |     | surfaces is subject to inadvertent contamination and   |
|       |     | the error is greater than the sensitivity of the test. |
|       |     | This should not be required for product contact        |
|       |     | surfaces that are sterilized prior to use on a         |
|       |     | per-batch.                                             |
+-------+-----+--------------------------------------------------------+
| Lines | E   | "As part of methods validation, the quality control    |
| 1     |     | laboratory should evaluate what media exposure         |
| 273-5 |     | conditions optimize recovery of low levels of          |
|       |     | environmental isolates."                               |
|       |     |                                                        |
|       |     | Remove from section and fit into Section B.            |
|       |     | Microbiological Media and Identification. (Brian need  |
|       |     | rationale.)                                            |
+-------+-----+--------------------------------------------------------+
| Line  | E   | "[We recommend]{.underline} the use of test methods    |
| 13    |     | that, upon evaluation, demonstrate increased accuracy, |
| 25-26 |     | sensitivity, and reproducibility."                     |
|       |     |                                                        |
|       |     | This is non-value added information - delete.          |
|       |     | Additionally, the use of the word "we" is too informal |
|       |     | for this type of document.                             |
+-------+-----+--------------------------------------------------------+
| Lines | E   | Section XI Sterility Testing. This section should be   |
| 1342  |     | pared down to include only those sections on sterility |
| -1399 |     | testing not covered by the USP. Duplication of         |
|       |     | information will eventually lead to contradictions.    |
|       |     | Point in fact, the current referenced USP \<71\>       |
|       |     | verbiage in footnote 12 will be eliminated when the    |
|       |     | new verbiage comes into effect in January. The only    |
|       |     | information that should be remaining is Section E.     |
|       |     | Investigation of Sterility Positives offers guidance   |
|       |     | not provided in \<71\> (minus the USP quote).          |
+-------+-----+--------------------------------------------------------+
| Lines | T   | \".. batch processing circumstances -Samples should be |
| 1     |     | taken in conjunction with processing interventions or  |
| 395-6 |     | excursions.\"                                          |
|       |     |                                                        |
|       |     | Allowed interventions should be simulated in the media |
|       |     | fill, thus demonstrating intervention acceptability.   |
|       |     | Therefore, additional sterility test samples should    |
|       |     | not have to taken after interventions during           |
|       |     | production. Further, this is an attempt to test        |
|       |     | quality into a product. Any suspect containers after   |
|       |     | an intervention should be discarded.                   |
+-------+-----+--------------------------------------------------------+
| Line  | T/E | "[We recommend]{.underline} the use of isolators to    |
| 13    |     | perform sterility testing. This is a well-established  |
| 51-53 |     | means for minimizing false positives."                 |
|       |     |                                                        |
|       |     | A statement needs to be added that excludes isolators  |
|       |     | used for sterility testing from this guidance          |
|       |     | document. This should be left to the manufacturer.     |
|       |     |                                                        |
|       |     | The use of the word "we" is too informal for this type |
|       |     | of document -- restructure sentence to read -- "The    |
|       |     | use of isolators is recommended to perform...Isolators |
|       |     | used for sterility testing should follow guidance as   |
|       |     | provided in USP \<1206\>""                             |
+-------+-----+--------------------------------------------------------+
| Lines | E   | "To more accurately monitor potential contamination    |
| 1     |     | sources, [we recommend]{.underline} you keep separate  |
| 445-6 |     | trends by product, container type, filling line, and   |
|       |     | personnel."                                            |
|       |     |                                                        |
|       |     | The use of the word "we" is too informal for this type |
|       |     | of document -- restructure sentence to read --         |
|       |     | "...sources, it is recommended separate trends are     |
|       |     | kept by product ..."                                   |
+-------+-----+--------------------------------------------------------+
| 1538  | E   | "However, users should not adopt a false sense of      |
| -1539 |     | security with these systems."                          |
|       |     |                                                        |
|       |     | Remove sentence. Serves no useful purpose as guidance. |
+-------+-----+--------------------------------------------------------+
| Line  | E   | Add the same verbiage to this Appendix 1 that is in    |
| 1540  |     | Lines 1721-23 of Appendix 2. "Except where otherwise   |
|       |     | noted below, the aseptic processing standards          |
|       |     | discussed elsewhere in this document should be applied |
|       |     | in Isolator technology."                               |
+-------+-----+--------------------------------------------------------+
| Line  | T   | "However, a leak in any of certain components of the   |
| 15    |     | system can constitute a significant breach of          |
| 47-48 |     | integrity."                                            |
|       |     |                                                        |
| Line  |     | "A faulty glove or sleeve (gauntlet) assembly          |
| 15    |     | represents a route of contamination and a critical     |
| 56-57 |     | breach of isolator integrity.                          |
|       |     |                                                        |
| Lines |     | "....holes in gloves and seams or other leaks.         |
| 1     |     | Breaches of integrity should be investigated and any   |
| 682-4 |     | product that may have been impacted by the breach      |
|       |     | rejected.                                              |
|       |     |                                                        |
|       |     | There is no clear indication that detection of a       |
|       |     | breach in a glove should result in batch termination.  |
|       |     | The isolator is usually positive pressure and/or       |
|       |     | sterile gloves are worn by operators and are           |
|       |     | frequently disinfected by IPA. If it can be            |
|       |     | demonstrated in media fills that a glove can be        |
|       |     | aseptically changed out or tie-off during, then this   |
|       |     | practice should be allowed in production to continue   |
|       |     | production.                                            |
+-------+-----+--------------------------------------------------------+
| Line  | T   | "...the inner part of the installed glove should be    |
| 15    |     | sanitized regularly and the operator should also wear  |
| 65-66 |     | s second pair of this gloves."                         |
|       |     |                                                        |
|       |     | The installed glove should not be sanitized with       |
|       |     | regularly with alcohol. Regular alcohol sanitization   |
|       |     | will more rapidly deteriorate the installed glove and  |
|       |     | put the glove more at risk for a breach. The installed |
|       |     | glove is initially decontaminated and unless the glove |
|       |     | handles a non‑decontaminated surface, there should be  |
|       |     | no need to treat it with alcohol. It would be a better |
|       |     | practice for the operator to wear gloves on their      |
|       |     | hands and regularly decontaminated those gloves with   |
|       |     | alcohol (making sure they are dry) before inserting    |
|       |     | their gloved hands into the installed gloves.          |
+-------+-----+--------------------------------------------------------+
| 1538  | E   | "However, users should not adopt a false sense of      |
| -1539 |     | security with these systems."                          |
|       |     |                                                        |
|       |     | Remove sentence. Information that serves no useful     |
|       |     | purpose.                                               |
+-------+-----+--------------------------------------------------------+
| 1757  | E   | "In contrast to nonpharmaceutical applications using   |
| -1759 |     | BFS machinery, control of air quality (i.e. particles) |
|       |     | is critical for sterile drug product manufacture.      |
|       |     |                                                        |
|       |     | Remove sentence. The guidance is already in lines      |
|       |     | 1749-1755 -- this is non-value added.                  |
+-------+-----+--------------------------------------------------------+
| Line  | T   | "An appropriate, quantified BI challenge should be     |
| 16    |     | placed on various materials..."                        |
| 59-61 |     |                                                        |
|       |     | Add, "The choice of BI can be supported either through |
|       |     | literature references or from laboratory generated     |
|       |     | data or a combination of both." It is not necessary to |
|       |     | challenge various materials if literature already      |
|       |     | provides information on materials used.                |
+-------+-----+--------------------------------------------------------+
| Lines | T   | "Microbiological and particulate monitoring should be  |
| 1837  |     | performed during operations, *provided the act of      |
|       |     | sampling does not interfere with the aseptic           |
|       |     | operation*."                                           |
|       |     |                                                        |
|       |     | For operations where sampling will interfere with      |
|       |     | aseptic operations, sampling should be performed       |
|       |     | immediately following operations.                      |
+-------+-----+--------------------------------------------------------+
| 1841  | E   | Suggestion 1 Remove paragraphs or rework them into     |
| -1856 |     | previous sections. These paragraphs are outside the    |
|       |     | scope of APPENDIX 3: PROCESSING PRIOR TO FILLING AND   |
|       |     | SEALING OPERATIONS.                                    |
|       |     |                                                        |
|       |     | Suggestion 2: Section B. may need to have a special    |
|       |     | section or guidance as this is a high risk therapy     |
|       |     | with innovative technologies and this seems to provide |
|       |     | a very vague recommendation compared with the rest of  |
|       |     | the document.                                          |
+-------+-----+--------------------------------------------------------+
| Line  | T   | Add definition for Controlled Environment. Per the     |
| 1971  |     | Institute of Validation Technology Dictionary,         |
|       |     | CONTROLLED ENVIRONMENT - Any area in an aseptic        |
|       |     | process system for which airborne particulate and      |
|       |     | microorganism levels are controlled to specific levels |
|       |     | appropriate to the activities conducted within that    |
|       |     | environment.                                           |
+-------+-----+--------------------------------------------------------+
| Line  | T   | "Decontamination -- A process which eliminates viable  |
| 19    |     | bioburden via use of sporicidal chemical agents."      |
| 85-86 |     |                                                        |
|       |     | This is a complete departure from the definitions of   |
|       |     | decontamination to date -- to require the use of a     |
|       |     | sporicidal agent. OSHA defines decontamination as, "   |
|       |     | the use of physical or chemical means to remove,       |
|       |     | inactivate, or destroy blood-borne pathogens on a      |
|       |     | surface or item to the point where they are no longer  |
|       |     | capable of transmitting infectious particles and the   |
|       |     | surface or item is rendered safe for handling, use or  |
|       |     | disposal \[29CFR 1910.1030\]. According to AAMI        |
|       |     | (Standards and recommended practices, 1995)            |
|       |     | decontamination generally refers to all pathogens      |
|       |     | (microorganisms capable of producing diseases or       |
|       |     | infections), not just those transmitted by human       |
|       |     | blood.                                                 |
+-------+-----+--------------------------------------------------------+
| Line  | T   | The definition for laminar is no longer be required    |
| 2022  |     | with the transition to the word unidirectional         |
+-------+-----+--------------------------------------------------------+
| Line  | T   | Overkill sterilization 6 log reduction of a heat       |
| 2028  |     | resistant organism                                     |
+-------+-----+--------------------------------------------------------+
| Line  | E   | "...usually less than 10^-6^...."                      |
| 20    |     |                                                        |
| 45-47 |     | Should be usually equal to or less than 10^-6^.        |
+-------+-----+--------------------------------------------------------+
| Line  | T   | The definition of ULPA filter is incorrect (e.g.,      |
| 22    |     | FDA\'s definition references 0.3 micrometer particle   |
| 49-50 |     | size). The definition should either be deleted because |
|       |     | there is no need for ULPA filters or the definition    |
|       |     | needs to correct. Use a definition that is already     |
|       |     | accepted by experts conversant in the technology. An   |
|       |     | ULPA filter is defined by IEST as \"a throwaway,       |
|       |     | extended-medium, dry-type filter in a rigid frame      |
|       |     | having a minimum particle-collection efficiency of     |
|       |     | 99.999% for particles 0.12 micrometer and larger.\"    |
+-------+-----+--------------------------------------------------------+