+----+-----------------------------------------------------------------+
| ** | **Comment**                                                     |
| Li |                                                                 |
| ne |                                                                 |
| Re |                                                                 |
| f. |                                                                 |
| ** |                                                                 |
+====+=================================================================+
| 70 | **Comment/Objection:** The sentence that reads: **"**There are  |
|    | basic differences between the production of sterile drug        |
|    | products using aseptic processing and production using terminal |
|    | sterilization." Should be changed to exclude terminally         |
|    | sterilized products from this guidance.                         |
|    |                                                                 |
|    | **Rationale:** As the guidance states there are basic           |
|    | differences between the production of terminally sterilized     |
|    | products sterile drug products using aseptic processing and     |
|    | production using terminal sterilization and it should be clear  |
|    | that this guidance does not apply to terminally sterilized      |
|    | products.                                                       |
|    |                                                                 |
|    | **Alternative Text:** There are basic differences between the   |
|    | production of sterile drug products using aseptic processing    |
|    | and production using terminal sterilization*[, and as such this |
|    | guidance does not apply to terminally sterilized                |
|    | products]{.underline}*.                                         |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection**: The sentence that reads "In such         |
| 14 | cases..." is a statement without guidance as to when such       |
|    | evaluation is required.                                         |
|    |                                                                 |
|    | **Rationale:** As stated in line 109 this guidance relates to   |
|    | CGMP issues and not how or why a product is developed.          |
|    |                                                                 |
|    | **Alternative Text:** Although this guidance document discusses |
|    | CGMP issues relating to the sterilization of components,        |
|    | containers, and closures, terminal sterilization of drug        |
|    | products is not addressed. ~~It is a well-accepted principle    |
|    | that sterile drugs should be manufactured using aseptic         |
|    | processing only 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.~~                                                   |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection**: The current sentence reads "The aseptic  |
| 36 | processing facility monitoring program should also assess       |
|    | conformance with specified clean area classifications under     |
|    | dynamic conditions on a routine basis." Does this mean routine  |
|    | environmental monitoring?                                       |
|    |                                                                 |
|    | **Rationale**: Statement is unclear                             |
|    |                                                                 |
|    | **Alternative Text:** The aseptic processing facility's routine |
|    | *[environmental]{.underline}* monitoring program should         |
|    | ~~also~~ assess ~~conformance with specified clean area         |
|    | classifications~~ *[the environment]{.underline}* under dynamic |
|    | conditions. A single action level or alert level result at an   |
|    | identified location should not automatically require the        |
|    | conducting of an investigation. Multiple alert and action level |
|    | results at an identified location should however prompt a       |
|    | formal investigation, based upon trend analysis."               |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection:** Footnote 'e' states: "Samples ... should |
| 52 | normally yield no microbiological contaminants" is inconsistent |
|    | with Table1 that sets the action level at 1 cfu.                |
|    |                                                                 |
|    | **Rationale**: Inconsistent                                     |
|    |                                                                 |
|    | Alternate text: Footnote 'e': ~~Samples ... should normally     |
|    | yield no microbiological contaminants" is inconsistent with     |
|    | Table1 that sets the action level at 1 cfu.~~ *[A target of no  |
|    | microbiological contaminants for samples from Class 100 (ISO 5) |
|    | environments should be the goal. Occasional microbial counts    |
|    | may be acceptable with proper investigation.]{.underline}*      |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection:**                                          |
| 67 |                                                                 |
|    | The sentence that reads "Particles are significant because they |
|    | can enter a product and contaminate it physically or, by acting |
|    | as a vehicle for microorganisms, biologically (Ref. 2)." is not |
|    | technically accurate.                                           |
|    |                                                                 |
|    | **Rationale:** Environmental particles are too small to         |
|    | "contaminate" a product physically. Visual and machine          |
|    | inspection would not detect the presence of these particles in  |
|    | the unlikely event they were to find their way into the         |
|    | finished product.                                               |
|    |                                                                 |
|    | **Alternate Text:** ~~Particles are significant because they    |
|    | can enter a product and contaminate it physically or, by acting |
|    | as a vehicle for microorganisms, biologically (Ref. 2)."~~      |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection:** Replace \"micron\" with \"micro meter\"  |
| 74 | throughout the document.                                        |
|    |                                                                 |
| 3  | **Rationale:** Harmonization                                    |
| 04 |                                                                 |
|    | **Alternate Text:** Replace \"micron\" with \"micro meter\"     |
| 3  |                                                                 |
| 10 |                                                                 |
|    |                                                                 |
| Fn |                                                                 |
| 7  |                                                                 |
|    |                                                                 |
| 9  |                                                                 |
| 69 |                                                                 |
|    |                                                                 |
| 9  |                                                                 |
| 76 |                                                                 |
|    |                                                                 |
| 20 |                                                                 |
| 01 |                                                                 |
|    |                                                                 |
| 20 |                                                                 |
| 49 |                                                                 |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection:** The term "Shift" needs defining          |
| 83 | precisely. It has no real meaning except as a team of people.   |
| &  | Here it is a time function apparently. If a Team (Shift) work   |
| 11 | for 2.5 hours and take a break, work 2.5 hours and have a       |
| 53 | second break, 2.5 hours again for a third break is this one,    |
|    | two or three shifts?                                            |
|    |                                                                 |
|    | **Rationale**: To promote consistency                           |
|    |                                                                 |
|    | **Recommended Definition:** A shift is a defined period of time |
|    | where a group of personnel carry out scheduled work activities, |
|    | as defined by the manufacturer.                                 |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection:** The term "certification" is used         |
| 92 | inconsistently throughout the document. This term is used       |
| &  | associated with qualification, classification and               |
| 3  | certification.                                                  |
| 38 |                                                                 |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection:** Delete the concept of point of use from  |
| 96 | the sentence "Air in critical areas should be supplied at the   |
|    | point of use as HEPA-filtered laminar flow air at a velocity    |
|    | sufficient to sweep particles away from the filling/closing     |
|    | area and maintain unidirectional airflow during operations" and |
|    | footnote 4 on page 6.                                           |
|    |                                                                 |
|    | **Rationale:** "Supplied at the point of use" is overly         |
|    | restrictive and the term "laminar" is incorrect. Unidirectional |
|    | airflow in isolators may not be necessary or desirable;         |
|    | likewise the requirement to maintain 0.45 to 0.51 m/s velocity. |
|    |                                                                 |
|    | **Alternate Text:** Delete footnote 4 and change sentence in    |
|    | line 198 to read:                                               |
|    |                                                                 |
|    | Air in critical areas should be ~~supplied at the point of use  |
|    | as~~ HEPA-filtered unidirectional ~~laminar~~ flow air at a     |
|    | velocity sufficient to sweep particles away from the            |
|    | filling/closing area and maintain unidirectional airflow during |
|    | operations. The velocity parameters established for each        |
|    | processing line should be justified and appropriate to maintain |
|    | unidirectional airflow and air quality under dynamic conditions |
|    | within a defined space (Ref. 3).~~4~~                           |
+----+-----------------------------------------------------------------+
| 2  | **Comment/Objection**: The sentence that reads "Air monitoring  |
| 14 | of critical areas should normally yield no microbiological      |
|    | contaminants" is inconsistent with Table1 that sets the action  |
|    | level at 1 cfu.                                                 |
|    |                                                                 |
|    | **Rationale**: Inconsistent, Contradicts lines ***146-152 note  |
|    | c***                                                            |
|    |                                                                 |
|    | **Alternate text:** *[A target of no microbiological            |
|    | contaminants for air monitoring samples from Class 100 (ISO 5)  |
|    | environments should be the goal. All excursions should receive  |
|    | investigation attention and occasional microbial counts may be  |
|    | acceptable with proper investigation.]{.underline}*             |
+----+-----------------------------------------------------------------+
| 2  | **Comment/Objection**: The text that reads "For example, a      |
| 38 | positive pressure differential of at least 12.5 Pascals         |
|    | (Pa)[^1] should be maintained at the interface between          |
|    | classified and unclassified areas. This same overpressure       |
|    | should be maintained between the aseptic processing room and    |
|    | adjacent rooms (with doors closed). "It should not be necessary |
|    | to maintain any specific value, as long as a correct pressure   |
|    | cascade is maintained (as discussed in line241).                |
|    |                                                                 |
|    | **Rationale**: Unnecessary specificity.                         |
|    |                                                                 |
|    | **Alternative Text**: "~~For example, a positive pressure       |
|    | differential of at least 12.5 Pascals (Pa)~~[^2] ~~should be    |
|    | maintained at the interface between classified and unclassified |
|    | areas. This same~~ Overpressure should be maintained between    |
|    | the aseptic processing room and adjacent rooms (with doors      |
|    | closed). *[It should not be necessary to maintain any specific  |
|    | value, as long as the correct pressure cascade is               |
|    | maintained.]{.underline}*                                       |
+----+-----------------------------------------------------------------+
| 2  | **Comment/Objection:** The sentence that reads **"**Pressure    |
| 43 | differentials between cleanrooms should be monitored            |
|    | continuously throughout each shift and frequently recorded, and |
|    | deviations from established limits should be investigated." is  |
|    | overly burdensome.                                              |
|    |                                                                 |
|    | **Rationale:** The requirement to frequently record values from |
|    | a validated system that are within specification is overly      |
|    | burdensome and should be changed. Many monitoring systems take  |
|    | continuous readings ever few seconds from multiple sites, 7     |
|    | days a week, 24 hours a day.                                    |
|    |                                                                 |
|    | **Alternative Text:** Pressure differentials between cleanrooms |
|    | should be monitored continuously throughout and recorded at the |
|    | *[beginning and end of each shift. All alarms]{.underline}*     |
|    | should be recorded, and deviations from established limits      |
|    | should be investigated.                                         |
+----+-----------------------------------------------------------------+
| 2  | **Comments/Objection:** The sentence that reads "For areas of   |
| 49 | higher air cleanliness, significantly higher air change rates   |
|    | will provide an increased level of air purification." might be  |
|    | misinterpreted and not always scientifically correct.           |
|    |                                                                 |
|    | **Rationale:** Higher air exchange rate dose not necessarily    |
|    | provide an improved air "purity" quality especially in a        |
|    | turbulent flow clean room.                                      |
|    |                                                                 |
|    | **Alternative Text:** [*An adequate air change rate should be   |
|    | established for a non-unidirectional flow clean area. The air   |
|    | change rate should be based on the ~~particle generating~~      |
|    | operations that will be performed in the area or other factors  |
|    | set by the manufacturer.* ~~Typically an exchange rate of 20    |
|    | per hour is sufficient, but under high particle generation      |
|    | processes, such as Blow-Fill-Seal or capping operations, higher |
|    | exchange rates may be needed to maintain the particle counts or |
|    | other factors within specifications~~.]{.underline} ~~For areas |
|    | of higher air cleanliness, significantly higher air change      |
|    | rates will provide an increased level of air purification.~~    |
+----+-----------------------------------------------------------------+
| 2  | **Comments/Objection:** The sentence that reads "Sterilized     |
| 72 | holding tanks and any contained liquids should be held under    |
|    | continuous overpressure to prevent microbial contamination." Is |
|    | too restrictive and does not recognize alternate approaches.    |
|    |                                                                 |
|    | **Rationale:** Manufacturing situations where receiving carboys |
|    | are employed or tanks that are properly sealed may not be       |
|    | amenable to constant overpressure. This should not be expected  |
|    | where practitioners have properly validated sterile holding     |
|    | systems, including media fill data.                             |
|    |                                                                 |
|    | **Alternative Text**: Sterilized holding tanks and any          |
|    | contained liquids should be held ~~under continuous             |
|    | overpressure~~ to prevent microbial contamination. ~~Safeguards |
|    | should be in place to prevent a pressure change that can result |
|    | in contamination due to back flow of nonsterile air or          |
|    | liquid.~~ *[The use of overpressure or non-pressurized systems  |
|    | such as those utilizing 0.2 micro meter vent filters are        |
|    | acceptable when properly validated.]{.underline}* ~~via media   |
|    | fills~~. "                                                      |
+----+-----------------------------------------------------------------+
| 2  | **Comment/Objection**: The sentence that reads "Filters should  |
| 79 | be integrity tested upon installation, and periodically         |
|    | thereafter (e.g., including end of use)." is not a common       |
|    | practice and requires increased human interventions, increasing |
|    | the risk to maintain a sterile set-up.                          |
|    |                                                                 |
|    | **Rationale**: 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.                                      |
|    |                                                                 |
|    | **Alternative Text**: ~~Filters should be integrity tested upon |
|    | installation, and periodically thereafter (e.g., including end  |
|    | of use*[).]{.underline}*~~*[Filters should be integrity tested  |
|    | prior to installation and prior to disposal as part of a        |
|    | preventative maintenance program. They should also be regularly |
|    | monitored in use for viable and non-viable particles. Any       |
|    | excursions in monitoring should prompt an investigation that    |
|    | might include integrity testing.]{.underline}*                  |
+----+-----------------------------------------------------------------+
| 2  | **Comment/Objection**: The sentence that reads "Among the       |
| 93 | filters that should be leak tested are those installed in dry   |
|    | heat depyrogenation tunnels commonly used to depyrogenate glass |
|    | vials." is potentially dangerous.                               |
|    |                                                                 |
|    | **Rationale:** The HEPA filters located in the heating zone of  |
|    | a hot air sterilizing tunnel are not there to sterilize the air |
|    | passing through as the air has been heated to a sterilizing     |
|    | temperature (\>300^o^C) prior to filtration. A particulate test |
|    | should be performed, at normal cleanroom testing frequency,     |
|    | with the tunnel cold to determine the level of particulates     |
|    | that may be being shed from potentially heat degraded filter    |
|    | media.                                                          |
|    |                                                                 |
|    | **Alternative text:** Among the filters that should be leak     |
|    | tested are those installed [in the cooling zone]{.underline} of |
|    | dry heat depyrogenation tunnels ~~commonly used to depyrogenate |
|    | glass vials.~~ A particulate test should be performed in the    |
|    | sterilization zone, at normal cleanroom testing frequency, with |
|    | the tunnel cold to determine the level of particulates that may |
|    | be shed.                                                        |
+----+-----------------------------------------------------------------+
| 3  | **Comment/Objection**: The sentence that contains "...a DOP     |
| 13 | challenge should introduce the aerosol upstream of the filter   |
|    | in a concentration ranging from approximately 25 to l00         |
|    | micrograms/liter of air at the filter\'s designed airflow       |
|    | rating" should remove DOP reference, and not be specific as to  |
|    | challenge.                                                      |
|    |                                                                 |
|    | **Rationale**: The mention of any specific challenge agent is   |
|    | too specific and could discourage technological advancements.   |
|    | The challenge should be sufficient to verify the filter's       |
|    | efficiency rating.                                              |
|    |                                                                 |
|    | **Alternative Text**: "a ~~DOP~~ challenge should introduce the |
|    | aerosol upstream of the filter in a concentration ~~ranging     |
|    | from approximately 25 to l00 micrograms/liter of air~~          |
|    | *[sufficient to detect leaks ~~verify the filter's efficiency   |
|    | rating~~]{.underline}* at the filter\'s designed airflow"       |
+----+-----------------------------------------------------------------+
| 3  | **Comment/Objection**: The text that reads "HEPA filter leak    |
| 26 | 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)." conveys that current industry practices  |
|    | are ineffective.                                                |
|    |                                                                 |
|    | **Rationale**: This statement implies that semi-annual velocity |
|    | across the filter is not frequent enough when it is standard    |
|    | industry practice today.                                        |
|    |                                                                 |
|    | **Alternative Text**: "HEPA filter leak testing alone is not    |
|    | sufficient to monitor filter performance [for ISO Class 5       |
|    | areas]{.underline}. ~~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).~~ *[It    |
|    | should be performed in conjunction with testing for             |
|    | ~~uniformity of~~ velocity (sufficient to demonstrate           |
|    | uni-directional airflow) across the filter on at least a        |
|    | semi-annual basis."]{.underline}*                               |
+----+-----------------------------------------------------------------+
| 3  | **Comment/Objection**: The sentence that reads "It is important |
| 28 | to conduct periodic monitoring of filter attributes such as     |
|    | uniformity of velocity across the filter (and relative to       |
|    | adjacent filters)" is too vague.                                |
|    |                                                                 |
|    | **Rationale**: What is meant by periodic? [Change "periodic" to |
|    | "semi-annual".]{.underline}                                     |
|    |                                                                 |
|    | **Alternative Text**: It is important to conduct ~~periodic~~   |
|    | semi-annual monitoring of filter attributes such as uniformity  |
|    | of velocity across the filter (and relative to adjacent         |
|    | filters).                                                       |
+----+-----------------------------------------------------------------+
| 3  | **Comment:** The sentence that reads "Airflow velocities are    |
| 31 | measured 6 inches from the filter face and at a defined         |
|    | distance proximal to the work surface for HEPA filters in the   |
|    | critical area." should not require measurements at the work     |
|    | surface.                                                        |
|    |                                                                 |
|    | **Rationale**: Velocity "at a defined distance proximal to the  |
|    | work surface" is too vague to implement. The closer you get to  |
|    | any equipment or surface the more variable the data will be due |
|    | to air changing direction due to influences of the surfaces,    |
|    | i.e. flat surface bounce back or proper flow away from product. |
|    | Whatever location is chosen should be used over time so that    |
|    | velocity comparisons could be reasonably made.                  |
|    |                                                                 |
|    | **Alternative Text**: 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."      |
+----+-----------------------------------------------------------------+
| 3  | **Comment:** (Spelling) sterility                               |
| 48 |                                                                 |
|    | **Rationale**: Incorrect spelling                               |
|    |                                                                 |
|    | **Alternative Text**: Use correct spelling of sterility         |
+----+-----------------------------------------------------------------+
| 3  | **Comment/Objection:** The sentence that reads "The flow of     |
| 54 | personnel should be designed to limit the frequency with which  |
|    | entries and exits are made to and from an aseptic processing    |
|    | room and, most significantly, its critical area." might be      |
|    | misinterpreted.                                                 |
|    |                                                                 |
|    | **Rationale:** This statement may cause confusion and lead less |
|    | knowledgeable organizations, to add inappropriate items in the  |
|    | aseptic processing room or critical area.                       |
|    |                                                                 |
|    | **Alternative Text:** The flow of personnel should be designed  |
|    | to limit the frequency with which entries and exits are made to |
|    | and from an aseptic processing room and, most significantly,    |
|    | its critical area. *[However, caution must be exercised when    |
|    | designing an aseptic processing room or critical area to        |
|    | balance the need for limiting personnel movement and exits with |
|    | the desire not to clutter the room or area with items only      |
|    | needed for exceptions.]{.underline}*                            |
+----+-----------------------------------------------------------------+
| 3  | **Comment/Objection:** Replace the word "prefastened" with      |
| 65 | "preassembled".                                                 |
|    |                                                                 |
|    | **Rationale**: The proposed term is better recognized and more  |
|    | descriptive.                                                    |
|    |                                                                 |
|    | **Alternative Text**: Rather than performing an aseptic         |
|    | connection, sterilizing the ~~prefastened~~                     |
|    | *[preassembled]{.underline}* connection using                   |
|    | sterilize-in-place (SIP) technology also can eliminate a        |
|    | significant aseptic manipulation.                               |
+----+-----------------------------------------------------------------+
| 3  | **Comment/Objection**: The sentence that reads "Facility design |
| 73 | should ensure that the area between a filling line and the      |
|    | lyophilizer and the transport and loading procedures provide    |
|    | Class 100 (ISO 5) protection" does not recognize the potential  |
|    | of closed containers moving through higher classified areas.    |
|    |                                                                 |
|    | **Rationale**: A closed container can protect partially         |
|    | stoppered vials from adventitious contamination and the         |
|    | proposed text will harmonize the FDA guidance with Annex 1      |
|    | paragraph 12 part 4. In addition, the current text is           |
|    | unnecessarily specific and may prevent future technological     |
|    | advances for the transport of partially closed containers from  |
|    | a fill line to a lyophilizer.                                   |
|    |                                                                 |
|    | **Alternative Text:** To prevent contamination, partially       |
|    | closed sterile product should be transferred only in critical   |
|    | areas *[or closed containers]{.underline} by [either            |
|    | transporting in a Class 100 (ISO 5) environment, with a Class   |
|    | 10,000 (ISO 6) background or in closed ~~sealed~~ transfer      |
|    | trays in a Class 10,000 (ISO 6) environment.]{.underline}*      |
+----+-----------------------------------------------------------------+
| 4  | **Comment/Objection**: The requirement that reads "With rare    |
| 03 | exceptions, drains are not considered appropriate for           |
|    | classified areas of the aseptic processing facility" is too     |
|    | broad.                                                          |
|    |                                                                 |
|    | **Rationale**: Drains are appropriate in certain areas of       |
|    | higher classification, such as Class 100,000.                   |
|    |                                                                 |
|    | **Alternative Text**: "With rare exceptions, drains are not     |
|    | considered appropriate for ~~classified areas~~ [*Class 100     |
|    | (ISO Class 5) areas* *through Class 10,000 (ISO Class           |
|    | 7)*]{.underline} of the aseptic processing facility"            |
+----+-----------------------------------------------------------------+
| 4  | **Comment/Objection:** The sentences that read "Supervisory     |
| 32 | personnel should routinely evaluate each operator's conformance |
|    | to written procedures during actual operations. Similarly, the  |
|    | quality control unit should provide regular oversight of        |
|    | adherence to established, written procedures and basic aseptic  |
|    | techniques during manufacturing operations." will create overly |
|    | burdensome documentation in order to be complaint with the      |
|    | requirements specified.                                         |
|    |                                                                 |
|    | **Rationale**: The requirement is unclear as to frequency and   |
|    | documentation requirements and is too specific as to who should |
|    | perform this evaluation.                                        |
|    |                                                                 |
|    | **Alternative Text:** *[Operator's conformance to written       |
|    | procedures and basic principles of aseptic technique should be  |
|    | evaluated ~~periodically~~ during actual                        |
|    | operations.]{.underline}*                                       |
+----+-----------------------------------------------------------------+
| 4  | **Comment/Objection:** The text that reads "Sterile instruments |
| 52 | (e.g., forceps) should always be used in the handling of        |
|    | sterilized materials. Between uses, instruments should be       |
|    | placed only in sterilized containers. Instruments should be     |
|    | replaced as necessary throughout an operation. "is too          |
|    | prescriptive.                                                   |
|    |                                                                 |
|    | **Rationale:** Instruments should be protected and maintained   |
|    | as sterile \-- there are ways to do this besides placing in     |
|    | sterilized containers \-- It is possible to sit them on         |
|    | sterilized surfaces in Class 100 air.                           |
|    |                                                                 |
|    | **Alternate Text:** Between uses, instruments should be         |
|    | *[protected such that their sterility is not compromised,       |
|    | e.g.:]{.underline}* placed ~~only~~ in sterilized containers.   |
|    | Instruments should be replaced as necessary throughout an       |
|    | operation.                                                      |
+----+-----------------------------------------------------------------+
| 4  | **Comment/Objection:** The dot point that reads **"**Keeping    |
| 56 | the entire body out of the path of unidirectional air." is too  |
|    | specific and does not provide adequate guidance.                |
|    |                                                                 |
|    | **Rationale**: Any intervention will result in disruption of    |
|    | unidirectional airflow. It is not practical to expect that      |
|    | there will never be the need for interventions.                 |
|    |                                                                 |
|    | **Alternative Text**: ~~Keeping the entire body out of the path |
|    | of unidirectional air.~~ *[Personnel should minimize            |
|    | interventions into the critical zones. Such interventions can   |
|    | adversely disrupt the unidirectional air flow and should        |
|    | therefore be designed to minimize both the extent and frequency |
|    | of occurrence.]{.underline}*                                    |
+----+-----------------------------------------------------------------+
| 4  | **Comment/Objection:** The dot point and subsequent sentence    |
| 39 | that reads "Contacting sterile materials only with sterile      |
| &  | instruments.                                                    |
| 4  |                                                                 |
| 41 | Sterile instruments (e.g., forceps) should always be used in    |
|    | the handling of sterilized materials." is too specific and does |
|    | not provide adequate guidance.                                  |
|    |                                                                 |
|    | **Rationale**: Certain assembly and connecting of sterilized    |
|    | surfaces with sterile tools is impossible, i.e. assembling and  |
|    | fitting sterilized filling pumps is impossible with forceps. .  |
|    |                                                                 |
|    | **Alternative Text**:                                           |
|    |                                                                 |
|    | Sterile instruments (e.g., forceps) should always be used in    |
|    | the handling of sterilized materials *[(Critical                |
|    | Surfaces)]{.underline}*. *[Equipment set-up activities          |
|    | typically present a unique set of challenges to using proper    |
|    | aseptic techniques. Direct contact between gloved hands and the |
|    | critical surfaces of sterilized equipment parts (surfaces which |
|    | subsequently have direct product contact) is to be              |
|    | avoided.]{.underline}*                                          |
+----+-----------------------------------------------------------------+
| 4  | **Comment/Objection**: The sentence that reads "Prior to and    |
| 72 | throughout aseptic operations, an operator should not engage in |
|    | any activity that poses an unreasonable contamination risk to   |
|    | the gown." is too vague.                                        |
|    |                                                                 |
|    | **Rationale**: too vague and needs to be strengthened           |
|    |                                                                 |
|    | **Alternative Text**: "an operator should ~~not engage in any   |
|    | activity that poses an unreasonable~~ *[be trained to           |
|    | minimize]{.underline}* contamination risk to the gown"          |
+----+-----------------------------------------------------------------+
| 4  | **Comment/Objection**: The sentence that states "Semi-annual or |
| 93 | Yearly requalification is sufficient for automated operations   |
|    | where personnel involvement is minimized." conveys that current |
|    | industry practices are ineffective.                             |
|    |                                                                 |
|    | **Rationale**: Semi-annual requalification is not necessary     |
|    | when an effective personnel monitoring program is in place.     |
|    |                                                                 |
|    | **Alternative Text**: ~~Semi-annual or~~ Yearly requalification |
|    | is sufficient for automated operations where personnel          |
|    | involvement is minimized. *[Gowning requalification may be      |
|    | repeated based either upon adverse monitoring trends, issues    |
|    | raised in the change control program and/or on a timed basis    |
|    | such as annually.]{.underline}*                                 |
+----+-----------------------------------------------------------------+
| 5  | **Comment/Objection**: The text that reads "It is important to  |
| 37 | characterize the microbial content of each component that could |
|    | be contaminated and establish appropriate acceptance limits     |
|    | based on information on bioburden. Knowledge of bioburden is    |
|    | critical in assessing whether the sterilization process is      |
|    | adequate" over-simplifies this issue.                           |
|    |                                                                 |
|    | **Rationale**: Only limited bioburden data for components       |
|    | subject to ~~overkill~~ [validated]{.underline} sterilization   |
|    | is necessary. The term limit should be replaced with level to   |
|    | be consistent with other concepts in the document.              |
|    |                                                                 |
|    | **Alternative Text**: It is important to characterize the       |
|    | microbial content of each component that could be contaminated  |
|    | and establish appropriate ~~acceptance limits~~ levels based on |
|    | information on bioburden. *[Only limited bioburden data for     |
|    | components subject to validated sterilization cycles is         |
|    | necessary]{.underline}*."                                       |
+----+-----------------------------------------------------------------+
| 5  | **Comment/Objection:** The text that reads "If a component is   |
| 51 | not adversely affected by heat, and is soluble, it can be made  |
|    | into a solution and subjected to steam sterilization, typically |
|    | in an autoclave or a fixed pressurized sterilize-in-place (SIP) |
|    | vessel" is stating that a water soluble component (recipient or |
|    | API) can be solubilized and steam sterilized during the product |
|    | manufacturing process.                                          |
|    |                                                                 |
|    | **Rationale:** This should be included in the regulatory        |
|    | application and should not be included in this document.        |
|    |                                                                 |
|    | **Alternative Text:** Delete the clause ~~If a component is not |
|    | adversely affected by heat, and is soluble, it can be made into |
|    | a solution and subjected to steam sterilization, typically in   |
|    | an autoclave or a fixed pressurized sterilize-in-place (SIP)    |
|    | vessel~~                                                        |
+----+-----------------------------------------------------------------+
| 5  | **Comment/Objection:** The text that reads "Parenteral products |
| 64 | are intended to be nonpyrogenic. There should be written        |
|    | procedures and appropriate specifications for acceptance or     |
|    | rejection of each lot of components that might contain          |
|    | endotoxins." is too restrictive of applied to all components.   |
|    |                                                                 |
|    | **Rationale:** Few components (actives and excipients) used in  |
|    | parenteral products are derived from sources liable to be       |
|    | endotoxic, such materials of natural origin, starches sugars    |
|    | etc., but are chemically synthesized and therefore are of low   |
|    | natural bio/endo -- burden.                                     |
|    |                                                                 |
|    | **Alternative Text:** Parenteral products are intended to be    |
|    | nonpyrogenic. There should be written procedures ~~and          |
|    | appropriate specifications for acceptance or rejection of each  |
|    | lot of components that might contain endotoxins~~ *[for the     |
|    | evaluation of components (active ingredients and excipients)    |
|    | for their potential to be contaminated with bacterial           |
|    | endotoxin. Where potential for contamination exists each        |
|    | received lot of material should be tested to appropriate        |
|    | specifications for acceptance or rejection. Any components      |
|    | failing to meet defined endotoxin limits should be              |
|    | rejected.]{.underline}*                                         |
+----+-----------------------------------------------------------------+
| 5  | **Comment/Objection**: "There should be written procedures and  |
| 65 | appropriate specifications for acceptance or rejection of each  |
|    | lot of components that might contain endotoxins" is too vague.  |
|    |                                                                 |
|    | **Rationale**: Guidance beyond stating that products should     |
|    | meet their release criteria for pyrogen or endotoxin level. It  |
|    | should be left up to each firm to determine what degree of      |
|    | ingredient or in-process testing is required to achieve that    |
|    | goal.                                                           |
|    |                                                                 |
|    | **Alternative Text**:                                           |
|    |                                                                 |
|    | *[Incoming components (ingredients) should be accepted          |
|    | according to specifications included in the regulatory          |
|    | submission. Any components failing to meet defined              |
|    | specifications should be rejected.]{.underline}*                |
+----+-----------------------------------------------------------------+
| 6  | **Comment/Objection**: The text that reads "At minimum, the     |
| 08 | initial rinses for the washing process should employ Purified   |
|    | Water, USP, of minimal endotoxin content, followed by final     |
|    | rinse(s) with WFI for parenteral products." does not recognize  |
|    | the fact that many washers use the finial rinse's Water for     |
|    | Injection as the water for their initial rinses.                |
|    |                                                                 |
|    | **Rationale**: Many washers use recycled final rinse water for  |
|    | initial rinses. This water is not tested to meet Purified       |
|    | Water, USP.                                                     |
|    |                                                                 |
|    | **Alternative Text**: At minimum, the initial rinses for the    |
|    | washing process should ~~employ~~ *[be sourced                  |
|    | from]{.underline}* at least Purified Water, USP, of minimal     |
|    | endotoxin content, followed by final rinse(s) with WFI for      |
|    | parenteral products. *[The use of recycled WFI from the final   |
|    | rinse for intermediate rinses is acceptable if                  |
|    | validated.]{.underline}*                                        |
+----+-----------------------------------------------------------------+
| 6  | **Comment/Objection:** Delete sentence about approval of        |
| 23 | validation protocols and results: "The finished dosage form     |
|    | manufacturer is responsible for the review and approval of the  |
|    | contractor\'s validation protocol and final validation report". |
|    |                                                                 |
|    | **Rationale**: This sentence implies that the finished dosage   |
|    | form manufacturer must formally approve protocols and reports,  |
|    | but more typically these will be reviewed without formal        |
|    | approval. In fact, many contractor's would not want other       |
|    | company personnel to approve their documents.                   |
|    |                                                                 |
|    | **Alternative Text**: Delete sentence. ~~The finished dosage    |
|    | form manufacturer is responsible for the review and approval of |
|    | the contractor\'s validation protocol and final validation      |
|    | report~~                                                        |
+----+-----------------------------------------------------------------+
| 6  | **Comment/Objection:** The sentence that reads "A container     |
| 29 | closure system that permits penetration of air, or              |
|    | microorganisms, is unsuitable for a sterile product." is not    |
|    | technically correct.                                            |
|    |                                                                 |
|    | **Rationale**: This is not necessarily true of air. Some        |
|    | plastic containers may have very low water vapor transmission   |
|    | levels, which over time (years) make the product unsuitable     |
|    | chemically, but has no negative impact on the microbiological   |
|    | quality of the product.                                         |
|    |                                                                 |
|    | **Alternative Text**: A container closure system that permits   |
|    | penetration of ~~air~~ *[microorganisms]{.underline}*, is       |
|    | unsuitable for a sterile product.                               |
+----+-----------------------------------------------------------------+
| 6  | **Comment/Objection**: The sentence that reads "Endotoxin       |
| 60 | control should be exercised for all product contact surfaces    |
|    | both prior to and after sterile filtration." is too vague and   |
|    | needs an example.                                               |
|    |                                                                 |
|    | **Rationale**: not common practice.                             |
|    |                                                                 |
|    | **Alternative Text**: Endotoxin control should be exercised for |
|    | all product contact surfaces both prior to and after sterile    |
|    | filtration. *[For example, promptly cleaning and drying         |
|    | equipment with validated procedures will help control           |
|    | endotoxins contamination.]{.underline}*                         |
+----+-----------------------------------------------------------------+
| 6  | **Comment/Objection**: The text that reads "Some clean-in-place |
| 64 | procedures employ initial rinses with appropriate high purity   |
|    | water and/or a cleaning agent (e.g., acid, base, surfactant),   |
|    | followed by final rinses with heated WFI." does not recognize   |
|    | the fact that many CIP systems use the finial rinse's Water for |
|    | Injection as the water for their initial rinses.                |
|    |                                                                 |
|    | **Rationale**: Many CIP systems use recycled final rinse water  |
|    | for initial rinses. This water is not tested to meet Purified   |
|    | Water, USP.                                                     |
|    |                                                                 |
|    | **Alternative Text**: Some clean-in-place procedures employ     |
|    | initial rinses with appropriate high purity water and/or a      |
|    | cleaning agent (e.g., acid, base, surfactant), followed by      |
|    | final rinses with heated WFI. *[The use of recycled WFI from    |
|    | the final rinse for intermediate rinses is acceptable if        |
|    | validated.]{.underline}*                                        |
+----+-----------------------------------------------------------------+
| 6  | **Comment/Objection:** Delete \"\...by validated cleaning       |
| 64 | procedures.\"                                                   |
|    |                                                                 |
|    | **Rationale:** Clarification that prevention of endotoxin       |
|    | build-up is acceptable.                                         |
|    |                                                                 |
|    | **Alternative Text:** Replace this phrase with \"\...by         |
|    | validated endotoxin control procedures.\"                       |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: The following sentence "Media fill       |
| 22 | studies should simulate aseptic manufacturing operations as     |
|    | closely as possible, incorporating a worst-case approach." can  |
|    | be misinterpreted.                                              |
|    |                                                                 |
|    | **Rationale**: Stacking all potential worst-case situations     |
|    | into each media run does not represent an appropriate challenge |
|    | simulating normal processing.                                   |
|    |                                                                 |
|    | **Alternative Text**: Media fill studies should simulate        |
|    | aseptic manufacturing operations as closely as possible. ~~,    |
|    | incorporating a worst-case approach. The~~ Media fill           |
|    | *[studies]{.underline}* ~~program~~ should *[be designed        |
|    | to]{.underline}* address applicable issues such as:             |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection:** The sentence that reads "Factors         |
| 26 | associated with the longest permitted run on the processing     |
|    | line." is vague and should either be clarified or deleted.      |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: The text in the dot point "number and    |
| 27 | type of normal interventions, atypical interventions,           |
|    | unexpected events (e.g., maintenance), stoppages, equipment     |
|    | adjustments or transfers" should not specify "number"           |
|    |                                                                 |
|    | **Rationale**: Number of typical interventions is proportional  |
|    | to the length of the operation.                                 |
|    |                                                                 |
|    | **Alternative Text**: ~~number and t~~Type of normal            |
|    | interventions, atypical interventions, unexpected events (e.g., |
|    | maintenance), stoppages, equipment adjustments or transfers     |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: The text in the dot point "number and    |
| 27 | type of normal interventions, atypical interventions,           |
|    | unexpected events (e.g., maintenance), stoppages, equipment     |
|    | adjustments or transfers" should not specify "number"           |
|    |                                                                 |
|    | **Rationale**:"Unexpected" should be clarified.                 |
|    |                                                                 |
|    | **Alternative Text**: ~~number and t~~Type of normal            |
|    | interventions, atypical interventions, *[~~anticipated and      |
|    | reasonably expected~~ infrequent permitted]{.underline}*        |
|    | ~~unexpected~~ events (e.g., maintenance), stoppages, equipment |
|    | adjustments or transfers                                        |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: The text in the dot point "operator      |
| 39 | fatigue" is unnecessary to be addressed during a normal media   |
|    | fill.                                                           |
|    |                                                                 |
|    | **Rationale**: Environmental and personnel monitoring is a      |
|    | better assessment of operator fatigue; this should not be       |
|    | required for media fill. We are aware of no published data that |
|    | correlate fatigue with increased contamination.                 |
|    |                                                                 |
|    | **Alternative Text**: Delete line. ~~operator fatigue~~         |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: "For example, the evaluation of a shift  |
| 57 | should address its unique time-related and operational          |
|    | features" is unclear                                            |
|    |                                                                 |
|    | **Rationale**: clarify or delete                                |
|    |                                                                 |
|    | **Alternative Text**: For example, the evaluation of a shift    |
|    | *[change]{.underline}* should address ~~its unique time-related |
|    | and operational features~~ *[the movement of personnel in and   |
|    | out of the aseptic processing and change rooms including        |
|    | de-gowning and gowning procedures.]{.underline}*                |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection:** The sentence that reads \" For example,  |
| 65 | facility and equipment modifications, line configuration        |
|    | changes, significant changes in personnel, anomalies in         |
|    | environmental testing results, container closure system changes |
|    | or, end product sterility testing showing contaminated products |
|    | may be cause for revalidation of the system." should remove the |
|    | concept of significant changes in personnel.                    |
|    |                                                                 |
|    | **Rationale:** Difficult to define and vague and changes in     |
|    | personnel are assessed in personnel qualification programs as   |
|    | defined by Section V Personnel Training, Qualification and      |
|    | Monitoring.                                                     |
|    |                                                                 |
|    | **Alternate Text:** "For example, facility and equipment        |
|    | modifications, line configuration changes, ~~significant        |
|    | changes in personnel,~~ anomalies in environmental testing      |
|    | results, container closure system changes or, end product       |
|    | sterility testing showing contaminated products may be cause    |
|    | for revalidation of the system."                                |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: The text that reads "The duration of     |
| 80 | aseptic processing operations is a major consideration in       |
|    | determining the size of the media fill run. Although the most   |
|    | accurate simulation model would be the full batch size and      |
|    | duration because it most closely simulates the actual           |
|    | production run, other appropriate models can be justified" is   |
|    | inconsistent.                                                   |
|    |                                                                 |
|    | **Rationale**: Elsewhere in this section the FDA specifies      |
|    | media fill sizes that are not representative of production      |
|    | duration. This sentence is not consistent with PQRI             |
|    | recommendations on the 'Concept Paper' or PDA Technical         |
|    | Documents.                                                      |
|    |                                                                 |
|    | The duration of the process simulation should be dictated by    |
|    | the time needed to prepare the required number of units and to  |
|    | include the activities to simulate necessary interventions.     |
|    |                                                                 |
|    | **Alternative Text**: Delete sentences. ~~The duration of       |
|    | aseptic processing operations is a major consideration in       |
|    | determining the size of the media fill run. Although the most   |
|    | accurate simulation model would be the full batch size and      |
|    | duration because it most closely simulates the actual           |
|    | production run, other appropriate models can be justified~~     |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: The sentence that reads "In any study    |
| 84 | protocol, the duration of the run and the overall study design  |
|    | should adequately mimic worst-case operating conditions and     |
|    | cover all manipulations that are performed in the actual        |
|    | processing operation" is inconsistent.                          |
|    |                                                                 |
|    | **Rationale**: Elsewhere in the document it mentions that       |
|    | atypical interventions may be rotated.                          |
|    |                                                                 |
|    | **Alternative Text**: In any study protocol, the duration of    |
|    | the run and the overall study design should adequately mimic    |
|    | *[appropriately designed]{.underline}* worst-case process       |
|    | operations. ~~conditions and cover all manipulations that are   |
|    | performed in the actual processing operation~~                  |
+----+-----------------------------------------------------------------+
| 7  | **Comment/Objection**: The sentence that reads "For             |
| 95 | lyophilization operations, unsealed containers should be        |
|    | exposed to pressurization and partial evacuation of the chamber |
|    | in a manner that simulates the process" is technically          |
|    | incorrect                                                       |
|    |                                                                 |
|    | **Rationale**: Containers should not be exposed to              |
|    | 'pressurization' and exposed only to a slight vacuum to         |
|    | simulate that portion of the lyophilization cycle.              |
|    |                                                                 |
|    | **Alternative Text**: For lyophilization operations, unsealed   |
|    | containers should be exposed to ~~pressurization and~~          |
|    | *[a]{.underline}* partial evacuation of the chamber in a manner |
|    | that simulates the process                                      |
+----+-----------------------------------------------------------------+
| 8  | **Comment/Objection**: The text that reads "The media fill      |
| 22 | program should adequately address the range of line speeds      |
|    | (e.g., by bracketing all vial sizes and fill volumes) employed  |
|    | during production. Each individual media fill run should        |
|    | evaluate a single worst-case line speed, and the speed chosen   |
|    | for each run during a study should be justified. For example,   |
|    | use of high line speed is often most appropriate in the         |
|    | evaluation of manufacturing processes characterized by frequent |
|    | interventions or a significant degree of manual manipulation.   |
|    | Use of slow line speed is generally" is contradictory.          |
|    |                                                                 |
|    | **Rationale**: One sentence says that the range of speeds       |
|    | should be addressed, while the other specifies" worst case".    |
|    |                                                                 |
|    | **Alternative Text**: The media fill program should adequately  |
|    | address the range of line speeds (e.g., by bracketing all       |
|    | containers ~~sizes and fill volumes~~) employed during          |
|    | production. Each individual media fill run should evaluate a    |
|    | single ~~worst-case~~ line speed, and the speed chosen for each |
|    | run during a study should be justified and documented. For      |
|    | example, use of high line speed is often most appropriate in    |
|    | the evaluation of manufacturing processes characterized by      |
|    | frequent interventions or a significant degree of manual        |
|    | manipulation. Use of slow line speed is generally appropriate   |
|    | for evaluating *conventional* manufacturing processes           |
|    | ~~characterized by~~ allowing prolonged                         |
|    | exposure*[s]{.underline}* of the sterile drug product and       |
|    | container closures in the aseptic area.                         |
+----+-----------------------------------------------------------------+
| 8  | **Comment/Objection**: The sentence that reads "To the extent   |
| 37 | standard operating procedures permit stressful conditions, it   |
|    | is important that media fills include analogous challenges to   |
|    | support the validity of these studies" is unnecessary and       |
|    | overly strict.                                                  |
|    |                                                                 |
|    | **Rationale:** This statement is too vague and may lead to      |
|    | misinterpretation and lead to an expectation that HVAC systems  |
|    | may be expected to be operated at their worst case conditions   |
|    | e.g. high humidity, low differential pressure and low air       |
|    | exchange rate. The purpose of a media fill is not to validate   |
|    | the HVAC system, that is undertaken as a separate exercise. The |
|    | purpose of a media fill is to ensure the critical interface of  |
|    | human operator and aseptic filling equipment can maintain an    |
|    | acceptable level of aseptic process integrity.                  |
|    |                                                                 |
|    | **Alternative Text:** To the extent standard operating          |
|    | procedures permit stressful conditions, *[e.g. maximum number   |
|    | of personnel present and elevated activity level]{.underline}*, |
|    | it is important that media fills include analogous challenges   |
|    | to support the validity of these studies. *[Stressful           |
|    | conditions should not include reconfiguration of HVAC systems   |
|    | to operate at worst case limits.]{.underline}*                  |
+----+-----------------------------------------------------------------+
| 8  | **Comment/Objection:**                                          |
| 44 |                                                                 |
|    | "Use of anaerobic growth media (e.g., fluid thioglycollate      |
|    | medium) would be appropriate in                                 |
|    |                                                                 |
|    | special circumstances" is unclear.                              |
|    |                                                                 |
|    | **Rationale**: All process gasses which come into contact with  |
|    | sterile materials must be filtered using a validated process. A |
|    | media fill is not undertaken to validate sterilization          |
|    | processes but to assess the filling/closing process and the     |
|    | operator interactions in that process. Incorporating nitrogen,  |
|    | for example, in the media fill and then utilizing an anaerobic  |
|    | media will not optimize the capture of the types of organisms   |
|    | responsible for media fill contamination -aerobic organisms.    |
|    |                                                                 |
|    | **Alternative Text**:                                           |
|    |                                                                 |
|    | Delete Sentence. ~~Use of anaerobic growth media (e.g., fluid   |
|    | thioglycollate medium) would be appropriate in~~                |
|    |                                                                 |
|    | ~~special circumstances~~                                       |
+----+-----------------------------------------------------------------+
| 8  | **Comment/Objection**: The text that reads "The media selected  |
| 45 | should be demonstrated to promote growth of USP \<71\>          |
|    | indicator microorganisms as well as representative isolates     |
|    | identified by environmental monitoring, personnel monitoring,   |
|    | and positive sterility test results." is unnecessary.           |
|    |                                                                 |
|    | **Rationale**: Growth Promotion testing of compendial organisms |
|    | is sufficient to demonstrate the viability of the media.        |
|    |                                                                 |
|    | **Alternative Text**: The media selected should be demonstrated |
|    | to promote growth of USP \<71\> indicator microorganisms ~~as   |
|    | well as representative isolates identified by environmental     |
|    | monitoring, personnel monitoring, and positive sterility test   |
|    | results~~.                                                      |
+----+-----------------------------------------------------------------+
| 8  | **Comment/Objection:** Remove the sentence \" There should be   |
| 78 | direct quality control unit oversight throughout any such       |
|    | examination.\"                                                  |
|    |                                                                 |
|    | **Rationale:** Requiring the use of clear containers should not |
|    | be an absolute requirement. Examination techniques which take   |
|    | advantage of special lighting conditions have been used         |
|    | successfully for examining containers for growth. Providing     |
|    | data which supports this means of examination should be         |
|    | sufficient. In other cases (ointments), contents are generally  |
|    | expressed from the container to facilitate examination of the   |
|    | filled units. A requirement for "direct quality unit oversight" |
|    | should not be mandated. Provided that personnel have the        |
|    | appropriate education, training and experience or combination   |
|    | thereof should be sufficient. A statement that any suspect      |
|    | containers should be evaluated by the microbiologist adequately |
|    | addresses the oversight role needed.                            |
|    |                                                                 |
|    | **Alternate Text:** ~~There should be direct quality control    |
|    | unit oversight throughout any such examination.~~ *[Containers  |
|    | used in the media fill should be the product containers or a    |
|    | suitable substitute. It is important to assure during the       |
|    | examination of media filled containers that contamination can   |
|    | be readily identified. Any suspect units identified during the  |
|    | examination should be brought to the immediate attention of the |
|    | QC microbiologist.]{.underline}*                                |
|    |                                                                 |
|    | ~~Clear containers with otherwise identical physical properties |
|    | should be used as a substitute for amber or other opaque        |
|    | containers to allow visual detection of microbial growth.~~ .   |
+----+-----------------------------------------------------------------+
| 9  | **Comment/Objection**: The text that reads "The ability of a    |
| 04 | media fill run to detect potential contamination from a given   |
|    | simulated activity should not be compromised by a large-scale   |
|    | line clearance, which can result in removal of a positive unit  |
|    | caused by an unrelated event or intervention" is contradictory. |
|    |                                                                 |
|    | **Rationale**: Elsewhere the guidance specifies that specific   |
|    | procedures for removal of units in production should be         |
|    | duplicated in process simulation.                               |
|    |                                                                 |
|    | **Alternative Text:** Delete clause. ~~The ability of a media   |
|    | fill run to detect potential contamination from a given         |
|    | simulated activity should not be compromised by a large-scale   |
|    | line clearance, which can result in removal of a positive unit  |
|    | caused by an unrelated event or intervention.~~                 |
+----+-----------------------------------------------------------------+
| 9  | **Comment/Objection:**                                          |
| 20 |                                                                 |
|    | The sentence that reads "The microorganisms should be           |
|    | identified to species level" is too specific.                   |
|    |                                                                 |
|    | **Rationale**:                                                  |
|    |                                                                 |
|    | It may not be possible to identify microorganisms to the        |
|    | species level.                                                  |
|    |                                                                 |
|    | **Alternative Text**:                                           |
|    |                                                                 |
|    | The microorganisms should be identified to species level, *[if  |
|    | possible]{.underline}*                                          |
+----+-----------------------------------------------------------------+
| FN | **Comment/Objection**: Footnote 9 at the bottom of page 26      |
| 9  | states "To assess contamination risk during initial aseptic     |
|    | setup (before fill), valuable information can be obtained by    |
|    | incubating all such units that may be normally removed." is not |
|    | consistent with other sections of the document.                 |
|    |                                                                 |
|    | **Rationale**: The media fill should simulate production        |
|    | practice. It has been FDA guidance for firms not to do testing  |
|    | "For Information Only".                                         |
|    |                                                                 |
|    | **Alternative Text**: Delete footnote. ~~To assess              |
|    | contamination risk during initial aseptic setup (before fill),  |
|    | valuable information can be obtained by incubating all such     |
|    | units that may be normally removed." is not consistent with     |
|    | other sections of the document~~                                |
+----+-----------------------------------------------------------------+
| 9  | **Comment/Objection**: Incorrect usage of "porosity".           |
| 69 |                                                                 |
| &  | **Rationale**: Pore size is the correct term; porosity is the   |
| 9  | ratio of filter void volume to total volume.                    |
| 72 |                                                                 |
|    | **Alternative Text**: Replace "porosity" with *[pore            |
|    | size]{.underline}*.                                             |
+----+-----------------------------------------------------------------+
| 10 | **Comment/Objection**: The sentence that reads "The specific    |
| 09 | type of filter used in commercial production should be          |
|    | evaluated in filter validation studies" is technically not      |
|    | accurate.                                                       |
|    |                                                                 |
|    | **Rationale**: The filter membrane is typically assessed in     |
|    | microbial retention studies, not the actual filter.             |
|    |                                                                 |
|    | **Alternative Text**: "The specific type of filter              |
|    | *[membrane]{.underline}* used in commercial production should   |
|    | be evaluated in filter validation studies                       |
+----+-----------------------------------------------------------------+
| 10 | **Comment/Objection**: The text that reads "After a filtration  |
| 17 | process is properly validated for a given product, process, and |
|    | filter, it is important to ensure that identical filter         |
|    | replacements (membrane or cartridge) used in production runs    |
|    | will perform in the same manner." is technically not accurate.  |
|    |                                                                 |
|    | **Rationale**: The filter membrane is typically assessed in     |
|    | microbial retention studies, not the actual filter              |
|    | configuration.                                                  |
|    |                                                                 |
|    | **Alternative Text**: After a filtration process is properly    |
|    | validated for a given product, process, and filter              |
|    | *[membrane]{.underline}*, it is important to ensure that        |
|    | identical filter *[membranes be]{.underline}* ~~replacements    |
|    | (membrane or cartridge)~~ used in production runs will perform  |
|    | in the same manner."                                            |
+----+-----------------------------------------------------------------+
| 10 | **Comment/Objection**: The sentence that reads "Those surfaces  |
| 33 | that are in the vicinity of sterile product or container        |
|    | closures, but do not directly contact the product should also   |
|    | be rendered sterile where reasonable contamination potential    |
|    | exists." Is overly burdensome and may not be technically        |
|    | feasible.                                                       |
|    |                                                                 |
|    | **Rationale**: Surfaces in the vicinity of sterile materials    |
|    | should not be required to be sterilized unless there is direct  |
|    | contact.                                                        |
|    |                                                                 |
|    | **Alternative Text**: Delete sentence. ~~Those surfaces that    |
|    | are in the vicinity of sterile product or container closures,   |
|    | but do not directly contact the product should also be rendered |
|    | sterile where reasonable contamination potential exists"        |
|    | presents unclear expectations\...~~                             |
+----+-----------------------------------------------------------------+
| 10 | **Comment/Objection:** The sentence that reads "Sterility of    |
| 42 | aseptic processing equipment should be maintained by            |
|    | batch-by-batch sterilization. " is not technologically feasible |
|    | for continuous processes.                                       |
|    |                                                                 |
|    | **Rationale:**  This gets into the whole definition of what is  |
|    | a Batch? The requirement should center around validation.       |
|    |  Sometimes it is better to leave things set up and keep running |
|    | than to continually tear down and intervene. There are many     |
|    | applications approved by the FDA where this equipment is        |
|    | sanitized rather than sterilized.                               |
|    |                                                                 |
|    | **Alternative Text:** ~~Sterility of~~ Sterilization /          |
|    | sanitization of aseptic processing equipment should *[be        |
|    | performed]{.underline}* *[at defined intervals (batch or        |
|    | campaign) and verified by periodic validation]{.underline}*     |
|    | ~~maintained by batch-by-batch sterilization~~.                 |
+----+-----------------------------------------------------------------+
| 10 | **Comment/Objection**: The sentence that reads "For both the    |
| 50 | validation studies and routine production, use of a specified   |
|    | load configuration should be documented in the batch records"   |
|    | is unnecessary.                                                 |
|    |                                                                 |
|    | **Rationale**: The use of maximum/minimum loads to qualify a    |
|    | range of loads is acceptable.                                   |
|    |                                                                 |
|    | **Alternative Text**: For both the validation studies and       |
|    | routine production, ~~use of a specified~~ *[the]{.underline}*  |
|    | load configuration should be documented in the batch records"   |
+----+-----------------------------------------------------------------+
| 11 | **Comment/Objection**: The sentence that reads "Air and surface |
| 65 | samples should be taken at the actual working site and at       |
|    | locations where significant activity or product exposure occurs |
|    | during production" is not a good practice.                      |
|    |                                                                 |
|    | **Rationale**: Air and surface samples should be taken at       |
|    | locations where significant activity or product exposure occurs |
|    | during production. It is inadvisable to take samples at the     |
|    | "actual working site" because of the potential for introducing  |
|    | product contamination.                                          |
|    |                                                                 |
|    | **Alternative Text**: Air and surface samples should be taken   |
|    | ~~at the actual working site and a~~t locations where           |
|    | significant activity or product exposure occurs during          |
|    | production.                                                     |
+----+-----------------------------------------------------------------+
| 10 | **Comment: Objection:** Remove \"age of sterilizer\" from the   |
| 73 | following sentence "The formal program providing for regular    |
|    | revalidation should consider the age of the sterilizer and its  |
|    | past performance."                                              |
|    |                                                                 |
|    | **Rationale:** Decision to requalify is not age dependent.      |
|    | NOTE: Sterilizers need not be completely revalidated            |
|    | periodically; requalification is more appropriate based on      |
|    | performance,                                                    |
|    |                                                                 |
|    | **Alternate Text:** ~~The formal program providing for regular  |
|    | revalidation should consider the age of the sterilizer and its  |
|    | past performance.~~ *[The frequency of requalification should   |
|    | take into account factors such as past performance of the       |
|    | equipment, preventive maintenance, and change control           |
|    | program.]{.underline}*                                          |
+----+-----------------------------------------------------------------+
| 10 | **Comment/Objection**: The text that reads "It is important     |
| 81 | that these studies assess temperature uniformity at various     |
|    | locations throughout the sterilizer to identify potential *cold |
|    | spots* where there can be insufficient heat to attain           |
|    | sterility" is not always necessary.                             |
|    |                                                                 |
|    | **Rationale**: In a porous load sterilization cycle, the        |
|    | variation of temperature will be minimal, and the               |
|    | identification of a 'cold spot' will be insignificant.          |
|    |                                                                 |
|    | **Alternative Text**: "It is important that these studies       |
|    | assess temperature uniformity at various locations throughout   |
|    | the sterilizer to ~~identify potential cold spots where there   |
|    | can be insufficient heat to attain sterility~~"                 |
+----+-----------------------------------------------------------------+
| 11 | **Comment/Objection**: The sentence that reads "The microbial   |
| 17 | count and D-value of a biological indicator should be confirmed |
|    | before a validation study" should reflect that D-value may be   |
|    | accepted via certification.                                     |
|    |                                                                 |
|    | **Rationale**: D-value analysis may be accepted via             |
|    | certification as described in the USP 26, \[55\], \[1035\] and  |
|    | \[1208\].                                                       |
|    |                                                                 |
|    | **Alternative Text**: Delete requirement for D-Value            |
|    | determination. The new test should read.                        |
|    |                                                                 |
|    | The microbial count ~~and D-value~~ of a biological indicator   |
|    | should be confirmed before a validation study" should reflect   |
|    | that D-value may be accepted via certification.                 |
+----+-----------------------------------------------------------------+
| 11 | **Comment/Objection**: The sentence that reads "Critical        |
| 70 | surface sampling should be performed at the conclusion of the   |
|    | aseptic processing operation to avoid direct contact with       |
|    | sterile surfaces during processing." is inconsistent with other |
|    | parts of the document.                                          |
|    |                                                                 |
|    | **Rationale**: Elsewhere in the document it states that         |
|    | monitoring of critical surfaces is not mandatory.               |
|    |                                                                 |
|    | **Alternative Text**: "*[When performed,]{.underline}*          |
|    | c~~C~~ritical surface sampling should be performed at the       |
|    | conclusion of the aseptic processing operation to avoid direct  |
|    | contact with sterile surfaces during processing".               |
+----+-----------------------------------------------------------------+
| 12 | **Comment/Objection:** The sentence that reads "A result at the |
| 07 | action level should prompt a more thorough investigation." is   |
|    | too prescriptive.                                               |
|    |                                                                 |
|    | **Rationale**: Single occurrences at an action level do not     |
|    | necessarily indicate an out-of-control situation, as spurious   |
|    | action levels do inevitably occur. As such, the automatic       |
|    | carrying out of this type of investigation is non-value-adding, |
|    | since it does not provide any concrete information upon which a |
|    | decision can be made, and as such the investigation is likely   |
|    | to be inconclusive. Of much greater value is the presence of a  |
|    | number of action level occurrences at a specific location,      |
|    | which may exhibit an unfavorable trend. In this situation,      |
|    | trending provides more concrete information available on which  |
|    | to make a decision, and as such as investigation is more likely |
|    | to be informative, and come to a firm conclusion which is       |
|    | indeed value-adding.                                            |
|    |                                                                 |
|    | **Alternative Text**: ~~A result at the action level should     |
|    | prompt a more thorough investigation.~~ A single action level   |
|    | result at an identified location should not automatically       |
|    | require the conducting of an investigation. Multiple action     |
|    | level results at an identified location should however prompt a |
|    | formal investigation, based upon trend analysis."               |
+----+-----------------------------------------------------------------+
| 12 | **Comment/Objection:** The text that reads                      |
| 24 |                                                                 |
|    | **"**The suitability, efficacy, and limitations of sanitization |
|    | agents and procedures should be assessed. The effectiveness of  |
|    | these sanitization agents and procedures should be measured by  |
|    | their ability to ensure that potential contaminants are         |
|    | adequately removed from surfaces (i.e., via obtaining samples   |
|    | before and after sanitization) "does not reflect scientific     |
|    | literature that documents efficacy of many sanitizers.          |
|    |                                                                 |
|    | **Rationale**: There are copious data available in the          |
|    | literature to support efficacy of sanitizing agents. It should  |
|    | not be necessary for firms to continually repeat this testing.  |
|    |                                                                 |
|    | **Alternative Text**: ~~The suitability, efficacy, and          |
|    | limitations of sanitization agents and procedures should be     |
|    | assessed. The effectiveness of these sanitization agents and    |
|    | procedures should be measured by their ability to ensure that   |
|    | potential contaminants are adequately removed from surfaces     |
|    | (i.e., via obtaining samples before and after sanitization.~~   |
|    | *[The routine surface monitoring program provides ongoing       |
|    | support for the efficacy of the sanitization                    |
|    | program.]{.underline}*                                          |
+----+-----------------------------------------------------------------+
| 12 | **Comment/Objection:** The sentence reads "Upon preparation,    |
| 29 | disinfectants should be rendered sterile, and used for a        |
|    | limited time, as specified by written procedures" is too        |
|    | specific.                                                       |
|    |                                                                 |
|    | **Rationale:** Line 1229 could be read as requiring             |
|    | sterilization post preparation. This effectively eliminates a   |
|    | common industry practice of purchasing sterile concentrated     |
|    | solutions and preparing, aseptically, use dilutions of          |
|    | sanitizing agents. Negates common and successful industry       |
|    | practice. What sense is there is filter sterilizing a solution  |
|    | that is self-sterilizing?                                       |
|    |                                                                 |
|    | **Alternative Text:**                                           |
|    |                                                                 |
|    | *[Disinfectants should be purchased sterile, aseptically        |
|    | prepared from sterile concentrated solutions or subject to      |
|    | filter sterilization. It is not generally required to filter    |
|    | sterilize sporicides.]{.underline}*                             |
+----+-----------------------------------------------------------------+
| 12 | **Comment/Objection**: Remove "ceilings" from the sentence that |
| 48 | reads "For example, product contact surfaces, floors, walls,    |
|    | ceilings, and equipment should be tested on a regular basis."   |
|    | because it is unnecessary.                                      |
|    |                                                                 |
|    | **Rationale**: Routine sampling of ceilings is unnecessary.     |
|    |                                                                 |
|    | **Alternative Text**: For example, product contact surfaces,    |
|    | floors, walls, ~~ceilings,~~ and equipment should be tested on  |
|    | a regular basis                                                 |
+----+-----------------------------------------------------------------+
| 12 | **Comment/Objection**: The sentence that reads ""At a minimum,  |
| 93 | the program should require species (or, where appropriate,      |
|    | genus) identification of microorganisms in these ancillary      |
|    | environments ......and to demonstrate that cleaning and         |
|    | sanitization procedures continue to be effective)" is too       |
|    | prescriptive.                                                   |
|    |                                                                 |
|    | **Rationale:**                                                  |
|    |                                                                 |
|    | The current text indicates that at a minimum the EM program     |
|    | should ID isolates from the less controlled environments, such  |
|    | as Class 100,000 (ISO 8) areas, to the species (or, where       |
|    | appropriate, genus) level at frequent intervals.                |
|    |                                                                 |
|    | The level of identification should be changed from              |
|    | identification to the species (or, where appropriate genus      |
|    | level) to "characterization"                                    |
|    |                                                                 |
|    | The requirement for an EM program that requires frequent        |
|    | identification of isolates from less controlled environments,   |
|    | such as Class 100,000 (ISO 8) areas, to the genus and species   |
|    | level is too great when evaluating the usefulness of the data   |
|    | obtained.                                                       |
|    |                                                                 |
|    | Morphologically representative environmental monitoring         |
|    | isolates from lesser controlled environments, such as           |
|    | Class100,000 (ISO 8) areas, should be characterized. This       |
|    | pertains to the detection of isolate types obtained from        |
|    | samples that breach the action level as well as the periodic    |
|    | characterization of isolate types below the action limit.       |
|    |                                                                 |
|    | The information gathered from this activity is helpful in       |
|    | understanding the general types of organisms present and if the |
|    | cleaning program needs to be adjusted. The intense amount of    |
|    | resources required to ID to the genus/species level does not    |
|    | provided added value in these areas over general                |
|    | characterization. The focus of genus/species identification     |
|    | should be placed on the samples taken closer to the aseptic     |
|    | operation.                                                      |
|    |                                                                 |
|    | **Alternate Text:**                                             |
|    |                                                                 |
|    | "At a minimum, the program should require species (or, where    |
|    | appropriate, genus) identification of microorganisms in these   |
|    | ancillary environments ......and to demonstrate that cleaning   |
|    | and sanitization procedures continue to be effective)."         |
|    |                                                                 |
|    | *["At a minimum the program should require morphologically      |
|    | representative environmental monitoring isolates to be          |
|    | characterized. This pertains to the detection of isolate types  |
|    | obtained from samples that breach the action level as well as   |
|    | the periodic characterization of isolate types below the action |
|    | limit."]{.underline}*                                           |
+----+-----------------------------------------------------------------+
| 12 | **Comment/Objection**: Definitions are needed for "Rapid        |
| 97 | genotypic methods" and "phenotypic techniques" used in the      |
|    | sentence "Rapid genotypic methods are recommended for purposes  |
|    | of identification, as these methods have been shown to be more  |
|    | accurate and precise than biochemical and phenotypic            |
|    | techniques."                                                    |
|    |                                                                 |
|    | **Rationale**: Biochemical, fatty acid methyl ester and other   |
|    | methods currently employed for microbiological identification   |
|    | are fit for purpose. The level of organism identification       |
|    | produced by current ID methods provides the information         |
|    | necessary for effective trending of contamination, product      |
|    | failure investigations and other studies.                       |
|    |                                                                 |
|    | Overall, FDA overstates the importance of identification to     |
|    | species level in the manufacturing context.                     |
|    |                                                                 |
|    | **Alternative Text**: Delete sentence. ~~Rapid genotypic        |
|    | methods are recommended for purposes of identification, as      |
|    | these methods have been shown to be more accurate and precise   |
|    | than biochemical and phenotypic techniques.~~                   |
+----+-----------------------------------------------------------------+
| 13 | **Comment/Objection**: The text that reads:" Total aerobic      |
| 05 | bacterial count can be obtained by incubating at 30 to 35^o^C   |
|  - | for 48 to 72 hours. Total combined yeast and mold count is      |
| 13 | generally obtained by incubating at 20 to 25^o^C for 5 to 7     |
| 07 | days." is too prescriptive and may inhibit the use of advanced  |
|    | technologies.                                                   |
|    |                                                                 |
|    | **Rationale**: Incubation of EM samples for 5 to 7 days is      |
|    | longer than most firms currently incubate these samples While   |
|    | it is possible that longer incubation times could result in the |
|    | recovery of some slower growing organisms, it is unlikely this  |
|    | would result in improved process control and it would further   |
|    | delay the availability of data for trend analysis. Also, the    |
|    | statement as currently written is not clear about requirements, |
|    | for example, it should be possible to incubate a sample plate   |
|    | at one temperature and then shift it to another. Unless it is   |
|    | possible to temperature shift sample plates the FDA requirement |
|    | as stated in the draft guideline would effectively double       |
|    | sampling requirements which would increase interventions in     |
|    | controlled areas and increase risk to the process. PDA does not |
|    | think the relatively low probability that additional sampling   |
|    | or incubation time increases recommended in the draft guideline |
|    | will increase process control, however could result in          |
|    | additional risk from sampling, will delay the availability of   |
|    | data and could substantially increase cost and incubation space |
|    | requirements                                                    |
|    |                                                                 |
|    | **Alternative Text**: ~~Total aerobic bacterial count can be    |
|    | obtained by incubating at 30 to 35^o^C for 48 to 72 hours.      |
|    | Total combined yeast and mold count is generally obtained by    |
|    | incubating at 20 to 25^o^C for 5 to 7 days~~.                   |
+----+-----------------------------------------------------------------+
| 13 | **Comment/Objection**: Definitions need to be provided for      |
| 09 | "Incoming lots of environmental monitoring media" and "prepared |
|    | media" in the sentence that reads "Incoming lots of             |
|    | environmental monitoring media should include positive and      |
|    | negative controls. Growth promotion testing should be performed |
|    | on all lots of prepared media." or the sentences need to be     |
|    | simplified.                                                     |
|    |                                                                 |
|    | **Rationale**: GPT should be performed on each lots of EM media |
|    | (prepared or not).                                              |
|    |                                                                 |
|    | **Alternative Text**: ~~Incoming lots of environmental          |
|    | monitoring media should include positive and negative controls. |
|    | Growth promotion testing should be performed on all lots of     |
|    | prepared media.~~                                               |
|    |                                                                 |
|    | Each lot of dehydrated or purchased-prepared media should       |
|    | include positive and negative controls. Negative controls are   |
|    | not required for terminally sterilized media. Where             |
|    | appropriate, inactivating agents should be used to prevent      |
|    | inhibition of growth by cleanroom disinfectants or product      |
|    | residuals (e.g., antibiotics).                                  |
+----+-----------------------------------------------------------------+
| 13 | **Comment/Objection**: The sentence that reads "A result        |
| 31 | outside the established specifications at a given location      |
|    | should be investigated." is inconsistent with other parts of    |
|    | the document.                                                   |
|    |                                                                 |
|    | **Rationale**: Environmental particulate values are not best    |
|    | classified by specifications; they have alert and action levels |
|    | like other environmental monitoring.                            |
|    |                                                                 |
|    | **Alternative Text**: A result outside the established          |
|    | ~~specifications~~ *[action levels]{.underline}* at a given     |
|    | location should be investigated.                                |
+----+-----------------------------------------------------------------+
| 13 | **Comment/Objection**: The section entitled "XI. Sterility      |
| 39 | Testing" is unnecessary in this document,                       |
|    |                                                                 |
|    | **Rationale**: Why not refer to USP rather than creating a new  |
|    | section in a guidance document. The risk of inconsistency and   |
|    | the two documents staying in sync is high.                      |
|    |                                                                 |
|    | **Alternative Text**: delete section.                           |
+----+-----------------------------------------------------------------+
| 13 | **Comment/Objection**: The sentence that reads "Study           |
| 63 | documentation should include evaluation of whether microbial    |
|    | recovery from inoculated controls and product samples is        |
|    | comparable throughout the incubation period" is included in     |
|    | USP.                                                            |
|    |                                                                 |
|    | **Rationale**: Already covered in USP, and harmonized with      |
|    | EP/JP.                                                          |
|    |                                                                 |
|    | **Alternative Text**: Delete clause. ~~Study documentation      |
|    | should include evaluation of whether microbial recovery from    |
|    | inoculated controls and product samples is comparable           |
|    | throughout the incubation period~~                              |
+----+-----------------------------------------------------------------+
| 13 | **Comment/Objection:** The text that reads "This limited        |
| 90 | sensitivity is why, for batch release purposes, it is important |
|    | that an appropriate number of units are tested,^11^ and that    |
|    | the samples uniformly represent: "is contradictory to USP.      |
|    |                                                                 |
|    | **Rationale**: There is potentially a serious legal issue here. |
|    | FDA recognizes USP test methods as "official." The guidance, as |
|    | written, seriously undermines this position.                    |
|    |                                                                 |
|    | How many units are "appropriate"?                               |
|    |                                                                 |
|    | **Alternative Text**: Delete sentence. ~~This limited           |
|    | sensitivity is why, for batch release purposes, it is important |
|    | that an appropriate number of units are tested,^11^ and that    |
|    | the samples uniformly represent:~~                              |
+----+-----------------------------------------------------------------+
| 13 | **Comment/Objection**: The text in the dot point that reads     |
| 95 | "the batch processing circumstances -- samples should be taken  |
|    | in conjunction with processing interventions or excursions" is  |
|    | excessive.                                                      |
|    |                                                                 |
|    | **Rationale**: There is insufficient justification of the value |
|    | in taking additional sterility samples for each intervention,   |
|    | and it would be impractical, especially when there is media     |
|    | fill data to support the intervention.                          |
|    |                                                                 |
|    | **Alternative Text**: Delete clause. ~~the batch processing     |
|    | circumstances -- samples should be taken in conjunction with    |
|    | processing interventions or excursions~~                        |
+----+-----------------------------------------------------------------+
| 14 | # **Comment/Objection**: Incorrect reference to USP.            |
| 24 |                                                                 |
|    | **Rationale**: Correction. USP uses Arabic numerals for volume  |
|    | numbers. The current volume is 26.                              |
|    |                                                                 |
|    | **Alternative Text**: Replace XXV with 26.                      |
+----+-----------------------------------------------------------------+
| 14 | **Comment/Objection:** The sentence that reads ". Nucleic       |
| 25 | acid-based methods are recommended for microbial identification |
|    | purposes." is overly burdensome.                                |
|    |                                                                 |
|    | **Rationale:** As with lines 1297-1298 but using a different    |
|    | term FDA are recommending nucleic acid based methods of         |
|    | microbiological identification.                                 |
|    |                                                                 |
|    | **Alternative Text**: Delete sentence. ~~Nucleic acid-based     |
|    | methods are recommended for microbial identification purposes~~ |
+----+-----------------------------------------------------------------+
| 14 | **Comment/Objection**: The sentence that reads "To more         |
| 45 | accurately monitor potential contamination sources, we          |
|    | recommend you keep separate trends by product, container type,  |
|    | filling line, and personnel." is too prescriptive.              |
|    |                                                                 |
|    | **Rationale**: These requirements are too prescriptive and each |
|    | firm much establish the type of trending that is appropriate    |
|    | for their production situation. This sentence is unclear and we |
|    | believe it to mean production trends but the section is located |
|    | in the laboratory section.                                      |
|    |                                                                 |
|    | **Alternative Text**: To more accurately monitor potential      |
|    | contamination sources, we recommend you keep separate trends by |
|    | *[appropriate categories such as]{.underline},* product,        |
|    | container type, filling line and production, *[sampling and     |
|    | testing]{.underline}* personnel.                                |
+----+-----------------------------------------------------------------+
| 15 | **Comment/Objection:** Replace \"included\" with \"reviewed\"   |
| 09 | in the following sentence "All in-process data must be included |
|  - | with the batch record documentation in accordance with section  |
| 15 | 211.188."                                                       |
| 11 |                                                                 |
|    | **Rationale:** Raw data might not always be part of the batch   |
|    | documentation                                                   |
|    |                                                                 |
|    | **Alternate Text:** All in-process data must be ~~included~~    |
|    | *[reviewed]{.underline}* prior to batch release.                |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection/ Rationale**: An isolator is a positive     |
| 54 | pressure enclosure designed to maintain a higher pressure then  |
| 7, | the surrounding areas.  This is analogous to a traditional      |
| 1  | clean room, where by the room pressure is higher then the areas |
| 55 | surrounding it.  A leak in the isolator or components does not  |
| 6, | automatically constitute a \"significant breach\" due to the    |
| 16 | positive pressure in the isolator system.  The advantage of an  |
| 82 | isolator is the removal of all direct human interaction from    |
|    | the product and process.  A well designed maintenance program   |
|    | is the critical requirement to assure the isolator and          |
|    | components do not degrade and go unnoticed.                     |
|    |                                                                 |
|    | **Alternative Text**: *[Breaches of integrity should be         |
|    | investigated. If it is determined that the product has been     |
|    | compromised, appropriate action shall be taken.]{.underline}*   |
+----+-----------------------------------------------------------------+
| 15 | **Comments/Objections**: The sentence that reads "Replacement   |
| 48 | frequencies should be established in written procedures that    |
|    | ensure parts will be changed before they breakdown or degrade." |
|    | has a requirement for replacement frequencies which is too      |
|    | vague.                                                          |
|    |                                                                 |
|    | **Rationale**: Add text to be consistent with manufacturer's    |
|    | recommendations unless the firm has data to support something   |
|    | different.                                                      |
|    |                                                                 |
|    | **Alternative Text**: Replacement frequencies should be         |
|    | established in written procedures *[and consistent with         |
|    | manufacturers' recommendations unless the firm has data to      |
|    | support different replacement frequencies. Replacement          |
|    | frequencies should]{.underline}* ~~that~~ ensure parts will be  |
|    | changed before they breakdown or degrade.                       |
+----+-----------------------------------------------------------------+
| 15 | **Comment/Objection**: The sentence that reads "Due to the      |
| 56 | potential for microbial migration through microscopic holes in  |
|  - | gloves and the lack of a highly sensitive glove integrity test, |
| 15 | the inner part of the installed glove should be sanitized       |
| 65 | regularly and the operator should also wear a second pair of    |
|    | thin gloves. " is impractical and may cause damage to the       |
|    | gloves. Control of glove integrity should be consistent with    |
|    | the requirements in conventional clean rooms.                   |
|    |                                                                 |
|    | **Rationale**: Sanitizing the inside of a glove would be        |
|    | difficult to perform efficaciously and could cause              |
|    | unpredictable adverse effects on the integrity of the glove.    |
|    |                                                                 |
|    | **Alternative Text**: Delete clause. ~~Due to the potential for |
|    | microbial migration through microscopic holes in gloves and the |
|    | lack of a highly sensitive glove integrity test, the inner part |
|    | of the installed glove should be sanitized regularly and the    |
|    | operator should also wear a second pair of thin gloves~~        |
+----+-----------------------------------------------------------------+
| 15 | # **Comment/Objection**: "Ster                                  |
| 87 | ilization" is used where "decontamination" is the correct term. |
|    |                                                                 |
|    | **Rationale**: Correction                                       |
|    |                                                                 |
|    | **Alternative Text**: Replace "sterilization" with              |
|    | "decontamination".                                              |
+----+-----------------------------------------------------------------+
| 15 | **Comment/Objection:** Replace \"0.07 to 0.2 water gauge\" with |
| 96 | (Pascal) in the sentence that reads "Positive air pressure      |
|    | differentials from the isolator to the surrounding environment  |
|    | have largely ranged from approximately 0.07\" to 0.2\" water    |
|    | gauge"                                                          |
|    |                                                                 |
|    | **Rationale:** This is too detailed; each isolator should have  |
|    | defined, validated differential pressure.                       |
|    |                                                                 |
|    | **Alternate Text:** ~~Positive air pressure differentials from  |
|    | the isolator to the surrounding environment have largely ranged |
|    | from approximately 0.07\" to 0.2\" water gauge~~ *[The isolator |
|    | shall be capable of operating within its specified differential |
|    | pressure range under all operating conditions.]{.underline}*    |
+----+-----------------------------------------------------------------+
| 16 | **Comment/Objection**: The sentence that reads "An aseptic      |
| 15 | processing isolator should not be located in an unclassified    |
|    | room" is unnecessarily strict.                                  |
|    |                                                                 |
|    | **Rationale**: As long as the area is controlled and the        |
|    | process validated, it should not require particulate air        |
|    | classification. Most conventional clean rooms have mouse holes  |
|    | that open directly into unclassified areas therefore the        |
|    | requirement for isolators should not be more restrictive.       |
|    |                                                                 |
|    | **Alternative Text**: Delete sentence. ~~An aseptic processing  |
|    | isolator should not be located in an unclassified room~~        |
+----+-----------------------------------------------------------------+
| 16 | # **Comment/                                                    |
| 29 | Objection**: Delete "Some transfer ports can have significant l |
|    | imitations, including marginal decontaminating capability (e.g. |
|    | , ultraviolet) or a design that has the potential to compromise |
|    |  isolation by allowing ingress of air from the surrounding room |
|    | . In the latter case, localized HEPA-filtered unidirectional ai |
|    | rflow cover in the area of such a port should be implemented."  |
|    |                                                                 |
|    | **Rationale**: If the transfer ports are inadequate or cannot   |
|    | be appropriately decontaminated, they should not be used; hence |
|    | there is no need for the deleted sentences.                     |
|    |                                                                 |
|    | **Alternative Text**: Delete sentence. ~~An aseptic processing  |
|    | isolator should not be located in an unclassified room~~        |
+----+-----------------------------------------------------------------+
| 16 | # **Comment/Objection**: The sentence that reads "F             |
| 48 | or example, to facilitate contact with the sterilan[t]{.underli |
|    | ne}, the glove apparatus should be fully extended with glove fi |
|    | ngers separated during the decontamination cycle" is incorrect. |
|    |                                                                 |
|    | **Rationale**: Incorrect usage.                                 |
|    |                                                                 |
|    | **Alternative Text** For example, to facilitate contact with    |
|    | the ~~sterilan~~ *[decontaminant]{.underline}*, the glove       |
|    | apparatus should be fully extended with glove fingers separated |
|    | during the decontamination cycle.                               |
+----+-----------------------------------------------------------------+
| 16 | **Comment/Objection**: The text that reads "For example,        |
| 64 | demonstration of a four-log reduction should be sufficient for  |
|    | introduction of controlled, very low bioburden materials into   |
|    | an aseptic processing isolator, including wrapped sterile       |
|    | supplies that are briefly exposed to the surrounding cleanroom  |
|    | environment" is incorrect.                                      |
|    |                                                                 |
|    | **Rationale**: Only properly decontaminated materials should be |
|    | introduced into the aseptic processing isolator.                |
|    |                                                                 |
|    | **Alternative Text**: "...four-log reduction should be          |
|    | sufficient for ~~introduction of controlled, very low bioburden |
|    | materials~~ *[decontamination of material containers to be      |
|    | brought]{.underline}* into an aseptic processing isolator,      |
|    | including the wrappers of sterile supplies ~~that are briefly   |
|    | exposed~~ ~~to the surrounding~~ ~~cleanroom environment~~..."  |
+----+-----------------------------------------------------------------+
| 17 | **Comment/Objection**: The sentence that reads "The classified  |
| 49 | environment surrounding BFS machinery should generally meet     |
|    | Class 10,000 (ISO 7) standards, but special design provisions   |
|    | (e.g., isolation technology) can justify an alternate           |
|    | classification" is too limiting.                                |
|    |                                                                 |
|    | **Rationale**: Many BFS machines are in less than Class 10,000  |
|    | areas with good results.                                        |
|    |                                                                 |
|    | **Alternative Text**: The classified environment surrounding    |
|    | BFS machinery should generally meet Class ~~10,000 (ISO 7)~~    |
|    | *[100,000 (ISO 8)]{.underline}* standards, but special design   |
|    | provisions (e.g., isolation technology) can justify an          |
|    | alternate classification.                                       |
+----+-----------------------------------------------------------------+
| 18 | **Comment/Objection**: The text that reads "It is critical that |
| 02 | the operation be designed and set-up to uniformly manufacture   |
|    | leak-proof units" is not technically accurate.                  |
|    |                                                                 |
|    | **Rationale**: No unit is "leak proof."                         |
|    |                                                                 |
|    | **Alternative Text**: It is critical that the operation be      |
|    | designed and set-up to uniformly manufacture                    |
|    | [~~leak-proof~~]{.underline} *integral* units" is not           |
|    | technically acc                                                 |
+----+-----------------------------------------------------------------+
| 1  | **Comment/Objection**: [Sterilyze]{.underline} should be        |
| 81 | *[sterilize]{.underline}*.                                      |
| 2, |                                                                 |
| 18 | **Rationale**: Correction                                       |
| 24 |                                                                 |
|    | **Alternative Text**: *[sterilize]{.underline}*                 |
+----+-----------------------------------------------------------------+
| 20 | > **Comment/Objection**: Delete the definition "[Laminar        |
| 22 | > flow]{.underline}- An airflow moving in a single direction    |
|    | > and in parallel layers at constant velocity from the          |
|    | > beginning to the end of a straight line vector."              |
|    |                                                                 |
|    | **Rationale**: This term is not used in the document, so it is  |
|    | unneeded in the Glossary.                                       |
|    |                                                                 |
|    | > **Alternative Text**: Delete the definition: ~~[Laminar       |
|    | > flow]{.underline}- An airflow moving in a single direction    |
|    | > and in parallel layers at constant velocity from the          |
|    | > beginning to the end of a straight line vector~~.             |
+----+-----------------------------------------------------------------+

[^1]:

[^2]: