# SCORECARD: PhRMA Comments on:

# Draft FDA Guidance "Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice" \[Docket No. 2003D--0382\]

# September 2003

##### Total Number of Changes Suggested: 118

+--------+----+-------------------------------+-----------------------+
| # S    | ** | **Comment**                   | **Rationale**         |
| ection | Gu |                               |                       |
|        | id |                               |                       |
|        | an |                               |                       |
|        | ce |                               |                       |
|        | Li |                               |                       |
|        | ne |                               |                       |
|        | ** |                               |                       |
+========+====+===============================+=======================+
| G      |    | There are some aspects of     |                       |
| eneral |    | this draft guidance document  |                       |
|        |    | that appear to improve global |                       |
|        |    | harmonization, for example,   |                       |
|        |    | approach to aseptic           |                       |
|        |    | processing vs. Terminal       |                       |
|        |    | Sterilization and approach to |                       |
|        |    | environmental monitoring at   |                       |
|        |    | rest & in operation (dynamic  |                       |
|        |    | condition). However, several  |                       |
|        |    | opportunities for this FDA    |                       |
|        |    | guidance to be harmonized     |                       |
|        |    | with European GMP             |                       |
|        |    | requirements, as included in  |                       |
|        |    | Annex 1, appeared to have     |                       |
|        |    | been missed. The creation of  |                       |
|        |    | a unified global aseptic      |                       |
|        |    | standard is both feasible and |                       |
|        |    | necessary, and should be      |                       |
|        |    | considered. The following     |                       |
|        |    | topics in the guidance appear |                       |
|        |    | to be in direct conflict with |                       |
|        |    | EU requirements and should be |                       |
|        |    | re-visited:                   |                       |
|        |    |                               |                       |
|        |    | -   Area classification (e.g. |                       |
|        |    |     US Class 100/ISO 5 vs. EU |                       |
|        |    |     Grade A)                  |                       |
|        |    |                               |                       |
|        |    | -   Introduction of a class   |                       |
|        |    |     1000 area                 |                       |
|        |    |                               |                       |
|        |    | -   Static/dynamic testing    |                       |
|        |    |     (static required in EU,   |                       |
|        |    |     dynamic in the US)        |                       |
|        |    |                               |                       |
|        |    | -   Five micron particle      |                       |
|        |    |     requirement (5 micron     |                       |
|        |    |     particle monitoring       |                       |
|        |    |     required in EU but not in |                       |
|        |    |     US)                       |                       |
|        |    |                               |                       |
|        |    | -   Cubic meter measurement   |                       |
|        |    |     (Volume requirement       |                       |
|        |    |     explicit in EU, but not   |                       |
|        |    |     in US)                    |                       |
|        |    |                               |                       |
|        |    | -   Requirements for          |                       |
|        |    |     unidirectional flow       |                       |
|        |    |     (Difference in philosophy |                       |
|        |    |     regarding provision of    |                       |
|        |    |     unidirectional flow)      |                       |
|        |    |                               |                       |
|        |    | -   Isolator background       |                       |
|        |    |     requirement (EU: Grade D, |                       |
|        |    |     US Class 100,000 -- Grade |                       |
|        |    |     C equivalent in dynamic   |                       |
|        |    |     condition)                |                       |
|        |    |                               |                       |
|        |    | -   Blow/fill/seal background |                       |
|        |    |     and critical zone         |                       |
|        |    |     monitoring requirement    |                       |
|        |    |     (EU background Grade C,   |                       |
|        |    |     US background Class       |                       |
|        |    |     10,000 -- Grade B         |                       |
|        |    |     equivalent in dynamic     |                       |
|        |    |     condition. Dynamic viable |                       |
|        |    |     monitoring only in        |                       |
|        |    |     critical area: US -- both |                       |
|        |    |     viable and non-viable.)   |                       |
|        |    |                               |                       |
|        |    | -   Area grading for          |                       |
|        |    |     component preparation     |                       |
|        |    |     (EU: Grade D, US Class    |                       |
|        |    |     100,000 -- Grade C        |                       |
|        |    |     equivalent in dynamic     |                       |
|        |    |     condition)                |                       |
|        |    |                               |                       |
|        |    | -   Averaging of              |                       |
|        |    |     microbiological results   |                       |
|        |    |                               |                       |
|        |    | -   Sterilizer load pattern   |                       |
|        |    |     record location           |                       |
|        |    |     (Validation documents in  |                       |
|        |    |     EU, batch record in US)   |                       |
+--------+----+-------------------------------+-----------------------+
| G      |    | The guidance includes various |                       |
| eneral |    | terminologies surrounding     |                       |
|        |    | investigation requirements    |                       |
|        |    | that may result in differing  |                       |
|        |    | expectations (regarding when  |                       |
|        |    | required and expected         |                       |
|        |    | investigation content). It is |                       |
|        |    | recommended that clear        |                       |
|        |    | descriptions of investigation |                       |
|        |    | requirements be included      |                       |
|        |    | wherever "investigation" is   |                       |
|        |    | mentioned throughout the      |                       |
|        |    | guidance document.            |                       |
|        |    | Alternatively, the term       |                       |
|        |    | "investigation" could be      |                       |
|        |    | added to the Glossary along   |                       |
|        |    | with a clear description of   |                       |
|        |    | expectations. The             |                       |
|        |    | expectations for              |                       |
|        |    | investigations should relate  |                       |
|        |    | to the relative risk          |                       |
|        |    | associated with the type of   |                       |
|        |    | event. This is exemplified by |                       |
|        |    | the very detailed description |                       |
|        |    | of expected investigation     |                       |
|        |    | approach for sterility test   |                       |
|        |    | positives in lines 1403-1498, |                       |
|        |    | but is less clear in other    |                       |
|        |    | sections of the draft         |                       |
|        |    | guidance. Some examples of    |                       |
|        |    | variations in terminology     |                       |
|        |    | used in the current draft     |                       |
|        |    | include the following:        |                       |
|        |    |                               |                       |
|        |    | -   Line 177: "documented as  |                       |
|        |    |     to cause and              |                       |
|        |    |     significance"             |                       |
|        |    |                               |                       |
|        |    | -   Line 215: "receive        |                       |
|        |    |     investigational           |                       |
|        |    |     attention"                |                       |
|        |    |                               |                       |
|        |    | -   Lines 245, 281:           |                       |
|        |    |     "investigated"            |                       |
|        |    |                               |                       |
|        |    | -   Line 523: "an             |                       |
|        |    |     investigation should be   |                       |
|        |    |     conducted promptly"       |                       |
|        |    |                               |                       |
|        |    | -   Lines 542-643:            |                       |
|        |    |     "investigated in accord   |                       |
|        |    |     with Section 211.192"     |                       |
|        |    |                               |                       |
|        |    | -   Line 1683: "investigated  |                       |
|        |    |     and any product that may  |                       |
|        |    |     have been impacted by the |                       |
|        |    |     breach rejected"          |                       |
|        |    |                               |                       |
|        |    | -   Lines 769-771:            |                       |
|        |    |     "comprehensive documented |                       |
|        |    |     investigation should be   |                       |
|        |    |     conducted to determine    |                       |
|        |    |     the origin of the         |                       |
|        |    |     contamination and the     |                       |
|        |    |     scope of the problem"     |                       |
|        |    |                               |                       |
|        |    | -   Lines 1183-1184:          |                       |
|        |    |     "remedial measures should |                       |
|        |    |     be taken"                 |                       |
|        |    |                               |                       |
|        |    | -   Line 1206: "urges         |                       |
|        |    |     attention to the          |                       |
|        |    |     approaching action        |                       |
|        |    |     conditions"               |                       |
|        |    |                               |                       |
|        |    | -   Line 1207: "more thorough |                       |
|        |    |     investigation"            |                       |
+--------+----+-------------------------------+-----------------------+
| G      |    | We recommend clarification in |                       |
| eneral |    | the scope, that the document  |                       |
|        |    | addresses aseptic "filling"   |                       |
|        |    | operations versus aseptic     |                       |
|        |    | (bulk) operations in general. |                       |
|        |    | For added clarification, we   |                       |
|        |    | recommend text revision to    |                       |
|        |    | note that guidance for bulk   |                       |
|        |    | operations is limited to      |                       |
|        |    | Appendix 3, and that other    |                       |
|        |    | sections of the document do   |                       |
|        |    | not apply. With lack of       |                       |
|        |    | specific differentiation,     |                       |
|        |    | field investigators may opt   |                       |
|        |    | to apply all requirements     |                       |
|        |    | outlined for filling          |                       |
|        |    | processes to bulk processes.  |                       |
+--------+----+-------------------------------+-----------------------+
| G      |    | Closed system processing is   |                       |
| eneral |    | not discussed. This           |                       |
|        |    | processing approach though,   |                       |
|        |    | is both sufficiently          |                       |
|        |    | different from the            |                       |
|        |    | traditional open system, and  |                       |
|        |    | widely utilized to warrant    |                       |
|        |    | mention and integration of    |                       |
|        |    | regulatory expectations       |                       |
|        |    | throughout the different      |                       |
|        |    | sections of the guidance.     |                       |
|        |    | Alternatively, the guidance   |                       |
|        |    | could exempt validated closed |                       |
|        |    | systems with validated CIP    |                       |
|        |    | processes from its scope.     |                       |
+--------+----+-------------------------------+-----------------------+
| G      |    | Specific guidance on          |                       |
| eneral |    | designing/building a barrier  |                       |
|        |    | facility should be considered |                       |
|        |    | through the issuance of a     |                       |
|        |    | separate guidance document on |                       |
|        |    | isolators.                    |                       |
+--------+----+-------------------------------+-----------------------+
| G      |    | The standardized use of       |                       |
| eneral |    | relevant terms throughout the |                       |
|        |    | guidance could reduce         |                       |
|        |    | potential confusion. Efforts  |                       |
|        |    | have been taken to define     |                       |
|        |    | terms in a glossary at the    |                       |
|        |    | end of the document, but the  |                       |
|        |    | use of these terms in the     |                       |
|        |    | text do not always match      |                       |
|        |    | their intended meaning. In    |                       |
|        |    | other cases, a specific       |                       |
|        |    | definition has not been       |                       |
|        |    | provided in the glossary for  |                       |
|        |    | a term apparently been used   |                       |
|        |    | as a synonym. Terms that are  |                       |
|        |    | sometimes used                |                       |
|        |    | interchangeably include:      |                       |
|        |    | processing room and           |                       |
|        |    | processing area, processing   |                       |
|        |    | zones and critical area,      |                       |
|        |    | processing line and clean     |                       |
|        |    | area, processing line and     |                       |
|        |    | critical area, clean area and |                       |
|        |    | critical area, processing     |                       |
|        |    | area and critical room,       |                       |
|        |    | qualification and             |                       |
|        |    | certification, limits or      |                       |
|        |    | specifications and levels,    |                       |
|        |    | controlled and classified.    |                       |
+--------+----+-------------------------------+-----------------------+
| G      |    | [21 CFR Regulation            | The non-descript      |
| eneral |    | Citations:]{.underline}       | nature of the         |
|        |    |                               | regulation results in |
|        |    | Throughout the draft guidance | different             |
|        |    | document, 21 CFR Part 210 and | interpretations       |
|        |    | 211 regulations are cited. We | during Pre-approval   |
|        |    | suggest that guidance be      | inspections and GMP   |
|        |    | provided to support each      | investigations.       |
|        |    | regulation cited.             |                       |
+--------+----+-------------------------------+-----------------------+
| II.B   | 7  | [Current Text:]{.underline}   | As the guidance       |
|        | 0- |                               | states there are      |
| Tec    | 71 | "There are basic differences  | basic differences     |
| hnical |    | between the production of     | between the           |
| Fra    |    | sterile drug products using   | production of         |
| mework |    | aseptic processing and        | terminally sterilized |
|        |    | production using terminal     | products sterile drug |
|        |    | sterilization."               | products using        |
|        |    |                               | aseptic processing    |
|        |    | [Comment:]{.underline}        | and production using  |
|        |    |                               | terminal              |
|        |    | This sentence should be       | sterilization and it  |
|        |    | changed to exclude terminally | should be clear that  |
|        |    | sterilized products from this | this guidance does    |
|        |    | guidance.                     | not apply to          |
|        |    |                               | terminally sterilized |
|        |    | [Proposed                     | products.             |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "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."                    |                       |
+--------+----+-------------------------------+-----------------------+
| III\.  | 1  | [Current Text:]{.underline}   | The scope of this     |
|        | 14 |                               | document is to        |
| Scope  | -1 | "In such cases, a             | discuss current GMP   |
|        | 15 | manufacturer can explore the  | issues and as such it |
|        |    | option of adding adjunct      | is inappropriate to   |
|        |    | processing steps to increase  | discuss product       |
|        |    | the level of sterility        | development and the   |
|        |    | confidence."                  | review process.       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The sentence is a statement   |                       |
|        |    | without guidance as to when   |                       |
|        |    | such evaluation is required.  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete sentence.              |                       |
+--------+----+-------------------------------+-----------------------+
| IV\.   | 1  | [Current Text:]{.underline}   | Statement is unclear. |
|        | 31 |                               |                       |
| Bui    | -1 | "Critical areas and support   |                       |
| ldings | 32 | areas of the aseptic          |                       |
| and    |    | processing operation should   |                       |
| Faci   |    | be classified and supported   |                       |
| lities |    | by microbiological and        |                       |
|        |    | particle data obtained during |                       |
|        |    | qualification studies."       |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | For clarity, we suggest       |                       |
|        |    | adding text and providing     |                       |
|        |    | particulate/microbial levels  |                       |
|        |    | to define *"critical areas"*  |                       |
|        |    | and *"support areas"*.        |                       |
+--------+----+-------------------------------+-----------------------+
| IV\.   | 1  | [Current Text:]{.underline}   | It is unclear whether |
|        | 36 |                               | the statement applies |
| Bui    |    | "The aseptic processing       | to routine            |
| ldings |    | facility monitoring program   | environmental         |
| and    |    | should also assess            | monitoring.           |
| Faci   |    | conformance with specified    |                       |
| lities |    | clean area classifications    |                       |
|        |    | under dynamic conditions on a |                       |
|        |    | routine basis."               |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision]{.underline}:        |                       |
|        |    |                               |                       |
|        |    | "The aseptic processing       |                       |
|        |    | facility's routine            |                       |
|        |    | environmental monitoring      |                       |
|        |    | program should assess the     |                       |
|        |    | environment under dynamic     |                       |
|        |    | conditions."                  |                       |
+--------+----+-------------------------------+-----------------------+
| IV\.   | 1  | [Current Text:]{.underline}   | Since the table       |
|        | 42 |                               | covers more than just |
| Bui    |    | **"**TABLE 1- Air             | air classification    |
| ldings |    | Classifications^a^"           | requirements (i.e.,   |
| and    |    |                               | microbial levels) and |
| Faci   |    | [Proposed                     | pertains solely to    |
| lities |    | Revision:]{.underline}        | aseptic processing    |
|        |    |                               | areas, we suggest     |
| Table  |    | "TABLE 1 - Air Monitoring for | revising the title of |
| 1      |    | Aseptic Processing"           | the table.            |
+--------+----+-------------------------------+-----------------------+
| IV\.   | 1  | [Current Text:]{.underline}   | We recommend the      |
|        | 42 |                               | value should be       |
| Bui    | -1 | *"*Clean Area Classification  | presented in the      |
| ldings | 44 | (0.5 µm particles/ft3)".      | table header of       |
| and    |    |                               | Column 1 as the       |
| Faci   |    | [Proposed                     | *maximum* number of   |
| lities |    | Revision:]{.underline}        | particles.            |
|        |    |                               |                       |
| Table  |    | "Clean Area Classification    |                       |
| 1      |    | (≥0.5 µm particles/ft3)"*.*   |                       |
+--------+----+-------------------------------+-----------------------+
| IV\.   | 1  | [Current Text:]{.underline}   |                       |
|        | 47 |                               |                       |
| Bui    | -1 | Footnote (b) -- "ISO 1644-1   |                       |
| ldings | 48 | designations provide platform |                       |
| and    |    | particle concentration values |                       |
| Faci   |    | for clean rooms in multiple   |                       |
| lities |    | industries. An ISO 5 particle |                       |
|        |    | concentration is equal to     |                       |
| Table  |    | Class 100 and approximately   |                       |
| 1      |    | equals EU Grade A."           |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest that there should  |                       |
|        |    | also be international         |                       |
|        |    | harmonization in              |                       |
|        |    | microbiological action        |                       |
|        |    | levels. The proposed          |                       |
|        |    | microbiological limits are    |                       |
|        |    | stricter than both the        |                       |
|        |    | current USP and the EU guide  |                       |
|        |    | Annex. The EU guide permits   |                       |
|        |    | averaging, which is not       |                       |
|        |    | mentioned in the FDA guidance |                       |
|        |    | and so presumably not         |                       |
|        |    | permitted.                    |                       |
+--------+----+-------------------------------+-----------------------+
| IV\.   | 1  | [Current Text:]{.underline}   |                       |
|        | 52 |                               |                       |
| Bui    |    | Footnote (e) -- "Samples from |                       |
| ldings |    | Class 100 (ISO 5)             |                       |
| and    |    | environments should normally  |                       |
| Faci   |    | yield no microbiological      |                       |
| lities |    | contaminants."                |                       |
|        |    |                               |                       |
| Table  |    | [Comment:]{.underline}        |                       |
| 1      |    |                               |                       |
|        |    | It is unclear why Table 1     |                       |
|        |    | includes the value of "1" if  |                       |
|        |    | Class 100 (ISO 5)             |                       |
|        |    | environments should "normally |                       |
|        |    | yield no microbiological      |                       |
|        |    | contaminants". Footnote (e)   |                       |
|        |    | adds confusion as to whether  |                       |
|        |    | the action level is 1 or      |                       |
|        |    | zero. We suggest adding a     |                       |
|        |    | note that averaging would be  |                       |
|        |    | consistent with EU GMP.       |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest that this footnote |                       |
|        |    | either be deleted, or         |                       |
|        |    | replaced with the following   |                       |
|        |    | text: "The count should be    |                       |
|        |    | \<1, as verified by           |                       |
|        |    | averaging."                   |                       |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 1  | [Current Text:]{.underline}   | The current text does |
|        | 59 |                               | not allow for the use |
| Cr     | -1 | "A critical area is one in    | of sealed carts to    |
| itical | 60 | which the sterilized drug     | transport products    |
| Area - |    | product, containers, and      | from the filling line |
| Class  |    | closures are exposed to       | to the lyophilizer    |
| 100    |    | environmental conditions      | without the use of    |
| (ISO   |    | designed to preserve          | elaborate transport   |
| 5)     |    | sterility."                   | carts.                |
|        |    |                               |                       |
|        |    | [Proposed Text:]{.underline}  |                       |
|        |    |                               |                       |
|        |    | "A critical area is one in    |                       |
|        |    | which the sterilized drug     |                       |
|        |    | product, containers, and      |                       |
|        |    | closures are exposed to       |                       |
|        |    | environmental conditions      |                       |
|        |    | designed to preserve          |                       |
|        |    | sterility. Some special       |                       |
|        |    | operations, such as transport |                       |
|        |    | of containers from the        |                       |
|        |    | filling line to a lyophilizer |                       |
|        |    | may occur via alternate       |                       |
|        |    | validated approaches, such as |                       |
|        |    | an over-pressurized sealed    |                       |
|        |    | transfer carts."              |                       |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 1  | [Current Text:]{.underline}   | Harmonization         |
|        | 74 | \"micron\"                    |                       |
| Cr     |    |                               |                       |
| itical | 3  | [Proposed Text:]{.underline}  |                       |
| Area - | 04 | Replace \"micron\" with       |                       |
| Class  |    | \"micro meter\"               |                       |
| 100    | 3  |                               |                       |
| (ISO   | 10 |                               |                       |
| 5)     |    |                               |                       |
|        | Fo |                               |                       |
|        | ot |                               |                       |
|        | no |                               |                       |
|        | te |                               |                       |
|        | 7  |                               |                       |
|        |    |                               |                       |
|        | 9  |                               |                       |
|        | 69 |                               |                       |
|        |    |                               |                       |
|        | 9  |                               |                       |
|        | 76 |                               |                       |
|        |    |                               |                       |
|        | 20 |                               |                       |
|        | 01 |                               |                       |
|        |    |                               |                       |
|        | 20 |                               |                       |
|        | 49 |                               |                       |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 1  | [Current Text:]{.underline}   |                       |
|        | 82 |                               |                       |
| Cr     | -1 | "Regular monitoring should be |                       |
| itical | 83 | performed during each shift". |                       |
| Area - |    |                               |                       |
| Class  |    | [Comment:]{.underline}        |                       |
| 100    |    |                               |                       |
| (ISO   |    | Qualify "regular".            |                       |
| 5)     |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Regular monitoring should be |                       |
|        |    | performed at least once       |                       |
|        |    | during each shift or as       |                       |
|        |    | appropriate."                 |                       |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 1  | "Shift" needs defining        |                       |
|        | 83 | precisely. It has no real     |                       |
| Cr     |    | meaning except as a team of   |                       |
| itical |    | people. Here it is a time     |                       |
| Area - |    | function apparently. If a     |                       |
| Class  |    | Team (Shift) works for 2.5    |                       |
| 100    |    | hours and takes a break,      |                       |
| (ISO   |    | works 2.5 hours and takes a   |                       |
| 5)     |    | second break, works 2.5 hours |                       |
|        |    | again and takes a third       |                       |
|        |    | break, is this considered     |                       |
|        |    | one, two or three shifts?     |                       |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 1  | [Current Text:]{.underline}   | The word 'laminar'    |
|        | 96 |                               | has been replaced     |
| Cr     | -1 | "Air in critical areas should | with unidirectional'  |
| itical | 98 | be supplied at the point of   | with this exception.  |
| Area - |    | use as HEPA-filtered laminar  |                       |
| Class  |    | flow air at a velocity        |                       |
| 100    |    | sufficient to sweep particles |                       |
| (ISO   |    | away from the filling/closing |                       |
| 5)     |    | area and maintain             |                       |
|        |    | unidirectional airflow during |                       |
|        |    | operations."                  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Air in critical areas should |                       |
|        |    | be supplied at a velocity     |                       |
|        |    | sufficient to sweep particles |                       |
|        |    | away from the filling/closing |                       |
|        |    | area and maintain             |                       |
|        |    | unidirectional airflow during |                       |
|        |    | operations."                  |                       |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 1  | [Current Text:]{.underline}   |                       |
|        | 98 |                               |                       |
| Cr     | -2 | "The velocity parameters      |                       |
| itical | 00 | established for each          |                       |
| Area - |    | processing line should be     |                       |
| Class  | Fo | justified and appropriate to  |                       |
| 100    | ot | maintain unidirectional       |                       |
| (ISO   | no | airflow and air quality under |                       |
| 5)     | te | dynamic conditions within a   |                       |
|        | 4  | defined space (Ref.3).^4^"    |                       |
|        |    |                               |                       |
|        |    | and                           |                       |
|        |    |                               |                       |
|        |    | Footnote 4: "A velocity from  |                       |
|        |    | 0.45 to 0.51 meters/second    |                       |
|        |    | (90 to 100 feet per minute)   |                       |
|        |    | is generally established,     |                       |
|        |    | with a range of plus or minus |                       |
|        |    | 20 percent around the set     |                       |
|        |    | point. Higher velocities may  |                       |
|        |    | be appropriate in operations  |                       |
|        |    | generating high levels of     |                       |
|        |    | particulates."                |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | For clarity, we suggest       |                       |
|        |    | adding text to define         |                       |
|        |    | "defined space".              |                       |
|        |    |                               |                       |
|        |    | With regard to Footnote 4, it |                       |
|        |    | is suggested that it is       |                       |
|        |    | clearly stated that this is a |                       |
|        |    | guidance value, which then    |                       |
|        |    | would be harmonized with the  |                       |
|        |    | EU GMPs, Annex 1.             |                       |
|        |    |                               |                       |
|        |    | Where it is scientifically    |                       |
|        |    | and technically justified &   |                       |
|        |    | validated, we suggest that    |                       |
|        |    | the option should be open to  |                       |
|        |    | use any alternative velocity  |                       |
|        |    | that is effective, not simply |                       |
|        |    | a "higher" one. Depending on  |                       |
|        |    | the exact facilities &        |                       |
|        |    | process, it may prove better  |                       |
|        |    | to use a lower, controlled,   |                       |
|        |    | velocity. Where this is       |                       |
|        |    | validated, the approach       |                       |
|        |    | should not be unnecessarily   |                       |
|        |    | proscribed. For example, if   |                       |
|        |    | smoke studies at lower        |                       |
|        |    | velocities show better        |                       |
|        |    | laminarity, then it should be |                       |
|        |    | acceptable to operate in this |                       |
|        |    | defined range.                |                       |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 2  | [Current Text:]{.underline}   | In line 159 critical  |
|        | 02 |                               | area is used and      |
|        | -2 | "Proper design and control    | defined. Although     |
|        | 03 | should prevent turbulence or  | design should seek to |
|        |    | stagnant air in the aseptic   | minimize turbulence   |
|        |    | processing line or clean      | or stagnant air in    |
|        |    | area."                        | the aseptic           |
|        |    |                               | processing line or    |
|        |    | [Proposed                     | clean area it may not |
|        |    | Revision:]{.underline}        | be possible to        |
|        |    |                               | totally eliminate     |
|        |    | "Proper design and control    | these situations. The |
|        |    | should prevent turbulence or  | guidance document     |
|        |    | stagnant air in the critical  | could also reword the |
|        |    | area."                        | sentence to suggest   |
|        |    |                               | minimizing turbulence |
|        |    |                               | or stagnant air in    |
|        |    |                               | the aseptic zone.     |
+--------+----+-------------------------------+-----------------------+
| IV.A   | 2  | [Current Text:]{.underline}   |                       |
|        | 14 |                               |                       |
| Cr     |    | "Air monitoring of critical   |                       |
| itical |    | areas should normally yield   |                       |
| Area - |    | no microbiological            |                       |
| Class  |    | contaminants"                 |                       |
| 100    |    |                               |                       |
| (ISO   |    | [Comment:]{.underline}        |                       |
| 5)     |    |                               |                       |
|        |    | The current text is           |                       |
|        |    | inconsistent with Table 1     |                       |
|        |    | that sets the action level at |                       |
|        |    | 1 cfu.                        |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "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."               |                       |
+--------+----+-------------------------------+-----------------------+
| IV.B   | 2  | [Current Text:]{.underline}   | Expand examples of    |
|        | 26 |                               | less critical         |
| Supp   | -2 | "An area classified at Class  | activities.           |
| orting | 27 | 100,000 (ISO 8) would be used |                       |
| Clean  |    | for less critical activities  |                       |
| Areas  |    | (such as initial equipment    |                       |
|        |    | preparation)."                |                       |
|        |    |                               |                       |
|        |    | [Proposed Text:]{.underline}  |                       |
|        |    |                               |                       |
|        |    | "An area classified at Class  |                       |
|        |    | 100,000 (ISO 8) would be used |                       |
|        |    | for less critical activities  |                       |
|        |    | (such as initial equipment    |                       |
|        |    | and component preparation)."  |                       |
+--------+----+-------------------------------+-----------------------+
| IV.B   | 2  | [Current Text:]{.underline}   | We suggest that the   |
|        | 29 |                               | additional category   |
| Supp   | -2 | *"*Depending on the           | ISO 6 (Class 1000) in |
| orting | 30 | operation, manufacturers can  | the context of        |
| Clean  |    | also classify this area as    | Pharmaceutical        |
| Areas  |    | Class 1,000 (ISO 6) or        | manufacturing should  |
|        |    | maintain the entire aseptic   | be deleted for the    |
|        |    | filling room at Class 100     | following reasons:    |
|        |    | (ISO 5)."                     |                       |
|        |    |                               | -   There is no real  |
|        |    | [Proposed                     |     technical need    |
|        |    | Revision:]{.underline}        |     for this class.   |
|        |    |                               |                       |
|        |    | Delete sentence.              | -   The category does |
|        |    |                               |     not exist in any  |
|        |    |                               |     other             |
|        |    |                               |     pharmaceutical    |
|        |    |                               |     references.       |
|        |    |                               |                       |
|        |    |                               | -   Strides should be |
|        |    |                               |     made toward       |
|        |    |                               |     international     |
|        |    |                               |     harmonization     |
|        |    |                               |     whereas the       |
|        |    |                               |     introduction of a |
|        |    |                               |     new class tends   |
|        |    |                               |     to move against   |
|        |    |                               |     this.             |
|        |    |                               |                       |
|        |    |                               | -   The               |
|        |    |                               |     microbiological   |
|        |    |                               |     criteria for this |
|        |    |                               |     category are new  |
|        |    |                               |     and are not       |
|        |    |                               |     consistent with   |
|        |    |                               |     any other         |
|        |    |                               |     existing document |
|        |    |                               |     on this topic,    |
|        |    |                               |     including the     |
|        |    |                               |     USP.              |
|        |    |                               |                       |
|        |    |                               | -   The proposed new  |
|        |    |                               |     category would    |
|        |    |                               |     generate          |
|        |    |                               |     uncertainty as to |
|        |    |                               |     what criteria     |
|        |    |                               |     would be          |
|        |    |                               |     expected,         |
|        |    |                               |     depending on the  |
|        |    |                               |     process (ref.     |
|        |    |                               |     Line 229          |
|        |    |                               |     "depending on the |
|        |    |                               |     operation")       |
+--------+----+-------------------------------+-----------------------+
| IV.C   | 2  | [Current Text:]{.underline}   | -   Unnecessary       |
|        | 38 |                               |     specificity. It   |
| Clean  | -2 | "For example, a positive      |     should not be     |
| Area   | 41 | pressure differential of at   |     necessary to      |
| Sepa   |    | least 12.5 Pascals (Pa)^1^    |     maintain any      |
| ration |    | should be maintained at the   |     specific value,   |
|        |    | interface between classified  |     as long as a      |
|        |    | and unclassified areas. This  |     correct cascade   |
|        |    | same overpressure should be   |     is maintained (as |
|        |    | maintained between the        |     discussed in line |
|        |    | aseptic processing room and   |     241).             |
|        |    | adjacent rooms (with doors    |                       |
|        |    | closed)."                     | -   The draft         |
|        |    |                               |     guidance          |
|        |    | [Proposed                     |     indicates that    |
|        |    | Revision:]{.underline}        |     differentials of  |
|        |    |                               |     12.5 Pascals need |
|        |    | "Overpressure should be       |     to be maintained  |
|        |    | maintained between the        |     with respect to   |
|        |    | aseptic processing room and   |     all rooms         |
|        |    | adjacent rooms of different   |     adjacent to an    |
|        |    | classification (with doors    |     aseptic           |
|        |    | closed)."                     |     processing room.  |
|        |    |                               |     If this includes  |
|        |    |                               |     rooms of the      |
|        |    |                               |                       |
|        |    |                               |    [same]{.underline} |
|        |    |                               |     classification,   |
|        |    |                               |     then this is in   |
|        |    |                               |     excess of         |
|        |    |                               |     existing GMP      |
|        |    |                               |     requirements,     |
|        |    |                               |     which require     |
|        |    |                               |     this differential |
|        |    |                               |     only between      |
|        |    |                               |     rooms of          |
|        |    |                               |     [d                |
|        |    |                               | ifferent]{.underline} |
|        |    |                               |     classification.   |
|        |    |                               |                       |
|        |    |                               | -   Due to the        |
|        |    |                               |     cumulative        |
|        |    |                               |     differential      |
|        |    |                               |     pressure steps,   |
|        |    |                               |     this may result   |
|        |    |                               |     in very high      |
|        |    |                               |     pressure          |
|        |    |                               |     (relative to      |
|        |    |                               |     ambient) at the   |
|        |    |                               |     central core. It  |
|        |    |                               |     may also cause    |
|        |    |                               |     problems with     |
|        |    |                               |     balancing the     |
|        |    |                               |     overall cascades  |
|        |    |                               |     of airflow /      |
|        |    |                               |     pressure          |
|        |    |                               |     differentials     |
|        |    |                               |     (e.g., where a    |
|        |    |                               |     hot air           |
|        |    |                               |     sterilizer        |
|        |    |                               |     tunnels is        |
|        |    |                               |     installed there   |
|        |    |                               |     would be a very   |
|        |    |                               |     high differential |
|        |    |                               |     between outlet    |
|        |    |                               |     and inlet to the  |
|        |    |                               |     tunnel).          |
+--------+----+-------------------------------+-----------------------+
| IV.C   | 2  | [Current Text:]{.underline}   | The requirement to    |
|        | 43 |                               | frequently record     |
| Clean  | -2 | "Pressure differentials       | values from a         |
| Area   | 45 | between cleanrooms should be  | validated system that |
| Sepa   |    | monitored continuously        | is within             |
| ration |    | throughout each shift and     | specification is      |
|        |    | frequently recorded, and      | overly burdensome and |
|        |    | deviations from established   | should be changed.    |
|        |    | limits should be              |                       |
|        |    | investigated."                |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Pressure differentials       |                       |
|        |    | between cleanrooms should be  |                       |
|        |    | monitored continuously        |                       |
|        |    | throughout and recorded at    |                       |
|        |    | the beginning and end of each |                       |
|        |    | shift. All alarms should be   |                       |
|        |    | recorded, and deviations from |                       |
|        |    | established limits should be  |                       |
|        |    | investigated."                |                       |
+--------+----+-------------------------------+-----------------------+
| IV.C   | 2  | [Current Text:]{.underline}   | The number of air     |
|        | 47 |                               | changes required      |
| Clean  | -2 | "For Class 100,000 (ISO 8)    | depends on multiple   |
| Area   | 49 | supporting rooms, airflow     | factors. Air changes  |
| Sepa   |    | sufficient to achieve at      | substantially higher  |
| ration |    | least 20 air changes per hour | than 20 per hour are  |
|        |    | would be typically            | normally unnecessary  |
|        |    | acceptable."                  | and may be difficult  |
|        |    |                               | to achieve depending  |
|        |    | [Proposed                     | on the size & design  |
|        |    | Revision:]{.underline}        | of the area.          |
|        |    |                               |                       |
|        |    | "For Class 100,000 (ISO 8)    |                       |
|        |    | supporting rooms, airflow     |                       |
|        |    | sufficient to achieve and     |                       |
|        |    | maintain the desired          |                       |
|        |    | classification is required.   |                       |
|        |    | Twenty or more air changes    |                       |
|        |    | per hour may be needed,       |                       |
|        |    | depending on the design and   |                       |
|        |    | use of the room."             |                       |
+--------+----+-------------------------------+-----------------------+
| IV.D.1 | 2  | [Current Text:]{.underline}   | Statement is unclear. |
|        | 64 |                               |                       |
| Me     | -2 | "Compressed gases such as     |                       |
| mbrane | 66 | air, nitrogen, and carbon     |                       |
|        |    | dioxide are often used in     |                       |
|        |    | cleanrooms and are frequently |                       |
|        |    | employed in operations        |                       |
|        |    | involving purging or          |                       |
|        |    | overlaying."                  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Compressed gases such as     |                       |
|        |    | air, nitrogen, and carbon     |                       |
|        |    | dioxide are often used in     |                       |
|        |    | cleanrooms and are frequently |                       |
|        |    | employed in operations        |                       |
|        |    | involving purging and/or      |                       |
|        |    | overlaying."                  |                       |
+--------+----+-------------------------------+-----------------------+
| IV.D.1 | 2  | [Current Text:]{.underline}   | -   Emphasis should   |
|        | 72 |                               |     be put on         |
| Me     | -2 | "Sterilized holding tanks and |     confirmation of   |
| mbrane | 73 | any contained liquids should  |     integrity rather  |
|        |    | be held under continuous      |     than an absolute  |
|        |    | overpressure to prevent       |     requirement to    |
|        |    | microbial contamination."     |     have overpressure |
|        |    |                               |     in all cases.     |
|        |    | [Proposed                     |     Overpressure on a |
|        |    | Revision:]{.underline}        |     holding vessel    |
|        |    |                               |     may adversely     |
|        |    | "Sterilized holding tanks and |     affect the        |
|        |    | any contained liquids should  |     filling process,  |
|        |    | be held under continuous      |     for example,      |
|        |    | overpressure to prevent       |     dosing            |
|        |    | microbial contamination.      |     consistency.      |
|        |    | Alternative techniques such   |     Hence, it is      |
|        |    | as pressure/vacuum testing of |     often technically |
|        |    | the vessel/system, use of     |     difficult to meet |
|        |    | continuous overpressure, or   |     the requirement   |
|        |    | properly validated            |     to have the       |
|        |    | non-pressurized systems may   |     holding vessels   |
|        |    | be appropriate."              |     always subjected  |
|        |    |                               |     to overpressure   |
|        |    |                               |     during the        |
|        |    |                               |     filling process.  |
|        |    |                               |     Positive pressure |
|        |    |                               |     maintenance is a  |
|        |    |                               |     good technique,   |
|        |    |                               |     but is not        |
|        |    |                               |     currently         |
|        |    |                               |     mandated by GMPs, |
|        |    |                               |     provided that the |
|        |    |                               |     vessel integrity  |
|        |    |                               |     and filter        |
|        |    |                               |     integrity are     |
|        |    |                               |     controlled.       |
|        |    |                               |                       |
|        |    |                               | -   Sterility can be  |
|        |    |                               |     maintained with   |
|        |    |                               |     other procedures, |
|        |    |                               |     such as sterile   |
|        |    |                               |     vent filters.     |
|        |    |                               |                       |
|        |    |                               | -   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   |
|        |    |                               |     via media fills.  |
+--------+----+-------------------------------+-----------------------+
| IV.D.1 | 2  | [Current Text:]{.underline}   | Vague requirement.    |
|        | 80 |                               |                       |
| Me     |    | "Filters also should be       |                       |
| mbrane |    | integrity tested upon         |                       |
|        |    | installation and periodically |                       |
|        |    | thereafter (e.g., including   |                       |
|        |    | at end of use)."              |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Filters also should be       |                       |
|        |    | integrity tested upon         |                       |
|        |    | installation and at least     |                       |
|        |    | once per year thereafter      |                       |
|        |    | (e.g., including at end of    |                       |
|        |    | use)."                        |                       |
+--------+----+-------------------------------+-----------------------+
| IV.D.2 | 2  | [Current Text:]{.underline}   |                       |
|        | 87 |                               |                       |
| Hig    | -2 | "Thereafter, leak tests       |                       |
| h-Effi | 89 | should be performed at        |                       |
| ciency |    | suitable time intervals for   |                       |
| Parti  |    | HEPA filters in the aseptic   |                       |
| culate |    | processing facility. For      |                       |
| Air    |    | example, such testing should  |                       |
| (HEPA) |    | be performed twice a year for |                       |
|        |    | the aseptic processing room." |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest that the minimum   |                       |
|        |    | frequencies for testing       |                       |
|        |    | should be based on ISO        |                       |
|        |    | recommendations (ISO          |                       |
|        |    | 14644-2). More frequent       |                       |
|        |    | testing may be done based on  |                       |
|        |    | risk analysis and routine     |                       |
|        |    | performance data. We also     |                       |
|        |    | suggest that testing be       |                       |
|        |    | performed twice per year in   |                       |
|        |    | the critical zone (ISO 5) and |                       |
|        |    | once per year for HEPA        |                       |
|        |    | filters in lower categories.  |                       |
+--------+----+-------------------------------+-----------------------+
| IV.D.2 | 2  | [Current Text:]{.underline}   | -   Testing HEPAs in  |
|        | 92 |                               |     dry heat          |
| Hig    | -2 | "Among the filters that       |     ovens/tunnels is  |
| h-Effi | 94 | should be leak tested are     |     dangerous due the |
| ciency |    | those installed in dry heat   |     volatility,       |
| Parti  |    | depyrogenation tunnels        |     combustibility,   |
| culate |    | commonly used to depyrogenate |     and potential     |
| Air    |    | glass vials."                 |     tox               |
| (HEPA) |    |                               | icity/carcinogenicity |
|        |    |                               |     of challenge      |
|        |    |                               |     materials when    |
|        |    |                               |     heated.           |
|        |    |                               |                       |
|        |    |                               | -   We suggest adding |
|        |    |                               |     text to provide   |
|        |    |                               |     clarification     |
|        |    |                               |     that leak tests   |
|        |    |                               |     on HEPA filters   |
|        |    |                               |     located in the    |
|        |    |                               |     heating zone of   |
|        |    |                               |     dry heat          |
|        |    |                               |     depyrogenation    |
|        |    |                               |     tunnels need to   |
|        |    |                               |     be conducted at   |
|        |    |                               |     the               |
|        |    |                               |     room-temperature  |
|        |    |                               |     state.            |
|        |    |                               |                       |
|        |    |                               | -   Feasibility       |
|        |    |                               |     should be based   |
|        |    |                               |     on tunnel type    |
|        |    |                               |     installed.        |
+--------+----+-------------------------------+-----------------------+
| IV.D.2 | 2  | [Current Text:]{.underline}   | -   Concerns that DOP |
|        | 97 |                               |     is a carcinogen   |
| Hig    | -2 | "Dioctylphthalate (DOP) and   |     have been raised; |
| h-Effi | 98 | Poly-alpha-olefin (PAO) are   |     it should not be  |
| ciency |    | examples of appropriate leak  |     proposed for use. |
| Parti  |    | testing aerosols."            |                       |
| culate |    |                               | -   Other leak        |
| Air    |    | [Proposed                     |     testing agents    |
| (HEPA) |    | Revision:]{.underline}        |     are also          |
|        |    |                               |     appropriate. We   |
|        |    | "Di-Ethyl-Hexyl-Phthalate     |     suggest that      |
|        |    | (DEHS) and Poly-alpha-olefin  |     Di-               |
|        |    | (PAO) are examples of         | Ethyl-Hexyl-Phthalate |
|        |    | appropriate leak testing      |     (DEHS) be added   |
|        |    | aerosols."                    |     to the list of    |
|        |    |                               |     appropriate leak  |
|        |    |                               |     testing aerosols, |
|        |    |                               |     as this is a      |
|        |    |                               |     well-defined      |
|        |    |                               |     compound with     |
|        |    |                               |     specific          |
|        |    |                               |     characteristics.  |
|        |    |                               |     We also suggest   |
|        |    |                               |     that a reference  |
|        |    |                               |     to the            |
|        |    |                               |     international     |
|        |    |                               |     standard EN1822   |
|        |    |                               |     be added to the   |
|        |    |                               |     guidance as it    |
|        |    |                               |     contains a list   |
|        |    |                               |     of proven and     |
|        |    |                               |     recommended       |
|        |    |                               |     aerosol           |
|        |    |                               |     materials.        |
+--------+----+-------------------------------+-----------------------+
| IV.D.2 | 3  | [Current Text:]{.underline}   |                       |
|        | 10 |                               |                       |
| Hig    | -3 | **"**Performing a leak test   |                       |
| h-Effi | 16 | without introducing a         |                       |
| ciency |    | sufficient upstream challenge |                       |
| Parti  |    | of particles of known size    |                       |
| culate |    | upstream of the filter is     |                       |
| Air    |    | ineffective for detecting     |                       |
| (HEPA) |    | leaks. For example, depending |                       |
|        |    | on the accuracy of the        |                       |
|        |    | photometer, a DOP challenge   |                       |
|        |    | should introduce the aerosol  |                       |
|        |    | upstream of the filter in a   |                       |
|        |    | concentration ranging from    |                       |
|        |    | approximately 25 to 100       |                       |
|        |    | micrograms/liter of air at    |                       |
|        |    | the filter's designed airflow |                       |
|        |    | rating. The leak test should  |                       |
|        |    | be done in place, and the     |                       |
|        |    | filter face scanned on the    |                       |
|        |    | downstream side with an       |                       |
|        |    | appropriate photometer probe, |                       |
|        |    | at a sampling rate of at      |                       |
|        |    | least one cubic foot per      |                       |
|        |    | minute."                      |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | -   The text is too specific  |                       |
|        |    |     regarding the challenge.  |                       |
|        |    |     The challenge should be   |                       |
|        |    |     sufficient to verify the  |                       |
|        |    |     filter's efficiency       |                       |
|        |    |     rating.                   |                       |
|        |    |                               |                       |
|        |    | -   See previous comments     |                       |
|        |    |     regarding DOP (line 296). |                       |
|        |    |                               |                       |
|        |    | -   We suggest that this      |                       |
|        |    |     section be revised to     |                       |
|        |    |     allow for the use of      |                       |
|        |    |     alternatives that provide |                       |
|        |    |     more modern and improved  |                       |
|        |    |     techniques, such as laser |                       |
|        |    |     counters. The draft       |                       |
|        |    |     guidance currently refers |                       |
|        |    |     only to photometers for   |                       |
|        |    |     the detection of          |                       |
|        |    |     particles. The laser      |                       |
|        |    |     counter method is a       |                       |
|        |    |     reference method in       |                       |
|        |    |     ISO/DIS 14644-3. The      |                       |
|        |    |     final guidance document   |                       |
|        |    |     should allow for          |                       |
|        |    |     developments and new      |                       |
|        |    |     techniques. The use of    |                       |
|        |    |     laser particle counters   |                       |
|        |    |     as detection instruments  |                       |
|        |    |     is now common in the      |                       |
|        |    |     Industry.                 |                       |
+--------+----+-------------------------------+-----------------------+
| IV.D.2 | 3  | [Current Text:]{.underline}   |                       |
|        | 26 |                               |                       |
| Hig    | -3 | "This testing is usually done |                       |
| h-Effi | 28 | only on a semi-annual basis.  |                       |
| ciency |    | It is important to conduct    |                       |
| Parti  |    | periodic monitoring of filter |                       |
| culate |    | attributes such as uniformity |                       |
| Air    |    | of velocity across the filter |                       |
| (HEPA) |    | (and relative to adjacent     |                       |
|        |    | filters)."                    |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | -   The intervals of regular  |                       |
|        |    |     monitoring are not        |                       |
|        |    |     specified, but there is   |                       |
|        |    |     an implication that it    |                       |
|        |    |     should be performed more  |                       |
|        |    |     regularly than once every |                       |
|        |    |     6 months. This may be     |                       |
|        |    |     unnecessarily frequent as |                       |
|        |    |     airflow velocity changes  |                       |
|        |    |     only occur gradually over |                       |
|        |    |     long periods of time. We  |                       |
|        |    |     suggest that velocity     |                       |
|        |    |     tests concurrent with the |                       |
|        |    |     filter leak testing       |                       |
|        |    |     should be adequate.       |                       |
|        |    |                               |                       |
|        |    | -   Current text is vague     |                       |
|        |    |     with regards to defining  |                       |
|        |    |     "periodic".               |                       |
+--------+----+-------------------------------+-----------------------+
| IV.D.2 | 3  | [Current Text:]{.underline}   | -   Six inches is an  |
|        | 30 |                               |     arbitrary         |
| Hig    | -3 | "Airflow velocities are       |     distance.         |
| h-Effi | 32 | measured 6 inches from the    |                       |
| ciency |    | filter face and at a defined  | -   The location of   |
| Parti  |    | distance proximal to the work |     velocity          |
| culate |    | surface for HEPA filters in   |     measurements      |
| Air    |    | the critical area".           |     should not be     |
| (HEPA) |    |                               |     prescribed by     |
|        |    | [Proposed                     |     FDA, only that    |
|        |    | Revision:]{.underline}        |     whatever location |
|        |    |                               |     is chosen that it |
|        |    | "Airflow velocities are       |     be used over time |
|        |    | measured 6 inches from the    |     so that velocity  |
|        |    | filter face or at a defined   |     comparisons could |
|        |    | distance proximal to the work |     be reasonably     |
|        |    | surface for HEPA filters in   |     made.             |
|        |    | the critical area."           |                       |
|        |    |                               | -   Redundant with    |
|        |    |                               |     requirements      |
|        |    |                               |     identified in     |
|        |    |                               |     line 200 and      |
|        |    |                               |     corresponding     |
|        |    |                               |     footnote.         |
|        |    |                               |                       |
|        |    |                               | -   The current text  |
|        |    |                               |     suggests an       |
|        |    |                               |     expansion of the  |
|        |    |                               |     requirement with  |
|        |    |                               |     measurement at    |
|        |    |                               |     two test site     |
|        |    |                               |     locations versus  |
|        |    |                               |     one.              |
+--------+----+-------------------------------+-----------------------+
| IV.E.  | 3  | [Current Text:]{.underline}   | Minor typographical   |
|        | 48 |                               | error (sterility).    |
| Design |    | **"**...high assurance of     |                       |
|        |    | sterilty (Ref. 4)."           |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | **"**...high assurance of     |                       |
|        |    | sterility (Ref. 4)."          |                       |
+--------+----+-------------------------------+-----------------------+
| IV.E   | 3  | [Current Text:]{.underline}   | For clarity, we       |
|        | 70 |                               | suggest rephrasing    |
| Design | -3 | "For example, lyophilization  | this sentence.        |
|        | 72 | processes include transfer of |                       |
|        |    | aseptically filled product in |                       |
|        |    | partially sealed containers." |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "For example, lyophilization  |                       |
|        |    | processes include transfer of |                       |
|        |    | aseptically filled product in |                       |
|        |    | partially sealed/closed       |                       |
|        |    | containers."                  |                       |
+--------+----+-------------------------------+-----------------------+
| IV.E   | 3  | [Current Text:]{.underline}   | -   The current       |
|        | 73 |                               |     wording could be  |
| Design | -3 | "Facility design should       |     interpreted as    |
|        | 75 | ensure that the area between  |     meaning that the  |
|        |    | a filling line and the        |     room itself must  |
|        |    | lyophilizer and the transport |     be classified to  |
|        |    | and loading procedures        |     ISO 5 in the area |
|        |    | provide Class 100 (ISO 5)     |     between filling   |
|        |    | protection"                   |     and the           |
|        |    |                               |     lyophilizer. We   |
|        |    | [Proposed                     |     suggest revising  |
|        |    | Revision:]{.underline}        |     the text so that  |
|        |    |                               |     the guidance      |
|        |    | "Facility design should       |     document simply   |
|        |    | ensure that the area between  |     states that the   |
|        |    | a filling line and the        |     protection should |
|        |    | lyophilizer and the transport |     be according to   |
|        |    | and loading procedures        |     ISO 5. There are  |
|        |    | provide ISO 5 protection"     |     several other     |
|        |    |                               |     methods of        |
|        |    |                               |     achieving this;   |
|        |    |                               |     for example       |
|        |    |                               |     isolator          |
|        |    |                               |     technology or     |
|        |    |                               |     laminar flow      |
|        |    |                               |     transfer carts.   |
|        |    |                               |                       |
|        |    |                               | -   Current wording   |
|        |    |                               |     does not          |
|        |    |                               |     recognize the     |
|        |    |                               |     potential of      |
|        |    |                               |     closed containers |
|        |    |                               |     moving through    |
|        |    |                               |     higher classified |
|        |    |                               |     areas. A closed   |
|        |    |                               |     container can     |
|        |    |                               |     protect partially |
|        |    |                               |     stoppered vials   |
|        |    |                               |     from adventitious |
|        |    |                               |     contamination.    |
+--------+----+-------------------------------+-----------------------+
| IV.E   | 3  | [Current Text:]{.underline}   |                       |
|        | 78 |                               |                       |
| Design | -3 | "Carefully designed curtains, |                       |
|        | 79 | rigid plastic shields, or     |                       |
|        |    | other barriers should be used |                       |
|        |    | in appropriate locations to   |                       |
|        |    | achieve significant           |                       |
|        |    | segregation of the aseptic    |                       |
|        |    | processing line."             |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Carefully designed curtains, |                       |
|        |    | rigid plastic shields, or     |                       |
|        |    | other barriers may be used in |                       |
|        |    | appropriate locations to      |                       |
|        |    | achieve significant           |                       |
|        |    | protection of the aseptic     |                       |
|        |    | processing line."             |                       |
+--------+----+-------------------------------+-----------------------+
| IV.E   | 4  | [Current Text:]{.underline}   | -   The glossary      |
|        | 03 |                               |     indicates the     |
| Design | -4 | "With rare exceptions, drains |     definition of     |
|        | 05 | are not considered            |     "aseptic          |
|        |    | appropriate for classified    |     processing        |
|        |    | areas of the aseptic          |     facility" as      |
|        |    | processing facility"          |     including the     |
|        |    |                               |     entire building,  |
|        |    | [Proposed                     |     not only the      |
|        |    | Revision:]{.underline}        |     aseptic zone.     |
|        |    |                               |                       |
|        |    | "With rare exceptions,        | -   We agree that     |
|        |    | facility drains are not       |     drains should not |
|        |    | considered appropriate for    |     be present in the |
|        |    | Class 100 (ISO Class 5) or    |     higher categories |
|        |    | Class 10,000 (ISO Class 7)    |     of classified     |
|        |    | areas of the aseptic          |     areas (e.g.,      |
|        |    | processing facility"          |     aseptic           |
|        |    |                               |     processing        |
|        |    |                               |     rooms). However,  |
|        |    |                               |     correctly         |
|        |    |                               |     designed drains   |
|        |    |                               |     are necessary in  |
|        |    |                               |     some of the lower |
|        |    |                               |     category areas,   |
|        |    |                               |     for example,      |
|        |    |                               |     locations of      |
|        |    |                               |     washers and       |
|        |    |                               |     compounding.      |
|        |    |                               |                       |
|        |    |                               | -   We suggest that   |
|        |    |                               |     the position set  |
|        |    |                               |     forth in the      |
|        |    |                               |     guidance document |
|        |    |                               |     should be more    |
|        |    |                               |     precisely         |
|        |    |                               |     defined. We also  |
|        |    |                               |     suggest           |
|        |    |                               |     harmonizing the   |
|        |    |                               |     position with the |
|        |    |                               |     EU GMPs,          |
|        |    |                               |     requiring that    |
|        |    |                               |     sinks and drains  |
|        |    |                               |     should be         |
|        |    |                               |     prohibited in     |
|        |    |                               |     "ISO 5" to "ISO   |
|        |    |                               |     7" areas          |
|        |    |                               |     (classified in    |
|        |    |                               |     dynamic state).   |
|        |    |                               |     Drains should be  |
|        |    |                               |     excluded from     |
|        |    |                               |     critical and      |
|        |    |                               |     direct support    |
|        |    |                               |     locations, but    |
|        |    |                               |     are required in   |
|        |    |                               |     some of the       |
|        |    |                               |     process rooms     |
|        |    |                               |     that are not      |
|        |    |                               |     directly          |
|        |    |                               |     connected to the  |
|        |    |                               |     critical aseptic  |
|        |    |                               |     operation.        |
|        |    |                               |                       |
|        |    |                               | -   The use of SIP    |
|        |    |                               |     and CIP is        |
|        |    |                               |     recommended in    |
|        |    |                               |     this guideline in |
|        |    |                               |     many areas as     |
|        |    |                               |     improving         |
|        |    |                               |     sterility         |
|        |    |                               |     assurance with    |
|        |    |                               |     regard to aseptic |
|        |    |                               |     connections.      |
|        |    |                               |     However, it must  |
|        |    |                               |     be recognized     |
|        |    |                               |     that all of these |
|        |    |                               |     systems require   |
|        |    |                               |     drains to remove  |
|        |    |                               |     CIP washes and or |
|        |    |                               |     steam condensate  |
|        |    |                               |     from the systems. |
+--------+----+-------------------------------+-----------------------+
| IV.E   | 4  | [Current Text:]{.underline}   | It is sometimes not   |
|        | 10 |                               | physically possible   |
| Design | -4 | "Equipment should not         | for certain pieces of |
|        | 11 | obstruct airflow and, in      | equipment not to      |
|        |    | critical areas, its design    | disturb airflow       |
|        |    | should not perturb airflow"   | patterns (stopper     |
|        |    |                               | hoppers, for          |
|        |    | [Proposed                     | instance; filling     |
|        |    | Revision:]{.underline}        | wheels will block     |
|        |    |                               | airflow to the vials  |
|        |    | "Equipment should be designed | below them).          |
|        |    | to minimize disturbances to   |                       |
|        |    | the airflow patterns"         |                       |
+--------+----+-------------------------------+-----------------------+
| V.A    | 4  | [Current Text:]{.underline}   | Existing procedures,  |
|        | 32 |                               | including routine     |
| Per    | -4 | "Supervisory personnel should | supervision,          |
| sonnel | 33 | routinely evaluate each       | documented training,  |
|        |    | operator's conformance to     | deviation records and |
|        |    | written procedures during     | internal audits are   |
|        |    | actual operations."           | adequate to give a    |
|        |    |                               | comprehensive         |
|        |    | [Proposed                     | control. The addition |
|        |    | Revision:]{.underline}        | of yet more           |
|        |    |                               | evaluation seems      |
|        |    | "There should be adequate     | unnecessarily         |
|        |    | supervision to ensure each    | complex.              |
|        |    | operator's conformance to     |                       |
|        |    | written procedures during     |                       |
|        |    | actual operations."           |                       |
+--------+----+-------------------------------+-----------------------+
| V.A    | 4  | [Current Text:]{.underline}   | Some direct contact   |
|        | 39 |                               | with equipment may be |
| Per    | -4 | -   "Contacting sterile       | necessary for         |
| sonnel | 42 |     material only with        | assembling equipment  |
|        |    |     sterile instruments       | in aseptic filling    |
|        |    |                               | suites or barriers.   |
|        |    | > Sterile instruments (e.g.   | For example,          |
|        |    | > forceps) should always be   | assembling and        |
|        |    | > used in the handling of     | fitting sterilized    |
|        |    | > sterilized materials."      | filling pumps is      |
|        |    |                               | impossible with       |
|        |    | [Comment:]{.underline}        | forceps. Since set up |
|        |    |                               | is notoriously the    |
|        |    | Current text is impractical.  | most hazardous part   |
|        |    |                               | of an aseptic         |
|        |    | [Proposed                     | operation, this       |
|        |    | Revision:]{.underline}        | clause should be      |
|        |    |                               | re-written or         |
|        |    | "Equipment set-up activities  | excluded because it   |
|        |    | typically present a unique    | is not possible to    |
|        |    | set of challenges to using    | comply with in        |
|        |    | proper aseptic techniques.    | practice.             |
|        |    | Direct contact between gloved |                       |
|        |    | hands and the critical        |                       |
|        |    | surfaces of sterilized        |                       |
|        |    | equipment parts (surface      |                       |
|        |    | which subsequently have       |                       |
|        |    | direct product contact) is to |                       |
|        |    | be avoided."                  |                       |
+--------+----+-------------------------------+-----------------------+
| V.A    | 4  | [Current Text:]{.underline}   |                       |
|        | 42 |                               |                       |
| Per    |    | "Between uses, instruments    |                       |
| sonnel |    | should be placed only in      |                       |
|        |    | sterilized containers".       |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The text indicates that       |                       |
|        |    | instruments are permitted     |                       |
|        |    | only to be stored in          |                       |
|        |    | sterilized containers. For    |                       |
|        |    | clarity, we suggest adding    |                       |
|        |    | text indicating that storage  |                       |
|        |    | of instruments can be         |                       |
|        |    | permitted in a protected      |                       |
|        |    | environment where the item    |                       |
|        |    | does not touch a              |                       |
|        |    | non-sterilized surface. For   |                       |
|        |    | example, instruments can be   |                       |
|        |    | stored in an appropriate      |                       |
|        |    | location under ISO 5          |                       |
|        |    | protective air.               |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Between uses, proper         |                       |
|        |    | procedures should be used to  |                       |
|        |    | maintain instrument           |                       |
|        |    | sterility. For example,       |                       |
|        |    | storage in an appropriate     |                       |
|        |    | location under ISO 5          |                       |
|        |    | protective air."              |                       |
+--------+----+-------------------------------+-----------------------+
| V.A    | 4  | [Current Text:]{.underline}   | Current sentence      |
|        | 43 |                               | unclear.              |
| Per    |    | "Instruments should be        |                       |
| sonnel |    | replaced as necessary         |                       |
|        |    | throughout an operation."     |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Instruments should be        |                       |
|        |    | replaced when any aspect of   |                       |
|        |    | sterility is thought to be    |                       |
|        |    | compromised so as to render   |                       |
|        |    | the instrument non sterile,   |                       |
|        |    | throughout the operation."    |                       |
+--------+----+-------------------------------+-----------------------+
| V.A    | 4  | [Current Text:]{.underline}   |                       |
|        | 72 |                               |                       |
| Per    | -4 | "Prior to and throughout      |                       |
| sonnel | 73 | aseptic operations, an        |                       |
|        |    | operator should not engage in |                       |
|        |    | any activity that poses an    |                       |
|        |    | unreasonable contamination    |                       |
|        |    | risk to the gown.**"**        |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Current text is too vague.    |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "An operator should be        |                       |
|        |    | trained to minimize           |                       |
|        |    | contamination risk to the     |                       |
|        |    | gown prior to and throughout  |                       |
|        |    | aseptic operations."          |                       |
+--------+----+-------------------------------+-----------------------+
| V.A    | 4  | [Current Text:]{.underline}   | Each firm should be   |
|        | 89 |                               | able to justify the   |
| Per    | -4 | "Gowning qualification should | rationale for gown    |
| sonnel | 90 | include microbiological       | test locations in     |
|        |    | surface sampling of several   | gown qualification.   |
|        |    | locations on a gown (e.g.     | Therefore, we         |
|        |    | glove fingers, facemask,      | recommend removing    |
|        |    | forearm, chest, other         | the examples in the   |
|        |    | sites)."                      | original text.        |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Gowning qualification should |                       |
|        |    | include microbiological       |                       |
|        |    | surface sampling of several   |                       |
|        |    | locations on a gown. Adequate |                       |
|        |    | rationale to justify gown     |                       |
|        |    | test locations should be      |                       |
|        |    | developed."                   |                       |
+--------+----+-------------------------------+-----------------------+
| V.A    | 4  | [Current Text:]{.underline}   |                       |
|        | 93 |                               |                       |
| Per    | -4 | "Semi-annual or yearly        |                       |
| sonnel | 94 | requalification is sufficient |                       |
|        |    | for automated operations      |                       |
|        |    | where personnel involvement   |                       |
|        |    | is minimized."                |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Semi-annual is not current    |                       |
|        |    | practice, and is more         |                       |
|        |    | stringent than cGMP.          |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Gowning requalification may  |                       |
|        |    | be repeated based either upon |                       |
|        |    | issues raised in the change   |                       |
|        |    | control program and/or on a   |                       |
|        |    | timed basis such as           |                       |
|        |    | annually."                    |                       |
+--------+----+-------------------------------+-----------------------+
| V.B    | 5  | [Current Text:]{.underline}   |                       |
|        | 03 |                               |                       |
| Labo   | -5 | "The basic principles of      |                       |
| ratory | 05 | training, aseptic technique,  |                       |
| Per    |    | and personnel qualification   |                       |
| sonnel |    | in aseptic manufacturing also |                       |
|        |    | are applicable to those       |                       |
|        |    | performing aseptic sampling   |                       |
|        |    | and microbiological           |                       |
|        |    | laboratory analysis".         |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete "and microbiological   |                       |
|        |    | laboratory analysis."         |                       |
|        |    |                               |                       |
|        |    | Add "Those performing         |                       |
|        |    | microbiological laboratory    |                       |
|        |    | analyses should have          |                       |
|        |    | appropriate education,        |                       |
|        |    | training, and experience in   |                       |
|        |    | microbiological techniques."  |                       |
+--------+----+-------------------------------+-----------------------+
| V.C    | 5  | [Current Text:]{.underline}   |                       |
|        | 15 |                               |                       |
| Moni   | -5 | "The quality control unit     |                       |
| toring | 17 | should establish a more       |                       |
| P      |    | comprehensive monitoring      |                       |
| rogram |    | program for operators         |                       |
|        |    | involved in operations, which |                       |
|        |    | are especially labor          |                       |
|        |    | intensive (i.e., those        |                       |
|        |    | requiring repeated or complex |                       |
|        |    | aseptic manipulations)."      |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest that this is an    |                       |
|        |    | unnecessary division that     |                       |
|        |    | effectively gives two classes |                       |
|        |    | of filling operators. This is |                       |
|        |    | very difficult to administer. |                       |
|        |    | Also, it is important that    |                       |
|        |    | all staff in the area         |                       |
|        |    | partaking in permitted        |                       |
|        |    | interventions are adequately  |                       |
|        |    | monitored. Having different   |                       |
|        |    | monitoring procedures may be  |                       |
|        |    | mistaken to indicate that     |                       |
|        |    | some simpler operations are   |                       |
|        |    | not critical, when in fact    |                       |
|        |    | they are.                     |                       |
|        |    |                               |                       |
|        |    | The most negative impact on   |                       |
|        |    | the product is created by the |                       |
|        |    | kind of intervention          |                       |
|        |    | performed by the operator and |                       |
|        |    | not by the degree of labor    |                       |
|        |    | intensiveness. All operators  |                       |
|        |    | who may take part in          |                       |
|        |    | permitted interventions that  |                       |
|        |    | could conceivably have a      |                       |
|        |    | potential risk of product     |                       |
|        |    | contamination must be         |                       |
|        |    | monitored. The                |                       |
|        |    | microbiological limits are    |                       |
|        |    | already very tight indeed and |                       |
|        |    | it is unreasonable to have    |                       |
|        |    | different classes of          |                       |
|        |    | "criticality".                |                       |
+--------+----+-------------------------------+-----------------------+
| VI.A   | 5  | [Current Text:]{.underline}   | The establishment of  |
|        | 37 |                               | washing cycles        |
| Comp   | -5 | "It is important to           | capable of routinely  |
| onents | 40 | characterize the microbial    | removing \> or = 3    |
|        |    | content of each component     | logs of pyrogen and   |
|        |    | that could be contaminated    | overkill cycles for   |
|        |    | and establish appropriate     | sterilization capable |
|        |    | acceptance limits based on    | of \> 6 logs of       |
|        |    | information on bioburden.     | inactivation of       |
|        |    | Knowledge of bioburden is     | highly resistant      |
|        |    | critical in assessing whether | spores obviate the    |
|        |    | the sterilization process is  | need for continuous   |
|        |    | adequate"                     | monitoring of         |
|        |    |                               | components and or     |
|        |    | [Comment:]{.underline} The    | drug products. It may |
|        |    | current text over-simplifies  | be appropriate for    |
|        |    | this issue.                   | less rugged processes |
|        |    |                               | to receive routine    |
|        |    | [Proposed                     | monitoring of         |
|        |    | Revision:]{.underline}        | bioburden or          |
|        |    |                               | pyroburden.           |
|        |    | Add: "Only limited bioburden  |                       |
|        |    | data for components subject   |                       |
|        |    | to overkill sterilization or  |                       |
|        |    | depyrogenation cycles is      |                       |
|        |    | necessary."                   |                       |
+--------+----+-------------------------------+-----------------------+
| VI.B.1 | 6  | [Current Text:]{.underline}   | Added clarification.  |
|        | 00 |                               |                       |
| Prepa  |    | "Pyrogen on plastic           |                       |
| ration |    | containers can be generally   |                       |
|        |    | removed by multiple WFI       |                       |
|        |    | rinses."                      |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Pyrogen on plastic           |                       |
|        |    | containers can be generally   |                       |
|        |    | removed by adequate           |                       |
|        |    | procedures such as multiple   |                       |
|        |    | hot (85° C) WFI rinses."      |                       |
+--------+----+-------------------------------+-----------------------+
| VI.B.1 | 6  | [Current Text:]{.underline}   | Many washers use      |
|        | 08 |                               | recycled final rinse  |
| Prepa  | -6 | "At minimum, the initial      | water for initial     |
| ration | 10 | rinses for the washing        | rinses. This water is |
|        |    | process should employ         | not tested to meet    |
|        |    | Purified Water, USP, of       | Purified Water, USP.  |
|        |    | minimal endotoxin content,    |                       |
|        |    | followed by final rinse(s)    |                       |
|        |    | with WFI for parenteral       |                       |
|        |    | products."                    |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Current text is too specific, |                       |
|        |    | and unnecessary.              |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "At minimum, the initial      |                       |
|        |    | rinses for the washing        |                       |
|        |    | process should be sourced     |                       |
|        |    | from 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 is acceptable if  |                       |
|        |    | validated."                   |                       |
+--------+----+-------------------------------+-----------------------+
| VI.B.1 | 6  | [Current Text:]{.underline}   | Added clarification.  |
|        | 18 |                               |                       |
| Prepa  | -6 | "Silicone used in the         |                       |
| ration | 20 | preparation of rubber stopper |                       |
|        |    | should meet appropriate       |                       |
|        |    | quality control criteria and  |                       |
|        |    | not have an adverse effect on |                       |
|        |    | the safety, quality, or       |                       |
|        |    | purity of the drug product."  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Silicone used in the         |                       |
|        |    | preparation of rubber         |                       |
|        |    | stoppers should meet          |                       |
|        |    | appropriate quality control   |                       |
|        |    | criteria and not have an      |                       |
|        |    | adverse effect on the safety, |                       |
|        |    | quality, or purity of the     |                       |
|        |    | drug product, as determined   |                       |
|        |    | by appropriate quality        |                       |
|        |    | control testing."             |                       |
+--------+----+-------------------------------+-----------------------+
| VI.B.2 | 6  | [Current Text:]{.underline}   | -   Some bag          |
|        | 29 |                               |     containers may    |
| Insp   | -6 | "A container closure system   |     have very low     |
| ection | 30 | that permits penetration of   |     water vapor       |
| of     |    | air, or microorganisms, is    |     transmission      |
| Con    |    | unsuitable for a sterile      |     levels, which     |
| tainer |    | product."                     |     over time (years) |
| C      |    |                               |     make the product  |
| losure |    | [Comment:]{.underline}        |     unsuitable        |
| System |    |                               |     chemically, but   |
|        |    | This is not necessarily true  |     has no negative   |
|        |    | of air.                       |     impact on the     |
|        |    |                               |     microbiological   |
|        |    | [Proposed                     |     quality of the    |
|        |    | Revision:]{.underline}        |     product.          |
|        |    |                               |                       |
|        |    | "A container closure system   | -   Penetration by    |
|        |    | that permits penetration of   |     air occurs in     |
|        |    | microorganisms is unsuitable  |     many forms of     |
|        |    | for a sterile product."       |     packaging that is |
|        |    |                               |     used for          |
|        |    |                               |     sterilization     |
|        |    |                               |     (e.g.             |
|        |    |                               |     sterilization     |
|        |    |                               |     packs & bags). It |
|        |    |                               |     is the            |
|        |    |                               |     penetration of    |
|        |    |                               |     microorganisms    |
|        |    |                               |     that is the risk  |
|        |    |                               |     in these cases.   |
|        |    |                               |     Hence, we suggest |
|        |    |                               |     that this         |
|        |    |                               |     statement is not  |
|        |    |                               |     correct in cases  |
|        |    |                               |     where the         |
|        |    |                               |     containing pack   |
|        |    |                               |     is designed to    |
|        |    |                               |     filter the air    |
|        |    |                               |     free of microbial |
|        |    |                               |     contaminants.     |
+--------+----+-------------------------------+-----------------------+
| VII    | 6  | [Current Text:]{.underline}   | It is unclear what is |
|        | 60 |                               | expected on this      |
| End    | -6 | "Endotoxin control should be  | point, particularly   |
| otoxin | 61 | exercised for all product     | regarding the         |
| C      |    | contact surfaces both prior   | frequency of both     |
| ontrol |    | to and after sterile          | prior to and after    |
|        |    | filtration."                  | sterilization. If     |
|        |    |                               | this statement        |
|        |    | [Comment:]{.underline}        | relates specifically  |
|        |    |                               | to cleaning           |
|        |    | We suggest that clarification | validation, then      |
|        |    | be provided regarding this    | perhaps it is a       |
|        |    | statement.                    | reasonable concept.   |
|        |    |                               | However, if it        |
|        |    | [Proposed                     | relates to routine    |
|        |    | Revision:]{.underline}        | testing, the approach |
|        |    |                               | seems unreasonable.   |
|        |    | "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  |                       |
|        |    | endotoxin contamination."     |                       |
+--------+----+-------------------------------+-----------------------+
| VII    | 6  | [Current Text:]{.underline}   | Many washers use      |
|        | 64 |                               | recycled final rinse  |
| End    | -6 | "Some clean-in-place          | water for initial     |
| otoxin | 66 | procedures employ initial     | rinses. This water is |
| C      |    | rinses with appropriate high  | not tested to meet    |
| ontrol |    | purity water and/or a         | Purified Water, USP.  |
|        |    | cleaning agent (e.g., acid,   |                       |
|        |    | base, surfactant), followed   |                       |
|        |    | by final rinses with heated   |                       |
|        |    | WFI."                         |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Some clean-in-place          |                       |
|        |    | procedures employ initial     |                       |
|        |    | rinses with appropriate       |                       |
|        |    | 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 is       |                       |
|        |    | acceptable if validated."     |                       |
+--------+----+-------------------------------+-----------------------+
| VIII\. | 6  | [Current Text:]{.underline}   | The current verbiage  |
|        | 75 |                               | in the guidance       |
| Time   | -6 | "Time limits should be        | suggests data are     |
| Limit  | 78 | established for each phase of | required to establish |
| ations |    | aseptic processing. Time      | all processing times. |
|        |    | limits should include, for    | A more effective      |
|        |    | example, the period between   | scientific approach   |
|        |    | the start of bulk product     | should be             |
|        |    | compounding and its           | recommended, such as  |
|        |    | filtration, filtration        | conducting a risk     |
|        |    | processes, product exposure   | based evaluation of   |
|        |    | while on the processing line, | all processing unit   |
|        |    | and storage of sterilized     | operations. The       |
|        |    | equipment, containers and     | assessment and the    |
|        |    | closures."                    | types of processes    |
|        |    |                               | used e.g. overkill    |
|        |    |                               | sterilization, should |
|        |    |                               | then be used to       |
|        |    |                               | determine which       |
|        |    |                               | process hold steps    |
|        |    |                               | may require the use   |
|        |    |                               | of data collection in |
|        |    |                               | order to set time     |
|        |    |                               | limits.               |
+--------+----+-------------------------------+-----------------------+
| VIII\. | 6  | [Current Text:]{.underline}   | Added clarification.  |
|        | 82 |                               |                       |
| Time   | -6 | "The total time for product   |                       |
| Limit  | 87 | filtration should be limited  |                       |
| ations |    | to an established maximum to  |                       |
|        |    | prevent microorganisms from   |                       |
|        |    | penetrating the filter. Such  |                       |
|        |    | a time limit should also      |                       |
|        |    | prevent a significant         |                       |
|        |    | increase in upstream          |                       |
|        |    | bioburden and endotoxin load. |                       |
|        |    | Sterilizing-grade filters     |                       |
|        |    | should generally be replaced  |                       |
|        |    | following each manufactured   |                       |
|        |    | lot. Because they can provide |                       |
|        |    | a substrate for microbial     |                       |
|        |    | attachment, maximum use times |                       |
|        |    | for those filters used        |                       |
|        |    | upstream for solution         |                       |
|        |    | clarification or particle     |                       |
|        |    | removal should also be        |                       |
|        |    | established and justified."   |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Add the following sentence to |                       |
|        |    | the end of the paragraph:     |                       |
|        |    |                               |                       |
|        |    | "Integrity testing before and |                       |
|        |    | after use should also be      |                       |
|        |    | specified in standard         |                       |
|        |    | operating procedures that are |                       |
|        |    | pertinent to the use of these |                       |
|        |    | filters and appropriate       |                       |
|        |    | investigations performed on   |                       |
|        |    | any lot suspected of being    |                       |
|        |    | compromised."                 |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.1 | 7  | [Current Text:]{.underline}   |                       |
|        | 22 |                               |                       |
| Study  | -7 | "Media fill studies should    |                       |
| Design | 24 | simulate aseptic              |                       |
|        |    | manufacturing operations as   |                       |
|        |    | closely as possible,          |                       |
|        |    | incorporating a worst-case    |                       |
|        |    | approach. The media fill      |                       |
|        |    | program should address        |                       |
|        |    | applicable issues such as:"   |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Stacking all potential        |                       |
|        |    | worst-case situations into    |                       |
|        |    | each media run does not       |                       |
|        |    | represent an appropriate      |                       |
|        |    | challenge simulating normal   |                       |
|        |    | processing.                   |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Media fill studies should    |                       |
|        |    | simulate aseptic              |                       |
|        |    | manufacturing operations as   |                       |
|        |    | closely as possible. Media    |                       |
|        |    | fill studies should be        |                       |
|        |    | designed to address           |                       |
|        |    | applicable issues such as:"   |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.1 | 7  | [Current Text:]{.underline}   | Number of typical     |
|        | 27 |                               | interventions is      |
| Study  |    | "...number and type of normal | proportional to the   |
| Design |    | interventions"                | length of the         |
|        |    |                               | operation. Should not |
|        |    | [Proposed                     | specify "number".     |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete "number"               |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.1 | 7  | [Current Text:]{.underline}   | -   We consider it to |
|        | 39 |                               |     be generally      |
| Study  |    | "....operator fatigue"        |     impractical to    |
| Design |    |                               |     artificially      |
|        |    | [Proposed                     |     simulate fatigue, |
|        |    | Revision:]{.underline}        |     as the process    |
|        |    |                               |     should be         |
|        |    | Delete "operator fatigue"     |     designed to       |
|        |    |                               |     minimize fatigue. |
|        |    |                               |                       |
|        |    |                               | -   Environmental and |
|        |    |                               |     personnel         |
|        |    |                               |     monitoring is a   |
|        |    |                               |     better assessment |
|        |    |                               |     of operator       |
|        |    |                               |     fatigue; this     |
|        |    |                               |     should not be     |
|        |    |                               |     required for      |
|        |    |                               |     media fill.       |
+--------+----+-------------------------------+-----------------------+
| IX.A.2 | 7  | [Current Text:]{.underline}   | Clarify.              |
|        | 57 |                               |                       |
| Fre    | -7 | "For example, the evaluation  |                       |
| quency | 58 | of a shift should address its |                       |
| and    |    | unique time-related and       |                       |
| Number |    | operational features"         |                       |
| of     |    |                               |                       |
| Runs   |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "For example, the evaluation  |                       |
|        |    | of a shift change should      |                       |
|        |    | address the movement of       |                       |
|        |    | personnel in and out of the   |                       |
|        |    | aseptic processing and change |                       |
|        |    | rooms including de-gowning    |                       |
|        |    | and gowning procedures."      |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.2 | 7  | [Current Text:]{.underline}   |                       |
|        | 58 |                               |                       |
| Fre    | -7 | "All personnel who enter the  |                       |
| quency | 60 | aseptic processing area,      |                       |
| and    |    | including technicians and     |                       |
| Number |    | maintenance personnel, should |                       |
| of     |    | participate in a medial fill  |                       |
| Runs   |    | at lease one a year."         |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Planned interventions during  |                       |
|        |    | media fills are logical and   |                       |
|        |    | reasonable, however,          |                       |
|        |    | requiring every person from   |                       |
|        |    | maintenance who may enter the |                       |
|        |    | aseptic area to participate   |                       |
|        |    | once a year may not be        |                       |
|        |    | practical.                    |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.3 | 7  | [Current Text:]{.underline}   | Elsewhere in this     |
|        | 80 |                               | section we specify    |
| Du     | -7 | "The duration of aseptic      | media fill sizes that |
| ration | 83 | processing operations is a    | are not               |
| of     |    | major consideration in        | representative of     |
| Runs   |    | determining the size of the   | production duration.  |
|        |    | 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"                    |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete sentences              |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.3 | 7  | [Current Text:]{.underline}   |                       |
|        | 83 |                               |                       |
| Du     | -7 | "In any study protocol, the   |                       |
| ration | 84 | duration of the run and the   |                       |
| of     |    | overall study design should   |                       |
| Runs   |    | adequately mimic worst-case   |                       |
|        |    | operating conditions and      |                       |
|        |    | cover all manipulations that  |                       |
|        |    | are performed in the actual   |                       |
|        |    | processing operation"         |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current text is           |                       |
|        |    | inconsistent. Elsewhere in    |                       |
|        |    | the document it mentions that |                       |
|        |    | atypical interventions may be |                       |
|        |    | rotated.                      |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "In any study protocol, the   |                       |
|        |    | duration of the run and the   |                       |
|        |    | overall study design should   |                       |
|        |    | adequately mimic appropriate  |                       |
|        |    | designed worst-case process   |                       |
|        |    | operations."                  |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.3 | 7  | [Current Text:]{.underline}   |                       |
|        | 95 |                               |                       |
| Du     | -7 | "For lyophilization           |                       |
| ration | 96 | operations, unsealed          |                       |
| of     |    | containers should be exposed  |                       |
| Runs   |    | to pressurization and partial |                       |
|        |    | evacuation of the chamber in  |                       |
|        |    | a manner that simulates the   |                       |
|        |    | process."                     |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current sentence is       |                       |
|        |    | incorrect. Containers should  |                       |
|        |    | not be exposed to             |                       |
|        |    | 'pressurization'.             |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "For lyophilization           |                       |
|        |    | operations, unsealed          |                       |
|        |    | containers should be exposed  |                       |
|        |    | to partial evacuation of the  |                       |
|        |    | chamber in a manner that      |                       |
|        |    | simulates the process. For    |                       |
|        |    | routine aerobic media fill    |                       |
|        |    | tests, precautions should be  |                       |
|        |    | taken that ensure that the    |                       |
|        |    | medium remains in an aerobic  |                       |
|        |    | state."                       |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.5 | 8  | [Current Text:]{.underline}   | One sentence says     |
|        | 22 |                               | that the range of     |
| Line   | -8 | "The media fill program       | speeds should be      |
| Speed  | 29 | should adequately address the | addressed, while the  |
|        |    | range of line speeds (e.g.,   | other specifies       |
|        |    | by bracketing all vial sizes  | "worst case".         |
|        |    | 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       |                       |
|        |    | appropriate for evaluating    |                       |
|        |    | manufacturing processes       |                       |
|        |    | characterized by prolonged    |                       |
|        |    | exposure of the sterile drug  |                       |
|        |    | product and container         |                       |
|        |    | closures in the aseptic       |                       |
|        |    | area."                        |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "The media fill program       |                       |
|        |    | should adequately address the |                       |
|        |    | range of line speeds (e.g.,   |                       |
|        |    | by bracketing all vial 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 allowing prolonged  |                       |
|        |    | exposure[s]{.underline} of    |                       |
|        |    | the sterile drug product and  |                       |
|        |    | container closures in the     |                       |
|        |    | aseptic area."                |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.6 | 8  | [Current Text:]{.underline}   | The statement is      |
|        | 37 |                               | unclear as to         |
| E      | -8 | "To the extent standard       | expectations and does |
| nviron | 39 | operating procedures permit   | not represent         |
| mental |    | stressful conditions, it is   | realistic conditions  |
| Co     |    | important that media fills    | for simulation.       |
| nsider |    | include analogous challenges  |                       |
| ations |    | to support the validity of    |                       |
|        |    | these studies"                |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current text is           |                       |
|        |    | unnecessary and overly        |                       |
|        |    | strict.                       |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete sentence               |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.7 | 8  | [Current Text:]{.underline}   | Growth Promotion      |
|        | 45 |                               | testing of compendial |
| Media  | -8 | "The media selected should be | organisms is          |
|        | 47 | demonstrated to promote       | sufficient to         |
|        |    | growth of USP \<71\>          | demonstrate the       |
|        |    | indicator microorganisms as   | viability of the      |
|        |    | well as representative        | media.                |
|        |    | isolates identified by        |                       |
|        |    | environmental monitoring,     |                       |
|        |    | personnel monitoring, and     |                       |
|        |    | positive sterility test       |                       |
|        |    | results"                      |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current text is           |                       |
|        |    | unnecessary.                  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete "as well as            |                       |
|        |    | representative isolates       |                       |
|        |    | identified by environmental   |                       |
|        |    | monitoring, personnel         |                       |
|        |    | monitoring, and positive      |                       |
|        |    | sterility test results".      |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.8 | 8  | [Current Text:]{.underline}   |                       |
|        | 77 |                               |                       |
| Incu   | -8 | "Each media-filled unit       |                       |
| bation | 78 | should be examined for        |                       |
| and    |    | contamination by personnel    |                       |
| Exami  |    | with appropriate education,   |                       |
| nation |    | training, and experience in   |                       |
| of     |    | microbiological techniques."  |                       |
| Media- |    |                               |                       |
| filled |    | [Comment:]{.underline}        |                       |
| Units  |    |                               |                       |
|        |    | For the inspectors (readers)  |                       |
|        |    | of vials it is important to   |                       |
|        |    | have regular eye examinations |                       |
|        |    | by an ophthalmologist. These  |                       |
|        |    | should be mandatory for those |                       |
|        |    | who investigate the content   |                       |
|        |    | of a contaminated vial.       |                       |
|        |    |                               |                       |
|        |    | Provided that the inspectors  |                       |
|        |    | are well trained and have a   |                       |
|        |    | good understanding as to what |                       |
|        |    | they are looking for, this    |                       |
|        |    | aspect is more important than |                       |
|        |    | having detailed experience in |                       |
|        |    | microbiological techniques.   |                       |
|        |    |                               |                       |
|        |    | Any detected or suspect       |                       |
|        |    | containers should be passed   |                       |
|        |    | on for further detailed       |                       |
|        |    | microbiological testing by an |                       |
|        |    | experienced microbiologist.   |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.8 | 8  | [Current Text:]{.underline}   |                       |
|        | 78 |                               |                       |
| Incu   | -8 | \"There should be direct      |                       |
| bation | 79 | quality control unit          |                       |
| and    |    | oversight throughout any such |                       |
| Exami  |    | examination."                 |                       |
| nation |    |                               |                       |
| of     |    | [Comment:]{.underline}        |                       |
| Media- |    |                               |                       |
| filled |    | Does not reflect routine      |                       |
| Units  |    | procedure.                    |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete sentence.              |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.8 | 8  | [Current Text:]{.underline}   | We suggest that other |
|        | 79 |                               | approaches should be  |
| Incu   | -8 | "Clear containers with        | permissible as an     |
| bation | 81 | otherwise identical physical  | occasional option for |
| and    |    | properties should be used as  | use if necessary, for |
| Exami  |    | a substitute for amber or     | example, transferring |
| nation |    | other opaque containers to    | to clear containers   |
| of     |    | allow visual detection of     | for inspection after  |
| Media- |    | microbial growth."            | incubation. For some  |
| filled |    |                               | particular containers |
| Units  |    |                               | it may not be         |
|        |    |                               | feasible to source a  |
|        |    |                               | visually clear        |
|        |    |                               | alternative.          |
+--------+----+-------------------------------+-----------------------+
| IX.A.8 | 8  | [Current Text:]{.underline}   |                       |
|        | 88 |                               |                       |
| Incu   | -8 | "After incubation is          |                       |
| bation | 93 | underway, any unit found to   |                       |
| and    |    | be damaged should be included |                       |
| Exami  |    | in the data for the media     |                       |
| nation |    | fill run, because the         |                       |
| of     |    | incubation of the units       |                       |
| Media- |    | simulates release to market". |                       |
| filled |    |                               |                       |
| Units  |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The handling of media fill    |                       |
|        |    | containers does               |                       |
|        |    | [not]{.underline} simulate    |                       |
|        |    | "release to market"           |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "After incubation is          |                       |
|        |    | underway, damaged units may   |                       |
|        |    | be found (i.e., nonintegral). |                       |
|        |    | Any decision to exclude such  |                       |
|        |    | incubated units (i.e.,        |                       |
|        |    | nonintegral) from the final   |                       |
|        |    | run tally should be fully     |                       |
|        |    | justified...."                |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.8 | 8  | [Current Text:]{.underline}   |                       |
|        | 98 |                               |                       |
| Incu   |    | Footnote ^9^ "To assess       |                       |
| bation |    | contamination risk during     |                       |
| and    |    | initial aseptic setup (before |                       |
| Exami  |    | fill), valuable information   |                       |
| nation |    | can be obtained by incubating |                       |
| of     |    | all such units that may be    |                       |
| Media- |    | normally removed".            |                       |
| filled |    |                               |                       |
| Units  |    | [Comment:]{.underline} Data   |                       |
|        |    | would have no relevance or    |                       |
|        |    | utility.                      |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete footnote               |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.8 | 9  | [Current Text:]{.underline}   | Elsewhere the         |
|        | 04 |                               | guidance specifies    |
| Incu   | -9 | "The ability of a media fill  | that specific         |
| bation | 06 | run to detect potential       | procedures for        |
| and    |    | contamination from a given    | removal of units in   |
| Exami  |    | simulated activity should not | production should be  |
| nation |    | be compromised by a           | duplicated in process |
| of     |    | large-scale line clearance,   | simulation.           |
| Media- |    | which can result in removal   |                       |
| filled |    | of a positive unit caused by  |                       |
| Units  |    | an unrelated event or         |                       |
|        |    | intervention"                 |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current text is           |                       |
|        |    | contradictory.                |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete clause                 |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.9 | 9  | [Current Text:]{.underline}   |                       |
|        | 16 |                               |                       |
| In     | -9 | "Video recording of media     |                       |
| terpre | 18 | fill has been found to be     |                       |
| tation |    | useful in identifying         |                       |
| of     |    | personnel practices that      |                       |
| Test   |    | could negatively impact the   |                       |
| R      |    | aseptic process."             |                       |
| esults |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The phrase indicating that    |                       |
|        |    | videotaping "has been found   |                       |
|        |    | to be useful" may initiate an |                       |
|        |    | approach by investigators     |                       |
|        |    | that will deem it mandatory.  |                       |
|        |    |                               |                       |
|        |    | While videotaping may be      |                       |
|        |    | useful in some cases, there   |                       |
|        |    | are no real grounds for       |                       |
|        |    | making it a requirement. The  |                       |
|        |    | same function could be        |                       |
|        |    | covered by the manual         |                       |
|        |    | observation and assessment by |                       |
|        |    | experienced QC and Production |                       |
|        |    | personnel.                    |                       |
+--------+----+-------------------------------+-----------------------+
| IX.A.9 | 9  | [Current Text:]{.underline}   | There is no guidance  |
|        | 35 |                               | on the subsequent     |
| In     |    | "When filling fewer than 5000 | steps when the limit  |
| terpre |    | units, no contaminated units  | is exceeded, as there |
| tation |    | should be detected."          | is for the other      |
| of     |    |                               | quantities.           |
| Test   |    | [Proposed                     |                       |
| R      |    | Revision:]{.underline}        |                       |
| esults |    |                               |                       |
|        |    | Add: "One contaminated unit   |                       |
|        |    | is considered cause for       |                       |
|        |    | revalidation, following an    |                       |
|        |    | investigation."               |                       |
+--------+----+-------------------------------+-----------------------+
| IX.B   | 1  | [Current Text:]{.underline}   |                       |
|        | 00 |                               |                       |
| Filt   | 1- | "Factors that can affect      |                       |
| ration | 10 | filter performance normally   |                       |
| Ef     | 02 | include (1) viscosity of the  |                       |
| ficacy |    | material to be filtered..."   |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Factors that can affect      |                       |
|        |    | filter performance normally   |                       |
|        |    | include (1) viscosity and     |                       |
|        |    | surface tension of the        |                       |
|        |    | material to be filtered,"     |                       |
+--------+----+-------------------------------+-----------------------+
| IX.B   | 1  | [Current Text:]{.underline}   |                       |
|        | 00 |                               |                       |
| Filt   | 9- | "The specific type of filter  |                       |
| ration | 10 | used in commercial production |                       |
| Ef     | 10 | should be evaluated in filter |                       |
| ficacy |    | validation studies."          |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline} We     |                       |
|        |    | suggest that text be added to |                       |
|        |    | clarify what "the specific    |                       |
|        |    | type of filter" means. As     |                       |
|        |    | stated, the phrase seems to   |                       |
|        |    | mean the actual unit (e.g.,   |                       |
|        |    | exact cartridge/capsule).     |                       |
|        |    | However, it is currently an   |                       |
|        |    | accepted practice to test for |                       |
|        |    | retention using flat stock    |                       |
|        |    | filter membranes.             |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "The specific type of filter  |                       |
|        |    | membrane used in commercial   |                       |
|        |    | production should be          |                       |
|        |    | evaluated in filter           |                       |
|        |    | validation studies."          |                       |
+--------+----+-------------------------------+-----------------------+
| IX.B   | 10 | [Current Text:]{.underline}   |                       |
|        | 27 |                               |                       |
| Filt   |    | "We recommend you consider    |                       |
| ration |    | use of sterilizing grade      |                       |
| Ef     |    | filters in series; this is a  |                       |
| ficacy |    | common practice."             |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Dual filtration               |                       |
|        |    | [is]{.underline} common       |                       |
|        |    | practice. However, the word   |                       |
|        |    | 'series' suggests two filters |                       |
|        |    | configured in one unit        |                       |
|        |    | operation (Tank A - Filter    |                       |
|        |    | 1 - Filter 2 - Tank B).       |                       |
|        |    | Redundant filtration can also |                       |
|        |    | be performed using single     |                       |
|        |    | filters in two successive     |                       |
|        |    | unit operations (Tank A -     |                       |
|        |    | Filter 1 - Tank B - Filter    |                       |
|        |    | 2 - Tank C).                  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "We recommend you consider    |                       |
|        |    | use of redundant sterilizing  |                       |
|        |    | grade filters; this is a      |                       |
|        |    | common practice."             |                       |
+--------+----+-------------------------------+-----------------------+
| IX.C   | 1  | [Current Text:]{.underline}   | Surfaces in the       |
|        | 03 |                               | vicinity of sterile   |
| S      | 3- | "Those surfaces that are in   | materials should not  |
| terili | 10 | the vicinity of sterile       | be required to be     |
| zation | 35 | product or container          | sterilized unless     |
| of     |    | closures, but do not directly | there is direct       |
| Equ    |    | contact the product should    | contact.              |
| ipment |    | also be rendered sterile      |                       |
| and    |    | where reasonable              |                       |
| Con    |    | contamination potential       |                       |
| tainer |    | exists"                       |                       |
| Cl     |    |                               |                       |
| osures |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current text presents     |                       |
|        |    | unclear expectations.         |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete sentence               |                       |
+--------+----+-------------------------------+-----------------------+
| IX.C.1 | 1  | [Current Text:]{.underline}   | The use of            |
|        | 05 |                               | maximum/minimum loads |
| Ster   | 0- | "For both the validation      | to qualify a range of |
| ilizer | 10 | studies and routine           | loads is acceptable.  |
| Q      | 52 | production, use of a          |                       |
| ualifi |    | specified load configuration  |                       |
| cation |    | should be documented in the   |                       |
| and    |    | batch records."               |                       |
| Vali   |    |                               |                       |
| dation |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "For both the validation      |                       |
|        |    | studies and routine           |                       |
|        |    | production, the load          |                       |
|        |    | configuration should be       |                       |
|        |    | documented in the batch       |                       |
|        |    | records."                     |                       |
+--------+----+-------------------------------+-----------------------+
| IX.C.1 | 1  | [Current Text:]{.underline}   |                       |
|        | 07 |                               |                       |
| Ster   | 3- | **"**The formal program       |                       |
| ilizer | 10 | providing for regular         |                       |
| Q      | 75 | revalidation should consider  |                       |
| ualifi |    | the age of the sterilizer and |                       |
| cation |    | its past performance. Change  |                       |
| and    |    | control procedures should     |                       |
| Vali   |    | adequately address issues     |                       |
| dation |    | such as a load configuration  |                       |
|        |    | change or a modification of   |                       |
|        |    | the sterilizer."              |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest that the testing   |                       |
|        |    | schedule should be            |                       |
|        |    | consistent, not dependent on  |                       |
|        |    | age. If there are valid       |                       |
|        |    | indications that the machine  |                       |
|        |    | is unreliable or              |                       |
|        |    | inconsistent, then it should  |                       |
|        |    | not be in use. The            |                       |
|        |    | effectiveness of the          |                       |
|        |    | sterilizer should be          |                       |
|        |    | established by validation,    |                       |
|        |    | maintenance and routine       |                       |
|        |    | review/assessment of cycle    |                       |
|        |    | parameters. If there are      |                       |
|        |    | concerns on reliability, they |                       |
|        |    | should be promptly addressed. |                       |
+--------+----+-------------------------------+-----------------------+
| IX     | 1  | [Current Text:]{.underline}   | In a porous load      |
| .C.1.a | 08 |                               | sterilization cycle,  |
|        | 1- | "It is important that these   | the variation of      |
| Qu     | 10 | studies assess temperature    | temperature will be   |
| alific | 83 | uniformity at various         | minimal, and the      |
| ation: |    | locations throughout the      | identification of a   |
| Empty  |    | sterilizer to identify        | 'cold spot' will be   |
| C      |    | potential *cold spots* where  | insignificant.        |
| hamber |    | there can be insufficient     |                       |
|        |    | heat to attain sterility"     |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "It is important that these   |                       |
|        |    | studies assess temperature    |                       |
|        |    | uniformity at various         |                       |
|        |    | locations throughout the      |                       |
|        |    | sterilizer."                  |                       |
+--------+----+-------------------------------+-----------------------+
| IX.C.2 | 1  | [Current Text:]{.underline}   |                       |
|        | 11 |                               |                       |
| Equ    | 7- | "The microbial count and      |                       |
| ipment | 11 | D-valve of a biological       |                       |
| Co     | 18 | indicator should be confirmed |                       |
| ntrols |    | before a validation study."   |                       |
| and    |    |                               |                       |
| Inst   |    | [Comment:]{.underline}        |                       |
| rument |    |                               |                       |
| Calib  |    | We suggest that text be added |                       |
| ration |    | to clarify the meaning of     |                       |
|        |    | "confirmed" in relation to    |                       |
|        |    | D-values. If the D-value of   |                       |
|        |    | an bioindicator must be       |                       |
|        |    | exactly confirmed before use  |                       |
|        |    | this would make it necessary  |                       |
|        |    | to have specific testing      |                       |
|        |    | devices (BIER vessels). This  |                       |
|        |    | is not currently a GMP        |                       |
|        |    | requirement.                  |                       |
|        |    |                               |                       |
|        |    | We suggest that a reasonable  |                       |
|        |    | approach would be to verify   |                       |
|        |    | the count and control the     |                       |
|        |    | storage and use conditions.   |                       |
|        |    | It should be acceptable to    |                       |
|        |    | take the supplier's figure    |                       |
|        |    | for the D value. An empirical |                       |
|        |    | kill/survival time test could |                       |
|        |    | be performed.                 |                       |
|        |    |                               |                       |
|        |    | We suggest that the approach  |                       |
|        |    | be consistent with current    |                       |
|        |    | Industry guidelines on steam  |                       |
|        |    | sterilization.                |                       |
+--------+----+-------------------------------+-----------------------+
| X.A.1  | 1  | [Current Text:]{.underline}   | -   The purpose of    |
|        | 15 |                               |     environmental     |
| G      | 2- | "The monitoring program       |     monitoring is to  |
| eneral | 11 | should cover all production   |     assess the        |
| W      | 54 | shifts and include air,       |     conditions around |
| ritten |    | floors, walls, and equipment  |     the critical      |
| P      | a  | surfaces, including the       |     filling operation |
| rogram | nd | critical surfaces that come   |     and adjacent      |
|        |    | in contact with the product,  |     support areas.    |
|        | 1  | container, and closures."     |     The               |
|        | 17 |                               |     product-contact   |
|        | 0- | and                           |     items should have |
|        | 11 |                               |     been sterilized   |
|        | 71 | "Critical surface sampling    |     and this verified |
|        |    | should be performed at the    |     parametrically    |
|        |    | conclusion of the aseptic     |     (sterilizer       |
|        |    | processing operation to avoid |     charts, etc) in   |
|        |    | direct contact with sterile   |     conjunction with  |
|        |    | surfaces during processing."  |     validation.       |
|        |    |                               |     Sampling these    |
|        |    | [Proposed                     |     surfaces would    |
|        |    | Revision:]{.underline}        |     effectively be a  |
|        |    |                               |     rudimentary test  |
|        |    | (Line 1170)"Monitoring is not |     for sterility,    |
|        |    | normally required on critical |     and as such much  |
|        |    | contact surfaces that have    |     less valuable     |
|        |    | been sterilized. When         |     than the          |
|        |    | performed, critical surface   |     sterilization     |
|        |    | sampling should be performed  |     monitoring data.  |
|        |    | at the conclusion of the      |                       |
|        |    | aseptic processing operation  | -   Elsewhere in the  |
|        |    | to avoid direct contact with  |     document it       |
|        |    | sterile surfaces during       |     states that       |
|        |    | processing".                  |     monitoring of     |
|        |    |                               |     critical surfaces |
|        |    |                               |     is not mandatory. |
+--------+----+-------------------------------+-----------------------+
| X      | 1  | [Current Text:]{.underline}   | The environmental     |
| .A.4.a | 24 |                               | monitoring should     |
|        | 7- | "Environmental monitoring     | concentrate on        |
| S      | 12 | should include testing of     | realistic risk to     |
| urface | 49 | various surfaces for          | product.              |
| Moni   |    | microbiological quality. For  |                       |
| toring |    | example, product contact      |                       |
|        |    | surfaces, floors, walls,      |                       |
|        |    | ceilings, and equipment       |                       |
|        |    | should be tested on a regular |                       |
|        |    | basis."                       |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | It should not be necessary to |                       |
|        |    | test ceilings.                |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Environmental monitoring     |                       |
|        |    | should include testing of     |                       |
|        |    | various surfaces for          |                       |
|        |    | microbiological quality. For  |                       |
|        |    | example, product contact      |                       |
|        |    | surfaces, floors, walls, and  |                       |
|        |    | equipment should be tested on |                       |
|        |    | a regular basis."             |                       |
+--------+----+-------------------------------+-----------------------+
| X.B    | 1  | [Current Text:]{.underline}   |                       |
|        | 28 |                               |                       |
| Mic    | 4- | "Environmental isolates often |                       |
| robiol | 12 | correlate with the            |                       |
| ogical | 86 | contaminants found in a media |                       |
| Media  |    | fill or product sterility     |                       |
| and    |    | testing failure, and the      |                       |
| Id     |    | overall environmental picture |                       |
| entifi |    | provides valuable information |                       |
| cation |    | for an investigation."        |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The incidence of microbial    |                       |
|        |    | recovery is low, and thus     |                       |
|        |    | correlation back to media     |                       |
|        |    | fills etc. is less likely.    |                       |
|        |    | The most likely correlation   |                       |
|        |    | is that the isolates are      |                       |
|        |    | typically from personnel.     |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "Environmental isolates may   |                       |
|        |    | correlate with the            |                       |
|        |    | contaminants found in a media |                       |
|        |    | fill or product sterility     |                       |
|        |    | testing failure, and the      |                       |
|        |    | overall environmental picture |                       |
|        |    | provides valuable information |                       |
|        |    | for an investigation."        |                       |
+--------+----+-------------------------------+-----------------------+
| X.B    | 1  | [Current Text:]{.underline}   | We consider these     |
|        | 29 |                               | recommendations to be |
| Mic    | 7- | "Rapid genotypic methods are  | too strongly          |
| robiol | 12 | recommended for purposes of   | suggested, as other   |
| ogical | 98 | identification, as these      | techniques are        |
| Media  |    | methods have been shown to be | adequate for the      |
| and    |    | more accurate and precise     | purposes of           |
| Id     |    | than biochemical and          | identification. Most  |
| entifi |    | phenotypic techniques."       | QC laboratories are   |
| cation |    |                               | currently using       |
|        |    | [Proposed                     | alternatives and very |
|        |    | Revision:]{.underline}        | few have the          |
|        |    |                               | capability to perform |
|        |    | Delete clause                 | genetic testing.      |
+--------+----+-------------------------------+-----------------------+
| X.E    | 1  | [Current Text:]{.underline}   |                       |
|        | 33 |                               |                       |
| Pa     | 1- | "A result outside the         |                       |
| rticle | 13 | established specifications at |                       |
| Moni   | 32 | a given location should be    |                       |
| toring |    | investigated."                |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Environmental particulate     |                       |
|        |    | values are not best           |                       |
|        |    | classified by specifications; |                       |
|        |    | they have alert and action    |                       |
|        |    | levels like other             |                       |
|        |    | environmental monitoring.     |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "A result outside the         |                       |
|        |    | established action levels at  |                       |
|        |    | a given location should be    |                       |
|        |    | investigated."                |                       |
+--------+----+-------------------------------+-----------------------+
| XI\.   | 13 | [Current                      |                       |
|        | 39 | Section:]{.underline}         |                       |
| Ste    |    |                               |                       |
| rility |    | "XI. Sterility Testing"       |                       |
| T      |    |                               |                       |
| esting |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current section is        |                       |
|        |    | unnecessary in this document. |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision]{.underline}         |                       |
|        |    |                               |                       |
|        |    | Delete section.               |                       |
+--------+----+-------------------------------+-----------------------+
| XI\.   | 1  | [Current Text:]{.underline}   |                       |
|        | 34 |                               |                       |
| Ste    | 8- | "If production facilities and |                       |
| rility | 13 | controls are significantly    |                       |
| T      | 52 | better than those for         |                       |
| esting |    | sterility testing, the danger |                       |
|        |    | exists of mistakenly          |                       |
|        |    | attributing a positive        |                       |
|        |    | sterility test result to a    |                       |
|        |    | faulty laboratory even when   |                       |
|        |    | the product could have, in    |                       |
|        |    | fact, been nonsterile.        |                       |
|        |    | Therefore, some manufacturing |                       |
|        |    | deficiency may go undetected. |                       |
|        |    | We recommend the use of       |                       |
|        |    | isolators to perform          |                       |
|        |    | sterility testing."           |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The current text is too       |                       |
|        |    | restrictive.                  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "We recommend the use of      |                       |
|        |    | isolators or other suitably   |                       |
|        |    | qualified areas and testing   |                       |
|        |    | systems to perform sterility  |                       |
|        |    | testing."                     |                       |
+--------+----+-------------------------------+-----------------------+
| XI.A   | 1  | [Current Text:]{.underline}   | We suggest that the   |
|        | 36 |                               | requirement to        |
| Choice | 3- | "Study documentation should   | evaluate throughout   |
| of     | 13 | include evaluation of whether | the incubation period |
| M      | 65 | microbial recovery from       | in order to show      |
| ethods |    | inoculated controls and       | comparability         |
|        |    | product samples is comparable | throughout the        |
|        |    | throughout the incubation     | incubation be deleted |
|        |    | period."                      | as it is in excess of |
|        |    |                               | compendial sterility  |
|        |    | [Proposed                     | test requirements.    |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete clause                 |                       |
+--------+----+-------------------------------+-----------------------+
| XI.C   | 1  | [Current Text:]{.underline}   |                       |
|        | 37 |                               |                       |
| Per    | 7- | "A written program should be  |                       |
| sonnel | 13 | in place to regularly update  |                       |
|        | 79 | training of personnel and     |                       |
|        |    | confirm acceptable sterility  |                       |
|        |    | testing practices."           |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest adding text        |                       |
|        |    | regarding the meaning of the  |                       |
|        |    | term 'regularly' in order to  |                       |
|        |    | be clear on the requirement.  |                       |
|        |    | Since it is already a GMP     |                       |
|        |    | requirement to keep training  |                       |
|        |    | up-to-date, it is not clear   |                       |
|        |    | as to whether this is an      |                       |
|        |    | additional requirement.       |                       |
+--------+----+-------------------------------+-----------------------+
| XI.D   | 13 | [Current Text:]{.underline}   | -   There is          |
|        | 95 |                               |     insufficient      |
| Sa     |    | "• the batch processing       |     justification of  |
| mpling |    | circumstances -- samples      |     the value in      |
| and    |    | should be taken in            |     taking additional |
| Incu   |    | conjunction with processing   |     sterility samples |
| bation |    | interventions or excursions"  |     for each          |
|        |    |                               |     intervention, and |
|        |    | [Proposed                     |     it would be       |
|        |    | Revision:]{.underline}        |     impractical,      |
|        |    |                               |     especially when   |
|        |    | Delete clause.                |     there is media    |
|        |    |                               |     fill data to      |
|        |    |                               |     support the       |
|        |    |                               |     intervention.     |
|        |    |                               |                       |
|        |    |                               | -   We suggest        |
|        |    |                               |     removing this     |
|        |    |                               |     sentence, as it   |
|        |    |                               |     is impossible to  |
|        |    |                               |     fulfill since     |
|        |    |                               |     firms are         |
|        |    |                               |     required to       |
|        |    |                               |     remove            |
|        |    |                               |     potentially       |
|        |    |                               |     contaminated      |
|        |    |                               |     units.            |
+--------+----+-------------------------------+-----------------------+
| X.E.1  | 1  | [Current Text:]{.underline}   | We consider these     |
|        | 42 |                               | recommendations to be |
| Id     | 5- | "Nucleic acid-based methods   | too strongly          |
| entifi | 14 | are recommended for microbial | suggested, as other   |
| cation | 26 | identification purposes."     | techniques are        |
| (speci |    |                               | adequate for the      |
| ation) |    | [Proposed                     | purposes of           |
| of the |    | Revision:]{.underline}        | identification. Most  |
| or     |    |                               | QC laboratories are   |
| ganism |    | Delete clause.                | currently using       |
| in the |    |                               | alternatives and very |
| ste    |    |                               | few have the          |
| rility |    |                               | capability to perform |
| test   |    |                               | genetic testing.      |
+--------+----+-------------------------------+-----------------------+
| XI.E.2 | 1  | [Current Text:]{.underline}   |                       |
|        | 44 |                               |                       |
| Record | 1- | "A sterility positive result  |                       |
| of     | 14 | can be viewed as indicative   |                       |
| labo   | 43 | of production or laboratory   |                       |
| ratory |    | problems and should be        |                       |
| tests  |    | investigated globally since   |                       |
| and    |    | such problems often can       |                       |
| devi   |    | extend beyond a single        |                       |
| ations |    | batch."                       |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest that text be added |                       |
|        |    | to clarify the term           |                       |
|        |    | 'globally', as many           |                       |
|        |    | individuals have interpreted  |                       |
|        |    | this term in different ways.  |                       |
|        |    | It is unclear if 'globally'   |                       |
|        |    | is regarded in the sense of   |                       |
|        |    | across the whole operation at |                       |
|        |    | a particular site or          |                       |
|        |    | 'globally' in the sense of    |                       |
|        |    | across different sites        |                       |
|        |    | worldwide.                    |                       |
+--------+----+-------------------------------+-----------------------+
| XI.E.2 | 1  | [Current Text:]{.underline}   |                       |
|        | 44 |                               |                       |
| Record | 5- | "To more accurately monitor   |                       |
| of     | 14 | potential contamination       |                       |
| labo   | 46 | sources, we recommend you     |                       |
| ratory |    | keep separate trends by       |                       |
| tests  |    | product, container type,      |                       |
| and    |    | filling line, and personnel." |                       |
| devi   |    |                               |                       |
| ations |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | This sentence is unclear.     |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "To more accurately monitor   |                       |
|        |    | potential contamination       |                       |
|        |    | sources, we recommend you     |                       |
|        |    | keep separate trends by       |                       |
|        |    | product, container type,      |                       |
|        |    | filling line and production,  |                       |
|        |    | sampling and testing          |                       |
|        |    | personnel."                   |                       |
+--------+----+-------------------------------+-----------------------+
| XI.E.2 | 1  | [Current Text:]{.underline}   |                       |
|        | 44 |                               |                       |
| Record | 5- | "To more accurately monitor   |                       |
| of     | 14 | potential contamination       |                       |
| labo   | 49 | sources, we recommend you     |                       |
| ratory |    | keep separate trends by       |                       |
| tests  |    | product, container type,      |                       |
| and    |    | filling line, and personnel.  |                       |
| devi   |    | Where the degree of sterility |                       |
| ations |    | test sample manipulation is   |                       |
|        |    | similar for a terminally      |                       |
|        |    | sterilized product and an     |                       |
|        |    | aseptically processed         |                       |
|        |    | product, a higher rate of     |                       |
|        |    | initial sterility failures    |                       |
|        |    | for the latter should be      |                       |
|        |    | taken as indicative of        |                       |
|        |    | aseptic processing production |                       |
|        |    | problems."                    |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | We suggest that since         |                       |
|        |    | incidence is very low for     |                       |
|        |    | failures in sterility         |                       |
|        |    | testing, especially when      |                       |
|        |    | using closed systems and      |                       |
|        |    | isolators, it is not          |                       |
|        |    | necessary to trend for each   |                       |
|        |    | of the categories.            |                       |
+--------+----+-------------------------------+-----------------------+
| XI.E.2 | 1  | [Current Text:]{.underline}   |                       |
|        | 45 |                               |                       |
| Record | 6- | *"*Where a laboratory has a   |                       |
| of     | 14 | good track record with        |                       |
| labo   | 58 | respect to errors, this       |                       |
| ratory |    | history can help remove the   |                       |
| tests  |    | lab as a source of            |                       |
| and    |    | contamination since chances   |                       |
| devi   |    | are higher that the           |                       |
| ations |    | contamination arose from      |                       |
|        |    | production."                  |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | The conclusion based purely   |                       |
|        |    | on good laboratory history is |                       |
|        |    | speculative and not very      |                       |
|        |    | helpful. Even with a good     |                       |
|        |    | laboratory history, mistakes  |                       |
|        |    | can occasionally occur.       |                       |
+--------+----+-------------------------------+-----------------------+
| XI.E.5 | 14 | [Current Text:]{.underline}   | During routine        |
|        | 81 |                               | bioburden testing,    |
| P      |    | "Trends in product bioburden  | only counts are       |
| roduct |    | should be reviewed (counts    | measured. Identity is |
| Pres   |    | and identity)".               | only determined if    |
| terili |    |                               | the bioburden exceeds |
| zation |    | [Proposed                     | the alert limit or at |
| Bio    |    | Revision:]{.underline}        | pre-determined        |
| burden |    |                               | intervals.            |
|        |    | Remove "identity"             |                       |
+--------+----+-------------------------------+-----------------------+
| XII    | 1  | [Current Text:]{.underline}   | -   We suggest that   |
|        | 50 |                               |     only batch        |
| Batch  | 9- | ***"***All in-process data    |     relevant data     |
| Record | 15 | must be included with the     |     should be added   |
| R      | 10 | batch record documentation in |     to the batch      |
| eview: |    | accordance with section       |     record. We        |
| P      |    | 211.188."                     |     suggest that      |
| rocess |    |                               |     system relevant   |
| C      |    | [Proposed                     |     data may be       |
| ontrol |    | Revision:]{.underline}        |     evaluated         |
| D      |    |                               |     separately and    |
| ocumen |    | ***"***All batch relevant     |     linked to batch   |
| tation |    | data must be included with    |     release with no   |
|        |    | the batch record              |     strict            |
|        |    | documentation in accordance   |     requirement to    |
|        |    | with section 211.188."        |     add them to the   |
|        |    |                               |     batch record.     |
|        |    |                               |                       |
|        |    |                               | -   Current text      |
|        |    |                               |     requires          |
|        |    |                               |     clarification.    |
|        |    |                               |     Environmental     |
|        |    |                               |     monitoring data   |
|        |    |                               |     is not routinely  |
|        |    |                               |     stored in batch   |
|        |    |                               |     records. Is this  |
|        |    |                               |     defined as        |
|        |    |                               |     in-process data?  |
+--------+----+-------------------------------+-----------------------+
| Ap     | 1  | [Current Text:]{.underline}   | An isolator is a      |
| pendix | 54 |                               | positive pressure     |
| 1      | 6- | \"Although no isolator unit   | enclosure designed to |
|        | 15 | forms an absolute seal, very  | maintain a higher     |
| A.1    | 48 | high integrity can be         | pressure then the     |
|        |    | achieved in a well-designed   | surrounding areas.    |
| G      |    | unit.  However, a leak in any | This is analogous to  |
| eneral |    | certain components of the     | a traditional clean   |
|        |    | system can constitute a       | room, where by the    |
|        |    | significant breach of         | room pressure is      |
|        |    | integrity.\"                  | higher then the areas |
|        |    |                               | surrounding it.  A    |
|        |    | [Comment:]{.underline}        | leak in the isolator  |
|        |    |                               | or components does    |
|        |    | The statements will mislead   | not automatically     |
|        |    | industry and                  | constitute            |
|        |    | investigators. Isolators are  | a \"significant       |
|        |    | not designed to have or       | breach\" due to the   |
|        |    | be \"an absolute seal\".      | positive pressure in  |
|        |    |                               | the isolator system.  |
|        |    | [Proposed                     | The advantage of an   |
|        |    | Revision:]{.underline}        | isolator, is the      |
|        |    |                               | removal of all direct |
|        |    | Remove both of these          | human interaction     |
|        |    | statements from the           | from the product and  |
|        |    | Guideline.                    | process.  A well      |
|        |    |                               | designed maintenance  |
|        |    |                               | program is the        |
|        |    |                               | critical requirement  |
|        |    |                               | to assure the         |
|        |    |                               | isolator and          |
|        |    |                               | components do         |
|        |    |                               | not degrade and go    |
|        |    |                               | unnoticed.            |
+--------+----+-------------------------------+-----------------------+
| Ap     | 15 | [Current Text:]{.underline}   | The glove is a part   |
| pendix | 56 |                               | of the whole aseptic  |
| 1      |    | \"A faulty glove or sleeve    | process.              |
|        |    | (gauntlet) assembly           | Environmental         |
| A.2    |    | represents a route of         | monitoring, to        |
|        |    | contamination and a critical  | include, air,         |
| Glove  |    | breach of isolator            | surfaces and gloves   |
| Int    |    | integrity."                   | should be utilized to |
| egrity |    |                               | determine the state   |
|        |    | [Comment:]{.underline}        | of the aseptic        |
|        |    |                               | process.              |
|        |    | A faulty glove does not       | Operators will enter  |
|        |    | immediately lead to a         | the gloves with a     |
|        |    | \"critical breach of isolator | sanitized glove over  |
|        |    | integrity\".                  | the naked hand.  This |
|        |    |                               | creates a barrier     |
|        |    | [Proposed                     | between the           |
|        |    | Revision:]{.underline}        | operator\'s skin and  |
|        |    |                               | the interior of a     |
|        |    | "A faulty glove or sleeve     | glove providing       |
|        |    | (gauntlet) assembly           | additional protection |
|        |    | represents a potential route  | should a pinhole      |
|        |    | of contamination."            | develop. The main     |
|        |    |                               | emphasis of this      |
|        |    |                               | paragraph should      |
|        |    |                               | be the maintenance    |
|        |    |                               | program.  The         |
|        |    |                               | r                     |
|        |    |                               | emaining requirements |
|        |    |                               | in this paragraph     |
|        |    |                               | state the critical    |
|        |    |                               | aspects of an         |
|        |    |                               | inclusive maintenance |
|        |    |                               | program.              |
+--------+----+-------------------------------+-----------------------+
| Ap     | 15 | [Current Text:]{.underline}   | This statement lacks  |
| pendix | 62 |                               | relevance, it will    |
| 1      |    | \"Such a breach can be of     | only serve to mislead |
|        |    | serious consequence.\"        | industry and          |
| A.2    |    |                               | investigators.  The   |
|        |    | [Comment:]{.underline}        | term \"can be\" is    |
| Glove  |    |                               | too open for          |
| Int    |    | The current text is           | interpretation and    |
| egrity |    | misleading.                   | may be applied as a   |
|        |    |                               | requirement.  As      |
|        |    | [Proposed                     | stated above, the     |
|        |    | Revision:]{.underline}        | gloves are one aspect |
|        |    |                               | in considering the    |
|        |    | Delete line                   | state of control in   |
|        |    |                               | the aseptic process.  |
+--------+----+-------------------------------+-----------------------+
| Ap     | 1  | [Current Text:]{.underline}   | Sanitizing the inside |
| pendix | 56 |                               | of a glove would be   |
| 1      | 5- | "...the inner part of the     | difficult to perform  |
|        | 15 | installed glove should be     | efficaciously.        |
| A.2    | 66 | sanitized regularly and the   |                       |
|        |    | operator should"              |                       |
| Glove  |    |                               |                       |
| Int    |    | [Comment:]{.underline}        |                       |
| egrity |    |                               |                       |
|        |    | The current text is           |                       |
|        |    | impractical.                  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Delete clause                 |                       |
+--------+----+-------------------------------+-----------------------+
| Ap     | 1  | [Current Text:]{.underline}   | For a closed isolator |
| pendix | 61 |                               | or an open isolator   |
| 1      | 1- | "The classification of the    | where mousehole       |
|        | 16 | environment surrounding the   | environments have     |
| B.4    | 15 | isolator should be based on   | additional local      |
|        |    | the design of its interfaces  | protection and/or are |
| Clean  |    | (e.g., transfer ports), as    | validated not to      |
| Area   |    | well as the number of         | entrain air, "Class   |
| Cla    |    | transfers into and out of the | 100,000 (ISO 8)"      |
| ssific |    | isolator. A Class 100,000     | should be defined as  |
| ations |    | (ISO 8) background can be     | in the "at rest"      |
|        |    | appropriate depending on      | state in order to be  |
|        |    | isolator design and           | harmonized with EU    |
|        |    | manufacturing situations."    | GMP grade D. We       |
|        |    |                               | suggest adding text   |
|        |    | [Proposed                     | to incorporate        |
|        |    | Revision:]{.underline}        | definitions that are  |
|        |    |                               | appropriate for both  |
|        |    | "The classification of the    | the EU and US. We     |
|        |    | environment surrounding the   | foresee issues of     |
|        |    | isolator should be based on   | interpretation        |
|        |    | the design of its interfaces  | between Europe and    |
|        |    | (e.g., transfer ports), as    | the US if there is no |
|        |    | well as the number of         | harmonization on this |
|        |    | transfers into and out of the | topic.                |
|        |    | isolator. A Class 100,000     |                       |
|        |    | (ISO 8 defined "at rest")     |                       |
|        |    | background can be appropriate |                       |
|        |    | depending on isolator design  |                       |
|        |    | and manufacturing             |                       |
|        |    | situations."                  |                       |
+--------+----+-------------------------------+-----------------------+
| Ap     | 1  | [Current Text:]{.underline}   |                       |
| pendix | 66 |                               |                       |
| 1      | 4- | "For example, demonstration   |                       |
|        | 16 | of a four-log reduction       |                       |
| D.2    | 66 | should be sufficient for      |                       |
|        |    | introduction of controlled,   |                       |
| Ef     |    | very low bioburden materials  |                       |
| ficacy |    | into an aseptic processing    |                       |
|        |    | isolator, including wrapped   |                       |
|        |    | sterile supplies that are     |                       |
|        |    | briefly exposed to the        |                       |
|        |    | surrounding cleanroom         |                       |
|        |    | environment."                 |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Only sterilized materials     |                       |
|        |    | should be introduced into the |                       |
|        |    | aseptic processing isolator.  |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "For example, demonstration   |                       |
|        |    | of a four-log reduction       |                       |
|        |    | should be sufficient for      |                       |
|        |    | decontamination of material   |                       |
|        |    | containers to be brought into |                       |
|        |    | an aseptic processing         |                       |
|        |    | isolator, including wrapped   |                       |
|        |    | sterile supplies."            |                       |
+--------+----+-------------------------------+-----------------------+
| Ap     | 16 | [Current Text:]{.underline}   | Technology and proper |
| pendix | 68 |                               | guidance on           |
| 1      |    | "The uniform distribution of  | decontaminating agent |
|        |    | the defined concentration of  | concentration         |
| D.2    |    | decontaminating agent should  | measurement are not   |
|        |    | also be evaluated concurrent  | adequate at this      |
| Ef     |    | with these studies (Ref.      | time. Evaluating      |
| ficacy |    | 15)."                         | distribution of agent |
|        |    |                               | does not require      |
|        |    |                               | setting               |
|        |    |                               | specifications to     |
|        |    |                               | measure against or    |
|        |    |                               | traceability to       |
|        |    |                               | routine production.   |
|        |    |                               | The addition of this  |
|        |    |                               | requirement does not  |
|        |    |                               | add value or assist   |
|        |    |                               | to ensure the         |
|        |    |                               | robustness of the     |
|        |    |                               | validated cycles      |
|        |    |                               | developed or used in  |
|        |    |                               | routine production.   |
+--------+----+-------------------------------+-----------------------+
| Ap     | 1  | [Current Text:]{.underline}   |                       |
| pendix | 74 |                               |                       |
| 2      | 9- | ***"***The classified         |                       |
|        | 17 | environment surrounding BFS   |                       |
| Bl     | 51 | machinery should generally    |                       |
| ow-Fil |    | meet Class 10,000 (ISO 7)     |                       |
| l-Seal |    | standards, but special design |                       |
| Tech   |    | provisions (e.g., isolation   |                       |
| nology |    | technology) can justify an    |                       |
|        |    | alternate classification."    |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | For Blow-Fill-Seal            |                       |
|        |    | applications, the text        |                       |
|        |    | indicates particular          |                       |
|        |    | requirements that are         |                       |
|        |    | potentially in excess of      |                       |
|        |    | current expectations. The     |                       |
|        |    | environment in which BFS      |                       |
|        |    | machine is located is         |                       |
|        |    | indicated as Class 10,000. If |                       |
|        |    | interpreted as in operation,  |                       |
|        |    | this is similar to EU grade B |                       |
|        |    | (EU GMPs require grade C).    |                       |
|        |    |                               |                       |
|        |    | Also, there are requirements  |                       |
|        |    | for endotoxin inactivation    |                       |
|        |    | studies on the molding        |                       |
|        |    | process that may be difficult |                       |
|        |    | to conduct.                   |                       |
+--------+----+-------------------------------+-----------------------+
| Ap     | 18 | [Current Text:]{.underline}   | Spelling              |
| pendix | 15 |                               |                       |
| 3      |    | "sterilyze"                   |                       |
|        |    |                               |                       |
| Proc   |    | [Proposed                     |                       |
| essing |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "sterilize"                   |                       |
+--------+----+-------------------------------+-----------------------+
| Ap     | 18 | [Current Text:]{.underline}   | spelling              |
| pendix | 25 |                               |                       |
| 3      |    | "sterilyzed"                  |                       |
|        |    |                               |                       |
| Proc   |    | [Proposed                     |                       |
| essing |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "sterilized"                  |                       |
+--------+----+-------------------------------+-----------------------+
| Ap     | 1  | [Current Text:]{.underline}   | -   Vessels may be    |
| pendix | 85 |                               |     utilized for long |
| 3      | 1- | "It is also important that    |     term storage of   |
|        | 18 | process simulations           |     sterile bulks and |
| A.     | 54 | incorporate storage of        |     holding of media  |
|        |    | product or transport to other |     in the tanks may  |
| A      |    | manufacturing areas. For      |     cause them to     |
| septic |    | instance, there should be     |     fail growth       |
| proc   |    | assurance of bulk vessel      |     promotion         |
| essing |    | integrity for specified       |     testing.          |
| from   |    | holding times. The transport  |                       |
| early  |    | of bulk tanks or other        | -   There are other   |
| m      |    | containers should be          |     engineering       |
| anufac |    | simulated as part of the      |     controls or       |
| turing |    | media fill."                  |     methods which may |
| steps  |    |                               |     be utilized to    |
|        |    | [Comment:]{.underline}        |     assess the        |
|        |    |                               |     container closure |
|        |    | We agree that the integrity   |     integrity of the  |
|        |    | of the process vessels used   |     vessels utilized  |
|        |    | to store sterile materials    |     for holding       |
|        |    | should be verified and that   |     sterile           |
|        |    | transport and disinfection of |     materials.        |
|        |    | materials into the aseptic    |                       |
|        |    | area should be simulated      |                       |
|        |    | during media fills. However,  |                       |
|        |    | we do not agree that the hold |                       |
|        |    | times must be simulated in    |                       |
|        |    | the fill or that the          |                       |
|        |    | transport of the vessels      |                       |
|        |    | themselves is necessary.      |                       |
+--------+----+-------------------------------+-----------------------+
| REFE   | 1  | [Proposed                     | The PDA published     |
| RENCES | 87 | Revision:]{.underline}        | Technical Reports are |
|        | 4- |                               | widely used in        |
|        | 19 | We suggest adding a reference | industry and provide  |
|        | 09 | to PDA Technical Reports 1,   | substantially more    |
|        |    | 2, 13, 22, 26, 28 and 36.     | complete information  |
|        |    |                               | on the topics covered |
|        |    |                               | in this guidance.     |
+--------+----+-------------------------------+-----------------------+
| Gl     | 1  | [Current Text:]{.underline}   |                       |
| ossary | 98 |                               |                       |
|        | 5- | "[                            |                       |
|        | 19 | Decontamination-]{.underline} |                       |
|        | 86 | A process that eliminates     |                       |
|        |    | viable bioburden via use of   |                       |
|        |    | sporicidal chemical agents."  |                       |
|        |    |                               |                       |
|        |    | [Comment:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | Current text is too specific. |                       |
|        |    |                               |                       |
|        |    | [Proposed                     |                       |
|        |    | Revision:]{.underline}        |                       |
|        |    |                               |                       |
|        |    | "[                            |                       |
|        |    | Decontamination-]{.underline} |                       |
|        |    | A process that eliminates     |                       |
|        |    | viable bioburden via use of   |                       |
|        |    | sporicidal chemical agents or |                       |
|        |    | other means (i.e. UV light,   |                       |
|        |    | etc.)."                       |                       |
+--------+----+-------------------------------+-----------------------+