AVENTIS BEHRING COMMENTS

**Guidance For Industry Draft Guidance for Industry: Sterile Drug
Products Produced by**

**Aseptic Processing - Current Good Manufacturing Practice**

+-----+-------+-----------------+--------------------+-----------------+
| **C | > *   | > **Current     | > **Recommended    | > **Comm        |
| omm | *Line | > Draft Text**  | > Revision**       | ent/Rationale** |
| ent | > Num |                 |                    |                 |
| Nu  | ber** |                 |                    |                 |
| mbe |       |                 |                    |                 |
| r** |       |                 |                    |                 |
+=====+=======+=================+====================+=================+
| 1   | 73-74 | "Terminal       |                    | The term        |
| .   |       | sterilization   |                    | "high-quality   |
|     |       | usually         |                    | environmental   |
|     |       | involves        |                    | conditions"     |
|     |       | filling and     |                    | should be       |
|     |       | sealing product |                    | defined.        |
|     |       | containers      |                    |                 |
|     |       | under           |                    |                 |
|     |       | high-quality    |                    |                 |
|     |       | environmental   |                    |                 |
|     |       | conditions."    |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 76-77 | "In most cases, |                    | > The term "low |
| .   |       | the product,    |                    | > bioburden"    |
|     |       | container, and  |                    | > should be     |
|     |       | closure have    |                    | > defined.      |
|     |       | low bioburden,  |                    |                 |
|     |       | but they are    |                    |                 |
|     |       | not sterile."   |                    |                 |
|     |       |                 |                    |                 |
|     |       | .               |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 81-83 | "Because there  | > \"Because there  | > Comment: The  |
| .   |       | is no process   | > is no process to | > term          |
|     |       | to sterilize    | > sterilize the    | > "extremely    |
|     |       | the product in  | > product in its   | > high-quality  |
|     |       | its final       | > final container, | > environment"  |
|     |       | container, it   | > it is critical   | > should be     |
|     |       | is critical     | > that containers  | > defined or    |
|     |       | that containers | > be filled and    | > eliminated.   |
|     |       | be filled and   | > sealed in a      |                 |
|     |       | sealed in an    | > high-quality     |                 |
|     |       | extremely       | > environment.\"   |                 |
|     |       | high-quality    |                    |                 |
|     |       | environment."   |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 88-89 | \"Each of these | > \"Each of these  | The phrase      |
| .   |       | aseptic         | > aseptic          | \"thorough      |
|     |       | manufacturing   | > manufacturing    | validation\"    |
|     |       | processes       | > processes        | implies that    |
|     |       | requires        | > requires         | there are two   |
|     |       | thorough        | > validation and   | levels of       |
|     |       | validation and  | > control.\"       | validation. For |
|     |       | control.\"      |                    | this reason it  |
|     |       |                 |                    | is suggested    |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"thorough\" be |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | [     | "In such cases, |                    | > The terms     |
| .   | 114-1 | a manufacturer  |                    | > "adjunct      |
|     | 15]{. | can explore the |                    | > processing    |
|     | under | option of       |                    | > steps" and    |
|     | line} | adding adjunct  |                    | > "sterility    |
|     |       | processing      |                    | > confidence"   |
|     |       | steps to        |                    | > should be     |
|     |       | increase the    |                    | > defined; or   |
|     |       | level of        |                    | > n             |
|     |       | sterility       |                    | otwithstanding, |
|     |       | confidence."    |                    | > delete them   |
|     |       |                 |                    | > since it is   |
|     |       | .               |                    | > not likely    |
|     |       |                 |                    | > that and SAL  |
|     |       |                 |                    | > of 10\^-3 can |
|     |       |                 |                    | > be exceeded   |
|     |       |                 |                    | > even if       |
|     |       |                 |                    | > "adjunct      |
|     |       |                 |                    | > processing    |
|     |       |                 |                    | > steps are     |
|     |       |                 |                    | > added".       |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 13    | \"Critical      | \"Critical areas   | > The phrase    |
| .   | 4-136 | areas and       | and supporting     | > \"support     |
|     |       | support areas   | clean areas of the | > areas\" is    |
|     |       | of the aseptic  | aseptic processing | > very broad    |
|     |       | processing      | operation should   | > and could be  |
|     |       | operation       | be classified and  | > interpreted   |
|     |       | should be       | supported by       | > to include    |
|     |       | classified and  | microbiological    | > ingredient    |
|     |       | supported by    | and particle data  | > storage areas |
|     |       | microbiological | obtained during    | > or other      |
|     |       | and particle    | qualification      | > widely        |
|     |       | data obtained   | studies.\"         | > varying areas |
|     |       | during          |                    | > beyond the    |
|     |       | qualification   |                    | > intention of  |
|     |       | studies.\"      |                    | > this guidance |
|     |       |                 |                    | > document. In  |
|     |       |                 |                    | > light of      |
|     |       |                 |                    | > language used |
|     |       |                 |                    | > later on, it  |
|     |       |                 |                    | > is suggested  |
|     |       |                 |                    | > that          |
|     |       |                 |                    | > \"support     |
|     |       |                 |                    | > areas\" be    |
|     |       |                 |                    | > changed to    |
|     |       |                 |                    | > \"supporting  |
|     |       |                 |                    | > clean         |
|     |       |                 |                    | > areas\", so   |
|     |       |                 |                    | > that the      |
|     |       |                 |                    | > definition    |
|     |       |                 |                    | > and           |
|     |       |                 |                    | >               |
|     |       |                 |                    |  specifications |
|     |       |                 |                    | > of \"clean    |
|     |       |                 |                    | > areas\"       |
|     |       |                 |                    | > provided      |
|     |       |                 |                    | > later in the  |
|     |       |                 |                    | > document are  |
|     |       |                 |                    | > clearly       |
|     |       |                 |                    | > associated    |
|     |       |                 |                    | > with this     |
|     |       |                 |                    | > thought.      |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 139   | "The following  |                    | > Comment:      |
| .   |       | table           |                    | > Table 1-Air   |
|     |       | summarizes      |                    | > C             |
|     |       | clean area air  |                    | lassifications, |
|     |       | classifications |                    | > references    |
|     |       | (Ref. 1)"       |                    | > ISO 14644-1,  |
|     |       |                 |                    | > however ISO   |
|     |       |                 |                    | > 14644-1 does  |
|     |       |                 |                    | > not contain   |
|     |       |                 |                    | > the           |
|     |       |                 |                    | >               |
|     |       |                 |                    | microbiological |
|     |       |                 |                    | > limits cited  |
|     |       |                 |                    | > in the table. |
|     |       |                 |                    | > The bracket   |
|     |       |                 |                    | > term "(Ref.   |
|     |       |                 |                    | > 1)" should    |
|     |       |                 |                    | > deleted,      |
|     |       |                 |                    | > because       |
|     |       |                 |                    | > adequate      |
|     |       |                 |                    | > reference to  |
|     |       |                 |                    | > ISO 14644-1   |
|     |       |                 |                    | > is given in   |
|     |       |                 |                    | > footnote b    |
|     |       |                 |                    | > (Lines        |
|     |       |                 |                    | > 147-148).     |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 152   | Samples from    | > Delete footnote  | In Table 1 the  |
| .   |       | Class 100 (ISO  |                    | value of "1" is |
|     | (foo  | 5) environments |                    | given. This     |
|     | tnote | should normally |                    | does not        |
|     | e)    | yield no        |                    | correspond to   |
|     |       | microbiological |                    | the term        |
|     |       | contaminants."  |                    | "normally yield |
|     |       |                 |                    | no              |
|     |       |                 |                    | microbiological |
|     |       |                 |                    | contaminants    |
+-----+-------+-----------------+--------------------+-----------------+
| 9   | 17    | [:]{.underline} |                    | The guidance    |
| .   | 3-175 | "...particle    |                    | should define   |
|     |       | count of no     |                    | the term "work  |
|     |       | more than 3520  |                    | site" to avoid  |
|     |       | in a size range |                    | mis             |
|     |       | of 0.5 micron   |                    | understandings. |
|     |       | and larger when |                    |                 |
|     |       | counted at      |                    |                 |
|     |       | representative  |                    |                 |
|     |       | locations       |                    |                 |
|     |       | normally not    |                    |                 |
|     |       | more than one   |                    |                 |
|     |       | foot away from  |                    |                 |
|     |       | the work        |                    |                 |
|     |       | site,..."       |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 18    | \"Measurements  | \"Measurements to  | The word        |
| 0.  | 3-185 | to confirm air  | confirm air        | \"zones\" is    |
|     |       | cleanliness in  | cleanliness in     | not defined and |
|     |       | aseptic         | aseptic processing | is used         |
|     |       | processing      | areas should be    | alternately     |
|     |       | zones should be | taken with the     | with \"area\".  |
|     |       | taken with the  | particle counting  | For             |
|     |       | particle        | probe oriented in  | consistency, it |
|     |       | counting probe  | the direction of   | is suggested    |
|     |       | oriented in the | oncoming airflow   | that the word   |
|     |       | direction of    | and at the sites   | \"zone\" be     |
|     |       | oncoming        | where there is     | replaced by     |
|     |       | airflow and at  | most potential     | \"area\"        |
|     |       | the sites where | risk to the        | throughout      |
|     |       | there is most   | exposed sterilized |                 |
|     |       | potential risk  | product and        |                 |
|     |       | to the exposed  | con                |                 |
|     |       | sterilized      | tainer-closures.\" |                 |
|     |       | product and     |                    |                 |
|     |       | contai          |                    |                 |
|     |       | ner-closures.\" |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 18    | Change from:    | Change to:         | The guidance    |
| 1.  | 6-188 |                 |                    | document        |
|     |       | \"Nonviable     | \"Nonviable        | provides no     |
|     |       | particle        | particle           | data justifying |
|     |       | monitoring with | monitoring with a  | the statement   |
|     |       | a remote        | remote counting    | that the remote |
|     |       | counting system | system is          | counting system |
|     |       | is generally    | generally less     | provides more   |
|     |       | less invasive   | invasive than the  | comprehensive   |
|     |       | than the use of | use of portable    | data than the   |
|     |       | portable        | particle counting  | portable        |
|     |       | particle        | units and is       | particle        |
|     |       | counting units  | recommended for    | counting units. |
|     |       | and provides    | this reason.\"     | And this is not |
|     |       | the most        |                    | necessarily the |
|     |       | comprehensive   |                    | case, as many   |
|     |       | data.\"         |                    | portable units  |
|     |       |                 |                    | could be put    |
|     |       |                 |                    | into place and  |
|     |       |                 |                    | operated for    |
|     |       |                 |                    | the same time   |
|     |       |                 |                    | period that the |
|     |       |                 |                    | remote units    |
|     |       |                 |                    | are in          |
|     |       |                 |                    | operation. In   |
|     |       |                 |                    | addition, the   |
|     |       |                 |                    | portable units  |
|     |       |                 |                    | provide more    |
|     |       |                 |                    | flexibility as  |
|     |       |                 |                    | to location and |
|     |       |                 |                    | therefore can   |
|     |       |                 |                    | provide more    |
|     |       |                 |                    | coverage of     |
|     |       |                 |                    | different areas |
|     |       |                 |                    | in a clean or   |
|     |       |                 |                    | critical area,  |
|     |       |                 |                    | which meets one |
|     |       |                 |                    | definition of   |
|     |       |                 |                    | \"c             |
|     |       |                 |                    | omprehensive.\" |
|     |       |                 |                    | Therefore it is |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the statement   |
|     |       |                 |                    | \"and provides  |
|     |       |                 |                    | the most        |
|     |       |                 |                    | comprehensive   |
|     |       |                 |                    | data\" be       |
|     |       |                 |                    | deleted.        |
|     |       |                 |                    | However, the    |
|     |       |                 |                    | point that the  |
|     |       |                 |                    | remote unit is  |
|     |       |                 |                    | less invasive   |
|     |       |                 |                    | does give a     |
|     |       |                 |                    | rationale for a |
|     |       |                 |                    | general         |
|     |       |                 |                    | recommendation, |
|     |       |                 |                    | and therefore   |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the phrase |
|     |       |                 |                    | \"and is        |
|     |       |                 |                    | recommended for |
|     |       |                 |                    | this reason\"   |
|     |       |                 |                    | be added.       |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 19    | "Air in         | "Air in critical   | The term        |
| 2.  | 6-198 | critical areas  | areas should be    | "laminar"       |
|     |       | should be       | supplied at the    | should be       |
|     |       | supplied at the | point of use as    | replaced by the |
|     |       | point of use as | HEPA-filtered      | term            |
|     |       | HEPA-filtered   | unidirectional     | "un             |
|     |       | laminar flow    | flow air at a      | idirectional.", |
|     |       | air at a        | velocity           | because laminar |
|     |       | velocity        | sufficient to      | airflow is not  |
|     |       | sufficient to   | sweep particles    | really          |
|     |       | sweep particles | away form the      | achievable.     |
|     |       | away form the   | filling/closing    | Further the     |
|     |       | filling/closing | area and maintain  | term "a         |
|     |       | area and        | unidirectional     | velocity        |
|     |       | maintain        | airflow during     | sufficient to   |
|     |       | unidirectional  | operations."       | sweep particles |
|     |       | airflow during  |                    | away" should be |
|     |       | operations."    |                    | described more  |
|     |       |                 |                    | exactly.        |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 19    | \"Air in        | \"Air in critical  | The phrase      |
| 3.  | 9-201 | critical areas  | areas should be    | \"point of      |
|     |       | should be       | supplied at the    | use\" has been  |
|     |       | supplied at the | working site as    | a contentious   |
|     |       | point of use as | HEPA-filtered      | issue in the    |
|     |       | HEPA-filtered   | laminar flow air   | past, as this   |
|     |       | laminar flow    | at a velocity      | may be          |
|     |       | air at a        | sufficient to      | considered to   |
|     |       | velocity        | sweep particles    | be at the HEPA  |
|     |       | sufficient to   | away from the      | face. To        |
|     |       | sweep particles | filling/closing    | clarify that    |
|     |       | away from the   | area and maintain  | the \"point of  |
|     |       | filling/closing | unidirectional     | use\" is at the |
|     |       | area and        | airflow during     | \"working       |
|     |       | maintain        | operations.\"      | height\" or     |
|     |       | unidirectional  |                    | \"work site\"   |
|     |       | airflow during  |                    | it is suggested |
|     |       | operations.\"   |                    | that the change |
|     |       |                 |                    | be made, which  |
|     |       |                 |                    | is consistent   |
|     |       |                 |                    | with the        |
|     |       |                 |                    | language on     |
|     |       |                 |                    | page 5 line     |
|     |       |                 |                    | 178.            |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 22    | Many support    | \"Many support     | The word        |
| 4.  | 2-224 | areas function  | areas function as  | \"zones\" is    |
|     |       | as zones in     | areas in which     | not defined and |
|     |       | which           | nonsterile         | is used         |
|     |       | nonsterile      | components,        | alternately     |
|     |       | components,     | formulated         | with \"area\".  |
|     |       | formulated      | products,          | For             |
|     |       | products,       | in-process         | consistency, it |
|     |       | in-process      | materials,         | is suggested    |
|     |       | materials,      | equipment, and     | that the word   |
|     |       | equipment, and  | container/closures | \"zone\" be     |
|     |       | con             | are prepared,      | replaced by     |
|     |       | tainer/closures | held, or           | \"area\"        |
|     |       | are prepared,   | transferred.\"     | throughout      |
|     |       | held, or        |                    |                 |
|     |       | transferred.\". |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | page  | \"A velocity    | \"A velocity from  | The original    |
| 5.  | 6,    | from 0.45 to    | 0.45 meters/second | statement       |
|     | foo   | 0.51            | (90 feet per       | provides for a  |
|     | tnote | meters/second   | minute) is         | range (+/- 20%  |
|     | 4     | (90 to 100 feet | generally          | ) around a      |
|     |       | per minute) is  | established, with  | range 0.45-0.51 |
|     |       | generally       | a range of plus or | with an         |
|     |       | established,    | minus 20 percent   | allowance for   |
|     |       | with a range of | around the         | higher          |
|     |       | plus or minus   | set-point. Higher  | velocities. It  |
|     |       | 20 percent      | velocities may be  | would be        |
|     |       | around the      | appropriate in     | similar to      |
|     |       | setpoint.       | operations         | providing a     |
|     |       | Higher          | generating high    | target, a range |
|     |       | velocities may  | levels of          | and then the    |
|     |       | be appropriate  | particulates.\"    | allowance for   |
|     |       | in operations   |                    | higher          |
|     |       | generating high |                    | velocities if   |
|     |       | levels of       |                    | needed, and     |
|     |       | particulates.\" |                    | this is the     |
|     |       |                 |                    | change          |
|     |       |                 |                    | suggested. In   |
|     |       |                 |                    | addition the    |
|     |       |                 |                    | suggested       |
|     |       |                 |                    | criteria        |
|     |       |                 |                    | provides for    |
|     |       |                 |                    | harmonization   |
|     |       |                 |                    | with the        |
|     |       |                 |                    | European GMPs.  |
|     |       |                 |                    | Harmonization   |
|     |       |                 |                    | of requirements |
|     |       |                 |                    | at the earliest |
|     |       |                 |                    | possible moment |
|     |       |                 |                    | (such as within |
|     |       |                 |                    | this guidance)  |
|     |       |                 |                    | is desirable to |
|     |       |                 |                    | more quickly    |
|     |       |                 |                    | reach to        |
|     |       |                 |                    | overall         |
|     |       |                 |                    | harmonization   |
|     |       |                 |                    | goals.          |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 22    | [:]{.underline} | delete             | The category    |
| 6.  | 9-230 | "Depending on   |                    | ISO 6 (Class    |
| []{ |       | the operation,  |                    | 1,000) is not   |
| .ma |       | manufacturers   |                    | common within   |
| rk} |       | can also        |                    | pharmaceutical  |
|     |       | classify this   |                    | manufacturing   |
|     |       | area as Class   |                    | and should be   |
|     |       | 1,000 (ISO 6)   |                    | deleted in the  |
|     |       | or maintain the |                    | guidance.       |
|     |       | entire aseptic  |                    |                 |
|     |       | filling room at |                    |                 |
|     |       | Class 100 (ISO  |                    |                 |
|     |       | 5)."            |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 23    | "For example, a |                    | Pressure        |
| 7.  | 8-241 | positive        |                    | differentials   |
|     |       | pressure        |                    | of 12.5 Pascals |
|     |       | differential of |                    | should only be  |
|     |       | at least 12.5   |                    | defined between |
|     |       | Pascals (Pa)    |                    | rooms of        |
|     |       | should be       |                    | different       |
|     |       | maintained at   |                    | classification, |
|     |       | the interface   |                    | not for all     |
|     |       | between         |                    | rooms adjacent  |
|     |       | classified and  |                    | to an aseptic   |
|     |       | unclassified    |                    | processing room |
|     |       | areas. This     |                    | (if these rooms |
|     |       | same            |                    | are of the same |
|     |       | overpressure    |                    | c               |
|     |       | should be       |                    | lassification). |
|     |       | maintained      |                    |                 |
|     |       | between the     |                    |                 |
|     |       | aseptic         |                    |                 |
|     |       | processing room |                    |                 |
|     |       | and adjacent    |                    |                 |
|     |       | rooms (with     |                    |                 |
|     |       | doors closed)." |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 24    | \"For example,  | \"For example, a   | The suggested   |
| 8.  | 2-243 | a positive      | positive pressure  | criteria        |
|     |       | pressure        | differential of at | provides for    |
|     |       | differential of | least 10 Pascals   | harmonization   |
|     |       | at least 12.5   | (Pa)5 should be    | with the        |
|     |       | Pascals (Pa)5   | maintained at the  | European GMPs.  |
|     |       | should be       | interface between  | Harmonization   |
|     |       | maintained at   | classified and     | of requirements |
|     |       | the interface   | unclassified       | at the earliest |
|     |       | between         | areas.\"           | possible moment |
|     |       | classified and  |                    | (such as within |
|     |       | unclassified    |                    | this guidance)  |
|     |       | areas.\"        |                    | is desirable to |
|     |       |                 |                    | more quickly    |
|     |       |                 |                    | reach to        |
|     |       |                 |                    | overall         |
|     |       |                 |                    | harmonization   |
|     |       |                 |                    | goals. In this  |
|     |       |                 |                    | case, the       |
|     |       |                 |                    | footnote on     |
|     |       |                 |                    | page 7 should   |
|     |       |                 |                    | also be changed |
|     |       |                 |                    | to read \"      |
|     |       |                 |                    | Equal to 0.041  |
|     |       |                 |                    | inches of water |
|     |       |                 |                    | gauge.\"        |
+-----+-------+-----------------+--------------------+-----------------+
| 1   | 26    | \"A compressed  | \"A compressed gas | Limits need to  |
| 9.  | 6-268 | gas should be   | should be of       | be provided to  |
|     |       | of appropriate  | appropriate purity | prevent ever    |
|     |       | purity (e.g.,   | (e.g., free from   | more costly     |
|     |       | free from oil   | oil \[\< x%\] and  | methodology     |
|     |       | and water       | water vapor\[ \< x | adoption.       |
|     |       | vapor) and its  | %\]) and its       |                 |
|     |       | microbiological | microbiological    |                 |
|     |       | and particle    | and particle       |                 |
|     |       | quality should  | quality should be  |                 |
|     |       | be equal to or  | equal to or better |                 |
|     |       | better than air | than air in the    |                 |
|     |       | in the          | environment into   |                 |
|     |       | environment     | which the gas is   |                 |
|     |       | into which the  | introduced.\"      |                 |
|     |       | gas is          |                    |                 |
|     |       | introduced.\"   |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 27    | "Sterilized     | Delete or revise   | During some     |
| 0.  | 2-273 | holding tanks   | to, \"Sterilized   | operations,     |
|     |       | and any         | holding tanks and  | overpressure is |
|     |       | contained       | any contained      | not feasible    |
|     |       | liquids should  | liquids should be  | (e.g., transfer |
|     |       | be held under   | held under         | of product      |
|     |       | continuous      | continuous         | between         |
|     |       | overpressure to | overpressure or    | vessels). The   |
|     |       | prevent         | the tanks should   | emphasis should |
|     |       | microbial       | be post use        | be put on       |
|     |       | contamination." | integrity checked  | confirmation of |
|     |       |                 | to prevent         | vessel          |
|     |       |                 | microbial          | integrity.      |
|     |       |                 | contamination, if  |                 |
|     |       |                 | there is no        |                 |
|     |       |                 | subsequent         |                 |
|     |       |                 | sterilizing        |                 |
|     |       |                 | filtration.\"      |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 28    | "Therefore,     |                    | The minimum     |
| 1.  | 7-289 | leak tests      |                    | frequencies for |
|     |       | should be       |                    | testing should  |
|     |       | performed at    |                    | be based on ISO |
|     |       | suitable time   |                    | recommendations |
|     |       | intervals for   |                    | (ISO 14644-2).  |
|     |       | HEPA filters in |                    |                 |
|     |       | the aseptic     |                    |                 |
|     |       | processing      |                    |                 |
|     |       | facility. For   |                    |                 |
|     |       | example, such   |                    |                 |
|     |       | testing should  |                    |                 |
|     |       | be performed    |                    |                 |
|     |       | twice a year    |                    |                 |
|     |       | for the aseptic |                    |                 |
|     |       | processing      |                    |                 |
|     |       | room."          |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 28    | \"Filters also  | \"Filters also     | If the maximum  |
| 2.  | 3-284 | should be       | should be          | time period     |
|     |       | integrity       | integrity tested   | between tests   |
|     |       | tested upon     | upon installation, | is one year,    |
|     |       | installation    | at end of use and  | periodic        |
|     |       | and             | after activities   | testing of air  |
|     |       | periodically    | that might damage  | or gas filters  |
|     |       | thereafter      | the filter. In no  | is not          |
|     |       | (e.g.,          | case should the    | necessary.      |
|     |       | including at    | time period        | After           |
|     |       | end of use).\"  | between integrity  | accidental      |
|     |       |                 | tests extend       | bumping or      |
|     |       |                 | beyond one year.\" | other           |
|     |       |                 |                    | mistreatment    |
|     |       |                 |                    | the filters may |
|     |       |                 |                    | need retesting  |
|     |       |                 |                    | to assure       |
|     |       |                 |                    | integrity.      |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 29    | [Lines          |                    | Di-Ethyl        |
| 3.  | 7-298 | 297-29          |                    | -Hexyl-Sebacate |
|     |       | 8:]{.underline} |                    | (DEHS) should   |
|     |       | "D              |                    | be added to the |
|     |       | ioctylphthalate |                    | list of         |
|     |       | (DOP) and       |                    | appropriate     |
|     |       | Po              |                    | leak testing    |
|     |       | ly-alpha-olefin |                    | aerosols, as    |
|     |       | (PAO) are       |                    | this is also    |
|     |       | examples of     |                    | commonly used.  |
|     |       | appropriate     |                    |                 |
|     |       | leak testing    |                    |                 |
|     |       | aerosols."      |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 33    | \"HEPA filter   | \"HEPA filter leak | There is no     |
| 4.  | 3-342 | leak testing    | testing alone is   | definition as   |
|     |       | alone is not    | not sufficient to  | to how much     |
|     |       | sufficient to   | monitor filter     | more frequently |
|     |       | monitor filter  | performance. This  | airflow         |
|     |       | performance.    | testing is usually | velocities      |
|     |       | This testing is | done only on a     | should be       |
|     |       | usually done    | semi-annual basis. | measured than   |
|     |       | only on a       | It is important to | the required    |
|     |       | semi-annual     | conduct periodic   | semi-annual     |
|     |       | basis. It is    | monitoring of      | leak testing.   |
|     |       | important to    | filter attributes  | Inasmuch as     |
|     |       | conduct         | such as uniformity | this is an      |
|     |       | periodic        | of velocity across | extraordinary   |
|     |       | monitoring of   | the filter (and    | event in the    |
|     |       | filter          | relative to        | critical area,  |
|     |       | attributes such | adjacent filters). | it should be    |
|     |       | as uniformity   | Variations in      | done at the     |
|     |       | of velocity     | velocity generally | minimal         |
|     |       | across the      | increase the       | necessary       |
|     |       | filter (and     | possibility of     | frequency, and  |
|     |       | relative to     | contamination, as  | quarterly is    |
|     |       | adjacent        | these changes      | suggested. In   |
|     |       | filters).       | (e.g., velocity    | addition, it is |
|     |       | Variations in   | reduction) can     | suggested that  |
|     |       | velocity        | have an effect on  | the word        |
|     |       | generally       | unidirectional     | \"regular\" be  |
|     |       | increase the    | airflow. Airflow   | replaced with   |
|     |       | possibility of  | velocities are     | \"periodic\"    |
|     |       | contamination,  | measured 6 inches  | for consistency |
|     |       | as these        | from the filter    | with the        |
|     |       | changes (e.g.,  | face and at a      | previous        |
|     |       | velocity        | defined distance   | sentence, and   |
|     |       | reduction) can  | proximal to the    | to change \"on  |
|     |       | have an effect  | work surface for   | the clean       |
|     |       | on              | HEPA filters in    | area\" to \"for |
|     |       | unidirectional  | the critical area. | the area\" as   |
|     |       | airflow.        | Periodic velocity  | the topic is    |
|     |       | Airflow         | monitoring can     | the critical    |
|     |       | velocities are  | provide useful     | area. This use  |
|     |       | measured 6      | data for the area  | of clean in     |
|     |       | inches from the | in which aseptic   | this sense      |
|     |       | filter face and | processing is      | could be        |
|     |       | at a defined    | performed, and     | confused with   |
|     |       | distance        | should be          | \"clean area\"  |
|     |       | proximal to the | performed at least | which has       |
|     |       | work surface    | quarterly. HEPA    | separate        |
|     |       | for HEPA        | filters should be  | requirements    |
|     |       | filters in the  | replaced when      | and limits than |
|     |       | critical area.  | nonuniformity of   | the \"critical  |
|     |       | Regular         | air velocity       | area.\"         |
|     |       | velocity        | across an area of  |                 |
|     |       | monitoring can  | the filter is      |                 |
|     |       | provide useful  | detected or        |                 |
|     |       | data on the     | airflow patterns   |                 |
|     |       | clean area in   | may be adversely   |                 |
|     |       | which aseptic   | affected.\"        |                 |
|     |       | processing is   |                    |                 |
|     |       | performed. HEPA |                    |                 |
|     |       | filters should  |                    |                 |
|     |       | be replaced     |                    |                 |
|     |       | when            |                    |                 |
|     |       | nonuniformity   |                    |                 |
|     |       | of air velocity |                    |                 |
|     |       | across an area  |                    |                 |
|     |       | of the filter   |                    |                 |
|     |       | is detected or  |                    |                 |
|     |       | airflow         |                    |                 |
|     |       | patterns may be |                    |                 |
|     |       | adversely       |                    |                 |
|     |       | affected.\"     |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 348   | "...clean area  | "...clean area are | The word        |
| 5.  |       | are essential   | essential to       | "sterilty" is   |
|     |       | to achieving    | achieving high     | misspelled.     |
|     |       | high assurance  | assurance of       |                 |
|     |       | of sterilty     | sterility (Ref.    |                 |
|     |       | (Ref. 4)."      | 4)."               |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 355   | \"sterilty\"    | \"sterility\"      | Spelling        |
| 6.  |       |                 |                    | correction.     |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 38    | \"Facility      | \"Facility design  | The requirement |
| 7.  | 0-382 | design should   | should ensure that | is for clean    |
|     |       | ensure that the | the area between a | (Class 100)     |
|     |       | area between a  | filling line and   | conditions      |
|     |       | filling line    | the lyophilizer    | between the     |
|     |       | and the         | and the transport  | filling area    |
|     |       | lyophilizer and | and loading        | and             |
|     |       | the transport   | procedures provide | lyophilizer,    |
|     |       | and loading     | Class 100 (ISO 5)  | and the         |
|     |       | procedures      | protection.        | guidance should |
|     |       | provide Class   | Alternate methods  | specify the     |
|     |       | 100 (ISO 5)     | of providing Class | what (the       |
|     |       | protection.\"   | 100 protection for | conditions) and |
|     |       |                 | partially closed   | not the how     |
|     |       |                 | sterile products   | (area           |
|     |       |                 | during transport   | cleanliness).   |
|     |       |                 | between the        | The additional  |
|     |       |                 | filling area and   | sentence        |
|     |       |                 | the lyophilizer    | provides        |
|     |       |                 | may be used, such  | allowance for   |
|     |       |                 | as transport       | alternate means |
|     |       |                 | trolleys with      | to same goal.   |
|     |       |                 | integral HEPA      |                 |
|     |       |                 | filtered air       |                 |
|     |       |                 | supply.\"          |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 28  | 41    | \"With rare     | \"With rare        | Since many      |
| . \ | 1-414 | exceptions,     | exceptions, drains | aseptic         |
| *\* |       | drains are not  | are not considered | processing      |
|     |       | considered      | appropriate for    | facilities      |
|     |       | appropriate for | critical areas.\"  | include the     |
|     |       | classified      |                    | washing of      |
|     |       | areas of the    |                    | containers, and |
|     |       | aseptic         |                    | the area in     |
|     |       | processing      |                    | which the       |
|     |       | facility.\"     |                    | containers are  |
|     |       |                 |                    | washed is       |
|     |       |                 |                    | classified, and |
|     |       |                 |                    | the waste water |
|     |       |                 |                    | must be         |
|     |       |                 |                    | disposed of,    |
|     |       |                 |                    | the sentence as |
|     |       |                 |                    | written is too  |
|     |       |                 |                    | restrictive. On |
|     |       |                 |                    | container       |
|     |       |                 |                    | washers the     |
|     |       |                 |                    | drain may be    |
|     |       |                 |                    | off the floor,  |
|     |       |                 |                    | with an         |
|     |       |                 |                    | air-break and   |
|     |       |                 |                    | contained       |
|     |       |                 |                    | within the      |
|     |       |                 |                    | machine, but it |
|     |       |                 |                    | is a drain by   |
|     |       |                 |                    | any other name. |
|     |       |                 |                    | The sentence    |
|     |       |                 |                    | has been        |
|     |       |                 |                    | adjusted        |
|     |       |                 |                    | appropriately   |
|     |       |                 |                    | to limit the    |
|     |       |                 |                    | restriction to  |
|     |       |                 |                    | critical areas, |
|     |       |                 |                    | not all         |
|     |       |                 |                    | classified      |
|     |       |                 |                    | areas.          |
+-----+-------+-----------------+--------------------+-----------------+
| 2   | 46    | Rapid movements | \"Rapid movements  | The term        |
| 9.  | 0-462 | can create      | can create         | \"critical      |
|     |       | unacceptable    | unacceptable       | zone\" is       |
|     |       | turbulence in   | turbulence in the  | apparently used |
|     |       | the critical    | critical area.     | as a synonym to |
|     |       | zone. Such      | Such movements     | \"critical      |
|     |       | movements       | disrupt the        | area\" as       |
|     |       | disrupt the     | airflow            | \"clean zone\"  |
|     |       | sterile field,  | laminarity,        | is              |
|     |       | presenting a    | presenting a       | c               |
|     |       | challenge       | challenge beyond   | ross-referenced |
|     |       | beyond intended | intended cleanroom | to \"clean      |
|     |       | cleanroom       | design and control | area.\" As      |
|     |       | design and      | parameters.\"      | such, for       |
|     |       | control         |                    | consistency and |
|     |       | parameters.\"   |                    | clarity, it is  |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | all such        |
|     |       |                 |                    | references be   |
|     |       |                 |                    | changed from    |
|     |       |                 |                    | \"critical      |
|     |       |                 |                    | zone\" to       |
|     |       |                 |                    | \"critical      |
|     |       |                 |                    | area.\"         |
|     |       |                 |                    | Furthermore,    |
|     |       |                 |                    | the aseptic     |
|     |       |                 |                    | processing area |
|     |       |                 |                    | is not a        |
|     |       |                 |                    | sterile area by |
|     |       |                 |                    | definition; it  |
|     |       |                 |                    | has not been    |
|     |       |                 |                    | sterilized. The |
|     |       |                 |                    | term \"sterile  |
|     |       |                 |                    | field\" is a    |
|     |       |                 |                    | misnomer that   |
|     |       |                 |                    | implies         |
|     |       |                 |                    | sterility of    |
|     |       |                 |                    | the area and    |
|     |       |                 |                    | should be       |
|     |       |                 |                    | changed for     |
|     |       |                 |                    | clarity.        |
|     |       |                 |                    | Therefore it is |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | \"sterile field |
|     |       |                 |                    | be replaced     |
|     |       |                 |                    | with \"airflow  |
|     |       |                 |                    | laminarity.\"   |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 46    | \"Personnel     | \"Personnel should | The word        |
| 0.  | 8-469 | should not      | not disrupt the    | \"zones\" is    |
|     |       | disrupt the     | path of            | not defined and |
|     |       | path of         | unidirectional     | is used         |
|     |       | unidirectional  | flow air in the    | alternately     |
|     |       | flow air in the | aseptic processing | with \"area\".  |
|     |       | aseptic         | area.\"            | For             |
|     |       | processing      |                    | consistency, it |
|     |       | zone.\"         |                    | is suggested    |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"zone\" be     |
|     |       |                 |                    | replaced by     |
|     |       |                 |                    | \"area\"        |
|     |       |                 |                    | throughout.     |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 47    | \"Also, an      | \"Also, an         | It is unclear   |
| 1.  | 6-477 | operator should | operator should    | whether         |
|     |       | refrain from    | refrain from       | \"direct        |
|     |       | speaking when   | speaking when      | proximity\"     |
|     |       | in direct       | within the         | means in the    |
|     |       | proximity to an | critical area of   | Class 100       |
|     |       | aseptic         | an aseptic         | laminar flow    |
|     |       | processing      | processing line.\" | area or next to |
|     |       | line.\"         |                    | it, but outside |
|     |       |                 |                    | the Critical    |
|     |       |                 |                    | Area. If it     |
|     |       |                 |                    | means the       |
|     |       |                 |                    | later, the      |
|     |       |                 |                    | statement is    |
|     |       |                 |                    | too general.    |
|     |       |                 |                    | For instance,   |
|     |       |                 |                    | outside the     |
|     |       |                 |                    | Critical Area   |
|     |       |                 |                    | but next to it  |
|     |       |                 |                    | could mean a    |
|     |       |                 |                    | person standing |
|     |       |                 |                    | next to an      |
|     |       |                 |                    | isolator. In    |
|     |       |                 |                    | this instance,  |
|     |       |                 |                    | the talking     |
|     |       |                 |                    | prohibition is  |
|     |       |                 |                    | too extreme.    |
|     |       |                 |                    | Therefore it is |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the phrase \"in |
|     |       |                 |                    | direct          |
|     |       |                 |                    | proximity to an |
|     |       |                 |                    | aseptic         |
|     |       |                 |                    | processing      |
|     |       |                 |                    | line\" be       |
|     |       |                 |                    | changed to      |
|     |       |                 |                    | \"within the    |
|     |       |                 |                    | critical area   |
|     |       |                 |                    | of an aseptic   |
|     |       |                 |                    | processing      |
|     |       |                 |                    | line.\"         |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 48    | \"Gowns should  | \"Gowns should be  | Once a gown is  |
| 2.  | 7-490 | be sterile and  | sterilized and     | donned, it      |
|     |       | nonshedding and | nonshedding and    | cannot be       |
|     |       | should cover    | should cover the   | considered      |
|     |       | the skin and    | skin and hair      | sterile.        |
|     |       | hair            | (face-masks,       | Elsewhere in    |
|     |       | (face-masks,    | hoods,             | the guidance,   |
|     |       | hoods,          | beard/moustache    | for instance,   |
|     |       | beard/moustache | covers, protective | in line 552     |
|     |       | covers,         | goggles, elastic   | where           |
|     |       | protective      | gloves, cleanroom  | containers and  |
|     |       | goggles,        | boots, and shoe    | closures are    |
|     |       | elastic gloves, | overcovers are     | discussed, the  |
|     |       | cleanroom       | examples of common | term sterilized |
|     |       | boots, and shoe | elements of        | is used. For    |
|     |       | overcovers are  | gowns).\"          | consistency and |
|     |       | examples of     |                    | clarity, it is  |
|     |       | common elements |                    | suggested that  |
|     |       | of gowns).\"    |                    | the term        |
|     |       |                 |                    | \"sterilized\"  |
|     |       |                 |                    | be used in      |
|     |       |                 |                    | place of        |
|     |       |                 |                    | \"sterile\" in  |
|     |       |                 |                    | this instance.  |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 58    | Endotoxin       | Endotoxin          | The mention of  |
| 3.  | 8-589 | \"challange     | \"challenge        | a specific      |
|     |       | studies should  | studies may be     | procedure can   |
|     |       | be performed    | performed with a   | discredit       |
|     |       | with a          | reconstituted      | alternative     |
|     |       | reconstituted   | endotoxin solution | equivalent      |
|     |       | endotoxin       | applied directly   | reliable        |
|     |       | solution        | onto the surface   | procedures      |
|     |       | applied         | being tested and   | and/or          |
|     |       | directly onto   | air-dried.\" The   | discourage      |
|     |       | the surface     | use of precoated   | technological   |
|     |       | being tested    | vials may also be  | advancements.   |
|     |       | and air-dried.  | acceptable.        |                 |
|     |       |                 |                    |                 |
|     |       |                 |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 62    | "A container    | The term "air, or" | Penetration by  |
| 4.  | 9-630 | closure system  | should be deleted  | air and other   |
|     |       | that permits    |                    | gases can occur |
|     |       | penetration of  |                    | without         |
|     |       | air, or         |                    | compromising    |
|     |       | microorganisms, |                    | product         |
|     |       | is unsuitable   |                    | sterility, e.g. |
|     |       | for a sterile   |                    | by diffusing    |
|     |       | product."       |                    | through         |
|     |       |                 |                    | elastomeric     |
|     |       |                 |                    | closures, or    |
|     |       |                 |                    | through         |
|     |       |                 |                    | sterilization   |
|     |       |                 |                    | bag membranes.. |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 63    | \"The finished  | \"The finished     | Normally, it    |
| 5.  | 4-636 | dosage form     | dosage form        | would be        |
|     |       | manufacturer is | manufacturer is    | expected that   |
|     |       | responsible for | responsible to     | \"approval\" of |
|     |       | the review and  | assure that the    | the protocol    |
|     |       | approval of the | contractor\'s      | and report be   |
|     |       | contractor\'s   | validation         | signatures by   |
|     |       | validation      | protocol and final | the             |
|     |       | protocol and    | validation report  | manufacturer on |
|     |       | final           | are in place and   | the protocol    |
|     |       | validation      | acceptable.\"      | and report.     |
|     |       | report.\"       |                    | Since the       |
|     |       |                 |                    | contractor may  |
|     |       |                 |                    | well be         |
|     |       |                 |                    | providing these |
|     |       |                 |                    | items for       |
|     |       |                 |                    | several         |
|     |       |                 |                    | manufacturers   |
|     |       |                 |                    | now, and more   |
|     |       |                 |                    | in the future,  |
|     |       |                 |                    | the concept     |
|     |       |                 |                    | that each       |
|     |       |                 |                    | manufacturer is |
|     |       |                 |                    | to sign the     |
|     |       |                 |                    | protocol (in    |
|     |       |                 |                    | advance of      |
|     |       |                 |                    | execution) and  |
|     |       |                 |                    | sign the report |
|     |       |                 |                    | is clearly      |
|     |       |                 |                    | untenable. The  |
|     |       |                 |                    | manufacturer    |
|     |       |                 |                    | need only       |
|     |       |                 |                    | assure that the |
|     |       |                 |                    | protocol and    |
|     |       |                 |                    | report are in   |
|     |       |                 |                    | place and       |
|     |       |                 |                    | appropriate,    |
|     |       |                 |                    | which may be    |
|     |       |                 |                    | done through    |
|     |       |                 |                    | audit, through  |
|     |       |                 |                    | signing the     |
|     |       |                 |                    | documents and   |
|     |       |                 |                    | other methods.  |
|     |       |                 |                    | The suggested   |
|     |       |                 |                    | changes reflect |
|     |       |                 |                    | this            |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 66    | "Endotoxin      | This sentence      | The risk of     |
| 6.  | 0-661 | control should  | should be deleted. | contaminating   |
|     |       | be exercised    |                    | product is      |
|     |       | for all product |                    | prevented by    |
|     |       | contact         |                    | product tests,  |
|     |       | surfaces both   |                    | equipment       |
|     |       | prior to and    |                    | qualification,  |
|     |       | after sterile   |                    | and validation  |
|     |       | filtration."    |                    | of cleaning or  |
|     |       |                 |                    | either dry heat |
|     |       |                 |                    | processes..     |
|     |       |                 |                    | Endotoxin       |
|     |       |                 |                    | control for     |
|     |       |                 |                    | product contact |
|     |       |                 |                    | surfaces prior  |
|     |       |                 |                    | and after every |
|     |       |                 |                    | routine sterile |
|     |       |                 |                    | filtration of   |
|     |       |                 |                    | no real         |
|     |       |                 |                    | benefit.        |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 66    | "Processes that |                    | This approach   |
| 7.  | 8-669 | are designed to |                    | is only         |
|     |       | achieve         |                    | applicable, if  |
|     |       | depyrogenation  |                    | the endotoxin   |
|     |       | should          |                    | concentration   |
|     |       | demonstrate a   |                    | before the      |
|     |       | 3-log reduction |                    | depyrogenation  |
|     |       | of endotoxin."  |                    | is known (e.g.  |
|     |       |                 |                    | for spiked      |
|     |       |                 |                    | "challenge      |
|     |       |                 |                    | vials" during   |
|     |       |                 |                    | validation). As |
|     |       |                 |                    | the starting    |
|     |       |                 |                    | concentration   |
|     |       |                 |                    | is not          |
|     |       |                 |                    | consistent, the |
|     |       |                 |                    | method has to   |
|     |       |                 |                    | be described    |
|     |       |                 |                    | more in detail  |
|     |       |                 |                    | (e.g., use of   |
|     |       |                 |                    | average         |
|     |       |                 |                    | endotoxin       |
|     |       |                 |                    | concentrations  |
|     |       |                 |                    | of the positive |
|     |       |                 |                    | controls as     |
|     |       |                 |                    | starting        |
|     |       |                 |                    | point). Another |
|     |       |                 |                    | possibility is  |
|     |       |                 |                    | to define the   |
|     |       |                 |                    | acceptance      |
|     |       |                 |                    | criteria as "\< |
|     |       |                 |                    | 1 Endotoxin     |
|     |       |                 |                    | Unit".          |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 66    | \"Equipment     | \"Following        | In many         |
| 8.  | 7-668 | should be dried | cleaning,          | instances, a    |
|     |       | following       | equipment should   | new batch is    |
|     |       | cleaning.\"     | be handled in such | processed by    |
|     |       |                 | a manner as to     | the equipment   |
|     |       |                 | prevent            | quickly         |
|     |       |                 | contamination      | following       |
|     |       |                 | otherwise affect   | cleaning. For   |
|     |       |                 | the safety, purity | intermediate    |
|     |       |                 | or potency of the  | purification    |
|     |       |                 | following product  | processes,      |
|     |       |                 | manufactured in    | using wet       |
|     |       |                 | the equipment(e.g. | equipment will  |
|     |       |                 | drying or setting  | not affect the  |
|     |       |                 | time limits        | safety, purity  |
|     |       |                 | between cleaning   | or potency of   |
|     |       |                 | and use).\"        | the             |
|     |       |                 |                    | intermediate    |
|     |       |                 |                    | materials;      |
|     |       |                 |                    | drying provides |
|     |       |                 |                    | no benefit. The |
|     |       |                 |                    | purpose of      |
|     |       |                 |                    | drying would    |
|     |       |                 |                    | appear to be to |
|     |       |                 |                    | limit the       |
|     |       |                 |                    | opportunities   |
|     |       |                 |                    | for             |
|     |       |                 |                    | microorganism   |
|     |       |                 |                    | growth. This    |
|     |       |                 |                    | would equally   |
|     |       |                 |                    | be met by       |
|     |       |                 |                    | setting time    |
|     |       |                 |                    | limits between  |
|     |       |                 |                    | cleaning and    |
|     |       |                 |                    | use, as well as |
|     |       |                 |                    | protecting the  |
|     |       |                 |                    | clean           |
|     |       |                 |                    | equipment. The  |
|     |       |                 |                    | suggested       |
|     |       |                 |                    | wording         |
|     |       |                 |                    | provides the    |
|     |       |                 |                    | necessary       |
|     |       |                 |                    | flexibility as  |
|     |       |                 |                    | well as         |
|     |       |                 |                    | specifies       |
|     |       |                 |                    | \"what\" is     |
|     |       |                 |                    | needed, rather  |
|     |       |                 |                    | than requiring  |
|     |       |                 |                    | the \"how.\"    |
+-----+-------+-----------------+--------------------+-----------------+
| 3   | 68    | "St             |                    | The term        |
| 9.  | 4-685 | erilizing-grade |                    | \"generally\"   |
|     |       | filters should  |                    | can be          |
|     |       | generally be    |                    | misinterpreted. |
|     |       | replaced        |                    | Specific        |
|     |       | following each  |                    | guidance would  |
|     |       | manufactured    |                    | be helpful.     |
|     |       | lot."           |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 68    | \"Maintenance   | \"The time limits  | The suggested   |
| 0.  | 9-690 | of in-process   | set for the        | wording is to   |
|     |       | quality at      | various production | make it clear   |
|     |       | different       | phases should be   | that it is the  |
|     |       | production      | supported with     | \"time          |
|     |       | phases should   | drug product       | limits\", which |
|     |       | be supported by | quality data."     | are the topic   |
|     |       | data.\"         |                    | of this         |
|     |       |                 |                    | section, that   |
|     |       |                 |                    | are to be       |
|     |       |                 |                    | supported by    |
|     |       |                 |                    | the data        |
|     |       |                 |                    | demonstrating   |
|     |       |                 |                    | appropriate     |
|     |       |                 |                    | levels of drug  |
|     |       |                 |                    | product quality |
|     |       |                 |                    | at the various  |
|     |       |                 |                    | production      |
|     |       |                 |                    | phases.         |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 70    | \"To ensure the | \"To ensure the    | The phrase      |
| 1.  | 1-702 | sterility of    | sterility of       | \"adequately    |
|     |       | products        | products           | validated\"     |
|     |       | purporting to   | purporting to be   | implies that    |
|     |       | be sterile,     | sterile, both      | there are two   |
|     |       | both            | sterilization and  | levels of       |
|     |       | sterilization   | aseptic filling    | validation,     |
|     |       | and aseptic     | and closing        | regular         |
|     |       | filling and     | operations must be | validation and  |
|     |       | closing         | validated          | the \"adequate  |
|     |       | operations must | (211.113).\"       | validation.\"   |
|     |       | be adequately   |                    | Nowhere in US   |
|     |       | validated       |                    | GMP or FDA      |
|     |       | (211.113).\"    |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word            |
|     |       |                 |                    | \"adequately\"  |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | validation of   |
|     |       |                 |                    | aseptic         |
|     |       |                 |                    | processes than  |
|     |       |                 |                    | does the single |
|     |       |                 |                    | word            |
|     |       |                 |                    | \"validation.\" |
|     |       |                 |                    | In addition,    |
|     |       |                 |                    | the GMP         |
|     |       |                 |                    | citation given  |
|     |       |                 |                    | (211.113) uses  |
|     |       |                 |                    | \"validation,\" |
|     |       |                 |                    | not             |
|     |       |                 |                    | \"adequately    |
|     |       |                 |                    | validated.\"    |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"adequately\"  |
|     |       |                 |                    | be deleted.     |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 722   | "Media fill     | Media fill studies | It is generally |
| 2.  | -724; | studies should  | should simulate    | not possible to |
|     | 739   | simulate        | aseptic            | artificially    |
|     |       | aseptic         | manufacturing      | simulate        |
|     |       | manufacturing   | operations as      | fatigue. The    |
|     |       | operations as   | closely as         | term in line    |
|     |       | closely as      | possible,          | 739 should be   |
|     |       | possible,       | incorporating a    | deleted.        |
|     |       | incorporating a | worst-case         |                 |
|     |       | worst-case      | approach.          |                 |
|     |       | approach. The   |                    |                 |
|     |       | media fill      |                    |                 |
|     |       | program should  |                    |                 |
|     |       | address         |                    |                 |
|     |       | applicable      |                    |                 |
|     |       | issues such     |                    |                 |
|     |       | as:";           |                    |                 |
|     |       |                 |                    |                 |
|     |       | "operator       |                    |                 |
|     |       | fatigue"        |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 75    | \"Media fills   | delete             | The phrase      |
| 3.  | 7-758 | should not be   |                    | \"unaccepted    |
|     |       | used to justify |                    | practice\" is a |
|     |       | an unacceptable |                    | vague term and  |
|     |       | practice.\"     |                    | is not defined  |
|     |       |                 |                    | within this     |
|     |       |                 |                    | document.       |
|     |       |                 |                    | People will     |
|     |       |                 |                    | differ as to    |
|     |       |                 |                    | what unaccepted |
|     |       |                 |                    | practices are.  |
|     |       |                 |                    | Since           |
|     |       |                 |                    | validation,     |
|     |       |                 |                    | such as         |
|     |       |                 |                    | validation of   |
|     |       |                 |                    | aseptic         |
|     |       |                 |                    | processes       |
|     |       |                 |                    | through media   |
|     |       |                 |                    | fills, are a    |
|     |       |                 |                    | justification   |
|     |       |                 |                    | of the process, |
|     |       |                 |                    | this statement  |
|     |       |                 |                    | is in fact      |
|     |       |                 |                    | contradictory.  |
|     |       |                 |                    | If there are    |
|     |       |                 |                    | specific        |
|     |       |                 |                    | concerns, or    |
|     |       |                 |                    | even examples,  |
|     |       |                 |                    | of practices    |
|     |       |                 |                    | that are        |
|     |       |                 |                    | objectionable   |
|     |       |                 |                    | or              |
|     |       |                 |                    | unacceptable,   |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that these be   |
|     |       |                 |                    | included here,  |
|     |       |                 |                    | rather than     |
|     |       |                 |                    | using this      |
|     |       |                 |                    | broad and vague |
|     |       |                 |                    | language.       |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 77    | \" Any changes  | \" Any changes or  | The outcome of  |
| 4.  | 3-778 | or events that  | events that have   | the events      |
|     |       | have the        | the potential to   | listed in this  |
|     |       | potential to    | affect the ability | sentence is     |
|     |       | affect the      | of the aseptic     | \"revalidation  |
|     |       | ability of the  | process to exclude | of the          |
|     |       | aseptic process | contamination from | system.\" This  |
|     |       | to exclude      | the sterilized     | is more         |
|     |       | contamination   | product should be  | rigorous than   |
|     |       | from the        | assessed through   | an additional   |
|     |       | sterilized      | additional media   | media fill run, |
|     |       | product should  | fills. For         | and is          |
|     |       | be assessed     | example, facility  | described on    |
|     |       | through         | and equipment      | this page as    |
|     |       | additional      | modifications,     | \"separate      |
|     |       | media fills.    | line configuration | media fills     |
|     |       | For example,    | changes,           | should be       |
|     |       | facility and    | significant        | repeated enough |
|     |       | equipment       | changes in         | times to ensure |
|     |       | modifications,  | personnel,         | that results    |
|     |       | line            | anomalies in       | are consistent  |
|     |       | configuration   | environmental      | and             |
|     |       | changes,        | testing results,   | meaningful.\"   |
|     |       | significant     | container closure  | Making a        |
|     |       | changes in      | system changes or, | requirement for |
|     |       | personnel,      | end product        | revalidation    |
|     |       | anomalies in    | sterility testing  | due to the      |
|     |       | environmental   | showing            | undefined       |
|     |       | testing         | contaminated       | \"anomalies in  |
|     |       | results,        | products may be    | environmental   |
|     |       | container       | cause for          | testing         |
|     |       | closure system  | additional media   | results\" is    |
|     |       | changes or, end | fills, or even     | overkill and    |
|     |       | product         | revalidation of    | unnecessary.    |
|     |       | sterility       | the system.\"      | The             |
|     |       | testing showing |                    | \"additional    |
|     |       | contaminated    |                    | media fills\"   |
|     |       | products may be |                    | stated in the   |
|     |       | cause for       |                    | first sentence  |
|     |       | revalidation of |                    | above provides  |
|     |       | the system.\"   |                    | the flexibility |
|     |       |                 |                    | and range of    |
|     |       |                 |                    | approaches to   |
|     |       |                 |                    | provide an      |
|     |       |                 |                    | appropriate     |
|     |       |                 |                    | level of media  |
|     |       |                 |                    | fills for the   |
|     |       |                 |                    | concerns noted, |
|     |       |                 |                    | while the       |
|     |       |                 |                    | re-validation   |
|     |       |                 |                    | of the line is  |
|     |       |                 |                    | a much more     |
|     |       |                 |                    | intensive       |
|     |       |                 |                    | effort. It is   |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the second      |
|     |       |                 |                    | sentence be     |
|     |       |                 |                    | reworded to     |
|     |       |                 |                    | include as an   |
|     |       |                 |                    | option          |
|     |       |                 |                    | \"additional    |
|     |       |                 |                    | media fills\"   |
|     |       |                 |                    | as noted above  |
|     |       |                 |                    | to reflect the  |
|     |       |                 |                    | broader list of |
|     |       |                 |                    | options.        |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 78    | \"Where data    | \"Where data from  | The phrase      |
| 5.  | 0-782 | from a media    | a media fill       | \"comprehensive |
|     |       | fill indicate   | indicate the       | documented      |
|     |       | the process may | process may not be | investigation\" |
|     |       | not be in       | in control, an     | implies that    |
|     |       | control, a      | investigation      | there are two   |
|     |       | comprehensive   | should be          | levels of       |
|     |       | documented      | conducted to       | investigations, |
|     |       | investigation   | determine the      | regular         |
|     |       | should be       | origin of the      | investigations  |
|     |       | conducted to    | contamination and  | and the more    |
|     |       | determine the   | the scope of the   | rigorous and    |
|     |       | origin of the   | problem.\"         | in-depth        |
|     |       | contamination   |                    | \"comprehensive |
|     |       | and the scope   |                    | in              |
|     |       | of the          |                    | vestigations.\" |
|     |       | problem.\"      |                    | Nowhere in US   |
|     |       |                 |                    | GMP or FDA      |
|     |       |                 |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word            |
|     |       |                 |                    | \"              |
|     |       |                 |                    | comprehensive\" |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"i             |
|     |       |                 |                    | nvestigation.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"              |
|     |       |                 |                    | comprehensive\" |
|     |       |                 |                    | be deleted. In  |
|     |       |                 |                    | addition, the   |
|     |       |                 |                    | GMP requirement |
|     |       |                 |                    | is that         |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | must be in      |
|     |       |                 |                    | documented      |
|     |       |                 |                    | form.           |
|     |       |                 |                    | Specifying      |
|     |       |                 |                    | \"documented\"  |
|     |       |                 |                    | in one case but |
|     |       |                 |                    | not in the      |
|     |       |                 |                    | others implies  |
|     |       |                 |                    | that some       |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | may not need to |
|     |       |                 |                    | be documented.  |
|     |       |                 |                    | Therefore it is |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the word        |
|     |       |                 |                    | \"documented\"  |
|     |       |                 |                    | also be         |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 81    | \"For           | \"For operations   | The suggested   |
| 6.  | 7-819 | operations with | with production    | wording         |
|     |       | production      | sizes under 5,000, | provides for    |
|     |       | sizes under     | the number of      | harmonization   |
|     |       | 5,000, the      | media filled units | with the        |
|     |       | number of media | should be equal to | current         |
|     |       | filled units    | or greater than    | practice vast   |
|     |       | should equal    | the maximum batch  | majority of     |
|     |       | the maximum     | size made on the   | industry, as    |
|     |       | batch size made | processing line    | well as         |
|     |       | on the          | (Ref. 8).\"        | harmonization   |
|     |       | processing line |                    | with the        |
|     |       | (Ref. 8).\"     |                    | European GMPs.  |
|     |       |                 |                    | Harmonization   |
|     |       |                 |                    | of requirements |
|     |       |                 |                    | at the earliest |
|     |       |                 |                    | possible moment |
|     |       |                 |                    | (such as within |
|     |       |                 |                    | this guidance)  |
|     |       |                 |                    | is desirable to |
|     |       |                 |                    | more quickly    |
|     |       |                 |                    | reach to        |
|     |       |                 |                    | overall         |
|     |       |                 |                    | harmonization   |
|     |       |                 |                    | goals.          |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 86    | # \"The prod    | The production     | The word        |
| 7.  | 5-869 | uction process  | process should be  | \"appropriate\" |
|     |       | should be accur | accurately         | is not as       |
|     |       | ately simulated | simulated using    | specific as     |
|     |       |  using media an | media and          | \"sufficient\"  |
|     |       | d conditions th | conditions that    | and does not as |
|     |       | at optimize det | optimize detection | clearly denote  |
|     |       | ection of any m | of any             | that there must |
|     |       | icrobiological  | microbiological    | be enough       |
|     |       | contamination.  | contamination.     | volume of media |
|     |       | Each unit shoul | Each unit should   | for the purpose |
|     |       | d be filled wit | be filled with a   | of coating the  |
|     |       | h an appropriat | sufficient         | interior of the |
|     |       | e quantity and  | quantity and type  | container and   |
|     |       | type of microbi | of microbial       | closure         |
|     |       | al growth mediu | growth medium to   | surfaces. In    |
|     |       | m to contact th | assure contact of  | addition,       |
|     |       | e inner contain | all inner          | including the   |
|     |       | er closure surf | container closure  | word \"all\"    |
|     |       | aces (when the  | surfaces (when the | clearly defines |
|     |       | unit is inverte | unit is inverted   | the             |
|     |       | d or thoroughly | or swirled) and    | requirement.    |
|     |       |  swirled) and p | permit visual      | Swirling the    |
|     |       | ermit visual de | detection of       | vial may not    |
|     |       | tection of micr | microbial          | coat all        |
|     |       | obial growth.\" | growth.\"          | surfaces, but   |
|     |       |                 |                    | inserting the   |
|     |       |                 |                    | word all makes  |
|     |       |                 |                    | it clear that   |
|     |       |                 |                    | all surfaces    |
|     |       |                 |                    | are to be       |
|     |       |                 |                    | coated,         |
|     |       |                 |                    | whatever the    |
|     |       |                 |                    | methodology     |
|     |       |                 |                    | used. Finally,  |
|     |       |                 |                    | the word        |
|     |       |                 |                    | \"thoroughly\"  |
|     |       |                 |                    | does not have a |
|     |       |                 |                    | clear           |
|     |       |                 |                    | operational     |
|     |       |                 |                    | definition, and |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | utility once    |
|     |       |                 |                    | the word        |
|     |       |                 |                    | \"all\" is      |
|     |       |                 |                    | inserted to     |
|     |       |                 |                    | provide the     |
|     |       |                 |                    | operational     |
|     |       |                 |                    | definition.     |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 87    | "Each           | "Each media-filled | To have         |
| 8.  | 7-878 | media-filled    | unit should be     | experience in   |
|     |       | unit should be  | examined for       | microbiological |
|     |       | examined for    | contamination by   | techniques is   |
|     |       | contamination   | personnel with     | not mandatory   |
|     |       | by personnel    | appropriate        | necessary for   |
|     |       | with            | education and      | the examination |
|     |       | appropriate     | training in        | of media-filled |
|     |       | education,      | microbiological    | units. This     |
|     |       | training, and   | techniques."       | term should be  |
|     |       | experience in   |                    | deleted.        |
|     |       | microbiological |                    |                 |
|     |       | techniques."    |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 4   | 89    | "If written     | "If written        | The footnote    |
| 9.  | 7-898 | procedures and  | procedures and     | should be       |
|     | and   | batch           | batch              | removed,        |
|     | foo   | documentation   | documentation are  | because         |
|     | tnote | are adequate,   | adequate, these    | obtained data   |
|     | 9     | these           | intervention units | would have no   |
|     |       | intervention    | do not need to be  | value, as it is |
|     |       | units do not    | incubated during   | not             |
|     |       | need to be      | media fills.       | representative  |
|     |       | incubated       |                    | of risks for    |
|     |       | during media    |                    | the actual      |
|     |       | fills.9";       |                    | product         |
|     |       |                 |                    |                 |
|     |       | "To assess      |                    |                 |
|     |       | contamination   |                    |                 |
|     |       | risk during     |                    |                 |
|     |       | initial aseptic |                    |                 |
|     |       | setup (before   |                    |                 |
|     |       | fill), valuable |                    |                 |
|     |       | information can |                    |                 |
|     |       | be obtained by  |                    |                 |
|     |       | incubating all  |                    |                 |
|     |       | such unites     |                    |                 |
|     |       | that may be     |                    |                 |
|     |       | normally        |                    |                 |
|     |       | removed."       |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 90    | \"Any decision  | \"Any decision to  | The phrase      |
| 0.  | 4-906 | to exclude such | exclude such       | \"fully         |
|     |       | incubated units | incubated units    | justified\"     |
|     |       | (i.e.,          | (i.e.,             | implies that    |
|     |       | nonintegral)    | nonintegral) from  | there are two   |
|     |       | from the final  | the final run      | levels of       |
|     |       | run tally       | tally should be    | justification,  |
|     |       | should be fully | justified and the  | regular         |
|     |       | justified and   | deviation          | justification   |
|     |       | the deviation   | explained in the   | and the more    |
|     |       | explained in    | media fill         | rigorous        |
|     |       | the media fill  | report.\"          | \"fully         |
|     |       | report.\"       |                    | justified.\"    |
|     |       |                 |                    | Nowhere in US   |
|     |       |                 |                    | GMP or FDA      |
|     |       |                 |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word \"fully\"  |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | justification   |
|     |       |                 |                    | at this point   |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"justified.\"  |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"fully\" be    |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 90    | \"If a          | \"If a correlation | The phrase      |
| 1.  | 6-908 | correlation     | emerges between    | \"thorough      |
|     |       | emerges between | difficult to       | investigation\" |
|     |       | difficult to    | detect damage and  | implies that    |
|     |       | detect damage   | microbial          | there are two   |
|     |       | and microbial   | contamination, an  | levels of       |
|     |       | contamination,  | investigation      | investigation,  |
|     |       | a thorough      | should be          | regular         |
|     |       | investigation   | conducted to       | investigation   |
|     |       | should be       | determine its      | and the more    |
|     |       | conducted to    | cause (see Section | rigorous and    |
|     |       | determine its   | VI.B).             | in-depth        |
|     |       | cause (see      |                    | \"thorough      |
|     |       | Section         |                    | i               |
|     |       | VI.B).\"        |                    | nvestigation.\" |
|     |       |                 |                    | Nowhere in US   |
|     |       |                 |                    | GMP or FDA      |
|     |       |                 |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word            |
|     |       |                 |                    | \"thorough\"    |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"i             |
|     |       |                 |                    | nvestigation.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"thorough\" be |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 91    | "Video          | delete             | This sentence   |
| 2.  | 6-917 | recording of    |                    | could indicate  |
|     |       | media fill has  |                    | that video      |
|     |       | been found to   |                    | recording is    |
|     |       | be useful in    |                    | mandatory. The  |
|     |       | identifying     |                    | identification  |
|     |       | personnel       |                    | of negative     |
|     |       | practices that  |                    | impact on the   |
|     |       | could           |                    | aseptic process |
|     |       | negatively      |                    | could also be   |
|     |       | impact the      |                    | covered by      |
|     |       | aseptic         |                    | other methods   |
|     |       | process."       |                    | (e.g., manual   |
|     |       |                 |                    | observation and |
|     |       |                 |                    | assessment by   |
|     |       |                 |                    | experienced     |
|     |       |                 |                    | personnel).     |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 93    | \"Any           | \"Contaminated     | The phrase      |
| 3.  | 6-937 | contaminated    | units should be    | \"fully         |
|     |       | unit should be  | considered as      | investigated\"  |
|     |       | considered as   | objectionable and  | implies that    |
|     |       | objectionable   | investigated. In   | there are two   |
|     |       | and fully       | the event of a     | levels of       |
|     |       | investigated.   | systemic failure,  | investigations, |
|     |       | The             | randomly selected  | regular         |
|     |       | microorganisms  | container should   | investigations  |
|     |       | should be       | be sampled for     | and the more    |
|     |       | identified to   | microorganism      | rigorous and    |
|     |       | species         | identification. If | in-depth \"full |
|     |       | level.\"        | fewer than 20      | i               |
|     |       |                 | container are      | nvestigation.\" |
|     |       |                 | contaminated, the  | Nowhere in US   |
|     |       |                 | microorganisms of  | GMP or FDA      |
|     |       |                 | each container     | guidance is the |
|     |       |                 | should be          | difference      |
|     |       |                 | identified to      | explained. The  |
|     |       |                 | species level.\"   | word \"fully\"  |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"              |
|     |       |                 |                    | investigated.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"fully\" be    |
|     |       |                 |                    | deleted. The    |
|     |       |                 |                    | implication of  |
|     |       |                 |                    | the first       |
|     |       |                 |                    | sentence is     |
|     |       |                 |                    | that every      |
|     |       |                 |                    | contaminated    |
|     |       |                 |                    | vial will be    |
|     |       |                 |                    | speciated.      |
|     |       |                 |                    | However, in the |
|     |       |                 |                    | event, however  |
|     |       |                 |                    | unlikely, of a  |
|     |       |                 |                    | system failure  |
|     |       |                 |                    | where many      |
|     |       |                 |                    | containers are  |
|     |       |                 |                    | contaminated,   |
|     |       |                 |                    | identification  |
|     |       |                 |                    | of              |
|     |       |                 |                    | microorganisms  |
|     |       |                 |                    | in each and     |
|     |       |                 |                    | every container |
|     |       |                 |                    | is a waste of   |
|     |       |                 |                    | resources       |
|     |       |                 |                    | better used to  |
|     |       |                 |                    | investigate and |
|     |       |                 |                    | correct the     |
|     |       |                 |                    | underlying      |
|     |       |                 |                    | problem.        |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 93    | \"In the case   | \"In the case of a | The phrase      |
| 4.  | 7-939 | of a media fill | media fill         | \"comprehensive |
|     |       | failure, a      | failure, an        | investigation\" |
|     |       | comprehensive   | investigation      | implies that    |
|     |       | investigation   | should be          | there are two   |
|     |       | should be       | conducted,         | levels of       |
|     |       | conducted,      | surveying all      | investigations, |
|     |       | surveying all   | possible causes of | regular         |
|     |       | possible causes | the                | investigations  |
|     |       | of the          | contamination.\"   | and the more    |
|     |       | c               |                    | rigorous and    |
|     |       | ontamination.\" |                    | in-depth        |
|     |       |                 |                    | \"comprehensive |
|     |       |                 |                    | in              |
|     |       |                 |                    | vestigations.\" |
|     |       |                 |                    | Nowhere in US   |
|     |       |                 |                    | GMP or FDA      |
|     |       |                 |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word            |
|     |       |                 |                    | \"              |
|     |       |                 |                    | comprehensive\" |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"i             |
|     |       |                 |                    | nvestigation.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"              |
|     |       |                 |                    | comprehensive\" |
|     |       |                 |                    | be deleted.     |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 94    | \"Recommended   | \"The target       | The suggested   |
| 5.  | 9-961 | criteria for    | should be zero     | criteria        |
|     |       | assessing state | contaminated       | provides for    |
|     |       | of aseptic line | units, but a       | harmonization   |
|     |       | control are as  | contamination rate | with the        |
|     |       | follows:        | less than 0.1%     | current         |
|     |       |                 | with 95%           | practice vast   |
|     |       | -   When        | confidence limits  | majority of     |
|     |       |     filling     | is acceptable. The | industry, as    |
|     |       |     fewer than  | manufacturer       | well as         |
|     |       |     5000 units, | should establish   | harmonization   |
|     |       |     no          | alert and action   | with the        |
|     |       |                 | limits based upon  | European GMPs.  |
|     |       |    contaminated | historical data of | Harmonization   |
|     |       |     units       | the firm, and any  | of requirements |
|     |       |     should be   | contamination      | at the earliest |
|     |       |     detected.   | should be          | possible moment |
|     |       |                 | investigated. In   | (such as within |
|     |       | ```{=html}      | particular: When   | this guidance)  |
|     |       | <!-- -->        | filling less than  | is desirable to |
|     |       | ```             | 4750 contains, no  | more quickly    |
|     |       | -   When        | contaminated units | reach to        |
|     |       |     filling     | should be          | overall         |
|     |       |     from 5,000  | detected. When     | harmonization   |
|     |       |     to 10,000   | filling from       | goals.          |
|     |       |     units:      | 4750 - 6300 units, |                 |
|     |       |                 | 1 contaminated     |                 |
|     |       | > \-- 1         | unit should result |                 |
|     |       | > contaminated  | in an              |                 |
|     |       | > unit should   | investigation,     |                 |
|     |       | > result in an  | including          |                 |
|     |       | >               | consideration of a |                 |
|     |       |  investigation, | repeat media fill. |                 |
|     |       | > including     | 2 contaminated     |                 |
|     |       | > consideration | units are          |                 |
|     |       | > of a repeat   | considered cause   |                 |
|     |       | > media fill.   | for revalidation,  |                 |
|     |       | >               | following          |                 |
|     |       | > \-- 2         | investigation. and |                 |
|     |       | > contaminated  | so forth for       |                 |
|     |       | > units are     | larger fills.\"    |                 |
|     |       | > considered    |                    |                 |
|     |       | > cause for     |                    |                 |
|     |       | > revalidation, |                    |                 |
|     |       | > following     |                    |                 |
|     |       | >               |                    |                 |
|     |       |  investigation. |                    |                 |
|     |       |                 |                    |                 |
|     |       | -   When        |                    |                 |
|     |       |     filling     |                    |                 |
|     |       |     more than   |                    |                 |
|     |       |     10,000      |                    |                 |
|     |       |     units:      |                    |                 |
|     |       |                 |                    |                 |
|     |       | > \-- 1         |                    |                 |
|     |       | > contaminated  |                    |                 |
|     |       | > unit should   |                    |                 |
|     |       | > result in an  |                    |                 |
|     |       | >               |                    |                 |
|     |       |  investigation. |                    |                 |
|     |       |                 |                    |                 |
|     |       | -   2           |                    |                 |
|     |       |                 |                    |                 |
|     |       |    contaminated |                    |                 |
|     |       |     units are   |                    |                 |
|     |       |     considered  |                    |                 |
|     |       |     cause for   |                    |                 |
|     |       |                 |                    |                 |
|     |       |   revalidation, |                    |                 |
|     |       |     following   |                    |                 |
|     |       |                 |                    |                 |
|     |       |  investigation. |                    |                 |
|     |       |     \"          |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 1008  | \"When          | \"When justified,  | The phrase      |
| 6.  | -1010 | sufficiently    | the effects of the | \"sufficiently  |
|     |       | justified, the  | product            | justified\"     |
|     |       | effects of the  | formulation on the | implies that    |
|     |       | product         | membrane\'s        | there are two   |
|     |       | formulation on  | integrity can be   | levels of       |
|     |       | the membrane\'s | assessed using an  | justification,  |
|     |       | integrity can   | appropriate        | regular         |
|     |       | be assessed     | alternate method"  | justification   |
|     |       | using an        |                    | and the more    |
|     |       | appropriate     |                    | rigorous        |
|     |       | alternate       |                    | \"sufficiently  |
|     |       | method.\"       |                    | justified.\"    |
|     |       |                 |                    | Nowhere in US   |
|     |       | .               |                    | GMP or FDA      |
|     |       |                 |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word            |
|     |       |                 |                    | \               |
|     |       |                 |                    | "sufficiently\" |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | justification   |
|     |       |                 |                    | at this point   |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"justified.\"  |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \               |
|     |       |                 |                    | "sufficiently\" |
|     |       |                 |                    | be deleted.     |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 1023  | \"Filter        | \"Filter           | There are three |
| 7.  | -1028 | validation      | validation         | different words |
|     |       | experiments,    | studies, including | used to         |
|     |       | including       | microbial          | describe the    |
|     |       | microbial       | challenges, need   | validation      |
|     |       | challenges,     | not be conducted   | activities in a |
|     |       | need not be     | in the actual      | short           |
|     |       | conducted in    | manufacturing      | paragraph, and  |
|     |       | the actual      | areas. However, it | it is not clear |
|     |       | manufacturing   | is essential that  | if these are    |
|     |       | areas. However, | laboratory studies | all different   |
|     |       | it is essential | simulate actual    | activities with |
|     |       | that laboratory | production         | different ends  |
|     |       | experiments     | conditions. The    | in mind, or     |
|     |       | simulate actual | specific type of   | merely          |
|     |       | production      | filter used in     | different words |
|     |       | conditions. The | commercial         | to describe the |
|     |       | specific type   | production should  | same activity.  |
|     |       | of filter used  | be evaluated in    | Since they do   |
|     |       | in commercial   | filter validation  | not appear to   |
|     |       | production      | studies. When the  | be defined      |
|     |       | should be       | more complex       | separately, it  |
|     |       | evaluated in    | filter validation  | is suggested    |
|     |       | filter          | studies go beyond  | that            |
|     |       | validation      | the capabilities   | \"studies,\"    |
|     |       | studies. When   | of the filter      | \"experiments\" |
|     |       | the more        | user, tests are    | and \"tests\"   |
|     |       | complex filter  | often conducted by | in this context |
|     |       | validation      | outside            | be all changed  |
|     |       | tests go beyond | laboratories or by | to a consistent |
|     |       | the             | filter             | term, such as   |
|     |       | capabilities of | manufacturers.\"   | \"studies\"     |
|     |       | the filter      |                    | chosen above,   |
|     |       | user, tests are |                    | for ease of     |
|     |       | often conducted |                    | reading and     |
|     |       | by outside      |                    | comprehension.  |
|     |       | laboratories or |                    |                 |
|     |       | by filter       |                    |                 |
|     |       | m               |                    |                 |
|     |       | anufacturers.\" |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 1117  | "The microbial  |                    | The term        |
| 8.  | -1118 | count and       |                    | "should be      |
|     |       | D-value of a    |                    | confirmed" in   |
|     |       | biological      |                    | relation to     |
|     |       | indicator       |                    | D-values should |
|     |       | should be       |                    | be described    |
|     |       | confirmed       |                    | more exactly.   |
|     |       | before a        |                    | Normally the    |
|     |       | validation      |                    | supplier        |
|     |       | study."         |                    | certifies the   |
|     |       |                 |                    | microbial count |
|     |       |                 |                    | and D-value. If |
|     |       |                 |                    | the D-value of  |
|     |       |                 |                    | a bioindicator  |
|     |       |                 |                    | must be         |
|     |       |                 |                    | confirmed       |
|     |       |                 |                    | before use,     |
|     |       |                 |                    | specific        |
|     |       |                 |                    | testing devices |
|     |       |                 |                    | are needed      |
|     |       |                 |                    | (this is not a  |
|     |       |                 |                    | current GMP     |
|     |       |                 |                    | requirement).   |
+-----+-------+-----------------+--------------------+-----------------+
| 5   | 1152  | "The monitoring | delete             | Critical        |
| 9.  | -1154 | program should  |                    | surface         |
|     |       | cover all       |                    | monitoring is   |
|     |       | production      |                    | not advisable   |
|     |       | shifts and      |                    | because these   |
|     |       | include air,    |                    | surfaces are    |
|     |       | floors, walls,  |                    | sterilized      |
|     |       | and equipment   |                    | using validated |
|     |       | surfaces,       |                    | processes.      |
|     |       | including the   |                    | Further the     |
|     |       | critical        |                    | monitoring of   |
|     |       | surfaces that   |                    | floors gives no |
|     |       | come in contact |                    | meaningful      |
|     |       | with the        |                    | information     |
|     |       | product,        |                    | about aseptic   |
|     |       | container, and  |                    | processing. The |
|     |       | closures."      |                    | purpose of      |
|     |       |                 |                    | environmental   |
|     |       |                 |                    | monitoring      |
|     |       |                 |                    | should be to    |
|     |       |                 |                    | assess the      |
|     |       |                 |                    | conditions      |
|     |       |                 |                    | around the      |
|     |       |                 |                    | critical        |
|     |       |                 |                    | filling         |
|     |       |                 |                    | operation and   |
|     |       |                 |                    | adjacent        |
|     |       |                 |                    | support areas.  |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1158  | \"Sampling size | \"Sampling size    | The wording     |
| 0.  | -1160 | should be       | should be          | "sufficient to  |
|     |       | sufficient to   | sufficient to      | optimize        |
|     |       | optimize        | optimize detection | detection" is   |
|     |       | detection of    | of environmental   | vague and       |
|     |       | environmental   | contaminants at    | should be       |
|     |       | contaminants at | levels that might  | explained       |
|     |       | levels that     | be expected in a   | further or      |
|     |       | might be        | given clean area.  | defined.        |
|     |       | expected in a   | For example a      |                 |
|     |       | given clean     | sampling size of   |                 |
|     |       | area.\"         | 25 cm² for class A |                 |
|     |       |                 | / class 100 / ISO  |                 |
|     |       |                 | 5 areas would be   |                 |
|     |       |                 | considered as      |                 |
|     |       |                 | typical.\"         |                 |
|     |       |                 |                    |                 |
|     |       |                 |                    |                 |
|     |       |                 |                    |                 |
|     |       |                 | Add example:       |                 |
|     |       |                 | \"Sampling size    |                 |
|     |       |                 | should be          |                 |
|     |       |                 | sufficient to      |                 |
|     |       |                 | optimize detection |                 |
|     |       |                 | of environmental   |                 |
|     |       |                 | contaminants at    |                 |
|     |       |                 | levels that might  |                 |
|     |       |                 | be expected in a   |                 |
|     |       |                 | given clean area.  |                 |
|     |       |                 | For example a      |                 |
|     |       |                 | sampling size of   |                 |
|     |       |                 | 25 cm² for class A |                 |
|     |       |                 | / class 100 / ISO  |                 |
|     |       |                 | 5 areas would be   |                 |
|     |       |                 | typical and        |                 |
|     |       |                 | sufficient.\"      |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1170  | "Critical       | delete             | Critical        |
| 1.  | -1171 | surface         |                    | surface         |
|     |       | sampling should |                    | monitoring is   |
|     |       | be performed at |                    | not advisable   |
|     |       | the conclusion  |                    | because these   |
|     |       | of the aseptic  |                    | surfaces are    |
|     |       | processing      |                    | sterilized      |
|     |       | operation to    |                    | using validated |
|     |       | avoid direct    |                    | processes.      |
|     |       | contact with    |                    | Further, the    |
|     |       | sterile         |                    | monitoring of   |
|     |       | surfaces during |                    | floors gives no |
|     |       | processing."    |                    | meaningful      |
|     |       |                 |                    | information     |
|     |       |                 |                    | about aseptic   |
|     |       |                 |                    | processing. The |
|     |       |                 |                    | purpose of      |
|     |       |                 |                    | environmental   |
|     |       |                 |                    | monitoring      |
|     |       |                 |                    | should be to    |
|     |       |                 |                    | assess the      |
|     |       |                 |                    | conditions      |
|     |       |                 |                    | around the      |
|     |       |                 |                    | critical        |
|     |       |                 |                    | filling         |
|     |       |                 |                    | operation and   |
|     |       |                 |                    | adjacent        |
|     |       |                 |                    | support areas.  |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1178  | "Because of the |                    | The matter and  |
| 2.  | -1180 | likelihood of   |                    | its             |
|     |       | false           |                    | implementation  |
|     |       | negatives,      |                    | of the term     |
|     |       | consecutive     |                    | "Increased      |
|     |       | growth results  |                    | incidence of    |
|     |       | are only one    |                    | contamination   |
|     |       | type of adverse |                    | over a given    |
|     |       | trend.          |                    | period" should  |
|     |       | Increased       |                    | be described.   |
|     |       | incidence of    |                    |                 |
|     |       | contamination   |                    |                 |
|     |       | over a given    |                    |                 |
|     |       | period is an    |                    |                 |
|     |       | equal or more   |                    |                 |
|     |       | significant     |                    |                 |
|     |       | trend to be     |                    |                 |
|     |       | tracked."       |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1189  | \"Critical      | Delete             | This sentence   |
| 3.  |       | surfaces that   |                    | is in the       |
|     |       | come in contact |                    | environmental   |
|     |       | with the        |                    | monitoring      |
|     |       | sterile product |                    | portion of the  |
|     |       | should be       |                    | guidance. It    |
|     |       | sterile.\"      |                    | provides no     |
|     |       |                 |                    | guidance for    |
|     |       |                 |                    | environmental   |
|     |       |                 |                    | monitoring, and |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that it be      |
|     |       |                 |                    | eliminated from |
|     |       |                 |                    | this section to |
|     |       |                 |                    | prevent         |
|     |       |                 |                    | confusion.      |
|     |       |                 |                    | There is no     |
|     |       |                 |                    | environmental   |
|     |       |                 |                    | monitoring that |
|     |       |                 |                    | can show or     |
|     |       |                 |                    | prove           |
|     |       |                 |                    | sterility, and  |
|     |       |                 |                    | it is not       |
|     |       |                 |                    | normally        |
|     |       |                 |                    | feasible to     |
|     |       |                 |                    | sample the      |
|     |       |                 |                    | product contact |
|     |       |                 |                    | surfaces in an  |
|     |       |                 |                    | aseptic filling |
|     |       |                 |                    | area, which are |
|     |       |                 |                    | the interior of |
|     |       |                 |                    | a vessel, the   |
|     |       |                 |                    | hoses, the      |
|     |       |                 |                    | vials and       |
|     |       |                 |                    | filling         |
|     |       |                 |                    | needles.        |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1197  | \"One should    | \"One should also  | Alert limits    |
| 4.  | -1199 | also consider   | consider           | should be based |
|     |       | environmental   | environmental      | on historical   |
|     |       | monitoring data | monitoring data    | data and action |
|     |       | from historical | from historical    | limits could be |
|     |       | databases,      | databases, media   | kept at         |
|     |       | media fills,    | fills, clean room  | guideline       |
|     |       | cleanroom       | qualification and  | limits          |
|     |       | qualification   | sanitization       | corresponding   |
|     |       | and             | studies, in        | to a defined    |
|     |       | sanitization    | developing         | clean room      |
|     |       | studies, in     | monitoring alert   | classification. |
|     |       | developing      | levels.\"          | Violation of    |
|     |       | monitoring      |                    | alert limits    |
|     |       | levels"         |                    | would initiate  |
|     |       |                 |                    | an evaluation   |
|     |       |                 |                    | of potential    |
|     |       |                 |                    | risks to the    |
|     |       |                 |                    | sterility       |
|     |       |                 |                    | assurance and   |
|     |       |                 |                    | increase the    |
|     |       |                 |                    | alertness of    |
|     |       |                 |                    | the responsible |
|     |       |                 |                    | departments for |
|     |       |                 |                    | processes in    |
|     |       |                 |                    | the aseptic     |
|     |       |                 |                    | filling area.   |
|     |       |                 |                    | This two limit  |
|     |       |                 |                    | approach is     |
|     |       |                 |                    | practical when  |
|     |       |                 |                    | the difference  |
|     |       |                 |                    | between alert   |
|     |       |                 |                    | and guideline   |
|     |       |                 |                    | limit is too    |
|     |       |                 |                    | narrow to have  |
|     |       |                 |                    | a third         |
|     |       |                 |                    | statistically   |
|     |       |                 |                    | significant     |
|     |       |                 |                    | limit, the      |
|     |       |                 |                    | action limit.   |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1205  | "Averaging of   | delete             | As averaging    |
| 5.  |       | results can     |                    | results is a    |
|     |       | mask            |                    | recommendation  |
|     |       | unacceptable    |                    | of EU GMP Annex |
|     |       | localized       |                    | 1.              |
|     |       | conditions."    |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1212  | "Trend reports  |                    | This            |
| 6.  | -1215 | should include  |                    | requirement     |
|     |       | data generated  |                    | means a radical |
|     |       | by location,    |                    | new approach.   |
|     |       | shift, lot,     |                    | The described   |
|     |       | room, operator, |                    | trending        |
|     |       | or other search |                    | criteria and    |
|     |       | parameters. The |                    | frequency       |
|     |       | quality control |                    | suggests the    |
|     |       | unit should be  |                    | use of a        |
|     |       | responsible for |                    | high-level      |
|     |       | producing       |                    | trending        |
|     |       | specialized     |                    | program.        |
|     |       | data reports    |                    | Therefore, the  |
|     |       | (e.g., a search |                    | specificity of  |
|     |       | on a particular |                    | reporting       |
|     |       | isolate over a  |                    | requirements    |
|     |       | year period)    |                    | should be       |
|     |       | with the goal   |                    | reduced.        |
|     |       | of              |                    |                 |
|     |       | investigating   |                    |                 |
|     |       | results beyond  |                    |                 |
|     |       | established     |                    |                 |
|     |       | levels and      |                    |                 |
|     |       | identifying any |                    |                 |
|     |       | appropriate     |                    |                 |
|     |       | follow-up       |                    |                 |
|     |       | actions."       |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1225  | "The            | delete             | Samples before  |
| 7.  | -1227 | effectiveness   |                    | sanitization    |
|     |       | of these        |                    | are normally    |
|     |       | sanitization    |                    | not taken.      |
|     |       | procedures      |                    |                 |
|     |       | should be       |                    |                 |
|     |       | measured by     |                    |                 |
|     |       | their ability   |                    |                 |
|     |       | to ensure that  |                    |                 |
|     |       | potential       |                    |                 |
|     |       | contaminants    |                    |                 |
|     |       | are adequately  |                    |                 |
|     |       | removed from    |                    |                 |
|     |       | surfaces (i.e., |                    |                 |
|     |       | via obtaining   |                    |                 |
|     |       | samples before  |                    |                 |
|     |       | and after       |                    |                 |
|     |       | sanitization)." |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1226  | \"Monitoring    | \"Monitoring the   | The phrase      |
| 8.  | -1230 | the             | microbiological    | \"more thorough |
|     |       | microbiological | quality of the     | investigation\" |
|     |       | quality of the  | environment should | implies that    |
|     |       | environment     | include both alert | there are two   |
|     |       | should include  | and action levels. | levels of       |
|     |       | both alert and  | Each individual    | investigation,  |
|     |       | action levels.  | sample result      | regular         |
|     |       | Each individual | should be          | investigation   |
|     |       | sample result   | evaluated for its  | and the more    |
|     |       | should be       | significance by    | rigorous and    |
|     |       | evaluated for   | comparison to the  | in-depth \"more |
|     |       | its             | alert or action    | thorough        |
|     |       | significance by | levels. Averaging  | i               |
|     |       | comparison to   | of results can     | nvestigation.\" |
|     |       | the alert or    | mask unacceptable  | Nowhere in US   |
|     |       | action levels.  | localized          | GMP or FDA      |
|     |       | Averaging of    | conditions. A      | guidance is the |
|     |       | results can     | result at the      | difference      |
|     |       | mask            | alert level urges  | explained. The  |
|     |       | unacceptable    | attention to the   | first three     |
|     |       | localized       | approaching action | sentences of    |
|     |       | conditions. A   | conditions. A      | this paragraph  |
|     |       | result at the   | result at the      | discuss the     |
|     |       | alert level     | action level       | routine         |
|     |       | urges attention | should prompt an   | evaluation of   |
|     |       | to the          | investigation.\"   | data against    |
|     |       | approaching     |                    | action levels.  |
|     |       | action          |                    | This routine    |
|     |       | conditions. A   |                    | evaluation is   |
|     |       | result at the   |                    | not and should  |
|     |       | action level    |                    | not be          |
|     |       | should prompt a |                    | considered an   |
|     |       | more thorough   |                    | investigation,  |
|     |       | i               |                    | but merely part |
|     |       | nvestigation.\" |                    | of the routine  |
|     |       |                 |                    | monitoring and  |
|     |       |                 |                    | assessment of   |
|     |       |                 |                    | the             |
|     |       |                 |                    | environmental   |
|     |       |                 |                    | monitoring. The |
|     |       |                 |                    | words \"more    |
|     |       |                 |                    | thorough\"      |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | investigations, |
|     |       |                 |                    | or              |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | in this         |
|     |       |                 |                    | particular case |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"i             |
|     |       |                 |                    | nvestigation.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the words  |
|     |       |                 |                    | \"more          |
|     |       |                 |                    | thorough\" be   |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 6   | 1243  | \"Written       | \"Written          | The phrase      |
| 9.  | -1244 | procedures      | procedures should  | \"most          |
|     |       | should define   | define the system  | responsible     |
|     |       | the system      | whereby the        | managers\" is   |
|     |       | whereby the     | responsible        | not defined and |
|     |       | most            | managers with the  | is unclear. It  |
|     |       | responsible     | authority and      | may refer to    |
|     |       | managers are    | responsibility to  | variously the   |
|     |       | regularly       | make improvements  | departmental    |
|     |       | informed and    | are regularly      | management      |
|     |       | updated on      | informed and       | within the      |
|     |       | trends and      | updated on trends  | Quality Control |
|     |       | in              | and                | Unit, the most  |
|     |       | vestigations.\" | investigations.\"  | senior          |
|     |       |                 |                    | management      |
|     |       |                 |                    | official at the |
|     |       |                 |                    | site, or even   |
|     |       |                 |                    | the CEO of the  |
|     |       |                 |                    | firm. The lack  |
|     |       |                 |                    | of definition   |
|     |       |                 |                    | would lead to   |
|     |       |                 |                    | unnecessary     |
|     |       |                 |                    | citations for   |
|     |       |                 |                    | not providing   |
|     |       |                 |                    | routine trend   |
|     |       |                 |                    | analysis        |
|     |       |                 |                    | reports (which  |
|     |       |                 |                    | may show        |
|     |       |                 |                    | improvement) to |
|     |       |                 |                    | CEOs. To        |
|     |       |                 |                    | clarify this    |
|     |       |                 |                    | sentence, it is |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the word        |
|     |       |                 |                    | \"most\" be     |
|     |       |                 |                    | deleted, and    |
|     |       |                 |                    | the responsible |
|     |       |                 |                    | managers is     |
|     |       |                 |                    | further         |
|     |       |                 |                    | clarified by    |
|     |       |                 |                    | adding \" with  |
|     |       |                 |                    | the authority   |
|     |       |                 |                    | and             |
|     |       |                 |                    | responsibility  |
|     |       |                 |                    | to make         |
|     |       |                 |                    | improvements.\" |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1247  | "Environmental  | "Environmental     | The             |
| 0.  | -1249 | monitoring      | monitoring should  | environmental   |
|     |       | should include  | include testing of | monitoring      |
|     |       | testing of      | various surfaces   | should          |
|     |       | various         | for                | concentrate on  |
|     |       | surfaces for    | microbiological    | surfaces with   |
|     |       | microbiological | quality. For       | realistic risk  |
|     |       | quality. For    | example, product   | to product, so  |
|     |       | example,        | contact surfaces,  | It should not   |
|     |       | product contact | and equipment      | be necessary to |
|     |       | surfaces,       | should be tested   | test ceilings   |
|     |       | floors, walls,  | on a regular       | and floors.     |
|     |       | ceilings, and   | basis."            |                 |
|     |       | equipment       |                    |                 |
|     |       | should be       |                    |                 |
|     |       | tested on a     |                    |                 |
|     |       | regular basis." |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1257  | \"Therefore a   | \"Therefore a      | For             |
| 1.  | -1259 | sound           | sound sanitization | consistency,    |
|     |       | disinfectant    | program also       | since this      |
|     |       | program also    | includes a         | section is      |
|     |       | includes a      | sporicidal agent,  | about           |
|     |       | sporicidal      | used according to  | sanitization,   |
|     |       | agent, used     | a written schedule | it is suggested |
|     |       | according to a  | and when           | that the word   |
|     |       | written         | environmental data | \               |
|     |       | schedule and    | suggest the        | "disinfectant\" |
|     |       | when            | presence of        | be changed to   |
|     |       | environmental   | sporeforming       | \"              |
|     |       | data suggest    | organisms.\"       | sanitization.\" |
|     |       | the presence of |                    | If not          |
|     |       | sporeforming    |                    | \"              |
|     |       | organisms.\"    |                    | sanitization\", |
|     |       |                 |                    | then            |
|     |       |                 |                    | \"disinfection  |
|     |       |                 |                    | would be a      |
|     |       |                 |                    | better choice   |
|     |       |                 |                    | of words.       |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1273  | "As part of     | delete             | Generally the   |
| 2.  | -1275 | methods         |                    | procedure of    |
|     |       | validation, the |                    | methods         |
|     |       | quality control |                    | validation in   |
|     |       | laboratory      |                    | conjunction     |
|     |       | should evaluate |                    | with microbial  |
|     |       | what media      |                    | methods is not  |
|     |       | exposure        |                    | clear. The      |
|     |       | conditions      |                    | required method |
|     |       | optimize        |                    | normally cannot |
|     |       | recovery of low |                    | be validated    |
|     |       | levels of       |                    | respectively it |
|     |       | environmental   |                    | would be very   |
|     |       | isolates."      |                    | complex and     |
|     |       |                 |                    | risky.          |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1297  | "Rapid          | "Rapid genotypic   | As other        |
| 3.  | -1298 | genotypic       | methods may be     | techniques are  |
|     |       | methods are     | used for purposes  | adequate for    |
|     |       | recommended for | of identification. | the purposes of |
|     |       | purposes of     | These methods have | identification, |
|     |       | identification, | been shown to be   | these binding   |
|     |       | as these        | more accurate and  | recommendations |
|     |       | methods have    | precise than       | should be       |
|     |       | been shown to   | biochemical and    | generalized.    |
|     |       | be more         | phenotypic         |                 |
|     |       | accurate and    | techniques."       |                 |
|     |       | precise than    |                    |                 |
|     |       | biochemical and |                    |                 |
|     |       | phenotypic      |                    |                 |
|     |       | techniques."    |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1310  | \"Monitoring of | \"Monitoring of    | The implication |
| 4.  | -1312 | critical and    | critical areas as  | of \"routine    |
|     |       | immediately     | well as personnel  | i               |
|     |       | surrounding     | operating within   | dentification\" |
|     |       | clean areas as  | the critical areas | implies that    |
|     |       | well as         | should include     | all colonies on |
|     |       | personnel       | routine            | all             |
|     |       | should include  | identification of  | environmental   |
|     |       | routine         | microorganisms to  | monitoring      |
|     |       | identification  | the species (or,   | samples should  |
|     |       | of              | where appropriate, | be identified,  |
|     |       | microorganisms  | genus) level. For  | including those |
|     |       | to the species  | clean areas,       | EM from clean   |
|     |       | (or, where      | morphologically    | areas. The      |
|     |       | appropriate,    | representative     | suggested       |
|     |       | genus) level.\" | environmental      | wording changes |
|     |       |                 | monitoring         | are in          |
|     |       |                 | isolates should be | conformance     |
|     |       |                 | identified to      | with the PDA\'s |
|     |       |                 | species level, if  | \"Points to     |
|     |       |                 | possible.\"        | Consider for    |
|     |       |                 |                    | Aseptic         |
|     |       |                 |                    | Processing\" in |
|     |       |                 |                    | [PDA Journal of |
|     |       |                 |                    | Pharmaceutical  |
|     |       |                 |                    | Science and     |
|     |       |                 |                    | Technolog       |
|     |       |                 |                    | y]{.underline}, |
|     |       |                 |                    | Volume 57,      |
|     |       |                 |                    | number 2, 2003  |
|     |       |                 |                    | Supplement,     |
|     |       |                 |                    | page 25.        |
|     |       |                 |                    |                 |
|     |       |                 |                    | However, if the |
|     |       |                 |                    | phrase          |
|     |       |                 |                    | \"immediately   |
|     |       |                 |                    | surrounding     |
|     |       |                 |                    | clean areas\"   |
|     |       |                 |                    | is meant to be  |
|     |       |                 |                    | the equivalent  |
|     |       |                 |                    | of the European |
|     |       |                 |                    | GMPs \"Class    |
|     |       |                 |                    | B\" area, then  |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | the wording be  |
|     |       |                 |                    | changed to      |
|     |       |                 |                    | reflect this    |
|     |       |                 |                    | meaning. In     |
|     |       |                 |                    | this case,      |
|     |       |                 |                    | perhaps the     |
|     |       |                 |                    | sentence could  |
|     |       |                 |                    | read:           |
|     |       |                 |                    | \"Monitoring of |
|     |       |                 |                    | critical and    |
|     |       |                 |                    | immediately     |
|     |       |                 |                    | surrounding     |
|     |       |                 |                    | clean areas     |
|     |       |                 |                    | (e.g. those     |
|     |       |                 |                    | areas within    |
|     |       |                 |                    | the same room   |
|     |       |                 |                    | as the aseptic  |
|     |       |                 |                    | filling line,   |
|     |       |                 |                    | but outside the |
|     |       |                 |                    | Class 100       |
|     |       |                 |                    | curtained area) |
|     |       |                 |                    | as well as      |
|     |       |                 |                    | personnel       |
|     |       |                 |                    | should include  |
|     |       |                 |                    | routine         |
|     |       |                 |                    | identification  |
|     |       |                 |                    | of              |
|     |       |                 |                    | microorganisms  |
|     |       |                 |                    | to the species  |
|     |       |                 |                    | (or, where      |
|     |       |                 |                    | appropriate,    |
|     |       |                 |                    | genus) level.\" |
|     |       |                 |                    | As it stands,   |
|     |       |                 |                    | EM isolates     |
|     |       |                 |                    | from a Class    |
|     |       |                 |                    | 100,000 room    |
|     |       |                 |                    | next to the     |
|     |       |                 |                    | aseptic filling |
|     |       |                 |                    | suite would be  |
|     |       |                 |                    | required to be  |
|     |       |                 |                    | 100%            |
|     |       |                 |                    | identified.     |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1395  | "The batch      | delete             | Processing      |
| 5.  | -1396 | processing      |                    | interventions   |
|     |       | circumstances   |                    | or excursions   |
|     |       | -- samples      |                    | are covered by  |
|     |       | should be taken |                    | media fill.     |
|     |       | in conjunction  |                    | This sentence   |
|     |       | with processing |                    | should be       |
|     |       | interventions   |                    | deleted,        |
|     |       | or excursions." |                    | because during  |
|     |       |                 |                    | routine         |
|     |       |                 |                    | sterility       |
|     |       |                 |                    | sampling,       |
|     |       |                 |                    | potentially     |
|     |       |                 |                    | contaminated    |
|     |       |                 |                    | units are       |
|     |       |                 |                    | removed.        |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1225  | "Nucleic        | "Nucleic           | As other        |
| 6.  | -1226 | acid-based      | acid-based methods | techniques are  |
|     |       | methods are     | may be used for    | adequate for    |
|     |       | recommended for | microbial          | the purposes of |
|     |       | microbial       | identification     | identification, |
|     |       | identification  | purposes."         | these binding   |
|     |       | purposes."      |                    | recommendations |
|     |       |                 |                    | should be       |
|     |       |                 |                    | generalized.    |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1226  | \"Because of    | \"Because of the   | The phrase      |
| 7.  | -1227 | the limited     | limited            | \"thoroughly    |
|     |       | sensitivity of  | sensitivity of the | investigated\"  |
|     |       | the test, any   | test, any positive | implies that    |
|     |       | positive result | result is          | there are two   |
|     |       | is considered a | considered a       | levels of       |
|     |       | serious CGMP    | serious CGMP issue | investigations, |
|     |       | issue that      | that should be     | regular         |
|     |       | should be       | investigated.\"    | investigations  |
|     |       | thoroughly      |                    | and the more    |
|     |       | investigated.\" |                    | rigorous and    |
|     |       |                 |                    | in-depth        |
|     |       |                 |                    | \"thorough      |
|     |       |                 |                    | in              |
|     |       |                 |                    | vestigations.\" |
|     |       |                 |                    | Nowhere in US   |
|     |       |                 |                    | GMP or FDA      |
|     |       |                 |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word            |
|     |       |                 |                    | \"thoroughly\"  |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"              |
|     |       |                 |                    | investigated.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"thoroughly\"  |
|     |       |                 |                    | be deleted.     |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1441  | "A sterility    |                    | The term        |
| 8.  | -1443 | positive result |                    | "investigated   |
|     |       | can be viewed   |                    | globally"       |
|     |       | as indicative   |                    | should be       |
|     |       | of production   |                    | defined.        |
|     |       | or laboratory   |                    |                 |
|     |       | problems and    |                    |                 |
|     |       | should be       |                    |                 |
|     |       | investigated    |                    |                 |
|     |       | globally since  |                    |                 |
|     |       | such problems   |                    |                 |
|     |       | often can       |                    |                 |
|     |       | extend beyond a |                    |                 |
|     |       | single batch."  |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 7   | 1444  | \"After         | \"After            | The phrase      |
| 9.  | -1446 | considering all | considering all    | \"comprehensive |
|     |       | relevant        | relevant factors   | written         |
|     |       | factors         | concerning the     | investigation\" |
|     |       | concerning the  | manufacture of the | implies that    |
|     |       | manufacture of  | product and        | there are two   |
|     |       | the product and | testing of the     | levels of       |
|     |       | testing of the  | samples, the       | investigations, |
|     |       | samples, the    | investigation      | regular         |
|     |       | comprehensive   | should include     | investigations  |
|     |       | written         | specific           | and the more    |
|     |       | investigation   | conclusions and    | rigorous and    |
|     |       | should include  | identify           | in-depth        |
|     |       | specific        | corrective         | \"comprehensive |
|     |       | conclusions and | actions.\"         | in              |
|     |       | identify        |                    | vestigations.\" |
|     |       | corrective      |                    | Nowhere in US   |
|     |       | actions.\"      |                    | GMP or FDA      |
|     |       |                 |                    | guidance is the |
|     |       |                 |                    | difference      |
|     |       |                 |                    | explained. The  |
|     |       |                 |                    | word            |
|     |       |                 |                    | \"              |
|     |       |                 |                    | comprehensive\" |
|     |       |                 |                    | provides no     |
|     |       |                 |                    | more guidance   |
|     |       |                 |                    | as to what is   |
|     |       |                 |                    | required for    |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | than does the   |
|     |       |                 |                    | single word     |
|     |       |                 |                    | \"i             |
|     |       |                 |                    | nvestigation.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"              |
|     |       |                 |                    | comprehensive\" |
|     |       |                 |                    | be deleted. In  |
|     |       |                 |                    | addition, the   |
|     |       |                 |                    | GMP requirement |
|     |       |                 |                    | is that         |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | must be in      |
|     |       |                 |                    | written form.   |
|     |       |                 |                    | Specifying      |
|     |       |                 |                    | \"written\" in  |
|     |       |                 |                    | one case but    |
|     |       |                 |                    | not in the      |
|     |       |                 |                    | others implies  |
|     |       |                 |                    | that some       |
|     |       |                 |                    | investigations  |
|     |       |                 |                    | may not need to |
|     |       |                 |                    | be written.     |
|     |       |                 |                    | Therefore it is |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the word        |
|     |       |                 |                    | \"written\"     |
|     |       |                 |                    | also be         |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1484  | \"Where a       | Where a laboratory | The phrase      |
| 0.  | -1489 | laboratory has  | has a good track   | \"thoroughly    |
|     |       | a good track    | record with        | investigated\"  |
|     |       | record with     | respect to errors, | implies that    |
|     |       | respect to      | this history can   | there are two   |
|     |       | errors, this    | help remove the    | levels of       |
|     |       | history can     | lab as a source of | investigations, |
|     |       | help remove the | contamination      | regular         |
|     |       | lab as a source | since chances are  | investigations  |
|     |       | of              | higher that the    | and the more    |
|     |       | contamination   | contamination      | rigorous and    |
|     |       | since chances   | arose from         | in-depth        |
|     |       | are higher that | production.        | \"thorough      |
|     |       | the             | However, the       | in              |
|     |       | contamination   | converse is not    | vestigations.\" |
|     |       | arose from      | true.              | Nowhere in US   |
|     |       | production.     | Specifically,      | GMP or FDA      |
|     |       | However, the    | where a laboratory | guidance is the |
|     |       | converse is not | has a poor track   | difference      |
|     |       | true.           | record, firms      | explained. The  |
|     |       | Specifically,   | should not assume  | word            |
|     |       | where a         | that the           | \"thoroughly\"  |
|     |       | laboratory has  | contamination is   | provides no     |
|     |       | a poor track    | automatically more | more guidance   |
|     |       | record, firms   | attributable to    | as to what is   |
|     |       | should not      | the laboratory and | required for    |
|     |       | assume that the | consequently       | investigations  |
|     |       | contamination   | overlook a genuine | than does the   |
|     |       | is              | production         | single word     |
|     |       | automatically   | problem.           | \"              |
|     |       | more            | Accordingly, all   | investigated.\" |
|     |       | attributable to | sterility          | For this reason |
|     |       | the laboratory  | positives should   | it is suggested |
|     |       | and             | be investigated.   | that the word   |
|     |       | consequently    |                    | \"thoroughly\"  |
|     |       | overlook a      |                    | be deleted.     |
|     |       | genuine         |                    |                 |
|     |       | production      |                    |                 |
|     |       | problem.        |                    |                 |
|     |       | Accordingly,    |                    |                 |
|     |       | all sterility   |                    |                 |
|     |       | positives       |                    |                 |
|     |       | should be       |                    |                 |
|     |       | thoroughly      |                    |                 |
|     |       | investigated.\" |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1609  | \"In most sound | "In most sound     | The term        |
| 1.  | -1610 | designs, air    | designs, air       | \"critical      |
|     |       | showers over    | showers over the   | zone\" is       |
|     |       | the critical    | critical area      | apparently used |
|     |       | zone once, and  | once, and then is  | as a synonym to |
|     |       | then is         | systematically     | \"critical      |
|     |       | systematically  | exhausted.\"       | area\" as       |
|     |       | exhausted.\"    |                    | \"clean zone\"  |
|     |       |                 |                    | is              |
|     |       |                 |                    | c               |
|     |       |                 |                    | ross-referenced |
|     |       |                 |                    | to \"clean      |
|     |       |                 |                    | area.\" As      |
|     |       |                 |                    | such, for       |
|     |       |                 |                    | consistency and |
|     |       |                 |                    | clarity, it is  |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | all such        |
|     |       |                 |                    | references be   |
|     |       |                 |                    | changed from    |
|     |       |                 |                    | \"critical      |
|     |       |                 |                    | zone\" to       |
|     |       |                 |                    | \"critical      |
|     |       |                 |                    | area.\"         |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1683  | \"A             | \"A                | The phrase      |
| 2.  | -1686 | decontamination | decontamination    | \"thorough      |
|     |       | method should   | method should be   | determination\" |
|     |       | be developed    | developed that     | implies that    |
|     |       | that renders    | renders the inner  | there are two   |
|     |       | the inner       | surfaces of the    | levels of       |
|     |       | surfaces of the | isolator free of   | determination,  |
|     |       | isolator free   | viable             | regular         |
|     |       | of viable       | microorganisms.    | determination   |
|     |       | microorganisms. | Decontamination    | and the more    |
|     |       | Decontamination | can be             | rigorous and    |
|     |       | can be          | accomplished using | in-depth        |
|     |       | accomplished    | a number of        | \"thorough      |
|     |       | using a number  | vaporized agents,  | d               |
|     |       | of vaporized    | although these     | etermination.\" |
|     |       | agents,         | agents possess     | Nowhere in US   |
|     |       | although these  | limited capability | GMP or FDA      |
|     |       | agents possess  | to penetrate       | guidance is the |
|     |       | limited         | obstructed or      | difference      |
|     |       | capability to   | covered surfaces.  | explained. The  |
|     |       | penetrate       | Process            | word            |
|     |       | obstructed or   | development and    | \"thorough\"    |
|     |       | covered         | validation studies | provides no     |
|     |       | surfaces.       | should include     | more guidance   |
|     |       | Process         | determination of   | as to what is   |
|     |       | development and | cycle              | required for a  |
|     |       | validation      | capability.\"      | determination   |
|     |       | studies should  |                    | of cycle        |
|     |       | include a       |                    | capability than |
|     |       | thorough        |                    | does the single |
|     |       | determination   |                    | word            |
|     |       | of cycle        |                    | \"d             |
|     |       | capability.\"   |                    | etermination.\" |
|     |       |                 |                    | For this reason |
|     |       |                 |                    | it is suggested |
|     |       |                 |                    | that the word   |
|     |       |                 |                    | \"thorough\" be |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | page  | \"If the        | \"Firms should     | The proposed    |
| 3.  | 48,   | various         | include evaluation | wording         |
|     | foo   | isolator        | of isolator        | clarifies the   |
|     | tnote | materials are   | material and       | concern that    |
|     |       | thoroughly      | porosity which may | the             |
|     |       | evaluated       | make the           | decontamination |
|     |       | during cycle    | decontamination    | of different    |
|     |       | development, a  | more difficult     | materials may   |
|     |       | firm might      | during the         | be more         |
|     |       | consider        | quantified BI      | difficult due   |
|     |       | placing more    | challenge of       | to their        |
|     |       | focus on        | isolator           | porosity or     |
|     |       | material        | decontamination    | other           |
|     |       | texture and     | efficacy.          | c               |
|     |       | porosity.\"     |                    | haracteristics. |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1777  | \"In addition,  | \"In addition, any | Elsewhere in    |
| 4.  | -1778 | any other       | other surface with | the guidance,   |
|     |       | surface with    | the potential to   | for instance,   |
|     |       | the potential   | contaminate the    | in line 552     |
|     |       | to contaminate  | sterile product    | where           |
|     |       | the sterile     | should be          | containers and  |
|     |       | product should  | sterilized.\"      | closures are    |
|     |       | be sterile.\"   |                    | discussed, the  |
|     |       |                 |                    | term sterilized |
|     |       |                 |                    | is used. For    |
|     |       |                 |                    | consistency and |
|     |       |                 |                    | clarity, it is  |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the term        |
|     |       |                 |                    | \"sterilized\"  |
|     |       |                 |                    | be used in      |
|     |       |                 |                    | place of        |
|     |       |                 |                    | \"sterile\" in  |
|     |       |                 |                    | this instance.  |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1793  | \"Furthermore,  | \"Furthermore,     | The word        |
| 5.  | -1794 | designs         | designs separating | \"zones\" is    |
|     |       | separating the  | the filling zone   | not defined and |
|     |       | filling zone    | from the           | is used         |
|     |       | from the        | surrounding        | alternately     |
|     |       | surrounding     | environment are    | with \"area\".  |
|     |       | environment are | important to       | For             |
|     |       | important to    | ensure product     | consistency, it |
|     |       | ensure product  | protection.\"      | is suggested    |
|     |       | protection.\"   |                    | that the word   |
|     |       |                 |                    | \"zone\" be     |
|     |       |                 |                    | replaced by     |
|     |       |                 |                    | \"area\"        |
|     |       |                 |                    | throughout.     |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1847  | \"sterilyze\"   | \"sterilize\"      | Correct the     |
| 6.  |       |                 |                    | spelling.       |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1857  | \"sterilyzed\"  | \"sterilized       | Correct the     |
| 7.  |       |                 |                    | spelling.       |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | 1989  | \"[Barrie       | \"[Bar             | The word        |
| 8.  | -1990 | r]{.underline}- | rier]{.underline}- | \"zones\" is    |
|     |       | A physical      | A physical         | not defined and |
|     |       | partition that  | partition that     | is used         |
|     |       | affords aseptic | affords aseptic    | alternately     |
|     |       | manufacturing   | manufacturing area | with \"area\".  |
|     |       | zone protection | protection by      | For             |
|     |       | by partially    | partially          | consistency, it |
|     |       | separating it   | separating it from | is suggested    |
|     |       | from the        | the surrounding    | that the word   |
|     |       | surrounding     | area.\"            | \"zone\" be     |
|     |       | area.\"         |                    | replaced by     |
|     |       |                 |                    | \"area\"        |
|     |       |                 |                    | throughout.     |
+-----+-------+-----------------+--------------------+-----------------+
| 8   | page  |                 | [Justificat        | The words       |
| 9.  | 59,   |                 | ion]{.underline} - | \"justified\"   |
|     | glo   |                 | Establishing       | and             |
|     | ssary |                 | documented         | \"              |
|     |       |                 | evidence, usually  | justification\" |
|     | refer |                 | based upon         | occurred        |
|     | ence: |                 | historical         | several times   |
|     | lines |                 | operational data   | in this         |
|     | 202,  |                 | or accepted        | guidance, as    |
|     | 698,  |                 | scientific theory, | does            |
|     | 757,  |                 | that supports the  | \"validation\"  |
|     | 794,  |                 | process or         | and             |
|     | 837,  |                 | establishes limits | \"q             |
|     | 906,  |                 | or action levels.  | ualification.\" |
|     | 914,  |                 |                    | Because both    |
|     | 979,  |                 |                    | words occur,    |
|     | 994,  |                 |                    | there is a      |
|     | 1008, |                 |                    | difference      |
|     | 1015, |                 |                    | between         |
|     | 1586, |                 |                    | justification   |
|     | 1691, |                 |                    | and validation. |
|     | 1693, |                 |                    | While there is  |
|     | 1706  |                 |                    | a FDA guidance  |
|     | and   |                 |                    | document        |
|     | 1781  |                 |                    | defining what   |
|     |       |                 |                    | validation is   |
|     |       |                 |                    | and consists    |
|     |       |                 |                    | of, there is no |
|     |       |                 |                    | document        |
|     |       |                 |                    | defining what   |
|     |       |                 |                    | \"              |
|     |       |                 |                    | justification\" |
|     |       |                 |                    | is or entails.  |
|     |       |                 |                    | Adding this     |
|     |       |                 |                    | definition      |
|     |       |                 |                    | provides        |
|     |       |                 |                    | minimal         |
|     |       |                 |                    | guidance to     |
|     |       |                 |                    | show that there |
|     |       |                 |                    | is a difference |
|     |       |                 |                    | in level of     |
|     |       |                 |                    | documentation   |
|     |       |                 |                    | and             |
|     |       |                 |                    | requirements    |
|     |       |                 |                    | for             |
|     |       |                 |                    | \"              |
|     |       |                 |                    | justification\" |
|     |       |                 |                    | as opposed to   |
|     |       |                 |                    | \"validation.\" |
+-----+-------+-----------------+--------------------+-----------------+
| 9   | 2013  | [Clean          | delete.            | The term        |
| 0.  |       | Zon             |                    | \"clean zone\"  |
|     |       | e]{.underline}- |                    | is not used in  |
|     |       | See Clean Area. |                    | the document,   |
|     |       |                 |                    | and therefore   |
|     |       |                 |                    | is not needed   |
|     |       |                 |                    | in the          |
|     |       |                 |                    | glossary. It is |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | this glossary   |
|     |       |                 |                    | entry be        |
|     |       |                 |                    | deleted.        |
+-----+-------+-----------------+--------------------+-----------------+
| 9   | 2015  | \"[Critical     | \"[Critical        | The first       |
| 1.  | -2017 | surface         | surf               | sentence of the |
|     |       | s]{.underline}- | aces]{.underline}- | definition is   |
|     |       | Surfaces that   | Surfaces that come | too broad or    |
|     |       | may come into   | into contact with  | could be        |
|     |       | contact with or | a sterilized       | broadly         |
|     |       | directly affect | product or the     | interpreted by  |
|     |       | a sterilized    | product contact    | an inspector to |
|     |       | product or its  | surfaces of its    | include all     |
|     |       | containers or   | containers or      | equipment in    |
|     |       | closures.       | closures. The      | the filling     |
|     |       | Critical        | interior of the    | area. The       |
|     |       | surfaces are    | elastomeric        | suggested       |
|     |       | rendered        | closure hopper on  | change is to    |
|     |       | sterile prior   | the aseptic        | specify the     |
|     |       | to the start of | filling line is a  | critical        |
|     |       | the             | critical surface   | surfaces as     |
|     |       | manufacturing   | as it touches the  | only those in   |
|     |       | operation, and  | sterilized product | contact with    |
|     |       | sterility is    | contact surface of | the sterilized  |
|     |       | maintained      | the elastomeric    | product or      |
|     |       | throughout      | closure. The       | sterilized      |
|     |       | processing.\"   | conveyor belt      | containers and  |
|     |       |                 | under a vial on    | closures. The   |
|     |       |                 | the aseptic        | second sentence |
|     |       |                 | filling line is    | is a            |
|     |       |                 | not a critical     | requirement,    |
|     |       |                 | surface as it does | and as such     |
|     |       |                 | not touch the      | should not be   |
|     |       |                 | sterilized product | contained in a  |
|     |       |                 | contact surface of | glossary. Such  |
|     |       |                 | the vial, which is | requirements,   |
|     |       |                 | the inside.\"      | if necessary,   |
|     |       |                 |                    | belong in the   |
|     |       |                 |                    | guidance        |
|     |       |                 |                    | proper, and it  |
|     |       |                 |                    | is suggested    |
|     |       |                 |                    | that the second |
|     |       |                 |                    | sentence        |
|     |       |                 |                    | therefore be    |
|     |       |                 |                    | deleted from    |
|     |       |                 |                    | the glossary    |
|     |       |                 |                    | definition. The |
|     |       |                 |                    | examples        |
|     |       |                 |                    | provided in the |
|     |       |                 |                    | suggested       |
|     |       |                 |                    | wording give a  |
|     |       |                 |                    | more clear      |
|     |       |                 |                    | understanding   |
|     |       |                 |                    | of where the    |
|     |       |                 |                    | definition      |
|     |       |                 |                    | applies and do  |
|     |       |                 |                    | not apply.      |
+-----+-------+-----------------+--------------------+-----------------+
| 9   | 2047  | \"[Interventio  | \"[Interven        | The term        |
| 2.  | -2049 | n]{.underline}- | tion]{.underline}- | \"critical      |
|     |       | An aseptic      | An aseptic         | zone\" is       |
|     |       | manipulation or | manipulation or    | apparently used |
|     |       | activity that   | activity that      | as a synonym to |
|     |       | occurs at the   | occurs in the      | \"critical      |
|     |       | critical        | critical area.\"   | area\" as       |
|     |       | zone.\"         |                    | \"clean zone\"  |
|     |       |                 | \"Closed isolator  | is              |
|     |       | and             | systems exclude    | c               |
|     |       |                 | external           | ross-referenced |
|     |       | \"Closed        | contamination from | to \"clean      |
|     |       | isolator        | the isolator's     | area.\" As      |
|     |       | systems exclude | critical area by   | such, for       |
|     |       | external        | accomplishing      | consistency and |
|     |       | contamination   | material transfer  | clarity, it is  |
|     |       | from the        | via aseptic        | suggested that  |
|     |       | isolator's      | connection to      | \"at the        |
|     |       | critical zone   | auxiliary          | critical zone\" |
|     |       | by              | equipment, rather  | be changed to   |
|     |       | accomplishing   | than use of        | \"in the        |
|     |       | material        | openings to the    | critical        |
|     |       | transfer via    | surrounding        | area.\"         |
|     |       | aseptic         | environment.\"     |                 |
|     |       | connection to   |                    |                 |
|     |       | auxiliary       |                    |                 |
|     |       | equipment,      |                    |                 |
|     |       | rather than use |                    |                 |
|     |       | of openings to  |                    |                 |
|     |       | the surrounding |                    |                 |
|     |       | environment.\"  |                    |                 |
+-----+-------+-----------------+--------------------+-----------------+
| 9   | lines | \"              | \"validation\"     | There is no     |
| 3.  | 704,  | qualification\" |                    | definition in   |
|     | 708,  |                 |                    | this guidance   |
|     | 765,  |                 |                    | as to what      |
|     | 768,  |                 |                    | qualification   |
|     | 1066, |                 |                    | is or means as  |
|     | 4069, |                 |                    | opposed to      |
|     | 1087, |                 |                    | validation      |
|     | 1096, |                 |                    | which is        |
|     | 1222, |                 |                    | defined within  |
|     | 1624, |                 |                    | the glossary.   |
|     | 1797, |                 |                    | For consistency |
|     | 1806, |                 |                    | and clarity, it |
|     | 1814  |                 |                    | is suggested    |
|     |       |                 |                    | that the single |
|     |       |                 |                    | term            |
|     |       |                 |                    | \"validation\"  |
|     |       |                 |                    | be used and     |
|     |       |                 |                    | will be         |
|     |       |                 |                    | understood to   |
|     |       |                 |                    | mean the        |
|     |       |                 |                    | appropriate     |
|     |       |                 |                    | studies         |
|     |       |                 |                    | necessary. If   |
|     |       |                 |                    | there is a      |
|     |       |                 |                    | specific        |
|     |       |                 |                    | meaning implied |
|     |       |                 |                    | by              |
|     |       |                 |                    | \"q             |
|     |       |                 |                    | ualification,\" |
|     |       |                 |                    | then it is      |
|     |       |                 |                    | suggested that  |
|     |       |                 |                    | the glossary be |
|     |       |                 |                    | updated or      |
|     |       |                 |                    | enough details  |
|     |       |                 |                    | be provided in  |
|     |       |                 |                    | the text to     |
|     |       |                 |                    | fully explain   |
|     |       |                 |                    | the meaning at  |
|     |       |                 |                    | that point.     |
+-----+-------+-----------------+--------------------+-----------------+
| 9   | lines | "vials\"        | \"containers\" or  | Throughout the  |
| 4.  | 645,  |                 | perhaps to         | rest of the     |
|     | 808,  |                 |                    | guidance the    |
|     | 945   |                 | \"containers, such | term            |
|     |       |                 | as vials,\"        | \"containers\"  |
|     |       |                 |                    | is used. With   |
|     |       |                 |                    | perhaps the     |
|     |       |                 |                    | exception of    |
|     |       |                 |                    | line 645,       |
|     |       |                 |                    | container is    |
|     |       |                 |                    | the more        |
|     |       |                 |                    | general term    |
|     |       |                 |                    | and it is       |
|     |       |                 |                    | suggested it be |
|     |       |                 |                    | used for        |
|     |       |                 |                    | consistency     |
|     |       |                 |                    | within the      |
|     |       |                 |                    | guidance.       |
+-----+-------+-----------------+--------------------+-----------------+