![](media/image1.wmf){width="1.2513888888888889in"
height="0.2263888888888889in"} B. Braun Medical Inc.

2525 McGaw Avenue

P.O. Box 19791

Irvine, California 92623

Telephone: (949) 660-2176

Fax: (949) 660-3292

**03 November 2003**

# Division of Dockets Management \[HFA-305\]

# Food and Drug Administration

## 5630 Fishers Lane, Room 1061

Rockville, MD 20852

Submitted Electronic by E-mail to **\<fdadockets@oc.fda.gov\>**

### **Guidance Document Reference:** Vol. 68 (September 5, 2003): Docket No. 03D-0382, CDER 1997112. Pages  52782-52783 \[FR Doc. 03-22576\] 

Dear Guidance Document Manager,

**Re:** Review Comments on "Sterile Drug Products Produced by Aseptic
Processing" Draft Guidance

B.Braun thanks the Agency for the opportunity to submit comments and
suggestions on the proposed "Sterile Drug Products Produced by Aseptic
Processing" guidance. B.Braun is a leading manufacturer of large and
small volume parenteral drug products. B.Braun started aseptic
processing with the development and approval of two of its cephalosporin
drug products packaged in the B.Braun Duplex® delivery system. Two of
B.Braun Duplex line products are: Cefazolin (NDA 50-779, approved
7/27/00) and Cefuroxime (NDA 50-780, approved 2/21/01). Please find
enclosed our comments to the above guidance document.

The comments have been prepared based on science and our experience in
aseptic process manufacturing. We hope you find the comments helpful in
finalizing an aseptic processing guidance that is clear, appropriate,
and consistent with current aseptic processing techniques. The comments
are summarized into "Issue," "Proposal," and "Objective of Proposal,"
for each line or section referenced. Current texts proposed for deletion
are in ~~strike through~~ and proposed new texts are
[underlined]{.underline}.

If you have any questions on these comments, please feel free to contact
me.

Sincerely,

Sgd

Qansy Salako, Ph.D.

Director, Regulatory Affairs

E-mail: qansy.salako@bbraun.com

+--------------+-------------------------------------------------------+
| **DOCUMENT** | **COMMENT**                                           |
+==============+=======================================================+
| Lines        | **Issue:** Footnote "a" does not allow it up to the   |
| 134-135, 146 | manufacturer to determine whether the classifications |
|              | must be met under static or dynamic conditions as     |
|              | written in ISO 14644-4, which is recognized in the    |
|              | USA.                                                  |
|              |                                                       |
|              | **Proposed:** Delete Footnote "a".                    |
|              |                                                       |
|              | **Objective of Proposed Modification:** To bring the  |
|              | FDA aseptic processing guidance document into         |
|              | alignment with ISO 14644-4.                           |
+--------------+-------------------------------------------------------+
| Line 143     | **Issue:** The active microbiological action levels   |
|              | shown in the columns labeled "Microbiological Active  |
|              | Air Action Levels" and "Microbiological Settling      |
|              | Plates Action Levels", should not be dictated as the  |
|              | limits should be established based on historical      |
|              | microbial data. If microbiological levels are listed  |
|              | in Table 1, they should be modified to those listed   |
|              | in Table 3 of USP \<1116\> Microbiological Evaluation |
|              | of Cleanrooms and Other Controlled Environments.      |
|              |                                                       |
|              | **Proposed:** Delete the columns labeled              |
|              | "Microbiological Active Air Action Levels" and        |
|              | "Microbiological Settling Plates Action Levels" in    |
|              | Table 1 or harmonize the values listed in the         |
|              | "Microbiological Active Air Action Levels" with those |
|              | listed in USP \<1116\>.                               |
|              |                                                       |
|              | **Objective of Proposed Modification:** To avoid      |
|              | confusion among manufacturers who currently use the   |
|              | levels listed in Table 3 of USP \<1116\>.             |
+--------------+-------------------------------------------------------+
| Line 248     | **Issue:** The number of air changes per hour shown   |
|              | for a Class 100,000 (ISO 8) area is 20 per hour, but  |
|              | in ISO 14644-4 a range of 10-20 per hour is given for |
|              | an ISO 8 area.                                        |
|              |                                                       |
|              | **Proposed:** "For Class 100,000 (ISO 8) supporting   |
|              | rooms, airflow sufficient to achieve ~~at least 20~~  |
|              | [10-20]{.underline} air changes per hour would be     |
|              | typically acceptable.                                 |
|              |                                                       |
|              | **Objective of Proposed Modification:** To harmonize  |
|              | the document with ISO 14644-4 and to avoid confusion  |
|              | among aseptic manufacturers.                          |
+--------------+-------------------------------------------------------+

+--------------+-------------------------------------------------------+
| **DOCUMENT** | **COMMENT**                                           |
+==============+=======================================================+
| Line 249     | **Issue:** The sentence, "For areas of higher air     |
|              | cleanliness, significantly higher air change rates    |
|              | will provide an increased level of air purification"  |
|              | is ambiguous.                                         |
|              |                                                       |
|              | **Proposed:** ~~For areas of higher air cleanliness,  |
|              | significantly higher air change rates will provide an |
|              | increased level of air purification~~. [In areas that |
|              | are ISO 8 (Class 100,000), ISO 7 (Class 10,000), and  |
|              | ISO 6 (Class 1,000); the number of air changes per    |
|              | hour should be 10-20, 30-70, and 70-160               |
|              | respectively.]{.underline}                            |
|              |                                                       |
|              | **Objective of Proposed Modification:** To harmonize  |
|              | the document with ISO 14644-4 and to avoid confusion  |
|              | among aseptic manufacturers.                          |
+--------------+-------------------------------------------------------+
| Line 262     | **Issue:** The sentence "A compressed gas should be   |
|              | of appropriate purity...", needs clarification by the |
|              | agency.                                               |
|              |                                                       |
|              | **Objective of Modification:** Enhance document       |
|              | clarity.                                              |
+--------------+-------------------------------------------------------+
| Line 348     | **Issue:** The word "sterility" is misspelled.        |
|              |                                                       |
|              | **Proposed:** ~~sterilty~~ [sterility]{.underline}    |
+--------------+-------------------------------------------------------+
| Line 491     | **Issue:** Regarding the statement, "Following an     |
|              | initial assessment of gowning, periodic               |
|              | requalification should monitor various gowning        |
|              | locations over a suitable period...," we believe that |
|              | once an individual has passed the initial gowning and |
|              | if that individual is monitored regularly (e.g.       |
|              | daily, each shift, etc.) throughout the year, a       |
|              | requalification would not be of value. Any personnel  |
|              | monitoring excursions during the requalification      |
|              | period would warrant immediate and appropriate        |
|              | corrective action (i.e. ban employee from entering    |
|              | the area until re-training and re-qualification are   |
|              | satisfactorily completed). If there are not any       |
|              | excursions for a particular individual during a       |
|              | requalification period, the individual is gowning     |
|              | satisfactorily.                                       |
|              |                                                       |
|              | **Proposed:** Following an initial ~~assessment of~~  |
|              | gowning [qualification]{.underline}, ~~periodic       |
|              | requalification~~ [routine monitoring]{.underline}    |
|              | should ~~monitor~~ [include]{.underline} various      |
|              | gowning locations ~~over a suitable period~~ to       |
|              | ensure the consistent acceptability of aseptic        |
|              | gowning technique.                                    |
+--------------+-------------------------------------------------------+
| Line 600     | **Issues:** A reference(s) should be included for the |
|              | sentence, "Pyrogen on plastic containers can be       |
|              | generally removed by multiple WFI rinses."            |
|              |                                                       |
|              | **Objective:** A reference(s) would provide the       |
|              | scientific basis this generalization.                 |
+--------------+-------------------------------------------------------+

+--------------+-------------------------------------------------------+
| **DOCUMENT** | **COMMENT**                                           |
+==============+=======================================================+
| Line 898     | **Issue:** Regarding Footnote 9, "To assess           |
|              | contamination risk during initial aseptic setup       |
|              | (before fill), valuable information can be obtained   |
|              | by incubating all such units that may be normally     |
|              | removed", we believe that if the units that are       |
|              | normally discarded during set-up but in the media     |
|              | fill are incubated for information purposes, will a   |
|              | positive growth result in an information unit         |
|              | (normally discarded unit) count as a contaminated     |
|              | unit with respect to the media fill                   |
|              | (re)qualification?                                    |
|              |                                                       |
|              | **Proposed:** To assess contamination risk during     |
|              | initial aseptic setup (before fill), valuable         |
|              | information can be obtained by incubating all such    |
|              | units that may be normally removed. [A positive       |
|              | growth in a vial that is normally discarded during    |
|              | initial setup does not result in a failing media fill |
|              | run, but should lead to an immediate investigation    |
|              | and appropriate corrective action.]{.underline}       |
|              |                                                       |
|              | **Objective of Proposal:** To clarify the agency's    |
|              | position regarding the impact of contaminated         |
|              | containers on a media fill that are normally          |
|              | discarded during production.                          |
+--------------+-------------------------------------------------------+
| Line 805     | **Issue:** The minimum run size for media fills has   |
|              | been historically 3,000 units. The 3,000 unit limit   |
|              | was based on a statistically valid justification.     |
|              |                                                       |
|              | **Proposed:** A generally acceptable starting point   |
|              | for run size is in the range of ~~5,000~~             |
|              | [3,000]{.underline} to 10,000 units.                  |
|              |                                                       |
|              | **Objective of Proposal:** To keep a statistically    |
|              | valid minimum container requirement for media fills.  |
+--------------+-------------------------------------------------------+
| Line 921     | **Issue:** It is not always possible to identify      |
|              | microorganisms to the species level.                  |
|              |                                                       |
|              | **Proposed:** [If possible, t]{.underline}~~T~~he     |
|              | microorganisms should be identified to species level. |
|              |                                                       |
|              | **Objective of Proposal:** Many organisms have not    |
|              | yet been identified, which sometimes makes            |
|              | identification to the species level, or even the      |
|              | genus level, impossible.                              |
+--------------+-------------------------------------------------------+
| Line 1117    | **Issue:** Clarification is needed regarding how far  |
|              | in advance the microbial count and D-value of a       |
|              | biological indicator should be confirmed before a     |
|              | validation study.                                     |
|              |                                                       |
|              | **Objective:** Enhance document clarity.              |
+--------------+-------------------------------------------------------+

+--------------+-------------------------------------------------------+
| **DOCUMENT** | **COMMENT**                                           |
+==============+=======================================================+
| Line 1326    | **Issue:** Historically, other suitable               |
|              | microbiological test methods (e.g. rapid test         |
|              | methods) should be allowed for use after they have    |
|              | been shown to be equivalent to (or better) than       |
|              | traditional methods.                                  |
|              |                                                       |
|              | **Objective:** To allow the use of alternative        |
|              | equivalent methods and to be consistent with USP.     |
+--------------+-------------------------------------------------------+
| # Line 1681  | **Issue:** A breach of isolator integrity should lead |
|              | to a decontamination cycle only if the breach could   |
|              | have impacted sterility in the isolator (e.g.         |
|              | positive pressure maintained in an isolator during a  |
|              | breach may not warrant a decontamination).            |
|              |                                                       |
|              | **Proposed:** A breach of isolator integrity should   |
|              | lead to a decontamination cycle [if positive pressure |
|              | was not maintained or if it is believed that the      |
|              | breach could have jeopardized sterility within the    |
|              | isolator]{.underline}.                                |
|              |                                                       |
|              | **Objective:** Not all breaches necessarily           |
|              | jeopardize isolator sterility (i.e. a "mouse hole" is |
|              | open to the environment, but positive pressure within |
|              | the isolator maintains sterility.)                    |
+--------------+-------------------------------------------------------+
| Line 1700    | **Issue:** Air quality should be monitored            |
|              | periodically during each shift." Please clarify as to |
|              | specifically which aspects of air quality (e.g.       |
|              | non-viable, viable, or both) are to be monitored per  |
|              | shift.                                                |
|              |                                                       |
|              | **Objective:** Enhance document clarity.              |
+--------------+-------------------------------------------------------+