## **Guidance for Industry**

**Sterile Drug Products Produced by**

**Aseptic Processing --- Current Good**

# **Manufacturing Practice**

### ***DRAFT GUIDANCE***

***Comments prepared by G Farquharson***

***24^th^ September 2003***

73: suggest \"\.....under high quality clean classified environmental
conditions\".

137: This clause is at conflict with line 176. This suggests that
environmental monitoring might be to a routine that is not every batch
or aseptic manipulation.

142: The table is basically fine, but should be rearranged to show the
current standard ISO 14644-1 in the first column, with the metric and
Imperial particle concentrations in the next 2 columns.

142: Classifications should be written fully for the avoidance of
confusion. ISO 14644-1, just like superseded FS 209E demands that we
define the class, particle size considered and occupancy state.

Example: ISO 5 at \>= 0.5 micron, in operation (former class 100).

157\. Would be better if this were called the Aseptic Core.

Line 176:

The 1 foot away rule can lead to meaningless monitoring or worse the
monitoring can itself cause disturbance to airflow or be a contamination
source itself.

Also is it correct to imply that this clause requires the use of
continuous or frequent automated monitoring of airborne particles
throughout the process operations?

The following is suggested: \" Air in the immediate proximity of exposed
sterilised containers/closures and filling/closing operations would be
of appropriate particle quality when the airborne particle concentration
is no more than 3520 in a size range of 0.5 micron and larger. The
locations selected should be representative of the contamination levels
in the zone considered, be close to but not compromise critical
operations such as filling and closing of containers, and provide
evidence of compromise of the controlled zone. Deviations from this
critical area monitoring parameter should be documented as to cause and
significance.

Line: 176 We can\'t say ISO 5 here because this would infer the
evaluation of the defined number of sample locations, taking the defined
sample size, and evaluating the data in accordance with ISO 14644-1.
Here we are talking about monitoring at certain selected critical
locations, sufficient frequently that we would see adverse events, and
doing a evaluation of the data to give us an indication of success or
failure.

185: Clear guidance is required for the sampling frequency and sample
size for such systems. Also guidance about the evaluation of data is
required.

196: The term laminar flow should be replaced by the term
\"unidirectional flow\" for consistency with ISO 14644-1, and 4.

217: It would be much better to step through the grades progressively.

After the aseptic core we have the Aseptic processing area APA. This
could be ISO 7 or ISO 6 or even ISO 5 at \>= 0.5 micron, in operation.

Then we have the supporting clean areas which are ISO 8 at \>= 0.5
micron, in operation.

The attached table shows how all this might work in the context with
other GMPs and ISO medical devices standards. The FDA guidance could
include this comparison for information.

205: Are smoke patterns an example of air pattern analysis? Are other
techniques such as CFD modelling accepted ?

Should airflow visualisation also include proving that defined
interventions don\'t have an adverse effect on the product or process.

238: The US market would like the Imperial equivalent also of 0.05 in
wg.

250: Suggest \" For areas of higher cleanliness, significantly higher
air change rates are likely to be required to achieve the levels of "in
operation" air cleanliness required.\"

241: Most pharmaceutical cleanroom are designed as door closed pressure
regimes. When doors open, the pressure difference equalises immediately
and reverts to a small leakage flow across the open door way (in the
same sense at the pressure gradient).

It will be very unlikely that there will be a controlling flow across
the open door. This type of open door solution is often used in
operating theatres in order to handle the continuous human traffic in
and out of the controlled space.

The phrase should be modified a little more: \"When doors are open, flow
from the cleaner to the less clean should be maintained to minimise the
ingress of airborne contamination.\"

258: Title says AIR, but clearly could be other gases.

Suggest separate D into 2 parts.

\>Compressed gas filtration.

\>Ventilation air filtration.

283: better \"HEPA Filters (High Efficiency Particulate Air).\"

289: Do you mean for the Aseptic core and the aspetic processing area?

If so these are excessive.

Suggest: \"In situ leak testing of HEPA filters should be undertaken
sufficiently frequently to provide confidence that the installation is
working effectively. Typical leak test interval for the aseptic core are
6 monthly, and 12 monthly for the aseptic processing area.

Leak test intervals can be increased to 12 and 24 monthly respectively,
provided that results of sequential tests provide confidence of
consistent performance of the system.\"

310: Better to refer to IEST RP 006.3, and/or to ISO 14644-3 annex B6.

304: This filter specification refers to US MIL 282, and as such should
be quoted because there are at least 2 other different filter test
standards in use in our industry. The aerosol for US MIL 282 has a size
distribution, with a significant percentage at 0.3 micron and greater.

330: Suggest \"\....can have an adverse effect on unidirectional
airflow.\"

312: Should not be specific about the use of DOP.

338: suggest \"\...\...\...., drug manufacrurers are responsible for
ensuring that equipment specifications, test methods, acceptance
criteria are defined, and that these essential certification activities
are conducted satisfactorily.\"

344: prefer \"Aseptic processes must be designed, configured and
operated to minimise the exposure of sterile articles\...\.....\"

376: Do FDA have an expectation for the protection to stoppered vials
before the application of the aluminium overseal?

368: It would be good here to add the importance working hard to achieve
a reliable robust process that does not require intervention to fix
problems. Intervention frequency, mean time between failures (MTBF),
should be monitored, hit targets and be continually improved. This is
also good business sense and potentially reduces the duration and
complexity of media process simulations.

385: I think this must mean \"\....interlocked door sets\...\"

403: This might be confusing. If the terms are sorted out to define the
different process areas, we could say \" With rare exceptions, drains
are not considered appropriate within the aseptic core or the aseptic
processing area. Where such drainage is required, the waste should be
piped out of the area to a drain in a less sensitive support or
technical area.\"

422: suggest \"A well-designed, maintained and operated aseptic
process\...\...\"

475: Should be \"\...who are currently qualified\...\...\...\"

496,497: What are \"\...gown quality\" and \"\...adhere to appropriate
aseptic method.\" I don\'t understand what is inferred by these phrases.

524: It is important to recognise that being demonstrably in control
provides the opportunity to reduce or adjust the monitoring programme to
ensure focus on the most difficult or most important zones.

553: There could be confusion here between sterilising a volume of
solution in a vessel and the process of sterilising the vessel in place
(SIP) typically before filling with solutions.

610: Why introduce this phrase WFI for Parenteral Products. Why not stay
with the earlier USP reference?

709: Should refer to \"\...media fill or media process simulation.\"

805: Why not simply refer to ISO 13408?

1089: Should be \"\...\...\...\...\....using the established and
documented steriliser loads\>\"

1331: As stated above, in-situ real-time particle monitoring cannot ever
be exactly equivalent to the formal multi-point classification process.
Therefore the words need to be adjusted here. Suggest: \" A result from
the monitoring system suggesting a likely deviation from the specified
classification at a given location should be investigated.\"

1517: See earlier note about the importance of accumulating the
frequency of unplanned stoppages and then acting upon the information
derived from this data.

1577: This incorrect. The acceptability of non-UDAF is totally dependent
upon the importance of particles and the source concentration. The
following text would be better: \"Non-unidirectional airflow (not
turbulent) may be acceptable within small closed isolators that have
insignificant internal particle sources, where non-viable particles are
of no significance and where there is no need to achieve segregation of
contamination risks inside the enclosure.

1609: Correct classification phrase should be used as stated above.

1701: Suggest adding: \"The design of the microbiological environmental
monitoring programme should be considered very carefully, since simple
importation of open cleanroom practice may in itself introduce a greater
contamination risk than those one is trying to detect.\"

1749: EU GMP has special dipensation to recognise that some old BFS
machines may meet the APA micro levels, but fail the ISO 7 \"in
operation\" for the APA. Should this be recognised here?

End of comments

***Gordon Farquharson***

**Bovis Lend Lease**

**Pharmaceutical Division**

Life Science Consultants, Engineers, Project & Construction Managers

Tanshire House, Shackleford Road

Elstead, Surrey, GU8 6LB

United Kingdom

Tel: +44 (0)1252 703 663

Fax: +44 (0)1252 703 684

Cellular +44 (0)7785 265 909

e-mail gordon.farquharson@bllpharma.com