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PDA Journal of

Pharmaceutical
Science and
Technical Report No. 36 Technology

Current Practices in the


Validation of Aseptic Processing2001

May/June 2002

Supplement TR36

Volume 56

Number 3

3 Bethesda Metro Center, Suite 1500, Bethesda, MD 20814


Phone: (301) 986-0293 Fax: (301) 986-0296
www.pda.org
Survey prepared, distributed, and compiled by:

James P. Agalloco, Agalloco & Associates


James E. Akers, Ph.D., Akers Kennedy & Associates
Russell E. Madsen, PDA
Current Practices
in the Validation of
Aseptic Processing2001

Technical Report No. 36

PDA

May/June 2002

Vol. 56, No. 3, May/June 2002, Supplement TR36 i


Introduction PDA 2001 Aseptic Processing Survey

The validation of aseptic processing continues to be a 1. In what country, or state, is your Aseptic Processing
major area of interest within the pharmaceutical indus- Area (APA) located?
try. Five years have passed since the last PDA survey
on this subject. While there have been no new broadly United States - 28 - California, Florida, Illinois,
applicable regulations or regulatory guidance since that North Carolina, Pennsylvania, Texas (2), Indiana,
time, there has been continued controversy over the Kansas, New Jersey, New York (3), US (4)
details of aseptic processing and process simulation
practice. Industry practices largely adhere to current International - 31 - Australia, Canada, Italy, Spain,
regulations and guidelines on aseptic processing by the Sweden (2), England, France, Germany, Hungary,
European Union (1), ISO (2), and FDA (3). The impact Indonesia, Ireland, Korea (3)
of PDAs TR #22 on Process Simulation Testing for
Aseptically Filled Products (4) is also apparent. No answer - 2

Over time, industry methods, practices, and limits have 2. What types of sterile products do you manufacture at
been modified to adapt to the changing circumstances. this site? Please mark all that apply.
The Pharmaceutical Manufacturers Association (now
PhRMA) in 1979 (5) and PDA in 1986 (6), 1992 (7), a. Large volume parenterals 10 23.3%
and 1996 (8) conducted surveys on this subject that b. Small volume parenterals 36 83.7%
have provided a clearer understanding of contemporary Solutions 16 37.2%
industry practice. This survey addresses the continu- Suspensions 5 11.6%
ing need to track industry practices in the validation of Lyophilized 11 25.6%
aseptic processing as it evolves. Powders 9 20.9%
c. Ophthalmic and/or otic solutions 11 25.6%
Questionnaires were sent to eighty-eight (88) firms d. Inhalation solutions 8 18.6%
that specifically agreed to participate with PDA in e. Ointments 3 7.0%
this effort. Forty-three (43) responses were received f. Biologicals 14 32.5%
representing both US and overseas locations. The re- g. Products for veterinary use 5 11.6%
sults were tabulated to provide both raw numerical and h. Medical devices - liquid based
percentage of total respondents. Where the respondents products 6 13.9%
provided comments (whether solicited or given volun- i. Medical devices - non-liquid
tarily), these comments are provided after the question. products 4 9.3%
Where more than one respondent provided essentially j. Other - please describe 2 4.6%
the same response selection and comment, they have
been consolidated and a number appears next to the Comments
response indicating the number of comments of that j. Drugs containing implants, control release
type. The nature and extent of the comments received devices
were extensive, and for this reason, the authors have j. Clinical supplies
chosen to combine similar responses. One of the major
benefits of surveying on a regular basis is the opportu- 3. How many different sterile product presentations (all
nity to follow the evolution of concepts and practices strengths and fill sizes of all products) do you manu-
over time. To that end, this survey instrument used many facture at this site?
questions that were nearly identical to those asked in
1992 and 1996. a. 05 8 19.0%
b. 6 49 14 33.3%
c. 50 99 6 14.3%
d. 100 149 6 14.3%
e. >150 9 21.4%

2 PDA Journal of Pharmaceutical Science and Technology


4. What percentage of your sterile products is manufac- Comments
tured using aseptic processing? b. The same product may be manufactured with
or without preservative; depends upon whether
a. Less than 25% 2 4.6% they are for multi-dose markets, i.e., US states
b. 25% to 50% 5 11.6% a multi-dose product will have a preser-
c. 51% to 75% 3 7.0% vative. Single dose of same product -- no
d. More than 75% 33 76.7% preservative.
d. All our products comply with USP but not with
5. Is this percentage an increase or a decrease from five A criteria from European Pharmacopoeia; 60%
years ago? comply with B criteria from European Phar-
macopoeia.
a. Increase 7 16.3% d. Liquid >75%; Powder, none.
b. Decrease 5 11.6%
c. Same 31 72.1%
Release/Quarantine Practices
Comments
a. No production five years ago. 8. If a process simulation* action level is exceeded
on a validated production line, what action do you
6. At your site, is aseptic processing used for products that take with regard to products manufactured on the
could be terminally sterilized? (For the purposes of this line prior to the media fill failure?
response, consider could be terminally sterilized to
mean a product and container/closure/delivery system a. Release 3 7.0%
that could withstand moist heat sterilization processes b. Release after investigation 6 13.9%
with a total accumulated F0 of 8 or more minutes.) c. Release only after an investigation
indicates good process control and
a. Yes 14 32.6% one or more successful additional
b. No 29 67.4% media fills are conducted 33 76.7%
d. Other action - please describe 4 9.3%
If yes, what percentage of the aseptically produced
products does this represent? Comments
2% (2), 5%, 10% (2), 20% (2), 30%, 35%, 47%, c. Plus double sterility test.
60%, 75%, 85% d. Release only after investigation could assure
SAL of products.
Comments d. No formal procedure. Never occurred, there-
a. We are manufacturing clinical supplies only, so fore, no test case.
information is not available at this time. d. Normally, release after investigation; however,
would depend upon number of contaminated
7. What percentage of your aseptically filled products units and types of organisms. Worst case: recall
contains an anti-microbial preservative that complies product.
with pharmacopoeial anti-microbial effectiveness test-
ing requirements? *Note: In this survey, the terms process simulation
test, media fill, and media fill test are used
a. None 14 33.3% interchangeably.
b. Less than 25% 11 26.2%
c. 25% to 50% 5 11.9%
d. 51% to 75% 4 9.5%
e. More than 75% 10 23.8%

Vol. 56, No. 3, May/June 2002, Supplement TR36 3


9. If a process simulation action level is exceeded on a b. Investigation will be conducted on all batches
line, what action do you take with regard to products of the last successful media fill; refer to QC for
manufactured on the line subsequent to the media fill further action.
failure? b. All before the last media fill and all post.
b. Before: Back to previous acceptable media fill.
a. Release 0 0.0% After: Lots filled after action limit and prior to
b. Release after investigation 1 2.3% obtaining satisfactory results for repeat media.
c. Release only after an investigation b. Six months (2)
indicates good process control and b. Since the last successful media fill on the affected
one or more successful additional line (3)
media fills are conducted 39 90.7% b. From previous media fill to the next media fill
d. Other action - please describe 4 9.3% (3).
b. Three months before failure and all lots after
Comments media fill are kept in QA.
c. Plus double sterility and stop production. b. Depends upon the outcome of the investigation!
d. Release only after investigation could assure SAL Worst case scenario: all lots produced since the
of products. last approved media fill.
d. Lots rejected unless assignable cause can be deter- c. No practice is in place due to manufacturing under
mined that was not present during the processing development.
of the product batches. c. Lots filled prior and post the failure will be dis-
d. Normally, release after investigation; however, positioned depending upon the outcome of the
would depend upon number of contaminated investigation. Lots filled post media fill are quar-
units and types of organisms. Worst case: recall antined until investigation results are known.
product. c. Hold lots for investigation and draft an action
memo for released lots.
10. Is positive action taken against a certain number of lots c. Once investigation is concluded and corrective
or over a certain time period in the event of a media action taken, we return to normal production.
fill failure? Never occurred, therefore, no test case.
c. Action would be taken on individual batches as
a. Yes - please specify number of lots far back and forward as necessary to fence in the
involved before and after the failure. 7 17.5% issue, based upon the individual investigation.
b. Yes - please specify time period This could go all the way back to the previous
involved before and after the failure. 15 37.5% media fill.
c. No - please describe your practice 7 17.5% d. Release only after an investigation indicates good
d. Other 11 27.5% process control and one or more successful ad-
ditional media fills is conducted.
Comments d. Dependent upon outcome of investigation (2)
a. All. d. No policy in place for this scenario; no history of
a. Any product manufactured between filling trials failure.
and the date of the failure and subsequent batches d. We stop the line until there are three successful
must be held in quarantine until the investigation media fills.
is complete. Aseptic product manufactured on the d. Investigation reveals the source of failure and de-
filling line, and still in company control, should pending upon the type of source, the number of
be quarantined until investigation is complete. lots or time period are considered. If it is needed,
a. All unreleased lots before and after the failures recall for certain lots should be performed.
are held until three successive media fills are per- d. Everything not yet released since the last success-
formed and found to meet acceptance criteria. ful process simulation test is placed on hold until
a. Three lots before and after. the investigation is complete and a successful
a. All lots after the failure. process simulation test is completed. (3)

4 PDA Journal of Pharmaceutical Science and Technology


11. Is positive action taken on production during a set c. Hold lots for investigation and draft an action
period of time before and after a media fill failure? memo for released lots.
c. If further investigation finds that there is a possible
a. Yes - please specify time period impact from equipment, facility, and/or personnel,
involved before and after failure 18 45.0% re-qualification would be required.
b. No - please describe your practice 9 22.5% c. Everything not yet released since the last success-
c. Other 13 32.5% ful process simulation test is placed on hold until
the investigation is complete and a successful
Comments process simulation test is completed. (3)
a. All periods involved. c. All lots manufactured during the prior six months
a. All before the last media fill and all post. would be investigated then an appropriate action
a. Production is on hold pending investigation. could be taken by QC, normally.
a. Between current and previous media fill
results (2). 12. In the event of an unsuccessful* revalidation media
a. Aseptic production ceases on the affected machine fill test, how many consecutive satisfactory tests must
until investigation is completed and satisfactory be completed before the production line is considered
repeat filling trial has been completed. Repeat trial re-qualified for manufacturing operations?
in triplicate on the container size implicated.
a. Before: Back to previous acceptable media fill. a. None 0 0.0%
After: Lots filled after action limit and prior to b. One 1 2.3%
obtaining satisfactory results for repeat media. c. Two 1 2.3%
a. Six months. d. Three 37 86.0%
a. Going back to the last successful media fill. (3) e. Other - please describe 6 13.9%
a. Depends upon the outcome of the investigation! * The test fails to meet the acceptance criteria.
Worst case scenario: all lots produced since the
last approved media fill. Comments
b. Depends upon investigation results. (2) d. If not able to invalidate media fill.
b. Implement corrective actions based upon the e. One: In case of identified failure cause after correc-
outcome of investigation. tion action. Two: In case of unidentified cause.
b. No practice is in place due to manufacturing under e. Based upon investigation, 1-3 may be performed.
development. e. If reason for failure is known, one. If reason for
b. Lots filled prior and post the failure will be dis- failure is not known, three. (2)
positioned depending upon the outcome of the e. If cause of failure is known, one only. If cause of
investigation. Lots filled post media fill are quar- failure is unknown or uncertain, three. In all cases,
antined until investigation results are known. an investigation is also conducted.
b. Once investigation is concluded and corrective e. One repeat if able to invalidate media fill.
action taken, we return to normal production.
Never occurred, therefore no test case. Frequency
b. Action would be taken on individual batches as far
back and forward as necessary to fence in the issue, 13. Do you routinely conduct revalidation media fills on
based upon the individual investigation. This could each filling line or machine on a regularly scheduled
go all the way back to the previous media fill. basis?
b. After the failure only.
c. Dependent upon outcome of the investi- a. Yes 43 100.0%
gation (3). b. No - please describe your practice 0 0.0%
c. We stop the line until there are three successful
media fills. Comments
c. It is difficult to take action before since we do not a. We do it quarterly, but the process used is not
know that we have a failure. determined in order to cover all processes.

Vol. 56, No. 3, May/June 2002, Supplement TR36 5


14. If yes, how often? c. If no assignable cause found.
c. QC management would assess the aseptic produc-
a. Weekly 0 0.0% tion area and determine a probably cause. If no
b. Monthly 0 0.0% assignable cause was found, a media fill would
c. Every other month 0 0.0% be requested.
d. Quarterly 2 4.6% c. EM monitoring data, sterile cleaning practice,
e. Semi-annually 36 83.7% sterilizing cycle, DOP, Royco of HVAC, LFs,
f. Annually 4 9.3% education, new operators.
g. Other - please define 1 2.3% c. Decision to conduct a media fill is based upon the
results of the sterility test failure investigation.
Comments c. If no cause can be identified from lab error or pro-
e. At minimum, each line typically has five or six cess error, a media fill test may be carried out.
due to new product container closure systems. c. Investigation into failure conducted against ma-
e. At least two media trials per year. However, to chine and batches taken if warranted.
validate/re-qualify operators, many lines are per- c. May require that production be stopped on the
forming up to six trials per year. line. Depends upon results of investigation of
g. Every fourth month. sterility test failure.
c. No revalidation is performed if a lab error is the
15. If a sterility test failure occurs, does this failure initi- cause of the failure.
ate a media fill test on the line that manufactured the c. If aseptic processing.
product that failed the sterility test? c. If cause is assigned to line failure.
c. An investigation will be initiated. If the investi-
a. Yes 12 27.9% gation doesnt show that the failure is due to a
b. No - please describe your practice 7 16.3% lab contamination, all steps in production will be
c. Sometimes - please explain the checked. Depending upon the results, an evalua-
decision factors that would lead tion will be done if a new media fill is necessary
your firm to require a re-validation to verify that the process is under control. For
media fill test to clear a sterility example, an upward trend of microorganisms in
test failure 24 55.8% the APA or a recently failed media fill could lead
to a revalidation.
Comments c. Would depend upon type of organism and if any
b. Initiates investigation and exception reports. (2) other failures from same line, e.g., two sterility
c. After investigation: lab failure = retest; no lab test failures with anaerobic organisms have
failure = batch rejected. investigation and anaerobic media fill.
c. Depends upon results of investigation and if ad-
ditional controls were positive. 16. How are your media fill tests distributed among dif-
c. Based upon investigation findings. (7) ferent shifts?
c. If the investigation determined the root cause to be
a failure in design or practice requiring significant a. Equally distributed across shifts 32 74.4%
change. (2) b. Distributed according to
c. Response to product test failure requires inves- production volumes 5 11.6%
tigation covering sterility testing and production c. No - please explain 6 14.0%
records/environments. Outcome of the manufactur-
ing investigation indicating production environment/ Comments
procedure may result in a media trial. (2) c. There is only one shift. (5)
c. Investigate to exclude analytical error or if some c. In some areas, media fills are performed which
obvious event has caused the failure. cover shift changeover. In other areas, because of
c. Cross-functional team assembled to investigate. their design and need for only one operator, we
Findings would decide if additional media fill have a rationale that states shift changeover has
necessary. no impact on integrity of process.

6 PDA Journal of Pharmaceutical Science and Technology


17. Are all aseptic fill and set-up personnel included in the good aseptic technique, then successfully partici-
process simulation program? pate in a process simulation study.
c. Process uses barrier technology, therefore, person-
a. Yes - on an annual basis 34 79.1% nel participate in the media fills, but they are not
b. Yes - please specify frequency 7 16.3% qualified.
c. Other - please describe your practice 1 2.3% c. Gowning certification only.
c. Gown qualification, personnel monitoring, media
Comments fill within six months.
a. Vial size on rotating basis.
b. Semi-annually. (6) 19. How many media fill tests must a new hire participate
c. Frequency depends upon type of intervention. in to be considered qualified to work on a specific
validated process?
18. Are personnel, including new hires, qualified to op-
erate in the APA through participation in a media a. None 13 30.9%
fill test? b. One 28 66.7%
c. Two 0 0.0%
a. Yes - using participation in an d. Three 2 4.8%
actual process simulation 31 72.1% e. Four or more 0 0.0%
b. No - please describe your practice 12 27.9%
Comments
Comments b. All training related to aseptic behavior.
c. They are qualified performing the job, but a b. But must perform all critical activities.
media fill is not scheduled to complete their b. Plus micro training, aseptic training, and repetitive
qualification. They will participate in the next (3x) gowning assessment.
scheduled media fill if a media fill is not sched-
uled at completion of their qualification. 20. If different filling set-ups and/or closure systems are
c. Operator certification program for aseptic utilized on a filling line, will your process simulation
technique and gowning, as well as GMP program address all combinations?
training. Due to media fill frequency opera-
tors generally participate in media fills within a. Yes 30 71.4%
about six weeks of employment. b. No - please explain your rationale 12 28.6%
c. No practice set up yet. Intention to make them
qualified with media fill as one part of the Comments
qualification. a. On a rotating basis according to product.
c. Using a hand fill simulation. b. Initial qualification would be yes, but routine
c. New hires are trained to work in aseptic pro- re-qualification would be about largest and
cessing areas via SOPs and on-the-job-train- smallest.
ing. They are cycled into media program after b. Worst case conditions will be investigated.
initial training has been completed. b. One simulation trial to one filling line.
c. We perform a specific training program and b. Bracket the largest/smallest vial/closure combina-
final validation in accordance with the SOP. tions. (2)
c. Qualification of an operator is based upon b. Different lines have different combinations to
training for gowning and aseptic practices. bracket all.
The operator can then operate in the aseptic b. Because we are in research, it is changing all the
processing area and participate in the next time.
media fill. b. We only do the minimum and maximum fill, based
c. New operators are scheduled for the first avail- upon line speed.
able media fill. b. All formats are covered; not all stoppers.
c. Prior to entering the APA, employees must pass a b. Worst case, large vial openings most difficult
broth test in a lab environment demonstrating fill set-up.

Vol. 56, No. 3, May/June 2002, Supplement TR36 7


21. Does your firm employ a minimum time duration for 23. Do you utilize the same filling line speed for process
media fill tests? simulations as that utilized in production for that
container?
a. Yes - not less than 1 hour 4 9.3%
b. Yes - not less than 2 hours 1 2.3% a. Yes 20 46.5%
c. Yes - not less than 3 hours 2 4.6% b. No - speed equal to slowest
d. Yes - four hours or more 1 2.3% normal fill speed on that line 15 34.9%
e. Yes - duration of fill process 16 37.2% c. No - speed equal to the highest
f. Yes - minimum number of filled normal speed on that line 2 4.6%
containers 24 55.8% d. No - other speed - please explain 9 20.9%
g. No - please describe your practice 6 13.9%
Comments
Comments b. Re-qualifications.
d. Typically, 8-16 hours. b. Majority of cases slowest (longest dwell time).
e. Including all worst cases. c. On certain high-speed fillers, >300/minute (high-
e. Start-Stop Approach: Actual minimal fill time est) is deemed worst case; units fall over and there
is not more than three hours. are more interventions.
f. 6,800 units d. The line speed is lower than the standard speed
f. Would normally fill for length of typical produc- due to the necessary equipment to dose the media
tion shift. < 6,300 units processed to cover all and represent worst case.
production intrusions. d. Process simulations require at least 25% of fill at
g. Both: minimum number of units to fill and the minimum speed, 25% normal/routine speed, 25%
whole duration of the process. maximum speed.
g. NLT to 60% of filling process duration. d. Currently, slower than normal production speed
g. Duration of the longest filling time. is used. In the future, this process and normal
g. Simulate 1-1/2 hours of empty running during production speed will be used.
some of the challenge. d. Initial Performance Qualification utilizes mini-
g. Plus necessary time for simulations. mum speed and approximate production speed.
d. Slowest filling speed and at the end of test, highest
speed.
Methods d. Combination of B and C.
d. Slowest speed for largest container and fastest
22. Is the fill volume of media employed the same as that speed for smallest container.
utilized in production? d. Slower and faster speeds are used during the chal-
lenge.
a. Yes 18 45.0% d. The speed that is considered as worst case for each
b. No - container size is too large 2 5.0% container size.
c. No 20 50.0%
24. Do your process simulation trials include inert gassing
Comments if used in production?
c. Half volume of a vial. (4)
c. Volume of media is greater than product a. Yes - using Fluid Thioglycollate
fill (2). medium and nitrogen 3 7.0%
c. Vial volume sufficient to promote growth. b. Yes - using Soybean Casein Digest
c. Sufficient media is added to ensure one-half of medium and nitrogen 4 9.3%
the vertical surface of container is covered. Units c. Yes - other method - please explain 15 34.9%
inverted during incubation. d. No - please explain 23 53.5%

8 PDA Journal of Pharmaceutical Science and Technology


Comments a. Depending upon the speed of the machine.
c. Using Soybean Casein Digest medium and com- a. Depending upon challenge time and production
pressed air. (3) complexity.
c. Using compressed air in place of N 2 with a. Conventional: NLT 10,000; high speed: NLT
SCDM. 30,000; FFS: NLT 15,000.
c. Compressed air. (4) a. In order to respect the minimum one-hour fill, high-
c. Sterile filtered air as part of production process. speed line tends to have more samples filled.
c. Soybean Casein and oxygen. a. Minimum of one-hour filling and 3,000 units,
c. Soybean Casein Digest medium and nitrogen. whichever is greater for each shift.
c. TSP medium and nitrogen. a. Depends upon commercial batch size.
c. SCDB and compressed air to simulate inert gas. (3) a. Actual number attained is dependent upon line
c. Inert gas is exchanged with air. speed with a minimum yield targeted.
d. Not used. (3) a. Higher speed lines are challenged with higher
d. Soybean Casein Digest medium without nitrogen. numbers of units.
d. Is considered worst case using air. a. If aseptic fill is validated for two days, the amount
d. Compressed filtered air. is doubled.
d. Inert gas is not used. b. Normally >6,300; exception is high-speed am-
d. SCD broth. poule m/c 10,000 units.
d. Purge needles, tubing, etc., installed; no gas
used. 26. Which media do you utilize for process simulation
d. Inert gassing is not used in production. trials on a regular basis?
d. During media fills that simulate processes utiliz-
ing nitrogen, sterile filtered air is utilized due to a. Soybean Casein Digest 39 90.7%
inhibitory microbial nature of nitrogen. b. Fluid Thioglycollate 3 7.0%
d. Inert gas replaced with air for duration of media c. Other - please specify 1 2.3%
fill(s).
d. Pressurized air is used instead of nitrogen, as our Comments
production lines apply both techniques (air and c. SCD with HEC or HPMC for ointment or gel
nitrogen). lines
d. No gassing.
d. Replace N2 with compressed air to increase the 27. Do you use exactly the same compounding and filtra-
challenge for growth. tion equipment in conducting a media fill test that you
d. Inert gases are not used to prevent product degra- use in actual production?
dation or exposure in our process.
d. Sterile filtered pressurized air instead of nitrogen. a. Yes 33 76.7%
d. Use SCD and compressed air. b. No 6 14.0%
c. Other - please describe 4 9.3%
25. Will the number of samples used in a process simula-
tion vary from line to line? Comments
c. Additional pre-filters are used.
a. Yes - please explain 15 34.9% d. The same fill line equipment used, however, ad-
b. No 28 65.1% ditional equipment is necessary for the media fill
dosing.
Comments d. Same compounding equipment and filter hous-
a. >6,300 units ings, but no filters.
a. Only one line. (3) d. Filtration is the same; compounding as close as
a. NLT 6,000 vials. possible.
a. Depends upon batch size. d. The same filling equipment is used, but not the
a. One of four lines fills at a faster speed. solution preparation equipment. (2)

Vol. 56, No. 3, May/June 2002, Supplement TR36 9


28. When performing process simulation trials, do 30. Does your process simulation program include the
you retain sterile media in sterile holding vessels following routine interventions?
to simulate standard manufacturing holding times
prior to filling? a. Weight/fill volume adjustment
Yes 38 88.4%
a. Yes 30 69.8% No 4 9.3%
b. No 13 30.2% N/A 0 0.0%
b. Component replenishment
Comments Yes 34 79.1%
a. Annually. No 4 9.3%
a. Overnight approach. N/A 0 0.0%
b. Yes, during the initial qualification of new c. Filter change
product. Yes 21 48.8%
b. Separate ventilation. No 16 37.2%
b. No sterile vessels. N/A 4 9.3%
d. Filling needle change
29. Do you inspect the filled containers prior to the end Yes 30 69.8%
of the full incubation period (14 days)? No 7 16.3%
N/A 3 7.0%
a. Yes - once after seven days e. Operator breaks
of incubation 25 58.1% Yes 40 93.0%
b. Yes - once, please specify No 2 4.6%
number of days of incubation 1 2.5% N/A 0 0.0%
c. Yes - twice, please specify f. Change in filling vessel
number of days of incubation 3 7.5% Yes 21 48.8%
d. Yes - three times, please specify No 19 44.2%
number of days of incubation 6 15.0% N/A 2 4.6%
e. No 8 20.0% g. Component change
Yes 20 46.5%
Comments No 16 37.2%
a. Eye drops. N/A 3 7.0%
b. 14 days h. Powder can changes
c. 7 days and 14 days (2) Yes 12 27.9%
c. 3 days and 7 days No 16 37.2%
d. 1, 4, 7, 10, 14 on a routine basis. N/A 12 27.9%
d. 2 or 3, 6 or 7, 14 (2) i. Dosing wheel, dosing disc changes
d. 3, 7, 14 (2) Yes 13 30.2%
d. 3, 5, 14 No 18 41.9%
e. If containers are opaque. N/A 10 23.2%
e. Ophthalmic ointments. j. Powder hopper changes
e. O n l y i n c a s e s o f s p e c i a l p r o b l e m s , a n Yes 6 13.9%
additional inspection after seven days is No 21 48.8%
performed. N/A 12 27.9%
e. Inspected prior to incubation and after k. Operator change
14 days. Yes 40 93.0%
No 1 2.3%
l. Other - please specify
Yes 17 39.5%
No 5 11.6%

10 PDA Journal of Pharmaceutical Science and Technology


Comments b. Until successful results are confirmed. If a
f. Only one vessel. failure occurs, the tape is filed with the inves-
j. Stopper. tigation report.
l. Equipment change out; reboot computers, b. Until results are approved. (2)
etc. b. Two years.
l. Stopper bowl change; pump changes. b. Next media fill.
l. Lyophilizer. d. But have Quality Assurance observe aseptic
l. Specific for each filling line. handling.
l. Too numerous to list here.
l. Container, stopper, cap jam, synchronization
failure. Growth Promotion Studies
l. Not really detailed in our program; done on
observation sheet. 32. When are growth promotion studies conducted on
l. Maintenance interventions. (2) each medium? Please mark all that apply.
l. Line adjustments, equipment replacement,
line jams. (3) a. Before filling 9 20.9%
l. All interventions that occur during routine b. After filling 7 16.3%
production. c. After incubation 36 83.7%
l. Simulation of in-process compounding d. Other - please explain 1 2.3%
sampling.
l. Use of sterile clarifying filters. Comments
l. Tip/cap track adjustments. a. Bulk sample from reactor.
l. Removal of jammed bodies. d. Before filling and after incubation.
l. Tube cap change out on ointment lines.
l. All filling lines have individual intrusion 33. In conducting growth promotion studies do you
rationales. These define all allowable use only pharmaceutical test organisms (e.g., those
intrusions in production (validated in recommended in USP <71> Sterility Testing)?
media fill). Will also include electrical/
engineering adjustments. a. Yes use only USP <71> organisms12 27.9%
b. No explain 30 69.8%
31. Do you routinely videotape process simulation
operations? Comments
Use organisms recommended by European
a. Yes 13 30.2% Pharmacopoeia. (3)
b. If yes, do you retain the tapes? 10 23.2% Suitability test organisms for the TGA, SUP, EP,
How long? (see comments) and BP. Sterility testing is included.
c. No 30 69.8% Environmental isolates and USP organisms. (21)
We use the European Ph organisms, plus two
Comments more frequently isolated from aseptic area.
a. All routine action concerning production. Range of organisms B. subtilis, C. albcans
a. Until end of incubation/reporting of trial. USP and facility isolates and S.aureus, ATCC
Video is used to formally assess production 6538.
operator technique. The strains have been chosen with respect to
b. Tapes are discarded if media fill is success- other growth promotion tests five different
ful. If investigation is required, tapes are strains are used.
retained to assist in investigation. Use organisms found during environmen-
b. Not yet determined. (2) tal monitoring of the media run and USP
b. Until batch is released. organisms.

Vol. 56, No. 3, May/June 2002, Supplement TR36 11


Incubation of Process Simulation Samples e. 15 to 20 days 0 0.0%
f. 21 days 0 0.0%
34. If you answered No to Question 33, how many species g. More than 21 days 0 0.0%
isolated from the aseptic processing environment do h. Other - please describe 1 2.3%
you include in the growth promotion test?
Comments
a. One 12 44.4% d. At least 14 days. Incubator rooms are thermally
b. Two 8 29.6% mapped. Some large vial sizes take longer to
c. Three 2 7.4% reach incubation temperature and will receive
d. Four 2 7.4% extra day of incubation.
e. More than four 4 14.8% h. NLT 7 days at 20-25C or 30-35C.

Comments 37. How do you insure the interior surfaces of the con-
e. Depends upon how many found during envi- tainer are contacted with media?
ronmental monitoring.
e. It depends upon what is recovered. a. Swirl and incubate top-side up 5 11.6%
e. It may also be from sterility test failure, if that is b. Invert one or more times, and
the reason for media fill, and from any positives incubate top-side up 22 51.2%
from previous media fill. c. Incubate all containers on their sides 2 4.6%
d. Incubate upside down 6 14.0%
35. What temperatures do you use to incubate process e. No special measures taken
simulation samples? If more than one temperature is (incubate randomly) 2 4.6%
utilized, please mark all that apply and explain your f. Other - please describe your practice 7 16.3%
practice.
Comments
a. 20 - 25C 38 88.4% d. Ointments.
b. 26 - 29C 0 0.0% f. Invert vials after reading each time, so every
c. 30 - 35C 40 93.0% three days switch from topside up to upside
d. 36 - 39C 0 0.0% down. (2)
e. 40 - 49C 0 0.0% f. Invert one or many times and incubate upside
down.
Comments f. Combination of C and D.
a. First seven days. (8) f. Swirl and incubate inverted.
a. For fungi. f. Incubate upside down for the first seven days and
a. Days 8-14. (2) topside down the last seven days.
a. Yeast and molds. (2) f. Swirl and incubate top side up for seven days.
c. This temperature is used when performing the Inspect at seven days, swirl, and invert for further
media fill for the AddVantage line. seven days.
c. Second seven days. (8)
c. For bacteria. 38. If you have found contaminated media fill test
c. Days 1-7. (2) units, what type of microorganism was most
c. All other process simulation studies. (2) prevalent?

36. How long do you incubate process simulation a. Gram positive rod 7 20.0%
containers? b. Gram positive coccus 31 88.6%
c. Gram negative rod 4 11.4%
a. Less than 7 days 0 0.0% d. Microaerophillic or anaerobic
b. 7 days 0 0.0% organism 1 2.8%
c. 8 -13 days 0 0.0% e. Molds 1 2.8%
d. 14 days 42 97.7% f. Yeasts 0 0.0%

12 PDA Journal of Pharmaceutical Science and Technology


Personnel Monitoring Comments
Ab. And after interventions
39. Are all personnel involved in media runs tested for the Ba. After processing
presence of microbes on their gowns and/or gloves? Bd. During routine personnel evaluation
Ca. After processing
a. Yes 39 90.7% Cb. And after interventions
b. No 4 9.3% Cd. Only required weekly
Da. After processing
40. If yes, which of the following sites are sampled? Mark Ea. After processing
all that apply. Ec. Rotate chest and shoulder sites
Ed. Only required weekly
A. Fingers (fingerprint or finger dab) Fb. Forehead
a. Upon entering the APA 7 17.9% Fb. Hoods
b. During the media fill test 20 51.3% Fb. Top of hood and back of gown
c. After the media fill test 30 76.9% Fb. Back, shoe covers, hood
d. Not tested 1 2.6% Fc. Goggles, wrist, neck
Fc. Waist, hood (2)
B. Palm or back of hand Fc. Shoulders
a. Upon entering the APA 3 7.7% Fc. Hood, armpit
b. During the media fill test 5 12.8% Fc. Head, both shoulders
c. After the media fill test 8 20.5% Fc. Stomach
d. Not tested 25 64.1%

C. Arms Environmental Monitoring, Aseptic Processing


a. Upon entering the APA 2 5.1%
b. During the media fill test 8 20.5% 41. What environmental sampling methods do you
c. After the media fill test 22 56.3% use in the filling room environment? If more
d. Not tested 11 28.2% than one method is utilized, please mark all
that apply.
D. Face-masks
a. Upon entering the APA 2 5.1% A. Microbiological Sampling Methods
b. During the media fill test 4 10.2% a. Swabs 23 53.5%
c. After the media fill test 16 41.0% b. RODAC or another form of
d. Not tested 20 51.3% surface sampling plates 42 97.7%
c. Settling plates 32 74.4%
E. Chest d. STA sampler 11 25.6%
a. Upon entering the APA 3 7.7% e. Electrostatic air sampler 2 4.6%
b. During the media fill test 9 23.1% f. Centrifugal sampler 20 46.5%
c. After the media fill test 25 64.1% g. Sieve-type sampler 8 18.6%
d. Not tested 7 17.9% h. Gelatin filter 4 9.3%
i. Other - please describe 7 16.3%
F. Other gown surfaces - please specify
a. Upon entering the APA 1 2.6% B. Total Particulate Air Monitoring Methods
b. During the media fill test 5 12.8% a. Continuous 14 32.5%
c. After the media fill test 17 43.6% b. Intermittent 28 65.1%
d. Not tested 15 38.5%

Vol. 56, No. 3, May/June 2002, Supplement TR36 13


Comments 45. If your monitoring approach is different for media
Af. Only during revalidation fill tests, how does it differ from routine or planned
Ai. SMA (4) production monitoring?
Ai. SAS (3)
Ai. MAS air sampler a. More locations than routine
Bb. Continuous in fill room for media fills; intermit- production 8 19.5%
tent in production b. More samples at same sites than
Bb. None routine production 11 26.8%
Bb. Limited monitoring during every shift. Continu- c. Same as routine production 23 56.1%
ous for full day 1x week. Continues during media d. Fewer locations than routine
fill (one-day trial). production 0 0.0%
e. Fewer samples at same sites
42. How frequently do you sample your APA for the than routine production 0 0.0%
presence of anaerobic organisms? f. Other - please describe 0 0.0%

a. Daily 2 4.6%
b. Weekly 4 9.3% Environmental Monitoring, Media Fills
c. Monthly 6 14.0%
d. Quarterly 5 11.6% 46. Are the microbial results obtained from process
e. Semi-annually 5 11.6% simulations used to establish the alert and/or
f. Annually 4 9.3% action levels used for environmental monitoring
g. Not at all 20 46.5% during routine production?

Comments a. Yes 6 13.9%


d. Swabs to FTM. b. No 30 69.8%
e. And daily when filling on one line. c. In part - please explain 8 18.6%
f. RODAC.
g. Performed only in conjunction with media fills. Comments
g. Historical data justified discontinuance on initial a. Every lot.
validation. b. Results are evaluated by intensive monitor-
ing at the validation stage.
43. If you test your APA environment for the presence b. Limits attained from environmental monitor-
of anaerobes, is this a result of potentially anaerobic ing validation.
process conditions? b. Pharmacopoeial guideline limits are used.
c. Alert and/or action levels were internally
a. Yes 10 31.2% based upon the results of the initial MFs.
b. No 22 68.8% Subsequent levels are based upon the analy-
sis of the annual EM data.
44. How frequently do you sample your APA for the c. Process simulations are included to obtain
presence of molds and yeasts? alert/action levels.
c. Done in addition to routine EM sampling
a. Daily 20 47.6% results (5).
b. Weekly 5 11.9% c. Consider trend for non-viable.
c. Monthly 5 11.9%
d. Quarterly 4 9.5% 47. To what extent are environmental isolates from
e. Semi-annually 2 4.8% process simulation runs identified?
f. Annually 4 9.5%
g. Not at all 2 4.8% a. Morphology only 0 0.0%
b. Gram stain 5 11.6%
Comments c. Genus 6 13.9%
a. Our media (TSIS) is able to detect both fungi d. Species 37 86.0%
and bacteria.

14 PDA Journal of Pharmaceutical Science and Technology


Comments In the following section, please identify all of the
b. Below alert/alarm levels. aseptic processing technologies (see descriptions be-
b. If sample is above alert limit. low) presently in use at your facility. The descriptions
d. Plus species, if possible. (4) are meant to broadly define the filling environment.
d. Above alert/alarm levels. Please complete the table for those technologies that
d. Class 100 area and OOS samples are identified. most resemble those within your facility. A separate
d. If sample is above action limit. page has been provided for each processing technol-
d. All isolates from Class 100 areas identified ogy. Please indicate your response in the appropriate
to species. columns.

48. To what extent are isolates from contaminated units a. Manual Filling - Gowned personnel
identified? perform the majority of aseptic
processing tasks, i.e., placing the
a. Morphology only 0 0.0% container under the filling head,
b. Gram stain 1 2.3% closing the container, sealing
c. Genus 3 7.0% the container. Human intervention
d. Species 41 95.3% is continuous and very intensive. 4 9.3%

Comments b. Semi-automated Filling -


d. C and D whenever possible. (2) Containers are transferred from
dry heat ovens by gowned personnel;
49. Do you follow the same environmental monitor- filling, closing and sealing are
ing strategy in prospective (PQ validation) media performed by machines. Trays
fill tests that you plan to use in conducting routine are manually loaded into lyophi-
monitoring of your new or modified facility? lizer. Continuous human
intervention. 13 30.2%
a. Yes 33 78.6%
b. No 9 21.4% c. Conventional Filling - Containers
are conveyed from dry heat
Comments tunnel to machine filling; closing
b. More during validation, then reduce. and sealing are performed by
machines. Fill weights manually
50. Do you follow the same environmental monitoring adjusted by gowned personnel.
strategy for revalidation media fill tests that you Human intervention is most
use in conducting routine production environmen- intensive during set-up, but
tal monitoring? routine interventions for
component charging, adjust-
a. Yes 39 90.7% ments, minor maintenance,
b. No 6 13.9% and weight checking occur. 16 37.2%

Comments
Do more.

Vol. 56, No. 3, May/June 2002, Supplement TR36 15


d. Advanced Conventional - Containers g. Open Isolator - Processing in a
are conveyed from dry heat decontaminated environment,
tunnel to machine filling; closing with discharge via a discharge
and sealing are performed by port into an adjacent lower
machines. Fill weights remotely classified environment. Filling
adjusted. Human intervention is and closure typically done using
limited to minor adjustments very highly automated equip-
and component charging. Fill ment. Usually employed for
machine equipped for CIP/SIP. high volume and/or high speed
Automated loading of lyophilizer. 7 16.3% filling operations. No human
intervention except through isola-
e. Form-Fill-Seal/Blow-Fill-Seal - tor system gloves or half-suits. 3 7.0%
Plastic containers formed/blow
molded in line immediately prior Comments
to filling. Molds and product b. EtO sterilizer.
contact filling parts are subjected c./d. All filling machines have some level of restricted
to CIP/SIP prior to start of access glove port protection. Only major inter-
the filling process. Human ventions require door open intrusion.
intervention rarely occurs, g. Barrier with totally separate Class 100 system re-
essentially an unmanned turns, etc. (800 air changes/hour) inside a Class
clean room process. 4 9.3% 100 environment. Human intervention when
needed (start-up and periodic issues such as
f. Closed Isolator - Full processing glass handling modifications). Media fills done
in a decontaminated environment. with barrier doors open and human intervention.
Transfers in and out are Normally, door totally closed during production.
accomplished using RTPs or All CIP/SIP; stoppers supplied to line CIP/SIP
specialized transfer systems only item requiring autoclave is stopper vibrating
that maintain the integrity of feed bowl.
the filling environment. Generally
restricted to low volume and/or
lower speed filling or assembly
operations. No human intervention
except through isolator system
gloves or half-suits. 2 4.6%

16 PDA Journal of Pharmaceutical Science and Technology


Manual Filling
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies

51. What percentage of your aseptically filled products is manufactured using


this technology?
a. >75% 2 28.6% 0 0.0% 0 0.0% 1 14.3% 1 14.3% 1 14.3%
b. 50 75% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 25 50% 1 14.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 14.3%
d. <25% 2 28.6% 1 14.3% 0 0.0% 1 14.3% 0 0.0% 1 14.3%

52. What is the minimum number of units filled?


a. <1,000 3 50.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 16.7%
b. 1,000 - 1,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 2,000 - 2,999 0 0.0% 0 0.0% 0 0.0% 1 16.7% 0 0.0% 1 16.7%
d. 3,000 - 3,999 2 33.3% 2 33.3% 0 0.0% 2 33.3% 0 0.0% 1 16.7%
e. 4,000 - 4,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 5,000 - 9,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. 10,000 - 14,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
h. 15,000 or more 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
i. Other 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

Vol. 56, No. 3, May/June 2002, Supplement TR36


53. Has the number in response to Question 52 increased in the
last three years?
a. Yes 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. No 5 83.3% 1 16.7% 0 0.0% 3 50.0% 0 0.0% 3 50.0%

54. How is your acceptance criterion defined? (0.1% is used in the


examples below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit (e.g., 3 50.0% 0 0.0% 0 0.0% 1 16.7% 0 0.0% 1 16.7%
0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. Another non-statistical approach - please describe 2 33.3% 1 16.7% 0 0.0% 2 33.3% 0 0.0% 2 33.3%
Comments: d. <0.1%
One positive alert, >1 action

55. Do you utilize an alert limit in addition to the acceptance criterion


(action limit)?
a. Yes - please describe how this limit has been set 3 50.0% 1 16.7% 0 0.0% 2 33.3% 0 0.0% 2 33.3%
b. No 2 33.3% 0 0.0% 0 0.0% 1 16.7% 0 0.0% 1 16.7%
Comments: a. At any positive case
One positive alert.

56. What acceptance criterion do you employ?


a. <0.05% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 0.05 - 0.09% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 0.10% 4 80.0% 0 0.0% 0 0.0% 2 40.0% 0 0.0% 2 40.0%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

57. Has the acceptance criterion for contamination been tightened in the last
three years?
a. Yes 1 16.7% 1 16.7% 0 0.0% 1 16.7% 0 0.0% 1 16.7%
b. No 4 66.7% 0 0.0% 0 0.0% 2 33.3% 0 0.0% 2 33.3%

17
18
Semi-Automated Filling
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies

58. What percentage of your aseptically filled products is manufactured


using this technology?
a. >75% 5 26.3% 2 10.5% 2 10.5% 1 5.3% 1 5.3% 1 5.3%
b. 50 75% 4 21.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 10.5%
c. 25 50% 2 10.5% 1 5.3% 0 0.0% 1 5.3% 0 0.0% 2 10.5%
d. <25% 6 31.6% 4 21.0% 0 0.0% 6 31.6% 0 0.0% 3 15.8%

59. What is the minimum number of units filled?


a. <1,000 1 5.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 5.0%
b. 1,000 - 1,999 1 5.0% 0 0.0% 0 0.0% 1 5.0% 0 0.0% 0 0.0%
c. 2,000 - 2,999 1 5.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. 3,000 - 3,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 4,000 - 4,999 2 10.0% 1 5.0% 0 0.0% 1 5.0% 0 0.0% 0 0.0%
f. 5,000 - 9,999 6 30.0% 4 20.0% 2 10.0% 1 5.0% 0 0.0% 3 15.0%
g. 10,000 - 14,999 2 10.0% 1 5.0% 0 0.0% 2 10.0% 0 0.0% 1 5.0%
h. 15,000 or more 3 15.0% 1 5.0% 0 0.0% 1 5.0% 1 5.0% 1 5.0%
i. Other 2 10.0% 1 5.0% 0 0.0% 2 10.0% 0 0.0% 2 10.0%

60. Has the number in response to question 59 increased in the last


three years?
a. Yes 4 20.0% 2 10.0% 0 0.0% 4 20.0% 0 0.0% 1 5.0%
b. No 13 65.0% 6 30.0% 2 10.0% 5 25.0% 1 5.0% 6 30.0%

61. How is your acceptance criterion defined? (0.1% is used in the


examples below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 1 5.3% 0 0.0% 0 0.0% 1 5.3% 0 0.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit 12 63.1% 5 26.3% 1 5.3% 6 31.6% 0 0.0% 7 36.8%
(e.g., 0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 1 5.3% 1 5.3% 1 5.3% 0 0.0% 1 5.3% 0 0.0%
d. Another non-statistical approach - please describe 3 15.8% 1 5.3% 0 0.0% 1 5.3% 0 0.0% 1 5.3%
Comments: d. <0.1%; 1 positive alert, >1 action

62. Do you utilize an alert limit in addition to the acceptance criterion


(action limit)?
a. Yes - please describe how this limit has been set 12 66.7% 6 33.3% 1 5.5% 5 27.8% 1 5.5% 6 33.3%
b. No 5 27.8% 1 5.5% 1 5.5% 3 16.7% 0 0.0% 2 11.8%
Comments: b. ISO (4); At any positive case; 5% of action level;
1 positive alert, >1 action; 0.02%; Target 0 positive limits

63. What acceptance criterion do you employ?


a. <0.05% 3 17.6% 0 0.0% 0 0.0% 2 11.8% 0 0.0% 0 0.0%
b. 0.05 - 0.09% 3 17.6% 2 11.8% 1 5.9% 1 5.9% 0 0.0% 0 0.0%
c. 0.10% 10 58.8% 4 23.5% 1 5.9% 4 23.5% 1 5.9% 7 41.2%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

64. Has the acceptance criterion for contamination been tightened in


the last three years?
a. Yes 7 38.9% 4 22.2% 2 11.1% 4 22.2% 0 0.0% 1 5.5%
b. No 10 55.5% 3 16.7% 0 0.0% 4 22.2% 1 5.5% 6 33.3%
Comments: a. Looking at reacting to any growth for the future.

PDA Journal of Pharmaceutical Science and Technology


Conventional Filling
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies

65. What percentage of your aseptically filled products is manufactured


using this technology?
a. >75% 8 30.8% 5 19.2% 1 3.8% 6 23.1% 3 11.5% 3 11.5%
b. 50 75% 7 26.9% 0 0.0% 0 0.0% 2 7.7% 1 3.8% 2 7.7%
c. 25 50% 3 11.5% 3 11.5% 0 0.0% 3 11.5% 0 0.0% 2 7.7%
d. <25% 1 3.8% 0 0.0% 0 0.0% 3 11.5% 2 7.7% 0 0.0%

66. What is the minimum number of units filled?


a. <1,000 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 1,000 - 1,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 2,000 - 2,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. 3,000 - 3,999 3 11.5% 2 7.7% 0 0.0% 2 7.7% 3 11.5% 0 0.0%
e. 4,000 - 4,999 3 11.5% 1 3.8% 0 0.0% 1 3.8% 2 7.7% 1 3.8%
f. 5,000 - 9,999 5 19.2% 1 3.8% 0 0.0% 2 7.7% 1 3.8% 3 11.5%
g. 10,000 - 14,999 5 19.2% 3 11.5% 1 3.8% 5 19.2% 0 0.0% 2 7.7%
h. 15,000 or more 4 15.4% 3 11.5% 0 0.0% 3 11.5% 1 3.8% 2 7.7%
i. Other 2 7.7% 0 0.0% 0 0.0% 1 3.8% 0 0.0% 0 0.0%

Vol. 56, No. 3, May/June 2002, Supplement TR36


67. Has the number in response to question 66 increased in the
last three years?
a. Yes 6 23.1% 2 7.7% 0 0.0% 5 19.2% 5 19.2% 2 7.7%
b. No 15 57.7% 7 26.9% 1 3.8% 8 30.8% 2 7.7% 6 23.1%

68. How is your acceptance criterion defined? (0.1% is used in the examples
below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 0 0.0% 1 4.0% 0 0.0% 0 0.0% 2 8.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit 16 64.0% 5 20.0% 0 0.0% 10 40.0% 4 16.0% 7 28.0%
(e.g., 0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 1 4.0% 1 4.0% 1 4.0% 0 0.0% 0 0.0% 0 0.0%
d. Another non-statistical approach - please describe 2 8.0% 1 4.0% 0 0.0% 1 4.0% 1 4.0% 1 4.0%
Comment: c. 5 in 10,000
d. 1 positive alert, >1 action
Solutions: 0 contamination units, irrespective of number of units filled.
Solids: 1 contaminated unit allowed in total of 3 PQ validation trials.

69. Do you utilize an alert limit in addition to the acceptance criterion


(action limit)?
a. Yes - please describe how this limit has been set 15 60.0% 6 24.0% 1 4.0% 8 32.0% 4 16.0% 7 28.0%
b. No 5 20.0% 2 8.0% 0 0.0% 4 16.0% 3 12.0% 1 4.0%

70. What acceptance criterion do you employ?


a. <0.05% 1 4.5% 2 9.1% 0 0.0% 2 9.1% 3 13.6% 0 0.0%
b. 0.05 - 0.09% 3 13.6% 2 9.1% 1 4.5% 0 0.0% 2 9.1% 1 4.5%
c. 0.10% 12 54.5% 2 9.1% 0 0.0% 7 31.8% 1 4.5% 5 22.7%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

71. Has the acceptance criterion for contamination been tightened in


the last three years?
a. Yes 6 24.0% 3 12.0% 0 0.0% 4 16.0% 6 24.0% 3 12.0%
b. No 14 56.0% 5 20.0% 1 4.0% 8 32.0% 1 4.0% 5 20.0%

19
20
Advanced Conventional Filling
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies

72. What percentage of your aseptically filled products is manufactured


using this technology?
a. >75% 2 22.2% 2 22.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 50 75% 1 11.1% 1 11.1% 0 0.0% 2 22.2% 0 0.0% 0 0.0%
c. 25 50% 1 11.1% 0 0.0% 0 0.0% 1 11.1% 0 0.0% 0 0.0%
d. <25% 2 22.2% 1 11.1% 0 0.0% 0 0.0% 0 0.0% 1 11.1%

73. What is the minimum number of units filled?


a. <1,000 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 1,000 - 1,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 2,000 - 2,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. 3,000 - 3,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 4,000 - 4,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 5,000 - 9,999 1 11.1% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. 10,000 - 14,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
h. 15,000 or more 5 55.5% 4 44.4% 0 0.0% 3 33.3% 0 0.0% 0 0.0%
i. Other 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 11.1%

74. Has the number in response to Question 73 increased in the last


three years?
a. Yes 2 22.2% 2 22.2% 0 0.0% 2 22.2% 0 0.0% 0 0.0%
b. No 4 44.4% 2 22.2% 0 0.0% 1 11.1% 0 0.0% 1 11.1%

75. How is your acceptance criterion defined? (0.1% is used in the


examples below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 1 12.5% 1 12.5% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit 3 37.5% 3 37.5% 0 0.0% 2 25.0% 0 0.0% 1 12.5%
(e.g., 0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 1 12.5% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. Another non-statistical approach - please describe 1 12.5% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Comments: c. 5 in 10,000
d. Zero contaminated units irrespective of number of units filled.

76. Do you utilize an alert limit in addition to the acceptance criterion


(action limit)?
a. Yes - please describe how this limit has been set 3 37.5% 2 25.0% 0 0.0% 1 12.5% 0 0.0% 1 12.5%
b. No 2 25.0% 1 12.5% 0 0.0% 1 12.5% 0 0.0% 0 0.0%
Comments: a. 1 in 10,000; Per ISO 13408

77. What acceptance criterion do you employ?


a. <0.05% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 0.05 - 0.09% 2 28.6% 1 14.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 0.10% 2 28.6% 2 28.6% 0 0.0% 2 28.6% 0 0.0% 1 14.3%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

78. Has the acceptance criterion for contamination been tightened in


the last three years?
a. Yes 2 25.0% 1 12.5% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. No 3 37.5% 2 25.0% 0 0.0% 2 25.0% 0 0.0% 1 12.5%
Comments: a. Initial qualification only.

PDA Journal of Pharmaceutical Science and Technology


Form-Fill-Seal/Blow-Fill-Seal
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies

79. What percentage of your aseptically filled products is manufactured


using this technology?
a. >75% 2 40.0% 1 20.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 50 75% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 25 50% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. <25% 3 60.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 20.0%

80. What is the minimum number of units filled?


a. <1,000 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 1,000 - 1,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 2,000 - 2,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. 3,000 - 3,999 2 40.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 4,000 - 4,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 5,000 - 9,999 2 40.0% 1 20.0% 0 0.0% 0 0.0% 0 0.0% 1 20.0%
g. 10,000 - 14,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
h. 15,000 or more 1 20.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
i. Other 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

Vol. 56, No. 3, May/June 2002, Supplement TR36


81. Has the number in response to question 80 increased in the
last three years?
a. Yes 2 40.0% 1 20.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. No 3 60.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 20.0%

82. How is your acceptance criterion defined? (0.1% is used in the


examples below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 2 40.0% 1 20.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit 3 60.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 20.0%
(e.g., 0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. Another non-statistical approach - please describe 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

83. Do you utilize an alert limit in addition to the acceptance criterion


(action limit)?
a. Yes - please describe how this limit has been set 3 60.0% 1 20.0% 0 0.0% 0 0.0% 0 0.0% 1 20.0%
b. No 2 40.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Comments: a. ISO; Per requirements of PDA, USP, Compendial

84. What acceptance criterion do you employ?


a. <0.05% 2 40.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 0.05 - 0.09% 1 20.0% 1 20.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 0.10% 2 40.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 20.0%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

85. Has the acceptance criterion for contamination been tightened in


the last three years?
a. Yes 1 20.0% 1 20.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. No 4 80.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 20.0%

21
22
Closed Isolator Filling
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies

86. What percentage of your aseptically filled products is manufactured


using this technology?
a. >75% 1 33.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 33.3%
b. 50 75% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 25 50% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. <25% 0 0.0% 0 0.0% 0 0.0% 1 33.3% 0 0.0% 0 0.0%

87. What is the minimum number of units filled?


a. <1,000 1 33.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 33.3%
b. 1,000 - 1,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 2,000 - 2,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. 3,000 - 3,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 4,000 - 4,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 5,000 - 9,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. 10,000 - 14,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
h. 15,000 or more 0 0.0% 0 0.0% 0 0.0% 1 33.3% 0 0.0% 0 0.0%
i. Other 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

88. Has the number in response to Question 87 increased in the


last three years?
a. Yes 0 0.0% 0 0.0% 0 0.0% 1 33.3% 0 0.0% 0 0.0%
b. No 1 33.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 33.3%

89. How is your acceptance criterion defined? (0.1% is used in the


examples below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit (e.g., 1 33.3% 0 0.0% 0 0.0% 1 33.3% 0 0.0% 0 0.0%
0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. Another non-statistical approach - please describe 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 33.3%
Comments: 0 positive, regardless of number of units filled.

90. Do you utilize an alert limit in addition to the acceptance criterion


(action limit)?
a. Yes - please describe how this limit has been set 0 0.0% 0 0.0% 0 0.0% 1 33.3% 0 0.0% 0 0.0%
b. No 1 33.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 33.3%
Comments: a. Alert = 1

91. What acceptance criterion do you employ?


a. <0.05% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 1 50.0%
b. 0.05 - 0.09% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 0.10% 1 50.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

92. Has the acceptance criterion for contamination been tightened in


the last three years?
a. Yes 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. No 1 33.3% 0 0.0% 0 0.0% 1 33.3% 0 0.0% 1 33.3%

PDA Journal of Pharmaceutical Science and Technology


Open Isolator Filling
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies

93. What percentage of your aseptically filled products is manufactured


using this technology?
a. >75% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 50 75% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 25 50% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. <25% 3 100.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 66.7%

94. What is the minimum number of units filled?


a. <1,000 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 1,000 - 1,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 2,000 - 2,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. 3,000 - 3,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 4,000 - 4,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 5,000 - 9,999 2 66.7% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 66.7%
g. 10,000 - 14,999 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
h. 15,000 or more 1 33.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
i. Other 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

Vol. 56, No. 3, May/June 2002, Supplement TR36


95. Has the number in response to question 94 increased in the
last three years?
a. Yes 1 33.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. No 2 66.7% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 66.7%

96. How is your acceptance criterion defined? (0.1% is used in the


examples below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 1 33.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit 2 66.7% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 66.7%
(e.g., 0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
d. Another non-statistical approach - please describe 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

97. Do you utilize an alert limit in addition to the acceptance criterion


(action limit)?
a. Yes - please describe how this limit has been set 3 100.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 66.7%
b. No 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Comments: a. ISO (2)
Alert = 1

98. What acceptance criterion do you employ?


a. <0.05% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. 0.05 - 0.09% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
c. 0.10% 2 100.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 100.0%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

99. Has the acceptance criterion for contamination been tightened in


the last three years?
a. Yes 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
b. No 3 100.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 2 66.7%

23
24
Data Composite
Question # Solutions Suspensions Ointments Freeze Dried Solids Clinical Supplies
Number of Responses 61 23 4 29 9 24
A. What is the minimum number of units filled?
a. <1,000 5 8.6% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 3 12.5%
b. 1,000 - 1,999 1 1.7% 0 0.0% 0 0.0% 1 3.4% 0 0.0% 0 0.0%
c. 2,000 - 2,999 1 1.7% 0 0.0% 0 0.0% 1 3.4% 0 0.0% 1 4.2%
d. 3,000 - 3,999 7 12.1% 3 13.0% 0 0.0% 4 13.8% 3 37.5% 1 4.2%
e. 4,000 - 4,999 5 8.6% 2 8.7% 0 0.0% 2 6.9% 3 37.5% 1 4.2%
f. 5,000 - 9,999 16 27.6% 5 21.7% 3 75.0% 3 10.3% 1 12.5% 9 37.5%
g. 10,000 - 14,999 7 12.1% 4 17.4% 1 25.0% 7 30.4% 0 0.0% 3 12.5%
h. 15,000 or more 15 25.9% 8 34.8% 0 0.0% 8 27.6% 2 25.0% 3 12.5%
i. Other 4 6.9% 1 4.3% 0 0.0% 3 10.3% 0 0.0% 3 12.5%
Number of Responses 58 23 4 29 8 23
B. Has the number in response to the previous question increased
in the last three years?
a. Yes 15 25.9% 7 30.4% 1 25.0% 12 41.4% 5 62.5% 3 13.0%
b. No 43 74.1% 16 69.6% 3 75.0% 17 58.6% 3 37.5% 20 87.0%
Number of Responses 56 21 3 25 8 24
C. How is your acceptance criterion defined? (0.1% is used in the
examples below.)
a. Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 5 8.9% 3 14.3% 0 0.0% 1 4.0% 2 25.0% 0 0.0%
5,000, etc.)
b. Use Poisson statistical derived approach with 95% confidence limit 40 71.4% 13 61.9% 1 33.3% 20 80.0% 4 50.0% 19 79.2%
(e.g., 0 in 3,000, 1 in 4,740, etc.)
c. Another statistical approach - please describe 3 5.4% 2 9.5% 2 66.7% 0 0.0% 1 12.5% 0 0.0%
d. Another non-statistical approach - please describe 8 14.3% 3 14.3% 0 0.0% 4 16.0% 1 12.5% 5 20.8%
Number of Responses 56 20 3 26 8 24
D. Do you utilize an alert limit in addition to the acceptance criterion
(action limit)?
a. Yes - please describe how this limit has been set 39 69.6% 16 80.0% 2 66.7% 17 65.4% 5 62.5% 19 79.2%
b. No 17 30.4% 4 25.0% 1 33.3% 9 34.6% 3 37.5% 5 20.8%
Number of Responses 48 16 3 20 7 20
E. What acceptance criterion do you employ?
a. <0.05% 6 12.5% 2 12.5% 0 0.0% 4 20.0% 3 42.6% 1 5.0%
b. 0.05 - 0.09% 9 18.8% 6 37.5% 2 66.7% 1 5.0% 2 28.6% 1 5.0%
c. 0.10% 33 68.8% 8 50.0% 1 33.3% 15 75.0% 2 28.6% 18 90.0%
d. 0.11 - 0.14% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
e. 0.15 - 0.2% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
f. 0.21 - 0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
g. >0.3% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%
Number of Responses 56 20 3 26 8 23
F. Has the acceptance criterion for contamination been tightened in
the last three years?
a. Yes 17 30.4% 10 50.0% 2 66.7% 9 34.6% 6 75.0% 5 21.7%
b. No 39 69.6% 10 50.0% 1 33.3% 17 65.4% 2 25.0% 18 78.3%

PDA Journal of Pharmaceutical Science and Technology


Blow/Form-Fill-Seal Products Comments
Other: Simulated sterile bulk powder dispensing.
If you do not produce this type of product at this site,
please skip to the next section. 103. Do you use a placebo material in lieu of the actual
product?
100. If your firm uses blow/form-fill-seal technology,
do you use a campaign manufacturing process? a. Yes 8 57.1%
b. No 5 35.7%
a. Yes 3 100.0%
b. No 2 66.7% Comments
a. TSB
101. If you answered Yes to Question 100, what is a. Not Applicable
the duration of your longest campaigned filling
operation? 104. If yes, how is the placebo material sterilized?

a. One day 0 0.0% a. Irradiation 3 21.4%


b. Two days 0 0.0% b. Gas sterilization 1 7.1%
c. Three days 0 0.0% c. Dry Heat 0 0.0%
d. Four days 0 0.0% d. Moist Heat 2 14.3%
e. Five days 1 50.0% e. Other 3 21.4%
f. Seven days 0 0.0%
g. Ten days 0 0.0% Comments
h. Fourteen days 0 0.0% a. For powder.
i. Other, please specify 1 50.0% e. Received sterile.
e. Sterilized during processing (moist heat and
Comments filtration)
i. 148 hours e. Bulk sterilization for vehicle.
e. Filtration.

Suspension Products 105. What placebo material do you use?

If you do not produce this type of product at this site, a. Mannitol 0 0.0%
please skip to the next section. b. Lactose 0 0.0%
c. Polyethylene glycol 0 0.0%
102. Does your suspension media fill test include the d. Diatomaceous earth 0 0.0%
following steps in the manufacturing process? e. Other - please describe 9 100.0%
Please mark all that apply.
Comments
a. Bulk sterilization of vehicle 11 78.6% e. Not Applicable
b. Simulation of powder addition 8 57.1% e. SCDM powder (4)
c. Simulated milling/homogenization e. Dextrose.
of Suspension 9 64.3% e. We use soybean without dextrose as solution and
d. Filling of media (simulated product) sterilized dextrose as powder to add.
into product containers 12 85.7% e. Sterile TSB or NaCMC

Vol. 56, No. 3, May/June 2002, Supplement TR36 25


Sterile Semi-Solid Products Freeze Dried Products

If you do not produce this type of product at this site, If you do not produce this type of product at this site, please
please skip to the next section. skip to the next section.

106. Does your semi-solid process simulation include the 110. In conducting the simulated lyophilization of media
following steps in the manufacturing process? Please during your media fill test, what level of vacuum do
mark all that apply. you establish for the lyophilizer chamber?

a. Bulk sterilization of vehicle 3 75.0% a. None 3 15.8%


b. Simulation of powder addition 4 100.0% b. <20 in. Hg 12 63.1%
c. Simulated milling/homogenization 3 75.0% c. 21 - 28 in. Hg 3 15.8%
d. Filling into product containers 3 75.0% d. >28 in. Hg 2 10.5%

Comments 111. How long do the media filled vials remain in the
d. Plastic, not glass containers. lyophilizer under vacuum?

107. Do you use a placebo material in lieu of filling the a. <2 hr. 9 47.4%
actual product? b. 2 - 8 hr. 2 10.5%
c. 9 - 24 hr. 4 21.0%
a. Yes 4 100.0% d. Full drying time 4 21.0%
b. No 0 0.0%
Comments
108. If yes, how is the placebo material sterilized? c. In lyophilizer, not under vacuum.
d. Three times until <20mHg and reintegration after
a. Irradiation 4 100.0% a complete night at ambient pressure.
b. Gas sterilization 0 0.0% Once per year, the longest drying cycle is simu-
c. Dry heat 0 0.0% lated.
d. Moist heat 0 0.0%
e. Other 1 25.0% 112. Do you freeze the media filled vials at any time during
the simulation procedure?
Comments
e. Filtration a. Yes - additional growth promotion
studies performed 1 5.0%
109. What placebo material do you use? b. Yes - no additional promotion
studies performed 2 10.0%
a. Mannitol 0 0.0% c. No 17 85.0%
b. Lactose 1 25.0%
c. Polyethylene glycol 0 0.0%
d. Diatomaceous earth 0 0.0% Sterile Dry Powder Products
e. Other - please describe 3 75.0%
If you do not produce this type of product at this site, please
Comments skip to the next section.
e. TSB and WFI.
e. Dextrose 113. Do you use media fill tests to validate aseptic powder
e. Sterile NaCMC filling operations?

a. Yes 12 100.0%
b. No - please describe your
validation approach 0 0.0%

26 PDA Journal of Pharmaceutical Science and Technology


Comments
114. How is the media fill test conducted, i.e., what is the d. Sterile dehydrated TSB.
sequence of steps? d. Whole manufacturing process is simulated with
all raw materials except the active substance. The
a. Powder filling on-line, followed result is a powder that is filled.
by liquid filling off-line 1 8.3%
b. Powder filling on-line, followed 119. To what extent do you monitor non-viable particulates
by liquid filling on-line 10 83.3% during sterile powder filling production operations?
c. Liquid filling on-line, followed Please mark all that apply.
by powder filling on-line 1 8.3%
d. Liquid filling off-line, followed a. Prior to filling 5 45.4%
by powder filling on-line 0 0.0% b. During filling 2 18.2%
e. Other - please describe 1 8.3% c. At end of filling 0 0.0%
d. During process simulation runs 3 27.3%
Comments e. Not at all 3 27.3%
e. Liquid fill on-line through powder filler. f. Other - please explain 2 18.2%

115. Does your powder media fill test include the following Comments
steps in the manufacturing process? Please mark all f. Filter integrity testing twice per year and non-
that apply. viable particle counting twice per year.
f. Monthly reclassification of all critical cabinets
a. Blending 3 25.0% with reference to FS 209 E, at rest.
b. Subdivision prior to filling 3 25.0%
c. Filling into product containers 12 100.0% 120. Do you use the same non-viable particulate moni-
toring volume and frequency during your media
116. Do you use a placebo material in lieu of filling the fill tests?
actual product?
a. Yes 8 80.0%
a. Yes 11 91.7% b. No 3 30.0%
b. No 1 8.3%
Comments
117. If yes, how is the placebo powder sterilized? b. Monthly reclassification of all critical cabinets
with reference to FS 209 E, at rest. Not during
a. Irradiation 10 100.0% media trials.
b. Gas sterilization 0 0.0%
c. Dry heat 0 0.0% 121. If you powder fill antibiotics, does your media fill test
d. Moist heat 1 10.0% utilize an agent which will inactivate trace antibiotics
e. Other 1 10.0% that might be present?

Comments a. Yes 8 80.0%


e. Aseptic processed and bulk lyophilized. b. No - please describe your practice 2 20.0%

118. What placebo material do you use? Comments


b. Inactivate area prior to media fill.
a. Mannitol 2 20.0%
b. Lactose 6 60.0%
c. Polyethylene glycol 2 20.0%
d. Diatomaceous earth 0 0.0%
e. Other - please describe 3 30.0%

Vol. 56, No. 3, May/June 2002, Supplement TR36 27


Research & Development (Clinical Trial Material) 124. What is the surrounding environment for closed iso-
lators utilized for aseptic filling in your facility?
If you do not produce clinical supplies at this site,
please skip to the next section. a. Class 100/ISO 5 (EU Grade A or B) 0 0.0%
b. Class 1,000/ISO 6 0 0.0%
122. How is the minimum number of media fill test units c. Class 10,000/ISO 7 (EU Grade C) 1 16.7%
filled in support of clinical supplies determined? d. Class 100,000/ISO 8 (EU Grade D) 5 83.3%
e. Controlled, but unclassified 0 0.0%
a. Fill only actual lot size 4 25.0% f. Other - please describe 0 0.0%
b. Arbitrary number greater than lot size2 12.5%
c. >3000 8 50.0% 125. What is the surrounding environment for open isola-
d. Other - please explain 3 18.7% tors utilized for aseptic filling in your facility?

Comments a. Class 100/ISO 5 (EU Grade A or B) 0 0.0%


d. Performed as part of routine processing practices. b. Class 1,000/ISO 6 0 0.0%
d. Minimum 6,500 or capacity of freeze dryer. c. Class 10,000/ISO 7 (EU Grade C) 1 25.0%
d. 4,750 d. Class 100,000/ISO 8 (EU Grade D 2 50.0%
e. Controlled, but unclassified 0 0.0%
f. Other - please describe 1 25.0%
Isolation/Barrier Technology
Comments
If you do not utilize these technologies at this site, f. No open isolators.
please skip to the next section.
126. If you use closed/open isolators for aseptic process-
123. What is the surrounding environment for closed iso- ing, do you employ a campaign strategy?
lators utilized for sterility testing in your facility?
a. Yes 4 50.0%
a. Class 100/ISO 5 (EU Grade A or B) 0 0.0% b. No 4 50.0%
b. Class 1,000/ISO 6 0 0.0%
c. Class 10,000/ISO 7 (EU Grade C) 0 0.0% 127. If you answered yes to Question 126, what is
d. Class 100,000/ISO 8 (EU Grade D) 0 0.0% the duration of your longest campaigned filling
e. Controlled, but unclassified 6 60.0% operation?
f. Other - please describe 4 40.0%
a. One day 0 0.0%
Comments b. Two days 1 25.0%
a. Isolation = CIP/SIP and never opened during pro- c. Three days 1 25.0%
cessing; Barrier = CIP/SIP or product path and d. Four days 0 0.0%
stopper handing, but unit can be opened ruing e. Five days 0 0.0%
process has own Class 100 environment. f. Seven days 1 25.0%
f. Unclassified, uncontrolled. g. Ten days 0 0.0%
f. Sterility tests are not performed in-house. h. Fourteen days 1 25.0%
f. Uncontrolled (2) i. Other, please specify 0 0.0%

28 PDA Journal of Pharmaceutical Science and Technology


128. What method(s) do you use to decontaminate your Comments
isolator systems? f. Statistical analysis.
f. Combination of C and D.
a. Chlorine dioxide 0 0.0% f. At initial validation Based upon intensive
b. Hydrogen peroxide vapor 6 66.7% monitoring, worst case sites are selected. Lev-
c. Microcondensing hydrogen peroxide 0 0.0% els will be adjusted based upon routine data.
d. Liquid hydrogen peroxide 1 11.1% Alert limits also have been generated based
e. Steam/hydrogen peroxide 0 0.0% upon routine data.
f. Peracetic acid 1 11.1%
g. Ozone 0 0.0% 131. Do the same microbial levels apply to all of the
Class 100/ISO 5 (EU Grade A) environments in
Comments your APA?
Other: Sanitizing solution system.
a. Yes 40 93.0%
129. If you surface decontaminate materials to bring into b. No 3 7.0%
your isolator, what method(s) do you use?
132. What is the surrounding environment to Class 100/
a. Hydrogen peroxide vapor 3 37.5% ISO 5 (EU Grade A) utilized for aseptic filling in your
b. Pulsed high intensity light 1 12.5% facility?
c. Ultraviolet light 1 12.5%
d. Liquid sporicide applied automatically0 0.0% a. Class 100/ISO 5 (EU Grade A)
e. Liquid sporicide applied manually 3 37.5% (laminar flow) 8 18.8%
f. Another method, please describe 3 37.5% b. Class 100/ISO 6 under static
conditions (EU Grade B)
Comments (non-laminar flow) 16 37.2%
f. All material brought into the isolator is moist heat c. Class 1,000/ISO 6 under static
sterilized into the isolator. (no activity) Conditions 1 2.3%
f. Sanitizing solution system. d. Class 1,000/ISO 6 under dynamic
(activity) Conditions 2 4.6%
e. Class 10,000/ISO 7 (EU Grade C)
Microbial Levels for Controlled Areas under static (no activity)
conditions 1 2.3%
130. How are quantitative airborne microbial levels for the f. Class 10,000/ISO 7 (EU Grade C)
APA determined? Please mark all that apply. under dynamic (activity)
conditions 16 37.2%
a. Based upon previous process g. Class 100,000/ISO 8 (EU Grade
simulation environmental data 1 2.3% D) under static (no activity)
b. Based upon previous production conditions 0 0.0%
environmental data 12 27.9% h. Class 100,000/ISO 8 (EU Grade D)
c. Based upon previous process under dynamic (activity)
simulation and production conditions 3 7.0%
environmental data 11 25.6% i. Other - please describe 2 4.6%
d. From published levels by
regulatory and/or compendial Comments
bodies (USP, EU, other) 36 83.7% i. Isolator with Grade D background.
e. Arbitrary level 1 2.3% i. Filling is performed in a closed isolator.
f. Other - please explain 3 7.0% i. Unclassified.

Vol. 56, No. 3, May/June 2002, Supplement TR36 29


133. Do the same microbial levels apply to the following 136. Does the same level apply to all surfaces within your
Class 10,000/ISO 7 (EU Grade C) environments in APA which are of the same environmental classifi-
your APA? Please mark all that apply. cation; e.g., Class 100/ISO 5 (EU Grade A), Class
10,000/ISO 7 (EU Grade C)?
a. Areas surrounding Class
100/ISO 5 (EU Grade A or B) 21 65.6% a. Yes 34 79.1%
b. Corridors 21 65.6% b. No 9 20.9%
c. Sterilizer/oven unload areas 19 59.4%
d. Storage areas 17 53.1% Comments
e. Gowning room exit 18 56.2% a. Except floors.
f. Gowning room entrance 15 46.9% b. Floors are different from walls and equipment.
g. Exit gown room (if present) 4 12.5%
137. Does the same level apply to similar surfaces in other
134. Do the same levels apply to other APAs on this APAs on the same site which are of the same environ-
site which are of the same environmental classifi- mental classification?
cation?
a. Yes 40 95.2%
a. Yes 37 94.9% b. No 2 4.8%
b. No 2 5.1%
Comments
Comments b. Only one APA
b. Only one APA.
138. Does your site have quantitative personnel monitor-
135 How are quantitative surface microbial levels for the ing microbial levels for its primary APA? Please
APA determined? Please mark all that apply. mark all that apply.

a. Based upon previous process a. Based upon previous process


simulation environmental data 1 2.3% simulation environmental data 1 2.4%
b. Based upon previous production b. Based upon previous production
environmental data 11 25.6% environmental data 13 31.7%
c. Based upon previous process c. Based upon previous process
simulation and production simulation and production
environmental data 11 25.6% environmental data 7 17.1%
d. From published levels by d. From published levels by
regulatory and/or compendial regulatory and/or compendial
bodies (USP, EU, other) 35 81.4% bodies (USP, EU, other) 33 80.5%
e. Arbitrary level 1 2.3% e. Arbitrary level 0 0.0%
f. Other - please explain 3 7.0% f. Other - please explain 5 12.2%

Comments Comments
f. Statistical analysis of historical data. f. Isolator.
f. Combination of C and D. f. Based upon Class 100/10,000 levels for APA.
f. At initial validation Based upon intensive f. Testing of gloves after manufacturing in isolator.
monitoring, worst case sites are selected. Lev- f. Combination of C and D.
els will be adjusted based upon routine data. f. At initial validation Based upon intensive moni-
Alert limits also have been generated based toring, worst case sites are selected. Levels will be
upon routine data. adjusted based upon routine data. Alert limits also
have been generated based upon routine data.

30 PDA Journal of Pharmaceutical Science and Technology


139. Does the same level apply to all personnel within your Comments
APA who work in areas of the same environmental d. Not applicable (4)
classification; e.g., Class 100/ISO 5 (EU Grade A),
Class 10,000/ISO 7 (EU Grade C)? 143. Is your site evaluating the following types of alterna-
tive terminal sterilization technologies for future sterile
a. Yes 36 90.0% products? Please mark all that apply.
b. No 4 10.0%
a. Gamma radiation 7 58.3%
140. Does the same level apply to personnel in similar b. X-ray radiation 0 0.0%
activities in other APAs at this site which are of the c. Microwave 1 8.3%
same environmental classification? d. Plasma 0 0.0%
e. Other - please describe 4 33.3%
a. Yes 34 91.9%
b. No 3 8.1% Comments
e. Not applicable (4).
Comments
b. Only one APA.
Aseptic Processing Technology

Terminal Sterilization and Aseptic Processing 144. Which of the following technologies is your site evalu-
ating for utilization in the preparation of its aseptically
141. Does your site employ the following types of heat filled products? Please mark all that apply.
sterilization processes for its current sterile products
after aseptic processing? Please mark all that apply. a. Closed isolators (cannot
exchange air from fill zone
a. Overkill cycles (F0 of 12 minutes to surrounding area where
or more, 15 minutes at 121.1C) personnel are located) (no
a 6-log or greater reduction of a direct openings, all transfers via
resistant bioindicator 19 70.4% closed containers)
b. Bioburden-biological indicator (decontaminated) 8 24.2%
cycles - a less than 6-log reduction b. Open isolators (can exchange air
of a resistant bioindicator 4 14.8% from fill zone to surrounding area
c. Bioburden cycles - a 6-log or where personnel are located)
greater reduction by post-filling (direct opening present for
lethal treatment of the most container exit) (decontaminated
resistant bioburden isolate. 2 7.4% while closed) 12 36.4%
d. Other - please describe 4 14.8% c. Restricted access barriers 9 27.3%
d. Sterilize-in-place 19 57.6%
Comments e. Robotic manipulation of sterile
d. Not applicable (4) materials 4 12.1%
f. Hermetically sealed gowns with
142. Is your site evaluating the following types of heat self-contained breathing apparatus 2 6.1%
sterilization processes for its future sterile products g. Form-fill-seal/Blow-fill-seal
after aseptic processing? Please mark all that apply. technology 4 12.1%
h. Electrophoretic air systems 0 0.0%
a. Overkill cycles 15 65.2% i. Other - please describe 3 9.1%
b. Bioburden-biological indicator
cycles 4 17.4% Comments
c. Bioburden cycles 3 13.0% a. For sterility testing.
d. Other - please describe 4 17.4% i. Not applicable (3).

Vol. 56, No. 3, May/June 2002, Supplement TR36 31


Other Issues h. Surface contaminants
i. Personnel contaminants
145. Please rank the following potential sources of con- j. Human error
tamination from most-likely to least-likely to cause k. Mechanical failure
problems in process simulations? 1-Most Likely, l. Failure of sterilizing filter
10-Least Likely m. Failure of HEPA filter
n. Other - please specify
a. Inadequate or improper sterilization
b. Inadequate or improper sanitization Comments
c. Transfer of materials within APA i. Glove hole in isolator.
d. Assembly of sterile equipment prior to use i. Interpreted as the effect this event would cause
e. Routine operations during aseptic process on the media fill, not as the likelihood of this
f. Non-routine operations during aseptic process event occurring.
g. Airborne contaminants

1 2 3 4 5 6 7 8 9 10
a. 6 2 0 0 2 1 1 2 2 22
13.9% 4.6% 0.0% 0.0% 4.6% 2.3% 2.3% 4.6% 4.6% 51.2%
b. 1 2 9 3 6 2 4 5 5 4
2.3% 4.6% 20.9% 7.0% 13.9% 4.6% 9.3% 11.6% 11.5% 9.3%
c. 3 1 3 7 4 3 4 11 1 4
7.0% 2.3% 7.0% 16.3% 9.3% 7.0% 9.3% 25.6% 2.3% 9.3%
d. 3 6 7 8 1 5 3 4 1 3
7.0% 13.9% 16.3% 18.6% 2.3% 11.6% 7.0% 9.3% 2.3% 7.0%
e. 2 3 1 1 10 1 2 7 3 11
4.6% 7.0% 2.3% 2.3% 23.2% 2.3% 4.6% 16.3% 7.0% 25.6%
f. 1 4 13 8 6 0 3 3 2 2
2.3% 9.3 30.2% 18.6% 13.9% 0.0% 7.0% 7.0% 4.6% 4.6%
g. 3 5 3 2 8 7 1 3 2 8
7.0% 11.6% 7.0% 4.6% 18.6% 16.3% 2.3% 7.0% 4.6% 18.6%
h. 2 5 3 1 6 5 7 2 3 7
4.6% 11.6% 7.0% 2.3% 13.9% 11.6% 16.3% 4.6% 7.0% 16.3%
i. 24 9 5 0 3 1 0 1 0 0
55.8% 20.9% 11.6% 0.0% 7.0% 2.3% 0.0% 2.3% 0.0% 0.0%
j. 11 19 3 3 3 1 0 2 0 0
25.6% 44.2% 7.0% 7.0% 7.0% 2.3% 0.0% 4.6% 0.0% 0.0%
k. 6 0 5 0 11 1 4 5 4 4
13.9% 0.0% 11.6% 0.0% 25.6% 2.3% 9.3% 11.6% 9.3% 9.3%
l. 5 1 0 0 4 1 3 3 5 14
11.6% 2.3% 0.0% 0.0% 9.3% 2.3% 7.0% 7.0% 11.6% 32.5%
m. 4 0 0 1 4 2 0 6 5 14
9.3% 0.0% 0.0% 2.3% 9.3% 4.6% 0.0% 13.9% 11.6% 32.5%
n. 0 0 0 0 2 0 0 0 0 4
0.0% 0.0% 0.0% 0.0% 4.6% 0.0% 0.0% 0.0% 0.0% 9.3%

32 PDA Journal of Pharmaceutical Science and Technology


140. What would you estimate the actual probability of a. All filled stoppered units must be incubated even
non-sterility associated with your aseptically filled if routine production procedures regard these as
products to be? rejects for whatever reason. The units must be iden-
tified and segregated from the rest of the filled units.
a. Less than 1 in 1,000 0 0.0% The results from these potentially rejected units
b. Less than 1 in 5,000 4 10.0% may or may not be used in the evaluation of the
c. Less than 1 in 10,000 4 10.0% trial, as they are for information purposes only.
d. Less than 1 in 50,000 5 12.5% b. If not removed at initial inspection, they remain
e. Less than 1 in 100,000 13 32.5% with the batch.
f. 1 in 100,000 or greater 14 35.0% b. Occasionally for information only.
b. Only integral units are incubated.
Comments
d. Total 20,000 units were filled; no failure 148. Do you incubate media filled containers that would
thus far. have been rejected for cosmetic defects during actual
d. Impossible to estimate. production operations?

147. Do you incubate damaged containers (loose or missing a. Yes - please explain 33 80.5%
stoppers, cracks) that are filled during process simula- b. No 8 19.5%
tion testing?
Comments
a. Yes - please explain 10 23.2% a. Mold defects. (2)
b. No 33 76.7% a. If the damage does not compromise unit integrity.
a. Identify damaged containers separated from ac-
Comments ceptable ones.
a. Identify damaged containers; separated for ac- a. Worst case.
ceptable ones. a. Cracks and others are rejected for production, but
a. All vials are incubated. not for media fills.
a. Only if seal integrity is not compromised. a. As long as the interior is not breached.
a. The only exceptions allowed from incubation a. Cosmetic defects are not allowed to be rejected
process are: missing stopper, missing cap tip for media fills.
(sprayer), broken. a. Leaking or damaged containers are identified and
a. Leaking or damaged containers are identified and recorded. These are incubated, however, if con-
recorded. These are incubated, however, if con- taminated; these are not continued to be incubated
taminated; these are not continued to be incubated alongside the remaining units. The contaminating
alongside the remaining units. The contaminating organism is identified to species level. This unit
organism is identified to species level. This unit (damaged and contaminated) is not included in
(damaged and contaminated) is not included in the determination of the contamination rate.
the determination of the contamination rate. a. All units incubated that have container integrity.
a. Any such defects not removed on initial inspec- a. All integral units are incubated.
tion (To) are, if subsequently detected, left with a. All properly stoppered, capped, uncracked vials,
the media fill. including short-filled or units with cosmetic de-
a. Reference purpose only; no impact on final test fects are incubated.
result. a. All non-damaged containers are incubated.
a. Potentially defective containers these are a. Evaluate entire filling operation.
marked as such. a. Scratched vials, dented seals, etc., are incubated.

Vol. 56, No. 3, May/June 2002, Supplement TR36 33


a. We do not inspect for cosmetic defects during media 151. What is the environment at point of fill utilized for
fills. All rejected integral containers are incubated. filling terminally sterilized products?
a. Yes, except for integral defects.
a. All ampoules except integrity test failure are a. Class 100/ISO 5 (EU Grade A)
incubated. (laminar flow) 10 90.9%
a. Units that are integral. (3) b. Class 100/ISO 6 under static
a. As long as closure is intact. conditions (EU Grade B) (non-
a. As long as sterile barrier is maintained. laminar flow) 1 9.1%
a. Containers that would have been rejected during c. Class 1,000/ISO 6 under static
actual production (for example, after interventions (no activity) Conditions 0 0.0%
and cosmetic defects) are incubated separately for d. Class 1,000/ISO 6 under dynamic
investigation purposes. (activity) Conditions 0 0.0%
a. All filled stoppered units must be incubated even e. Class 10,000/ISO 7 (EU Grade C)
if routine production procedures regard these as under static (no activity) conditions 1 9.1%
rejects for whatever reason. The units must be iden- f. Class 10,000/ISO 7 (EU Grade C)
tified and segregated from the rest of the filled units. under dynamic (activity) conditions 0 0.0%
The results from these potentially rejected units g. Class 100,000/ISO 8 (EU Grade D)
may or may not be used in the evaluation of the under static (no activity) conditions 0 0.0%
trial, as they are for information purposes only. h. Class 100,000/ISO 8 (EU Grade D)
under dynamic (activity) conditions 0 0.0%
149 What percentage of media fills you complete are totally i. Other - please describe 0 0.0%
free of any contaminated units?
152. What is the surrounding environment utilized for
a. < 25% 0 0.0% terminally sterilized products?
b. 25-50% 0 0.0%
c. 50-75% 3 7.0% a. Class 100/ISO 5 (EU Grade A)
d. 75% or more 40 93.0% (laminar flow) 2 18.1%
b. Class 100/ISO 6 under static
150. Have we overlooked a significant concern or fact conditions (EU Grade B) (non-
regarding aseptic processing? laminar flow) 4 36.4%
c. Class 1,000/ISO 6 under static
a. Yes - please explain 5 12.8% (no activity) Conditions 0 0.0%
b. No 34 87.2% d. Class 1,000/ISO 6 under dynamic
(activity) Conditions 1 9.1%
Comments e. Class 10,000/ISO 7 (EU Grade C)
a. No questions regarding campaign filling/media fill under static (no activity) conditions 3 27.3%
validation or maximum machine set-up times, for f. Class 10,000/ISO 7 (EU Grade C)
aseptically filled or powders. under dynamic (activity) conditions 3 27.3%
a Validation by media fill of maximum storage time g. Class 100,000/ISO 8 (EU Grade D)
of m/c parts, components, etc., before use. under static (no activity) conditions 0 0.0%
a. Training of operators to visually inspect trials, h. Class 100,000/ISO 8 (EU Grade D)
i.e., use of low level contaminants compare units under dynamic (activity) conditions 0 0.0%
using range of organisms. i. Other - please describe 0 0.0%
a. Reconciliation of media filled units.

34 PDA Journal of Pharmaceutical Science and Technology


Conclusion worldwide continue to have considerable latitude in the
design of their aseptic processing validation program.
The results of this survey continue to demonstrate the
diversity of approaches utilized in the industry for the Acknowledgments
validation of aseptic processing. While there were several
areas where the methods are becoming quite uniform, con- This survey would have been impossible without the
siderable variation is certainly present across the industry. respondents who spent a great deal of time in answering
Many of the differences can be traced to the differing the questions, and developing their comments. Pamela
product types, facility sizes, and levels of technology pres- Jones, CreaTech, provided invaluable support in per-
ent within the surveyed firms. Parenteral manufacturers forming the tedious task of data entry.

References 5. Korczynski, M., Validation of Aseptic Process by Me-


dia FillsSurvey Report and Discussion, in Proceed-
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PMA (1979).
2. ISO/DIS 13048-1, Aseptic Processing of Health
Care ProductsPart 1: General Requirements, 6. Agalloco, J. and Gordon, B., Current Practices in the
(1996). Use of Media Fills for the Validation of Aseptic Process-
ing, J. Parent. Sci. Tech., Vol. 41, No. 4, PDA (1987).
3. Guideline on Sterile Drug Products Produced by
Aseptic Processing, CDER and ORA, Food and 7. Technical Report No. 17, Current Practices in the
Drug Administration, (1987). Validation of Aseptic Processing1992, J. Parent. Sci.
Tech., Vol. 47, No. 2, (S1), PDA (1993).
4. Technical Report No. 22, Process Simulation
Testing for Aseptically Filled Products, PDA 8. Technical Report No. 24, Current Practices in the
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(1996). Technol., Vol. 51, No. S2, PDA (1997).

Vol. 56, No. 3, May/June 2002, Supplement TR36 35


PDA Journal of
Pharmaceutical Science and Technology
Supplement TR36 Volume 56
May/June 2002 EDITOR: Lee Kirsch No. 3
c/o The University of Iowa
Pharmacy Building, S223
Iowa City, IA 52242, USA
(319) 384-4408
pda-journal@uiowa.edu
Editorial Assistant: Madhu Gokhale

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PDA Journal of
Pharmaceutical
Science and
Technical Report No. 36 Technology

Current Practices in the


Validation of Aseptic Processing2001

May/June 2002

Supplement TR36

Volume 56

Number 3

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