TR 36 2002 Current Practices of Aseptic Processing - 2001

Technical Report No. 36

PDA Journal of Pharmaceutical Science and Technology

Current Practices in the Validation of Aseptic Processing—2001

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 Processing–2001 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 major area of interest within the pharmaceutical industry. Five years have passed since the last PDA survey on this subject. While there have been no new broadly applicable regulations or regulatory guidance since that time, there has been continued controversy over the details of aseptic processing and process simulation practice. Industry practices largely adhere to current regulations and guidelines on aseptic processing by the European Union (1), ISO (2), and FDA (3). The impact of PDA’s TR #22 on “Process Simulation Testing for Aseptically Filled Products” (4) is also apparent.

1.

Over time, industry methods, practices, and limits have been modified to adapt to the changing circumstances. The Pharmaceutical Manufacturers Association (now PhRMA) in 1979 (5) and PDA in 1986 (6), 1992 (7), and 1996 (8) conducted surveys on this subject that have provided a clearer understanding of contemporary industry practice. This survey addresses the continuing need to track industry practices in the validation of aseptic processing as it evolves.

2.

Questionnaires were sent to eighty-eight (88) firms that specifically agreed to participate with PDA in this effort. Forty-three (43) responses were received representing both US and overseas locations. The results were tabulated to provide both raw numerical and percentage of total respondents. Where the respondents provided comments (whether solicited or given voluntarily), these comments are provided after the question. Where more than one respondent provided essentially the same response selection and comment, they have been consolidated and a number appears next to the response indicating the number of comments of that type. The nature and extent of the comments received were extensive, and for this reason, the authors have chosen to combine similar responses. One of the major benefits of surveying on a regular basis is the opportunity to follow the evolution of concepts and practices over time. To that end, this survey instrument used many questions that were nearly identical to those asked in 1992 and 1996.

2

In what country, or state, is your Aseptic Processing Area (APA) located? United States - 28 - California, Florida, Illinois, North Carolina, Pennsylvania, Texas (2), Indiana, Kansas, New Jersey, New York (3), US (4) International - 31 - Australia, Canada, Italy, Spain, Sweden (2), England, France, Germany, Hungary, Indonesia, Ireland, Korea (3) No answer - 2 What types of sterile products do you manufacture at this site? Please mark all that apply. a. b.

c. d. e. f. g. h. i. j.

Large volume parenterals Small volume parenterals Solutions Suspensions Lyophilized Powders Ophthalmic and/or otic solutions Inhalation solutions Ointments Biologicals Products for veterinary use Medical devices - liquid based products Medical devices - non-liquid products Other - please describe

10 36 16 5 11 9 11 8 3 14 5

23.3% 83.7% 37.2% 11.6% 25.6% 20.9% 25.6% 18.6% 7.0% 32.5% 11.6%

6

13.9%

4 2

9.3% 4.6%

Comments j. Drugs containing implants, control release devices j. Clinical supplies 3.

How many different sterile product presentations (all strengths and fill sizes of all products) do you manufacture at this site? a. b. c. d. e.

0–5 6 – 49 50 – 99 100 – 149 >150

8 14 6 6 9

19.0% 33.3% 14.3% 14.3% 21.4%


4.

What percentage of your sterile products is manufactured using aseptic processing? a. b. c. d.

5.

Less than 25% 25% to 50% 51% to 75% More than 75%

2 5 3 33

Comments b. The same product may be manufactured with or without preservative; depends upon whether they are for multi-dose markets, i.e., US states a multi-dose product will have a preservative. Single dose of same product -- no preservative. d. All our products comply with USP but not with A criteria from European Pharmacopoeia; 60% comply with B criteria from European Pharmacopoeia. d. Liquid >75%; Powder, none.

4.6% 11.6% 7.0% 76.7%

Is this percentage an increase or a decrease from five years ago? a. b. c.

Increase Decrease Same

7 5 31

16.3% 11.6% 72.1%

Release/Quarantine Practices Comments a. No production five years ago. 6.

8.

At your site, is aseptic processing used for products that could be terminally sterilized? (For the purposes of this response, consider “could be terminally sterilized” to mean a product and container/closure/delivery system that could withstand moist heat sterilization processes with a total accumulated F0 of 8 or more minutes.) a. b.

Yes No

14 29

If a process simulation* action level is exceeded on a validated production line, what action do you take with regard to products manufactured on the line prior to the media fill failure? a. b. c.

32.6% 67.4% d.

If yes, what percentage of the aseptically produced products does this represent? 2% (2), 5%, 10% (2), 20% (2), 30%, 35%, 47%, 60%, 75%, 85% Comments a. We are manufacturing clinical supplies only, so information is not available at this time. 7.

What percentage of your aseptically filled products contains an anti-microbial preservative that complies with pharmacopoeial anti-microbial effectiveness testing requirements? a. b. c. d. e.

None Less than 25% 25% to 50% 51% to 75% More than 75%

14 11 5 4 10


33.3% 26.2% 11.9% 9.5% 23.8%

Release Release after investigation Release only after an investigation indicates good process control and one or more successful additional media fills are conducted Other action - please describe

3 6

7.0% 13.9%

33 4

76.7% 9.3%

Comments c. Plus double sterility test. d. Release only after investigation could assure SAL of products. d. No formal procedure. Never occurred, therefore, no test case. d. Normally, release after investigation; however, would depend upon number of contaminated units and types of organisms. Worst case: recall product. *Note: In this survey, the terms process simulation test, media fill, and media fill test are used interchangeably.

3

9.

If a process simulation action level is exceeded on a line, what action do you take with regard to products manufactured on the line subsequent to the media fill failure? a. b. c.

d.

Release 0 Release after investigation 1 Release only after an investigation indicates good process control and one or more successful additional media fills are conducted 39 Other action - please describe 4

b.

b. b.

0.0% 2.3% b. b. 90.7% 9.3%

b. b.

Comments c. Plus double sterility and stop production. d. Release only after investigation could assure SAL of products. d. Lots rejected unless assignable cause can be determined that was not present during the processing of the product batches. d. Normally, release after investigation; however, would depend upon number of contaminated units and types of organisms. Worst case: recall product. 10. Is positive action taken against a certain number of lots or over a certain time period in the event of a media fill failure?

b.

c. c.

c. c.

c. a. b. c. d.

Yes - please specify number of lots involved before and after the failure. Yes - please specify time period involved before and after the failure. No - please describe your practice Other

7

17.5%

15 7 11

37.5% 17.5% 27.5%

Comments a. All. a. Any product manufactured between filling trials and the date of the failure and subsequent batches must be held in quarantine until the investigation is complete. Aseptic product manufactured on the filling line, and still in company control, should be quarantined until investigation is complete. a. All unreleased lots before and after the failures are held until three successive media fills are performed and found to meet acceptance criteria. a. Three lots before and after. a. All lots after the failure.

4

d.

d. d. d. d.

d.

Investigation will be conducted on all batches of the last successful media fill; refer to QC for further action. All before the last media fill and all post. Before: Back to previous acceptable media fill. After: Lots filled after action limit and prior to obtaining satisfactory results for repeat media. Six months (2) Since the last successful media fill on the affected line (3) From previous media fill to the next media fill (3). Three months before failure and all lots after media fill are kept in QA. Depends upon the outcome of the investigation! Worst case scenario: all lots produced since the last approved media fill. No practice is in place due to manufacturing under development. Lots filled prior and post the failure will be dispositioned depending upon the outcome of the investigation. Lots filled post media fill are quarantined until investigation results are known. Hold lots for investigation and draft an action memo for released lots. Once investigation is concluded and corrective action taken, we return to normal production. Never occurred, therefore, no test case. Action would be taken on individual batches as far back and forward as necessary to fence in the issue, based upon the individual investigation. This could go all the way back to the previous media fill. Release only after an investigation indicates good process control and one or more successful additional media fills is conducted. Dependent upon outcome of investigation (2) No policy in place for this scenario; no history of failure. We stop the line until there are three successful media fills. Investigation reveals the source of failure and depending upon the type of source, the number of lots or time period are considered. If it is needed, recall for certain lots should be performed. Everything not yet released since the last successful process simulation test is placed on hold until the investigation is complete and a successful process simulation test is completed. (3)


11. Is positive action taken on production during a set period of time before and after a media fill failure?

c. c.

a. b. c.

Yes - please specify time period involved before and after failure 18 No - please describe your practice 9 Other 13

45.0% 22.5% 32.5%

Comments a. All periods involved. a. All before the last media fill and all post. a. Production is on hold pending investigation. a. Between current and previous media fill results (2). a. Aseptic production ceases on the affected machine until investigation is completed and satisfactory repeat filling trial has been completed. Repeat trial in triplicate on the container size implicated. a. Before: Back to previous acceptable media fill. After: Lots filled after action limit and prior to obtaining satisfactory results for repeat media. a. Six months. a. Going back to the last successful media fill. (3) a. Depends upon the outcome of the investigation! Worst case scenario: all lots produced since the last approved media fill. b. Depends upon investigation results. (2) b. Implement corrective actions based upon the outcome of investigation. b. No practice is in place due to manufacturing under development. b. Lots filled prior and post the failure will be dispositioned depending upon the outcome of the investigation. Lots filled post media fill are quarantined until investigation results are known. b. Once investigation is concluded and corrective action taken, we return to normal production. Never occurred, therefore no test case. b. Action would be taken on individual batches as far back and forward as necessary to fence in the issue, based upon the individual investigation. This could go all the way back to the previous media fill. b. After the failure only. c. Dependent upon outcome of the investigation (3). c. We stop the line until there are three successful media fills. c. It is difficult to take action before since we do not know that we have a failure.


c.

c.

Hold lots for investigation and draft an action memo for released lots. If further investigation finds that there is a possible impact from equipment, facility, and/or personnel, re-qualification would be required. Everything not yet released since the last successful process simulation test is placed on hold until the investigation is complete and a successful process simulation test is completed. (3) All lots manufactured during the prior six months would be investigated then an appropriate action could be taken by QC, normally.

12. In the event of an unsuccessful* revalidation media fill test, how many consecutive satisfactory tests must be completed before the production line is considered re-qualified for manufacturing operations? a. None 0 0.0% b. One 1 2.3% c. Two 1 2.3% d. Three 37 86.0% e. Other - please describe 6 13.9% * The test fails to meet the acceptance criteria. Comments d. If not able to invalidate media fill. e. One: In case of identified failure cause after correction action. Two: In case of unidentified cause. e. Based upon investigation, 1-3 may be performed. e. If reason for failure is known, one. If reason for failure is not known, three. (2) e. If cause of failure is known, one only. If cause of failure is unknown or uncertain, three. In all cases, an investigation is also conducted. e. One repeat if able to invalidate media fill. Frequency 13. Do you routinely conduct revalidation media fills on each filling line or machine on a regularly scheduled basis? a. b.

Yes 43 100.0% No - please describe your practice 0 0.0%

Comments a. We do it quarterly, but the process used is not determined in order to cover all processes.

5

14. If yes, how often? a. b. c. d. e. f. g.

Weekly Monthly Every other month Quarterly Semi-annually Annually Other - please define

c. c. 0 0 0 2 36 4 1

0.0% 0.0% 0.0% 4.6% 83.7% 9.3% 2.3%

Comments e. At minimum, each line typically has five or six due to new product container closure systems. e. At least two media trials per year. However, to validate/re-qualify operators, many lines are performing up to six trials per year. g. Every fourth month.

c.

c. c. c. c.

c. 15. If a sterility test failure occurs, does this failure initiate a media fill test on the line that manufactured the product that failed the sterility test? a. b. c.

Yes 12 No - please describe your practice 7 Sometimes - please explain the decision factors that would lead your firm to require a re-validation media fill test to clear a sterility test failure 24

27.9% 16.3%

55.8%

Comments b. Initiates investigation and exception reports. (2) c. After investigation: lab failure = retest; no lab failure = batch rejected. c. Depends upon results of investigation and if additional controls were positive. c. Based upon investigation findings. (7) c. If the investigation determined the root cause to be a failure in design or practice requiring significant change. (2) c. Response to product test failure requires investigation covering sterility testing and production records/environments. Outcome of the manufacturing investigation indicating production environment/ procedure may result in a media trial. (2) c. Investigate to exclude analytical error or if some obvious event has caused the failure. c. Cross-functional team assembled to investigate. Findings would decide if additional media fill necessary.

6

c. c. c.

c.

If no assignable cause found. QC management would assess the aseptic production area and determine a probably cause. If no assignable cause was found, a media fill would be requested. EM monitoring data, sterile cleaning practice, sterilizing cycle, DOP, Royco of HVAC, LFs, education, new operators. Decision to conduct a media fill is based upon the results of the sterility test failure investigation. If no cause can be identified from lab error or process error, a media fill test may be carried out. Investigation into failure conducted against machine and batches taken if warranted. May require that production be stopped on the line. Depends upon results of investigation of sterility test failure. No revalidation is performed if a lab error is the cause of the failure. If aseptic processing. If cause is assigned to line failure. An investigation will be initiated. If the investigation doesn’t show that the failure is due to a lab contamination, all steps in production will be checked. Depending upon the results, an evaluation will be done if a new media fill is necessary to verify that the process is under control. For example, an upward trend of microorganisms in the APA or a recently failed media fill could lead to a revalidation. Would depend upon type of organism and if any other failures from same line, e.g., two sterility test failures with anaerobic organisms – have investigation and anaerobic media fill.

16. How are your media fill tests distributed among different shifts? a. b. c.

Equally distributed across shifts Distributed according to production volumes No - please explain

32

74.4%

5 6

11.6% 14.0%

Comments c. There is only one shift. (5) c. In some areas, media fills are performed which cover shift changeover. In other areas, because of their design and need for only one operator, we have a rationale that states shift changeover has no impact on integrity of process.


17. Are all aseptic fill and set-up personnel included in the process simulation program? c. a. b. c.

Yes - on an annual basis 34 Yes - please specify frequency 7 Other - please describe your practice 1

79.1% 16.3% 2.3%

Comments a. Vial size on rotating basis. b. Semi-annually. (6) c. Frequency depends upon type of intervention. 18. Are personnel, including new hires, qualified to operate in the APA through participation in a media fill test? a. b.

Yes - using participation in an actual process simulation 31 No - please describe your practice 12

72.1% 27.9%

Comments c. They are qualified performing the job, but a media fill is not scheduled to complete their qualification. They will participate in the next scheduled media fill if a media fill is not scheduled at completion of their qualification. c. Operator certification program for aseptic technique and gowning, as well as GMP training. Due to media fill frequency operators generally participate in media fills within about six weeks of employment. c. No practice set up yet. Intention to make them qualified with media fill as one part of the qualification. c. Using a “hand fill” simulation. c. New hires are trained to work in aseptic processing areas via SOPs and on-the-job-training. They are cycled into media program after initial training has been completed. c. We perform a specific training program and final validation in accordance with the SOP. c. Qualification of an operator is based upon training for gowning and aseptic practices. The operator can then operate in the aseptic processing area and participate in the next media fill. c. New operators are scheduled for the first available media fill. c. Prior to entering the APA, employees must pass a “broth test” in a lab environment demonstrating


c. c.

good aseptic technique, then successfully participate in a process simulation study. Process uses barrier technology, therefore, personnel participate in the media fills, but they are not qualified. Gowning certification only. Gown qualification, personnel monitoring, media fill within six months.

19. How many media fill tests must a new hire participate in to be considered qualified to work on a specific validated process? a. b. c. d. e.

None One Two Three Four or more

13 28 0 2 0

30.9% 66.7% 0.0% 4.8% 0.0%

Comments b. All training related to aseptic behavior. b. But must perform all critical activities. b. Plus micro training, aseptic training, and repetitive (3x) gowning assessment. 20. If different filling set-ups and/or closure systems are utilized on a filling line, will your process simulation program address all combinations? a. b.

Yes 30 No - please explain your rationale 12

71.4% 28.6%

Comments a. On a rotating basis according to product. b. Initial qualification would be yes, but routine re-qualification would be about largest and smallest. b. Worst case conditions will be investigated. b. One simulation trial to one filling line. b. Bracket the largest/smallest vial/closure combinations. (2) b. Different lines have different combinations to bracket all. b. Because we are in research, it is changing all the time. b. We only do the minimum and maximum fill, based upon line speed. b. All formats are covered; not all stoppers. b. Worst case, large vial openings – most difficult fill set-up.

7

21. Does your firm employ a minimum time duration for media fill tests? a. b. c. d. e. f. g.

Yes - not less than 1 hour 4 Yes - not less than 2 hours 1 Yes - not less than 3 hours 2 Yes - four hours or more 1 Yes - duration of fill process 16 Yes - minimum number of filled containers 24 No - please describe your practice 6

9.3% 2.3% 4.6% 2.3% 37.2% 55.8% 13.9%

Comments d. Typically, 8-16 hours. e. Including all worst cases. e. “Start-Stop” Approach: Actual minimal fill time is not more than three hours. f. 6,800 units f. Would normally fill for length of typical production shift. < 6,300 units processed to cover all production intrusions. g. Both: minimum number of units to fill and the whole duration of the process. g. NLT to 60% of filling process duration. g. Duration of the longest filling time. g. Simulate 1-1/2 hours of empty running during some of the challenge. g. Plus necessary time for simulations.

Methods 22. Is the fill volume of media employed the same as that utilized in production? a. b. c.

Yes No - container size is too large No

18 2 20

45.0% 5.0% 50.0%

Comments c. Half volume of a vial. (4) c. Volume of media is greater than product fill (2). c. Vial volume sufficient to promote growth. c. Sufficient media is added to ensure one-half of the vertical surface of container is covered. Units inverted during incubation.

8

23. Do you utilize the same filling line speed for process simulations as that utilized in production for that container? a. b. c. d.

Yes No - speed equal to slowest normal fill speed on that line No - speed equal to the highest normal speed on that line No - other speed - please explain

20

46.5%

15

34.9%

2 9

4.6% 20.9%

Comments b. Re-qualifications. b. Majority of cases slowest (longest dwell time). c. On certain high-speed fillers, >300/minute (highest) is deemed worst case; units fall over and there are more interventions. d. The line speed is lower than the standard speed due to the necessary equipment to dose the media and represent worst case. d. Process simulations require at least 25% of fill at minimum speed, 25% normal/routine speed, 25% maximum speed. d. Currently, slower than normal production speed is used. In the future, this process and normal production speed will be used. d. Initial Performance Qualification utilizes minimum speed and approximate production speed. d. Slowest filling speed and at the end of test, highest speed. d. Combination of B and C. d. Slowest speed for largest container and fastest speed for smallest container. d. Slower and faster speeds are used during the challenge. d. The speed that is considered as worst case for each container size. 24. Do your process simulation trials include inert gassing if used in production? a. b. c. d.

Yes - using Fluid Thioglycollate medium and nitrogen Yes - using Soybean Casein Digest medium and nitrogen Yes - other method - please explain No - please explain

3

7.0%

4 15 23

9.3% 34.9% 53.5%


Comments c. Using Soybean Casein Digest medium and compressed air. (3) c. Using compressed air in place of N 2 with SCDM. c. Compressed air. (4) c. Sterile filtered air as part of production process. c. Soybean Casein and oxygen. c. Soybean Casein Digest medium and nitrogen. c. TSP medium and nitrogen. c. SCDB and compressed air to simulate inert gas. (3) c. Inert gas is exchanged with air. d. Not used. (3) d. Soybean Casein Digest medium without nitrogen. d. Is considered worst case using air. d. Compressed filtered air. d. Inert gas is not used. d. SCD broth. d. Purge needles, tubing, etc., installed; no gas used. d. Inert gassing is not used in production. d. During media fills that simulate processes utilizing nitrogen, sterile filtered air is utilized due to inhibitory microbial nature of nitrogen. d. Inert gas replaced with air for duration of media fill(s). d. Pressurized air is used instead of nitrogen, as our production lines apply both techniques (air and nitrogen). d. No gassing. d. Replace N2 with compressed air to increase the challenge for growth. d. Inert gases are not used to prevent product degradation or exposure in our process. d. Sterile filtered pressurized air instead of nitrogen. d. Use SCD and compressed air. 25. Will the number of samples used in a process simulation vary from line to line? a. b.

Yes - please explain No

15 28

Comments a. >6,300 units a. Only one line. (3) a. NLT 6,000 vials. a. Depends upon batch size. a. One of four lines fills at a faster speed.


34.9% 65.1%

a. a. a. a. a. a. a. a. a. b.

Depending upon the speed of the machine. Depending upon challenge time and production complexity. Conventional: NLT 10,000; high speed: NLT 30,000; FFS: NLT 15,000. In order to respect the minimum one-hour fill, highspeed line tends to have more samples filled. Minimum of one-hour filling and 3,000 units, whichever is greater for each shift. Depends upon commercial batch size. Actual number attained is dependent upon line speed with a minimum yield targeted. Higher speed lines are challenged with higher numbers of units. If aseptic fill is validated for two days, the amount is doubled. Normally >6,300; exception is high-speed ampoule m/c – 10,000 units.

26. Which media do you utilize for process simulation trials on a regular basis? a. b. c.

Soybean Casein Digest Fluid Thioglycollate Other - please specify

39 3 1

90.7% 7.0% 2.3%

Comments c. SCD with HEC or HPMC for ointment or gel lines 27. Do you use exactly the same compounding and filtration equipment in conducting a media fill test that you use in actual production? a. b. c.

Yes No Other - please describe

33 6 4

76.7% 14.0% 9.3%

Comments c. Additional pre-filters are used. d. The same fill line equipment used, however, additional equipment is necessary for the media fill dosing. d. Same compounding equipment and filter housings, but no filters. d. Filtration is the same; compounding as close as possible. d. The same filling equipment is used, but not the solution preparation equipment. (2)

9

28. When performing process simulation trials, do you retain sterile media in sterile holding vessels to simulate standard manufacturing holding times prior to filling? a. b.

Yes No

30 13

30. Does your process simulation program include the following routine interventions? a.

69.8% 30.2% b.

Comments a. Annually. a. Overnight approach. b. Yes, during the initial qualification of new product. b. Separate ventilation. b. No sterile vessels.

c.

d. 29. Do you inspect the filled containers prior to the end of the full incubation period (14 days)? a. b. c. d. e.

Yes - once after seven days of incubation Yes - once, please specify number of days of incubation Yes - twice, please specify number of days of incubation Yes - three times, please specify number of days of incubation No

e. 25

58.1%

1

2.5%

3

7.5%

6 8

15.0% 20.0%

f.

Comments a. Eye drops. b. 14 days c. 7 days and 14 days (2) c. 3 days and 7 days d. 1, 4, 7, 10, 14 on a routine basis. d. 2 or 3, 6 or 7, 14 (2) d. 3, 7, 14 (2) d. 3, 5, 14 e. If containers are opaque. e. Ophthalmic ointments. 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 additional inspection after seven days is performed. e. Inspected prior to incubation and after 14 days.

g.

h.

i.

j.

k.

l.

10

Weight/fill volume adjustment Yes 38 No 4 N/A 0 Component replenishment Yes 34 No 4 N/A 0 Filter change Yes 21 No 16 N/A 4 Filling needle change Yes 30 No 7 N/A 3 Operator breaks Yes 40 No 2 N/A 0 Change in filling vessel Yes 21 No 19 N/A 2 Component change Yes 20 No 16 N/A 3 Powder can changes Yes 12 No 16 N/A 12 Dosing wheel, dosing disc changes Yes 13 No 18 N/A 10 Powder hopper changes Yes 6 No 21 N/A 12 Operator change Yes 40 No 1 Other - please specify Yes 17 No 5

88.4% 9.3% 0.0% 79.1% 9.3% 0.0% 48.8% 37.2% 9.3% 69.8% 16.3% 7.0% 93.0% 4.6% 0.0% 48.8% 44.2% 4.6% 46.5% 37.2% 7.0% 27.9% 37.2% 27.9% 30.2% 41.9% 23.2% 13.9% 48.8% 27.9% 93.0% 2.3% 39.5% 11.6%


Comments f. Only one vessel. j. Stopper. l. Equipment change out; reboot computers, etc. l. Stopper bowl change; pump changes. l. Lyophilizer. l. Specific for each filling line. l. Too numerous to list here. l. Container, stopper, cap jam, synchronization failure. l. Not really detailed in our program; done on observation sheet. l. Maintenance interventions. (2) l. Line adjustments, equipment replacement, line jams. (3) l. All interventions that occur during routine production. l. Simulation of in-process compounding sampling. l. Use of sterile clarifying filters. l. Tip/cap track adjustments. l. Removal of jammed bodies. l. Tube cap change out on ointment lines. l. All filling lines have individual intrusion rationales. These define all allowable intrusions in production (validated in media fill). Will also include electrical/ engineering adjustments. 31. Do you routinely videotape process simulation operations? a. b. c.

Yes If yes, do you retain the tapes? How long? (see comments) No

13 10

30.2% 23.2%

30

69.8%

Comments a. All routine action concerning production. a. Until end of incubation/reporting of trial. Video is used to formally assess production operator technique. b. Tapes are discarded if media fill is successful. If investigation is required, tapes are retained to assist in investigation. b. Not yet determined. (2) b. Until batch is released.


b.

b. b. b. d.

Until successful results are confirmed. If a failure occurs, the tape is filed with the investigation report. Until results are approved. (2) Two years. Next media fill. But have Quality Assurance observe aseptic handling.

Growth Promotion Studies 32. When are growth promotion studies conducted on each medium? Please mark all that apply. a. b. c. d.

Before filling After filling After incubation Other - please explain

9 7 36 1

20.9% 16.3% 83.7% 2.3%

Comments a. Bulk sample from reactor. d. Before filling and after incubation. 33. In conducting growth promotion studies do you use only pharmaceutical test organisms (e.g., those recommended in USP <71> Sterility Testing)? a. b.

Yes – use only USP <71> organisms12 27.9% No – explain 30 69.8%

Comments Use organisms recommended by European Pharmacopoeia. (3) Suitability test organisms for the TGA, SUP, EP, and BP. Sterility testing is included. Environmental isolates and USP organisms. (21) We use the European Ph organisms, plus two more frequently isolated from aseptic area. Range of organisms – B. subtilis, C. albcans USP and facility isolates and S.aureus, ATCC 6538. The strains have been chosen with respect to other growth promotion tests – five different strains are used. Use organisms found during environmental monitoring of the media run and USP organisms.

11

Incubation of Process Simulation Samples 34. If you answered No to Question 33, how many species isolated from the aseptic processing environment do you include in the growth promotion test? a. b. c. d. e.

One Two Three Four More than four

12 8 2 2 4

44.4% 29.6% 7.4% 7.4% 14.8%

Comments e. Depends upon how many found during environmental monitoring. e. It depends upon what is recovered. e. It may also be from sterility test failure, if that is the reason for media fill, and from any positives from previous media fill. 35. What temperatures do you use to incubate process simulation samples? If more than one temperature is utilized, please mark all that apply and explain your practice. a. b. c. d. e.

20 - 25ºC 26 - 29ºC 30 - 35ºC 36 - 39ºC 40 - 49ºC

38 0 40 0 0

88.4% 0.0% 93.0% 0.0% 0.0%

Comments a. First seven days. (8) a. For fungi. a. Days 8-14. (2) a. Yeast and molds. (2) c. This temperature is used when performing the media fill for the AddVantage line. c. Second seven days. (8) c. For bacteria. c. Days 1-7. (2) c. All other process simulation studies. (2) 36. How long do you incubate process simulation containers? a. b. c. d.

12

Less than 7 days 7 days 8 -13 days 14 days

0 0 0 42

0.0% 0.0% 0.0% 97.7%

e. f. g. h.

15 to 20 days 21 days More than 21 days Other - please describe

0 0 0 1

0.0% 0.0% 0.0% 2.3%

Comments d. At least 14 days. Incubator rooms are thermally mapped. Some large vial sizes take longer to reach incubation temperature and will receive extra day of incubation. h. NLT 7 days at 20-25°C or 30-35°C. 37. How do you insure the interior surfaces of the container are contacted with media? a. b. c. d. e. f.

Swirl and incubate top-side up 5 Invert one or more times, and incubate top-side up 22 Incubate all containers on their sides 2 Incubate upside down 6 No special measures taken (incubate randomly) 2 Other - please describe your practice 7

11.6% 51.2% 4.6% 14.0% 4.6% 16.3%

Comments d. Ointments. f. Invert vials after reading each time, so every three days switch from topside up to upside down. (2) f. Invert one or many times and incubate upside down. f. Combination of C and D. f. Swirl and incubate inverted. f. Incubate upside down for the first seven days and topside down the last seven days. f. Swirl and incubate top side up for seven days. Inspect at seven days, swirl, and invert for further seven days. 38. If you have found contaminated media fill test units, what type of microorganism was most prevalent? a. b. c. d. e. f.

Gram positive rod Gram positive coccus Gram negative rod Microaerophillic or “anaerobic” organism Molds Yeasts

7 31 4

20.0% 88.6% 11.4%

1 1 0

2.8% 2.8% 0.0%


Personnel Monitoring 39. Are all personnel involved in media runs tested for the presence of microbes on their gowns and/or gloves? a. b.

Yes No

39 4

90.7% 9.3%

40. If yes, which of the following sites are sampled? Mark all that apply. A. a. b. c. d.

Fingers (fingerprint or finger dab) Upon entering the APA 7 During the media fill test 20 After the media fill test 30 Not tested 1

17.9% 51.3% 76.9% 2.6%

B. a. b. c. d.

Palm or back of hand Upon entering the APA During the media fill test After the media fill test Not tested

3 5 8 25

7.7% 12.8% 20.5% 64.1%

C. a. b. c. d.

Arms Upon entering the APA During the media fill test After the media fill test Not tested

2 8 22 11

5.1% 20.5% 56.3% 28.2%

D. a. b. c. d.

Face-masks Upon entering the APA During the media fill test After the media fill test Not tested

2 4 16 20

5.1% 10.2% 41.0% 51.3%

E. a. b. c. d.

Chest Upon entering the APA During the media fill test After the media fill test Not tested

3 9 25 7

7.7% 23.1% 64.1% 17.9%

F. a. b. c. d.

Other gown surfaces - please specify Upon entering the APA 1 During the media fill test 5 After the media fill test 17 Not tested 15

2.6% 12.8% 43.6% 38.5%

Comments Ab. And after interventions Ba. After processing Bd. During routine personnel evaluation Ca. After processing Cb. And after interventions Cd. Only required weekly Da. After processing Ea. After processing Ec. Rotate chest and shoulder sites Ed. Only required weekly Fb. Forehead Fb. Hoods Fb. Top of hood and back of gown Fb. Back, shoe covers, hood Fc. Goggles, wrist, neck Fc. Waist, hood (2) Fc. Shoulders Fc. Hood, armpit Fc. Head, both shoulders Fc. Stomach

Environmental Monitoring, Aseptic Processing


41. What environmental sampling methods do you use in the filling room environment? If more than one method is utilized, please mark all that apply. A. Microbiological Sampling Methods a. Swabs 23 b. RODAC or another form of surface sampling plates 42 c. Settling plates 32 d. STA sampler 11 e. Electrostatic air sampler 2 f. Centrifugal sampler 20 g. Sieve-type sampler 8 h. Gelatin filter 4 i. Other - please describe 7

53.5% 97.7% 74.4% 25.6% 4.6% 46.5% 18.6% 9.3% 16.3%

B. Total Particulate Air Monitoring Methods a. Continuous 14 32.5% b. Intermittent 28 65.1%

13

Comments Af. Only during revalidation Ai. SMA (4) Ai. SAS (3) Ai. MAS air sampler Bb. Continuous in fill room for media fills; intermittent in production Bb. None Bb. Limited monitoring during every shift. Continuous for full day 1x week. Continues during media fill (one-day trial).

45. If your monitoring approach is different for media fill tests, how does it differ from routine or planned production monitoring? a. b. c. d. e.

42. How frequently do you sample your APA for the presence of anaerobic organisms? a. b. c. d. e. f. g.

Daily Weekly Monthly Quarterly Semi-annually Annually Not at all

2 4 6 5 5 4 20

4.6% 9.3% 14.0% 11.6% 11.6% 9.3% 46.5%

Comments d. Swabs to FTM. e. And daily when filling on one line. f. RODAC. g. Performed only in conjunction with media fills. g. Historical data justified discontinuance on initial validation. 43. If you test your APA environment for the presence of anaerobes, is this a result of potentially anaerobic process conditions? a. b.

Yes No

10 22

31.2% 68.8%

44. How frequently do you sample your APA for the presence of molds and yeasts? a. b. c. d. e. f. g.

Daily Weekly Monthly Quarterly Semi-annually Annually Not at all

20 5 5 4 2 4 2

47.6% 11.9% 11.9% 9.5% 4.8% 9.5% 4.8%

Comments a. Our media (TSIS) is able to detect both fungi and bacteria. 14

f.

More locations than routine production More samples at same sites than routine production Same as routine production Fewer locations than routine production Fewer samples at same sites than routine production Other - please describe

8

19.5%

11 23

26.8% 56.1%

0

0.0%

0 0

0.0% 0.0%

Environmental Monitoring, Media Fills 46. Are the microbial results obtained from process simulations used to establish the alert and/or action levels used for environmental monitoring during routine production? a. b. c.

Yes No In part - please explain

6 30 8

13.9% 69.8% 18.6%

Comments a. Every lot. b. Results are evaluated by intensive monitoring at the validation stage. b. Limits attained from environmental monitoring validation. b. Pharmacopoeial guideline limits are used. c. Alert and/or action levels were internally based upon the results of the initial MFs. Subsequent levels are based upon the analysis of the annual EM data. c. Process simulations are included to obtain alert/action levels. c. Done in addition to routine EM sampling results (5). c. Consider trend for non-viable. 47. To what extent are environmental isolates from process simulation runs identified? a. b. c. d.

Morphology only Gram stain Genus Species

0 5 6 37

0.0% 11.6% 13.9% 86.0%


Comments b. Below alert/alarm levels. b. If sample is above alert limit. d. Plus species, if possible. (4) d. Above alert/alarm levels. d. Class 100 area and OOS samples are identified. d. If sample is above action limit. d. All isolates from Class 100 areas identified to species. 48. To what extent are isolates from contaminated units identified? a. b. c. d.

Morphology only Gram stain Genus Species

0 1 3 41

In the following section, please identify all of the aseptic processing technologies (see descriptions below) presently in use at your facility. The descriptions are meant to broadly define the filling environment. Please complete the table for those technologies that most resemble those within your facility. A separate page has been provided for each processing technology. Please indicate your response in the appropriate columns. a.

0.0% 2.3% 7.0% 95.3% b.

Comments d. C and D whenever possible. (2) 49. Do you follow the same environmental monitoring strategy in prospective (PQ validation) media fill tests that you plan to use in conducting routine monitoring of your new or modified facility? a. b.

Yes No

33 9

78.6% 21.4%

Comments b. More during validation, then reduce. 50. Do you follow the same environmental monitoring strategy for revalidation media fill tests that you use in conducting routine production environmental monitoring? a. b.

Yes No

39 6

90.7% 13.9%

c.

Manual Filling - Gowned personnel perform the majority of aseptic processing tasks, i.e., placing the container under the filling head, closing the container, sealing the container. Human intervention is continuous and very intensive. 4

9.3%

Semi-automated Filling Containers are transferred from dry heat ovens by gowned personnel; filling, closing and sealing are performed by machines. Trays are manually loaded into lyophilizer. Continuous human intervention. 13

30.2%

Conventional Filling - Containers are conveyed from dry heat tunnel to machine filling; closing and sealing are performed by machines. Fill weights manually adjusted by gowned personnel. Human intervention is most intensive during set-up, but routine interventions for component charging, adjustments, minor maintenance, and weight checking occur. 16

37.2%

Comments Do more.


15

d.

e.

f.

16

Advanced Conventional - Containers are conveyed from dry heat tunnel to machine filling; closing and sealing are performed by machines. Fill weights remotely adjusted. Human intervention is limited to minor adjustments and component charging. Fill machine equipped for CIP/SIP. Automated loading of lyophilizer. 7 Form-Fill-Seal/Blow-Fill-Seal Plastic containers formed/blow molded in line immediately prior to filling. Molds and product contact filling parts are subjected to CIP/SIP prior to start of the filling process. Human intervention rarely occurs, essentially an unmanned clean room process.

g.

16.3%

4

9.3%

Closed Isolator - Full processing in a decontaminated environment. Transfers in and out are accomplished using RTPs or specialized transfer systems that maintain the integrity of 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%

Open Isolator - Processing in a decontaminated environment, with discharge via a discharge port into an adjacent lower classified environment. Filling and closure typically done using very highly automated equipment. Usually employed for high volume and/or high speed filling operations. No human intervention except through isolator system gloves or half-suits.

3

7.0%

Comments b. EtO sterilizer. c./d. All filling machines have some level of restricted access glove port protection. Only “major” interventions require door open intrusion. g. Barrier with totally separate Class 100 system returns, etc. (800 air changes/hour) inside a Class 100 environment. Human intervention when needed (start-up and periodic issues – such as glass handling modifications). Media fills done with barrier doors open and human intervention. Normally, door totally closed during production. All CIP/SIP; stoppers supplied to line CIP/SIP only item requiring autoclave is stopper vibrating feed bowl.



17

What is the minimum number of units filled? <1,000 1,000 - 1,999 2,000 - 2,999 3,000 - 3,999 4,000 - 4,999 5,000 - 9,999 10,000 - 14,999 15,000 or more Other

Has the number in response to Question 52 increased in the last three years? Yes No

52. a. b. c. d. e. f. g. h. i.

53.

Has the acceptance criterion for contamination been tightened in the last three years? Yes No

57.

a. b.

What acceptance criterion do you employ? <0.05% 0.05 - 0.09% 0.10% 0.11 - 0.14% 0.15 - 0.2% 0.21 - 0.3% >0.3%

56. a. b. c. d. e. f. g.

Do you utilize an alert limit in addition to the acceptance criterion (action limit)? a. Yes - please describe how this limit has been set b. No Comments: a. At any positive case One positive alert.

55.

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 5,000, etc.) b. Use Poisson statistical derived approach with 95% confidence limit (e.g., 0 in 3,000, 1 in 4,740, etc.) c. Another statistical approach - please describe d. Another non-statistical approach - please describe Comments: d. <0.1% One positive alert, >1 action

54.

a. b.

a. b. c. d.

What percentage of your aseptically filled products is manufactured using this technology? >75% 50 75% 25 50% <25%

51.

Question #

0.0% 33.3%

0 2

1 4

0 0 4 0 0 0 0

16.7% 66.7%

0.0% 0.0% 80.0% 0.0% 0.0% 0.0% 0.0%

50.0% 33.3%

50.0%

3

3 2

0.0%

0.0% 83.3%

50.0% 0.0% 0.0% 33.3% 0.0% 0.0% 0.0% 0.0% 0.0%

28.6% 0.0% 14.3% 28.6%

0

0 5

3 0 0 2 0 0 0 0 0

2 0 1 2

Solutions

0 1

0

0

0 1

0 0 0 2 0 0 0 0 0

0 0 0 1

1 0

0 0 0 0 0 0 0

1 0

16.7% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

16.7% 0.0%

0.0% 16.7%

0.0%

0.0%

0.0% 16.7%

0.0% 0.0% 0.0% 33.3% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 14.3%

Suspensions

Manual Filling

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Ointments

1 2

0 0 2 0 0 0 0

2 1

0 2

1

0

0 3

0 0 1 2 0 0 0 0 0

1 0 0 1

16.7% 33.3%

0.0% 0.0% 40.0% 0.0% 0.0% 0.0% 0.0%

33.3% 16.7%

0.0% 33.3%

16.7%

0.0%

0.0% 50.0%

0.0% 0.0% 16.7% 33.3% 0.0% 0.0% 0.0% 0.0% 0.0%

14.3% 0.0% 0.0% 14.3%

Freeze Dried

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

1 14.3% 0 0.0% 0 0.0% 0 0.0%

Solids

1 2

0 0 2 0 0 0 0

2 1

0 2

1

0

0 3

1 0 1 1 0 0 0 0 0

1 0 1 1

16.7% 33.3%

0.0% 0.0% 40.0% 0.0% 0.0% 0.0% 0.0%

33.3% 16.7%

0.0% 33.3%

16.7%

0.0%

0.0% 50.0%

16.7% 0.0% 16.7% 16.7% 0.0% 0.0% 0.0% 0.0% 0.0%

14.3% 0.0% 14.3% 14.3%

Clinical Supplies

18



Has the number in response to question 59 increased in the last three years? Yes No

59. a. b. c. d. e. f. g. h. i.

60.


Has the acceptance criterion for contamination been tightened in the last three years? a. Yes b. No Comments: a. Looking at reacting to any growth for the future.

64.

63. a. b. c. d. e. f. g.

Do you utilize an alert limit in addition to the acceptance criterion (action limit)? a. Yes - please describe how this limit has been set b. No Comments: b. ISO (4); At any positive case; 5% of action level; 1 positive alert, >1 action; 0.02%; Target 0 positive limits

62.

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 5,000, etc.) b. Use Poisson statistical derived approach with 95% confidence limit (e.g., 0 in 3,000, 1 in 4,740, etc.) c. Another statistical approach - please describe d. Another non-statistical approach - please describe Comments: d. <0.1%; 1 positive alert, >1 action

61.

a. b.

a. b. c. d.


58.

Question #

5.0% 5.0% 5.0% 0.0% 10.0% 30.0% 10.0% 15.0% 10.0%

26.3% 21.0% 10.5% 31.6%

1 1

1 3

7 38.9% 10 55.5%

3 17.6% 3 17.6% 10 58.8% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

12 66.7% 5 27.8%

4 3

0 2 4 0 0 0 0

6 1

5

12 63.1% 5.3% 15.8%

0

2 6

0 0 0 0 1 4 1 1 1

2 0 1 4

22.2% 16.7%

0.0% 11.8% 23.5% 0.0% 0.0% 0.0% 0.0%

33.3% 5.5%

5.3% 5.3%

26.3%

0.0%

10.0% 30.0%

0.0% 0.0% 0.0% 0.0% 5.0% 20.0% 5.0% 5.0% 5.0%

10.5% 0.0% 5.3% 21.0%

Suspensions

5.3%

1

4 20.0% 13 65.0%

1 1 1 0 2 6 2 3 2

5 4 2 6

Solutions

Semi-Automated Filling

2 0

0 1 1 0 0 0 0

1 1

1 0

1

0

0 2

0 0 0 0 0 2 0 0 0

2 0 0 0

11.1% 0.0%

0.0% 5.9% 5.9% 0.0% 0.0% 0.0% 0.0%

5.5% 5.5%

5.3% 0.0%

5.3%

0.0%

0.0% 10.0%

0.0% 0.0% 0.0% 0.0% 0.0% 10.0% 0.0% 0.0% 0.0%

10.5% 0.0% 0.0% 0.0%

Ointments

4 4

2 1 4 0 0 0 0

5 3

0 1

6

1

4 5

0 1 0 0 1 1 2 1 2

1 0 1 6

22.2% 22.2%

11.8% 5.9% 23.5% 0.0% 0.0% 0.0% 0.0%

27.8% 16.7%

0.0% 5.3%

31.6%

5.3%

20.0% 25.0%

0.0% 5.0% 0.0% 0.0% 5.0% 5.0% 10.0% 5.0% 10.0%

5.3% 0.0% 5.3% 31.6%

Freeze Dried

0 1

0 0 1 0 0 0 0

1 0

1 0

0

0

0 1

0 0 0 0 0 0 0 1 0

1 0 0 0

0.0% 5.5%

0.0% 0.0% 5.9% 0.0% 0.0% 0.0% 0.0%

5.5% 0.0%

5.3% 0.0%

0.0%

0.0%

0.0% 5.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 5.0% 0.0%

5.3% 0.0% 0.0% 0.0%

Solids

1 6

0 0 7 0 0 0 0

6 2

0 1

7

0

1 6

1 0 0 0 0 3 1 1 2

1 2 2 3

5.5% 33.3%

0.0% 0.0% 41.2% 0.0% 0.0% 0.0% 0.0%

33.3% 11.8%

0.0% 5.3%

36.8%

0.0%

5.0% 30.0%

5.0% 0.0% 0.0% 0.0% 0.0% 15.0% 5.0% 5.0% 10.0%

5.3% 10.5% 10.5% 15.8%

Clinical Supplies


19



66. a. b. c. d. e. f. g. h. i.

67.



70. a. b. c. d. e. f. g.

71.

a. b.

a. b.

Do you utilize an alert limit in addition to the acceptance criterion (action limit)? Yes - please describe how this limit has been set No

69.

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 5,000, etc.) b. Use Poisson statistical derived approach with 95% confidence limit (e.g., 0 in 3,000, 1 in 4,740, etc.) c. Another statistical approach - please describe d. Another non-statistical approach - please describe 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.

68.

a. b.

a. b. c. d.


65.

Question #

0.0% 0.0% 0.0% 11.5% 11.5% 19.2% 19.2% 15.4% 7.7%

30.8% 26.9% 11.5% 3.8%

1 1

1 2

6 24.0% 14 56.0%

1 4.5% 3 13.6% 12 54.5% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

15 60.0% 5 20.0%

3 5

2 2 2 0 0 0 0

6 2

5

16 64.0% 4.0% 8.0%

1

2 7

0 0 0 2 1 1 3 3 0

5 0 3 0

12.0% 20.0%

9.1% 9.1% 9.1% 0.0% 0.0% 0.0% 0.0%

24.0% 8.0%

4.0% 4.0%

20.0%

4.0%

7.7% 26.9%

0.0% 0.0% 0.0% 7.7% 3.8% 3.8% 11.5% 11.5% 0.0%

19.2% 0.0% 11.5% 0.0%

Suspensions

0.0%

0

6 23.1% 15 57.7%

0 0 0 3 3 5 5 4 2

8 7 3 1

Solutions

Conventional Filling

0 1

0 1 0 0 0 0 0

1 0

1 0

0

0

0 1

0 0 0 0 0 0 1 0 0

1 0 0 0

0.0% 4.0%

0.0% 4.5% 0.0% 0.0% 0.0% 0.0% 0.0%

4.0% 0.0%

4.0% 0.0%

0.0%

0.0%

0.0% 3.8%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 3.8% 0.0% 0.0%

3.8% 0.0% 0.0% 0.0%

Ointments

0.0%

19.2% 30.8%

0.0% 0.0% 0.0% 7.7% 3.8% 7.7% 19.2% 11.5% 3.8%

23.1% 7.7% 11.5% 11.5%

4 8

2 0 7 0 0 0 0

8 4

0 1

16.0% 32.0%

9.1% 0.0% 31.8% 0.0% 0.0% 0.0% 0.0%

32.0% 16.0%

0.0% 4.0%

10 40.0%

0

5 8

0 0 0 2 1 2 5 3 1

6 2 3 3

Freeze Dried

8.0%

0.0% 4.0%

6 24.0% 1 4.0%

3 13.6% 2 9.1% 1 4.5% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

4 16.0% 3 12.0%

0 1

4 16.0%

2

5 19.2% 2 7.7%

0 0.0% 0 0.0% 0 0.0% 3 11.5% 2 7.7% 1 3.8% 0 0.0% 1 3.8% 0 0.0%

3 11.5% 1 3.8% 0 0.0% 2 7.7%

Solids

3 5

0 1 5 0 0 0 0

7 1

0 1

7

0

2 6

0 0 0 0 1 3 2 2 0

3 2 2 0

12.0% 20.0%

0.0% 4.5% 22.7% 0.0% 0.0% 0.0% 0.0%

28.0% 4.0%

0.0% 4.0%

28.0%

0.0%

7.7% 23.1%

0.0% 0.0% 0.0% 0.0% 3.8% 11.5% 7.7% 7.7% 0.0%

11.5% 7.7% 7.7% 0.0%

Clinical Supplies

20




73. a. b. c. d. e. f. g. h. i.

74.

Comments:

a. Initial qualification only.


78.

a. b.


77. a. b. c. d. e. f. g.

Do you utilize an alert limit in addition to the acceptance criterion (action limit)? a. Yes - please describe how this limit has been set b. No Comments: a. 1 in 10,000; Per ISO 13408

76.

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 5,000, etc.) b. Use Poisson statistical derived approach with 95% confidence limit (e.g., 0 in 3,000, 1 in 4,740, etc.) c. Another statistical approach - please describe d. Another non-statistical approach - please describe Comments: c. 5 in 10,000 d. Zero contaminated units irrespective of number of units filled.

75.

a. b.

a. b. c. d.


72.

Question #

12.5% 12.5%

1 1

2 3

0 2 2 0 0 0 0

25.0% 37.5%

0.0% 28.6% 28.6% 0.0% 0.0% 0.0% 0.0%

37.5% 25.0%

37.5%

3

3 2

12.5%

22.2% 44.4%

0.0% 0.0% 0.0% 0.0% 0.0% 11.1% 0.0% 55.5% 0.0%

22.2% 11.1% 11.1% 22.2%

1

2 4

0 0 0 0 0 1 0 5 0

2 1 1 2

Solutions

1 2

0 1 2 0 0 0 0

2 1

0 0

3

1

2 2

0 0 0 0 0 0 0 4 0

2 1 0 1

12.5% 25.0%

0.0% 14.3% 28.6% 0.0% 0.0% 0.0% 0.0%

25.0% 12.5%

0.0% 0.0%

37.5%

12.5%

22.2% 22.2%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 44.4% 0.0%

22.2% 11.1% 0.0% 11.1%

Suspensions

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Ointments

0 0 0 0

Advanced Conventional Filling

0 2

0 0 2 0 0 0 0

1 1

0 0

2

0

2 1

0 0 0 0 0 0 0 3 0

0 2 1 0

0.0% 25.0%

0.0% 0.0% 28.6% 0.0% 0.0% 0.0% 0.0%

12.5% 12.5%

0.0% 0.0%

25.0%

0.0%

22.2% 11.1%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 33.3% 0.0%

0.0% 22.2% 11.1% 0.0%

Freeze Dried

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Solids

0 1

0 0 1 0 0 0 0

1 0

0 0

1

0

0 1

0 0 0 0 0 0 0 0 1

0 0 0 1

0.0% 12.5%

0.0% 0.0% 14.3% 0.0% 0.0% 0.0% 0.0%

12.5% 0.0%

0.0% 0.0%

12.5%

0.0%

0.0% 11.1%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 11.1%

0.0% 0.0% 0.0% 11.1%

Clinical Supplies


21



How is your acceptance criterion defined? (0.1% is used in the examples below.) Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 5,000, etc.) Use Poisson statistical derived approach with 95% confidence limit (e.g., 0 in 3,000, 1 in 4,740, etc.) Another statistical approach - please describe Another non-statistical approach - please describe

80. a. b. c. d. e. f. g. h. i.

81.

82.


85.

a. b.


84. a. b. c. d. e. f. g.

Do you utilize an alert limit in addition to the acceptance criterion (action limit)? a. Yes - please describe how this limit has been set b. No Comments: a. ISO; Per requirements of PDA, USP, Compendial

83.

c. d.

b.

a.

a. b.

a. b. c. d.


79.

Question #

0.0% 0.0%

0 0

1 4

2 1 2 0 0 0 0

20.0% 80.0%

40.0% 20.0% 40.0% 0.0% 0.0% 0.0% 0.0%

60.0% 40.0%

60.0%

3

3 2

40.0%

40.0% 60.0%

0.0% 0.0% 0.0% 40.0% 0.0% 40.0% 0.0% 20.0% 0.0%

40.0% 0.0% 0.0% 60.0%

2

2 3

0 0 0 2 0 2 0 1 0

2 0 0 3

Solutions

1 0

0 1 0 0 0 0 0

1 0

0 0

0

1

1 0

0 0 0 0 0 1 0 0 0

1 0 0 0

20.0% 0.0%

0.0% 20.0% 0.0% 0.0% 0.0% 0.0% 0.0%

20.0% 0.0%

0.0% 0.0%

0.0%

20.0%

20.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 20.0% 0.0% 0.0% 0.0%

20.0% 0.0% 0.0% 0.0%

Suspensions

Form-Fill-Seal/Blow-Fill-Seal

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Ointments

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Freeze Dried

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Solids

0 1

0 0 1 0 0 0 0

1 0

0 0

1

0

0 1

0 0 0 0 0 1 0 0 0

0 0 0 1

0.0% 20.0%

0.0% 0.0% 20.0% 0.0% 0.0% 0.0% 0.0%

20.0% 0.0%

0.0% 0.0%

20.0%

0.0%

0.0% 20.0%

0.0% 0.0% 0.0% 0.0% 0.0% 20.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 20.0%

Clinical Supplies

22




87. a. b. c. d. e. f. g. h. i.

88.


92.

a. b.


91. a. b. c. d. e. f. g.

Do you utilize an alert limit in addition to the acceptance criterion (action limit)? a. Yes - please describe how this limit has been set b. No Comments: a. Alert = 1

90.

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

89.

a. b.

a. b. c. d.


86.

Question #

0.0% 0.0%

0 0

0 1

0 0 1 0 0 0 0

0.0% 33.3%

0.0% 0.0% 50.0% 0.0% 0.0% 0.0% 0.0%

0.0% 33.3%

33.3%

1

0 1

0.0%

0.0% 33.3%

33.3% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

33.3% 0.0% 0.0% 0.0%

0

0 1

1 0 0 0 0 0 0 0 0

1 0 0 0

Solutions

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Suspensions

Closed Isolator Filling

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Ointments

0 1

0 0 0 0 0 0 0

1 0

0 0

1

0

1 0

0 0 0 0 0 0 0 1 0

0 0 0 1

0.0% 33.3%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

33.3% 0.0%

0.0% 0.0%

33.3%

0.0%

33.3% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 33.3% 0.0%

0.0% 0.0% 0.0% 33.3%

Freeze Dried

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Solids

0 1

1 0 0 0 0 0 0

0 1

0 1

0

0

0 1

1 0 0 0 0 0 0 0 0

1 0 0 0

0.0% 33.3%

50.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 33.3%

0.0% 33.3%

0.0%

0.0%

0.0% 33.3%

33.3% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

33.3% 0.0% 0.0% 0.0%

Clinical Supplies


23



How is your acceptance criterion defined? (0.1% is used in the examples below.) Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 5,000, etc.) Use Poisson statistical derived approach with 95% confidence limit (e.g., 0 in 3,000, 1 in 4,740, etc.) Another statistical approach - please describe Another non-statistical approach - please describe

94. a. b. c. d. e. f. g. h. i.

95.

96.


99.

a. b.


98. a. b. c. d. e. f. g.

Do you utilize an alert limit in addition to the acceptance criterion (action limit)? a. Yes - please describe how this limit has been set b. No Comments: a. ISO (2) Alert = 1

97.

c. d.

b.

a.

a. b.

a. b. c. d.


93.

Question #

66.7% 0.0% 0.0%

2 0 0

0 0.0% 3 100.0%

0 0.0% 0 0.0% 2 100.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0%

3 100.0% 0 0.0%

33.3%

33.3% 66.7%

0.0% 0.0% 0.0% 0.0% 0.0% 66.7% 0.0% 33.3% 0.0%

1

1 2

0 0 0 0 0 2 0 1 0

0 0.0% 0 0.0% 0 0.0% 3 100.0%

Solutions

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Suspensions

Open Isolator Filling

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Ointments

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Freeze Dried

0 0

0 0 0 0 0 0 0

0 0

0 0

0

0

0 0

0 0 0 0 0 0 0 0 0

0 0 0 0

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0%

0.0% 0.0%

0.0%

0.0%

0.0% 0.0%

0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 0.0%

Solids

0 2

0 0 2 0 0 0 0

2 0

0 0

2

0

0 2

0 0 0 0 0 2 0 0 0

0 0 0 2

0.0% 66.7%

0.0% 0.0% 100.0% 0.0% 0.0% 0.0% 0.0%

66.7% 0.0%

0.0% 0.0%

66.7%

0.0%

0.0% 66.7%

0.0% 0.0% 0.0% 0.0% 0.0% 66.7% 0.0% 0.0% 0.0%

0.0% 0.0% 0.0% 66.7%

Clinical Supplies

24


a. b.

F.

E. a. b. c. d. e. f. g.

a. b.

D.

c. d.

b.

a.

C.

a. b.

B.

A. a. b. c. d. e. f. g. h. i.

Question # Number of Responses What is the minimum number of units filled? <1,000 1,000 - 1,999 2,000 - 2,999 3,000 - 3,999 4,000 - 4,999 5,000 - 9,999 10,000 - 14,999 15,000 or more Other Number of Responses Has the number in response to the previous question increased in the last three years? Yes No Number of Responses How is your acceptance criterion defined? (0.1% is used in the examples below.) Fixed percentage of total number of units filled (e.g., 1 in 1,000, 5 in 5,000, etc.) Use Poisson statistical derived approach with 95% confidence limit (e.g., 0 in 3,000, 1 in 4,740, etc.) Another statistical approach - please describe Another non-statistical approach - please describe Number of Responses Do you utilize an alert limit in addition to the acceptance criterion (action limit)? Yes - please describe how this limit has been set No Number of Responses What acceptance criterion do you employ? <0.05% 0.05 - 0.09% 0.10% 0.11 - 0.14% 0.15 - 0.2% 0.21 - 0.3% >0.3% Number of Responses Has the acceptance criterion for contamination been tightened in the last three years? Yes No 13 61.9% 2 9.5% 3 14.3% 20 16 80.0% 4 25.0% 16 2 12.5% 6 37.5% 8 50.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 20 10 50.0% 10 50.0%

40 71.4% 3 5.4% 8 14.3% 56 39 69.6% 17 30.4% 48 6 12.5% 9 18.8% 33 68.8% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 56 17 30.4% 39 69.6%

14.3%

3

5

8.9%

7 30.4% 16 69.6% 21

15 25.9% 43 74.1% 56

0.0% 0.0% 0.0% 13.0% 8.7% 21.7% 17.4% 34.8% 4.3%

0 0 0 3 2 5 4 8 1 23

5 1 1 7 5 16 7 15 4 58

8.6% 1.7% 1.7% 12.1% 8.6% 27.6% 12.1% 25.9% 6.9%

Suspensions 23

Solutions 61

Data Composite

2 1

0 2 1 0 0 0 0 3

2 1 3

2 0 3

1

0

1 3 3

0 0 0 0 0 3 1 0 0 4

66.7% 33.3%

0.0% 66.7% 33.3% 0.0% 0.0% 0.0% 0.0%

66.7% 33.3%

66.7% 0.0%

33.3%

0.0%

25.0% 75.0%

0.0% 0.0% 0.0% 0.0% 0.0% 75.0% 25.0% 0.0% 0.0%

Ointments 4 0.0% 3.4% 3.4% 13.8% 6.9% 10.3% 30.4% 27.6% 10.3%

4.0%

9 34.6% 17 65.4%

4 20.0% 1 5.0% 15 75.0% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 26

17 65.4% 9 34.6% 20

0 0.0% 4 16.0% 26

20 80.0%

1

12 41.4% 17 58.6% 25

0 1 1 4 2 3 7 8 3 29

Freeze Dried 29 0.0% 0.0% 0.0% 37.5% 37.5% 12.5% 0.0% 25.0% 0.0%

Solids

6 75.0% 2 25.0%

3 42.6% 2 28.6% 2 28.6% 0 0.0% 0 0.0% 0 0.0% 0 0.0% 8

5 62.5% 3 37.5% 7

1 12.5% 1 12.5% 8

4 50.0%

2 25.0%

5 62.5% 3 37.5% 8

0 0 0 3 3 1 0 2 0 8

9

5 18

1 1 18 0 0 0 0 23

19 5 20

0 5 24

19

0

3 20 24

3 0 1 1 1 9 3 3 3 23

21.7% 78.3%

5.0% 5.0% 90.0% 0.0% 0.0% 0.0% 0.0%

79.2% 20.8%

0.0% 20.8%

79.2%

0.0%

13.0% 87.0%

12.5% 0.0% 4.2% 4.2% 4.2% 37.5% 12.5% 12.5% 12.5%

Clinical Supplies 24

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. 100. If your firm uses blow/form-fill-seal technology, do you use a campaign manufacturing process? a. b.

Yes No

3 100.0% 2 66.7%

101. If you answered Yes to Question 100, what is the duration of your longest campaigned filling operation? a. b. c. d. e. f. g. h. i.

One day Two days Three days Four days Five days Seven days Ten days Fourteen days Other, please specify

0 0 0 0 1 0 0 0 1

0.0% 0.0% 0.0% 0.0% 50.0% 0.0% 0.0% 0.0% 50.0%

Comments i. 148 hours

Suspension Products

102. Does your suspension media fill test include the following steps in the manufacturing process? Please mark all that apply.

d.

Bulk sterilization of vehicle Simulation of powder addition Simulated milling/homogenization of Suspension Filling of media (simulated product) into product containers

a. b.

Yes No

8 5

57.1% 35.7%

Comments a. TSB a. Not Applicable 104. If yes, how is the placebo material sterilized? a. b. c. d. e.

Irradiation Gas sterilization Dry Heat Moist Heat Other

3 1 0 2 3

21.4% 7.1% 0.0% 14.3% 21.4%

Comments a. For powder. e. Received sterile. e. Sterilized during processing (moist heat and filtration) e. Bulk sterilization for vehicle. e. Filtration. 105. What placebo material do you use?

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

a. b. c.

103. Do you use a placebo material in lieu of the actual product?

11 8

78.6% 57.1%

9

64.3%

12

85.7%


a. b. c. d. e.

Mannitol Lactose Polyethylene glycol Diatomaceous earth Other - please describe

0 0.0% 0 0.0% 0 0.0% 0 0.0% 9 100.0%

Comments e. Not Applicable e. SCDM powder (4) e. Dextrose. e. We use soybean without dextrose as solution and sterilized dextrose as powder to add. e. Sterile TSB or NaCMC

25

Sterile Semi-Solid Products

Freeze Dried Products



106. Does your semi-solid process simulation include the following steps in the manufacturing process? Please mark all that apply.

110. In conducting the simulated lyophilization of media during your media fill test, what level of vacuum do you establish for the lyophilizer chamber?

a. b. c. d.

Bulk sterilization of vehicle Simulation of powder addition Simulated milling/homogenization Filling into product containers

3 75.0% 4 100.0% 3 75.0% 3 75.0%

107. Do you use a placebo material in lieu of filling the actual product? Yes No

4 100.0% 0 0.0%

108. If yes, how is the placebo material sterilized? a. b. c. d. e.

Irradiation Gas sterilization Dry heat Moist heat Other

4 100.0% 0 0.0% 0 0.0% 0 0.0% 1 25.0%

Comments e. Filtration

Mannitol Lactose Polyethylene glycol Diatomaceous earth Other - please describe

Comments e. TSB and WFI. e. Dextrose e. Sterile NaCMC

a. b. c. d.

15.8% 63.1% 15.8% 10.5%

b. 0 1 0 0 3

0.0% 25.0% 0.0% 0.0% 75.0%

<2 hr. 2 - 8 hr. 9 - 24 hr. Full drying time

9 2 4 4

47.4% 10.5% 21.0% 21.0%

112. Do you freeze the media filled vials at any time during the simulation procedure?

c.

Yes - additional growth promotion studies performed 1 Yes - no additional promotion studies performed 2 No 17

5.0% 10.0% 85.0%

Sterile Dry Powder Products If you do not produce this type of product at this site, please skip to the next section. 113. Do you use media fill tests to validate aseptic powder filling operations? a. b.

26

3 12 3 2

Comments c. In lyophilizer, not under vacuum. d. Three times until <20mHg and reintegration after a complete night at ambient pressure. Once per year, the longest drying cycle is simulated.

a.

109. What placebo material do you use? a. b. c. d. e.

None <20 in. Hg 21 - 28 in. Hg >28 in. Hg

111. How long do the media filled vials remain in the lyophilizer under vacuum?

Comments d. Plastic, not glass containers.

a. b.

a. b. c. d.

Yes No - please describe your validation approach

12 100.0% 0

0.0%


114. How is the media fill test conducted, i.e., what is the sequence of steps? a. b. c. d. e.

Powder filling on-line, followed by liquid filling off-line Powder filling on-line, followed by liquid filling on-line Liquid filling on-line, followed by powder filling on-line Liquid filling off-line, followed by powder filling on-line Other - please describe

1

8.3%

10

83.3%

1

8.3%

0 1

0.0% 8.3%

Comments e. Liquid fill on-line through powder filler. 115. Does your powder media fill test include the following steps in the manufacturing process? Please mark all that apply. a. b. c.

Blending Subdivision prior to filling Filling into product containers

3 25.0% 3 25.0% 12 100.0%

116. Do you use a placebo material in lieu of filling the actual product? a. b.

Yes No

11 1

91.7% 8.3%

117. If yes, how is the placebo powder sterilized? a. b. c. d. e.

Irradiation Gas sterilization Dry heat Moist heat Other

10 100.0% 0 0.0% 0 0.0% 1 10.0% 1 10.0%

118. What placebo material do you use? Mannitol Lactose Polyethylene glycol Diatomaceous earth Other - please describe

119. To what extent do you monitor non-viable particulates during sterile powder filling production operations? Please mark all that apply. a. b. c. d. e. f.

Prior to filling During filling At end of filling During process simulation runs Not at all Other - please explain

5 2 0 3 3 2

45.4% 18.2% 0.0% 27.3% 27.3% 18.2%

Comments f. Filter integrity testing twice per year and nonviable particle counting twice per year. f. Monthly reclassification of all critical cabinets with reference to FS 209 E, at rest. 120. Do you use the same non-viable particulate monitoring volume and frequency during your media fill tests? a. b.

Yes No

8 3

80.0% 30.0%

Comments b. Monthly reclassification of all critical cabinets with reference to FS 209 E, at rest. Not during media trials. 121. If you powder fill antibiotics, does your media fill test utilize an agent which will inactivate trace antibiotics that might be present? a. b.

Comments e. Aseptic processed and bulk lyophilized.

a. b. c. d. e.

Comments d. Sterile dehydrated TSB. d. Whole manufacturing process is simulated with all raw materials except the active substance. The result is a powder that is filled.

Yes No - please describe your practice

8 2

80.0% 20.0%

Comments b. Inactivate area prior to media fill. 2 6 2 0 3


20.0% 60.0% 20.0% 0.0% 30.0%

27

Research & Development (Clinical Trial Material) If you do not produce clinical supplies at this site, please skip to the next section. 122. How is the minimum number of media fill test units filled in support of clinical supplies determined? a. b. c. d.

Fill only actual lot size 4 Arbitrary number greater than lot size2 >3000 8 Other - please explain 3

25.0% 12.5% 50.0% 18.7%

Comments d. Performed as part of routine processing practices. d. Minimum 6,500 or capacity of freeze dryer. d. 4,750

124. What is the surrounding environment for closed isolators utilized for aseptic filling in your facility? a. b. c. d. e. f.

Class 100/ISO 5 (EU Grade A or B) 0 Class 1,000/ISO 6 0 Class 10,000/ISO 7 (EU Grade C) 1 Class 100,000/ISO 8 (EU Grade D) 5 Controlled, but unclassified 0 Other - please describe 0

0.0% 0.0% 16.7% 83.3% 0.0% 0.0%

125. What is the surrounding environment for open isolators utilized for aseptic filling in your facility? a. b. c. d. e. f.

Class 100/ISO 5 (EU Grade A or B) 0 Class 1,000/ISO 6 0 Class 10,000/ISO 7 (EU Grade C) 1 Class 100,000/ISO 8 (EU Grade D 2 Controlled, but unclassified 0 Other - please describe 1

0.0% 0.0% 25.0% 50.0% 0.0% 25.0%

Isolation/Barrier Technology If you do not utilize these technologies at this site, please skip to the next section. 123. What is the surrounding environment for closed isolators utilized for sterility testing in your facility? a. b. c. d. e. f.

Class 100/ISO 5 (EU Grade A or B) Class 1,000/ISO 6 Class 10,000/ISO 7 (EU Grade C) Class 100,000/ISO 8 (EU Grade D) Controlled, but unclassified Other - please describe

0 0 0 0 6 4

0.0% 0.0% 0.0% 0.0% 60.0% 40.0%

Comments a. Isolation = CIP/SIP and never opened during processing; Barrier = CIP/SIP or product path and stopper handing, but unit can be opened ruing process – has own Class 100 environment. f. Unclassified, uncontrolled. f. Sterility tests are not performed in-house. f. Uncontrolled (2)

28

Comments f. No open isolators. 126. If you use closed/open isolators for aseptic processing, do you employ a campaign strategy? a. b.

Yes No

4 4

50.0% 50.0%

127. If you answered yes to Question 126, what is the duration of your longest campaigned filling operation? a. b. c. d. e. f. g. h. i.

One day Two days Three days Four days Five days Seven days Ten days Fourteen days Other, please specify

0 1 1 0 0 1 0 1 0

0.0% 25.0% 25.0% 0.0% 0.0% 25.0% 0.0% 25.0% 0.0%


128. What method(s) do you use to decontaminate your isolator systems? a. b. c. d. e. f. g.

Chlorine dioxide 0 Hydrogen peroxide vapor 6 Microcondensing hydrogen peroxide 0 Liquid hydrogen peroxide 1 Steam/hydrogen peroxide 0 Peracetic acid 1 Ozone 0

0.0% 66.7% 0.0% 11.1% 0.0% 11.1% 0.0%

Comments Other: Sanitizing solution system. 129. If you surface decontaminate materials to bring into your isolator, what method(s) do you use? a. b. c. d. e. f.

Hydrogen peroxide vapor 3 Pulsed high intensity light 1 Ultraviolet light 1 Liquid sporicide applied automatically0 Liquid sporicide applied manually 3 Another method, please describe 3

37.5% 12.5% 12.5% 0.0% 37.5% 37.5%

Comments f. All material brought into the isolator is moist heat sterilized into the isolator. f. Sanitizing solution system.

Comments f. Statistical analysis. f. Combination of C and D. f. At initial validation – Based upon intensive monitoring, worst case sites are selected. Levels will be adjusted based upon routine data. Alert limits also have been generated based upon routine data. 131. Do the same microbial levels apply to all of the Class 100/ISO 5 (EU Grade A) environments in your APA? a. b.

a. b.

c. d.

Microbial Levels for Controlled Areas

a. b. c.

d.

e. f.

Based upon previous process simulation environmental data Based upon previous production environmental data Based upon previous process simulation and production environmental data From published levels by regulatory and/or compendial bodies (USP, EU, other) Arbitrary level Other - please explain

40 3

f.

g.

Class 100/ISO 5 (EU Grade A) (laminar flow) 8 Class 100/ISO 6 under static conditions (EU Grade B) (non-laminar flow) 16 Class 1,000/ISO 6 under static (no activity) Conditions 1 Class 1,000/ISO 6 under dynamic (activity) Conditions 2 Class 10,000/ISO 7 (EU Grade C) under static (no activity) conditions 1 Class 10,000/ISO 7 (EU Grade C) under dynamic (activity) conditions 16 Class 100,000/ISO 8 (EU Grade D) under static (no activity) conditions 0 Class 100,000/ISO 8 (EU Grade D) under dynamic (activity) conditions 3 Other - please describe 2

1

2.3%

12

27.9%

h.

11

25.6%

i.

36 1 3

83.7% 2.3% 7.0%

Comments i. Isolator with Grade D background. i. Filling is performed in a closed isolator. i. Unclassified.


93.0% 7.0%

132. What is the surrounding environment to Class 100/ ISO 5 (EU Grade A) utilized for aseptic filling in your facility?

e.

130. How are quantitative airborne microbial levels for the APA determined? Please mark all that apply.

Yes No

18.8%

37.2% 2.3% 4.6%

2.3%

37.2%

0.0%

7.0% 4.6%

29

133. Do the same microbial levels apply to the following Class 10,000/ISO 7 (EU Grade C) environments in your APA? Please mark all that apply. a. b. c. d. e. f. g.

Areas surrounding Class 100/ISO 5 (EU Grade A or B) Corridors Sterilizer/oven unload areas Storage areas Gowning room exit Gowning room entrance Exit gown room (if present)

21 21 19 17 18 15 4

65.6% 65.6% 59.4% 53.1% 56.2% 46.9% 12.5%

134. Do the same levels apply to other APAs on this site which are of the same environmental classification? a. b.

Yes No

37 2

94.9% 5.1%

135 How are quantitative surface microbial levels for the APA determined? Please mark all that apply.

b. c.

d.

e. f.


Yes No

34 9

79.1% 20.9%

Comments a. Except floors. b. Floors are different from walls and equipment. 137. Does the same level apply to similar surfaces in other APAs on the same site which are of the same environmental classification? a. b.

Yes No

40 2

95.2% 4.8%

138. Does your site have quantitative personnel monitoring microbial levels for its primary APA? Please mark all that apply. a.

1

2.3% b.

11

25.6% c.

11

25.6% d.

35 1 3

81.4% 2.3% 7.0%

Comments f. Statistical analysis of historical data. f. Combination of C and D. f. At initial validation – Based upon intensive monitoring, worst case sites are selected. Levels will be adjusted based upon routine data. Alert limits also have been generated based upon routine data.

30

a. b.

Comments b. Only one APA

Comments b. Only one APA.

a.

136. Does the same level apply to all surfaces within your APA which are of the same environmental classification; e.g., Class 100/ISO 5 (EU Grade A), Class 10,000/ISO 7 (EU Grade C)?

e. f.


1

2.4%

13

31.7%

7

17.1%

33 0 5

80.5% 0.0% 12.2%

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


139. Does the same level apply to all personnel within your APA who work in areas of the same environmental classification; e.g., Class 100/ISO 5 (EU Grade A), Class 10,000/ISO 7 (EU Grade C)? a. b.

Yes No

36 4

90.0% 10.0%

140. Does the same level apply to personnel in similar activities in other APAs at this site which are of the same environmental classification? a. b.

Yes No

34 3

91.9% 8.1%

Comments d. Not applicable (4) 143. Is your site evaluating the following types of alternative terminal sterilization technologies for future sterile products? Please mark all that apply. a. b. c. d. e.

Gamma radiation X-ray radiation Microwave Plasma Other - please describe

7 0 1 0 4

58.3% 0.0% 8.3% 0.0% 33.3%

Comments e. Not applicable (4).

Comments b. Only one APA. Aseptic Processing Technology Terminal Sterilization and Aseptic Processing 141. Does your site employ the following types of heat sterilization processes for its current sterile products after aseptic processing? Please mark all that apply. a.

b.

c.

d.

Overkill cycles (F0 of 12 minutes or more, 15 minutes at 121.1ºC) – a 6-log or greater reduction of a resistant bioindicator Bioburden-biological indicator cycles - a less than 6-log reduction of a resistant bioindicator Bioburden cycles - a 6-log or greater reduction by post-filling lethal treatment of the most resistant bioburden isolate. Other - please describe

19

144. Which of the following technologies is your site evaluating for utilization in the preparation of its aseptically filled products? Please mark all that apply. a.

70.4% b.

4

14.8%

2 4

7.4% 14.8%

Comments d. Not applicable (4)

c. d. e. f.

142. Is your site evaluating the following types of heat sterilization processes for its future sterile products after aseptic processing? Please mark all that apply. a. b. c. d.

Overkill cycles Bioburden-biological indicator cycles Bioburden cycles Other - please describe

g.

Closed isolators (cannot exchange air from fill zone to surrounding area where personnel are located) (no direct openings, all transfers via closed containers) (decontaminated) 8 Open isolators (can exchange air from fill zone to surrounding area where personnel are located) (direct opening present for container exit) (decontaminated while closed) 12 Restricted access barriers 9 Sterilize-in-place 19 Robotic manipulation of sterile materials 4 Hermetically sealed gowns with self-contained breathing apparatus 2 Form-fill-seal/Blow-fill-seal technology 4 Electrophoretic air systems 0 Other - please describe 3

15

65.2%

h. i.

4 3 4

17.4% 13.0% 17.4%

Comments a. For sterility testing. i. Not applicable (3).


24.2%

36.4% 27.3% 57.6% 12.1% 6.1% 12.1% 0.0% 9.1%

31

Other Issues

h. i. j. k. l. m. n.

145. Please rank the following potential sources of contamination from most-likely to least-likely to cause problems in process simulations? 1-Most Likely, 10-Least Likely a. b. c. d. e. f. g.

a. b. c. d. e. f. g. h. i. j. k. l. m. n.

32

Inadequate or improper sterilization Inadequate or improper sanitization Transfer of materials within APA Assembly of sterile equipment prior to use Routine operations during aseptic process Non-routine operations during aseptic process Airborne contaminants

1 6 13.9% 1 2.3% 3 7.0% 3 7.0% 2 4.6% 1 2.3% 3 7.0% 2 4.6% 24 55.8% 11 25.6% 6 13.9% 5 11.6% 4 9.3% 0 0.0%

2 2 4.6% 2 4.6% 1 2.3% 6 13.9% 3 7.0% 4 9.3 5 11.6% 5 11.6% 9 20.9% 19 44.2% 0 0.0% 1 2.3% 0 0.0% 0 0.0%

3 0 0.0% 9 20.9% 3 7.0% 7 16.3% 1 2.3% 13 30.2% 3 7.0% 3 7.0% 5 11.6% 3 7.0% 5 11.6% 0 0.0% 0 0.0% 0 0.0%

4 0 0.0% 3 7.0% 7 16.3% 8 18.6% 1 2.3% 8 18.6% 2 4.6% 1 2.3% 0 0.0% 3 7.0% 0 0.0% 0 0.0% 1 2.3% 0 0.0%

Surface contaminants Personnel contaminants Human error Mechanical failure Failure of sterilizing filter Failure of HEPA filter Other - please specify

Comments i. Glove hole in isolator. i. Interpreted as the effect this event would cause on the media fill, not as the likelihood of this event occurring.

5 2 4.6% 6 13.9% 4 9.3% 1 2.3% 10 23.2% 6 13.9% 8 18.6% 6 13.9% 3 7.0% 3 7.0% 11 25.6% 4 9.3% 4 9.3% 2 4.6%

6 1 2.3% 2 4.6% 3 7.0% 5 11.6% 1 2.3% 0 0.0% 7 16.3% 5 11.6% 1 2.3% 1 2.3% 1 2.3% 1 2.3% 2 4.6% 0 0.0%

7 1 2.3% 4 9.3% 4 9.3% 3 7.0% 2 4.6% 3 7.0% 1 2.3% 7 16.3% 0 0.0% 0 0.0% 4 9.3% 3 7.0% 0 0.0% 0 0.0%

8 2 4.6% 5 11.6% 11 25.6% 4 9.3% 7 16.3% 3 7.0% 3 7.0% 2 4.6% 1 2.3% 2 4.6% 5 11.6% 3 7.0% 6 13.9% 0 0.0%

9 2 4.6% 5 11.5% 1 2.3% 1 2.3% 3 7.0% 2 4.6% 2 4.6% 3 7.0% 0 0.0% 0 0.0% 4 9.3% 5 11.6% 5 11.6% 0 0.0%

10 22 51.2% 4 9.3% 4 9.3% 3 7.0% 11 25.6% 2 4.6% 8 18.6% 7 16.3% 0 0.0% 0 0.0% 4 9.3% 14 32.5% 14 32.5% 4 9.3%


140. What would you estimate the actual probability of non-sterility associated with your aseptically filled products to be? a. b. c. d. e. f.

Less than 1 in 1,000 Less than 1 in 5,000 Less than 1 in 10,000 Less than 1 in 50,000 Less than 1 in 100,000 1 in 100,000 or greater

0 4 4 5 13 14

0.0% 10.0% 10.0% 12.5% 32.5% 35.0%

Comments d. Total 20,000 units were filled; no failure thus far. d. Impossible to estimate. 147. Do you incubate damaged containers (loose or missing stoppers, cracks) that are filled during process simulation testing? a. b.


10 33

23.2% 76.7%

Comments a. Identify damaged containers; separated for acceptable ones. a. All vials are incubated. a. Only if seal integrity is not compromised. a. The only exceptions allowed from incubation process are: missing stopper, missing cap tip (sprayer), broken. a. Leaking or damaged containers are identified and recorded. These are incubated, however, if contaminated; these are not continued to be incubated alongside the remaining units. The contaminating organism is identified to species level. This unit (damaged and contaminated) is not included in the determination of the contamination rate. a. Any such defects not removed on initial inspection (To) are, if subsequently detected, left with the media fill. a. Reference purpose only; no impact on final test result. a. Potentially defective containers – these are marked as such.


a.

b. b. b.

All filled stoppered units must be incubated even if routine production procedures regard these as rejects for whatever reason. The units must be identified and segregated from the rest of the filled units. The results from these potentially rejected units may or may not be used in the evaluation of the trial, as they are for information purposes only. If not removed at initial inspection, they remain with the batch. Occasionally for information only. Only integral units are incubated.

148. Do you incubate media filled containers that would have been rejected for cosmetic defects during actual production operations? a. b.


33 8

80.5% 19.5%

Comments a. Mold defects. (2) a. If the damage does not compromise unit integrity. a. Identify damaged containers separated from acceptable ones. a. Worst case. a. Cracks and others are rejected for production, but not for media fills. a. As long as the interior is not breached. a. Cosmetic defects are not allowed to be rejected for media fills. a. Leaking or damaged containers are identified and recorded. These are incubated, however, if contaminated; these are not continued to be incubated alongside the remaining units. The contaminating organism is identified to species level. This unit (damaged and contaminated) is not included in the determination of the contamination rate. a. All units incubated that have container integrity. a. All integral units are incubated. a. All properly stoppered, capped, uncracked vials, including short-filled or units with cosmetic defects are incubated. a. All non-damaged containers are incubated. a. Evaluate entire filling operation. a. Scratched vials, dented seals, etc., are incubated.

33

a. a. a. a. a. a. a.

a.

We do not inspect for cosmetic defects during media fills. All rejected integral containers are incubated. Yes, except for integral defects. All ampoules except integrity test failure are incubated. Units that are integral. (3) As long as closure is intact. As long as sterile barrier is maintained. Containers that would have been rejected during actual production (for example, after interventions and cosmetic defects) are incubated separately for investigation purposes. All filled stoppered units must be incubated even if routine production procedures regard these as rejects for whatever reason. The units must be identified and segregated from the rest of the filled units. The results from these potentially rejected units may or may not be used in the evaluation of the trial, as they are for information purposes only.

149 What percentage of media fills you complete are totally free of any contaminated units? a. b. c. d.

< 25% 25-50% 50-75% 75% or more

0 0 3 40

0.0% 0.0% 7.0% 93.0%

151. What is the environment at point of fill utilized for filling terminally sterilized products? a. b.

c. d. e. f. g. h. i.

a. b.

c. Yes - please explain No

5 34

12.8% 87.2%

Comments a. No questions regarding campaign filling/media fill validation or maximum machine set-up times, for aseptically filled or powders. a Validation by media fill of maximum storage time of m/c parts, components, etc., before use. a. Training of operators to visually inspect trials, i.e., use of low level contaminants compare units using range of organisms. a. Reconciliation of media filled units.

34

90.9%

9.1% 0.0% 0.0% 9.1% 0.0% 0.0% 0.0% 0.0%

152. What is the surrounding environment utilized for terminally sterilized products?

150. Have we overlooked a significant concern or fact regarding aseptic processing? a. b.

Class 100/ISO 5 (EU Grade A) (laminar flow) 10 Class 100/ISO 6 under static conditions (EU Grade B) (nonlaminar flow) 1 Class 1,000/ISO 6 under static (no activity) Conditions 0 Class 1,000/ISO 6 under dynamic (activity) Conditions 0 Class 10,000/ISO 7 (EU Grade C) under static (no activity) conditions 1 Class 10,000/ISO 7 (EU Grade C) under dynamic (activity) conditions 0 Class 100,000/ISO 8 (EU Grade D) under static (no activity) conditions 0 Class 100,000/ISO 8 (EU Grade D) under dynamic (activity) conditions 0 Other - please describe 0

d. e. f. g. h. i.

Class 100/ISO 5 (EU Grade A) (laminar flow) Class 100/ISO 6 under static conditions (EU Grade B) (nonlaminar flow) Class 1,000/ISO 6 under static (no activity) Conditions Class 1,000/ISO 6 under dynamic (activity) Conditions Class 10,000/ISO 7 (EU Grade C) under static (no activity) conditions Class 10,000/ISO 7 (EU Grade C) under dynamic (activity) conditions Class 100,000/ISO 8 (EU Grade D) under static (no activity) conditions Class 100,000/ISO 8 (EU Grade D) under dynamic (activity) conditions Other - please describe

2

18.1%

4

36.4%

0

0.0%

1

9.1%

3

27.3%

3

27.3%

0

0.0%

0 0

0.0% 0.0%


Conclusion The results of this survey continue to demonstrate the diversity of approaches utilized in the industry for the validation of aseptic processing. While there were several areas where the methods are becoming quite uniform, considerable variation is certainly present across the industry. Many of the differences can be traced to the differing product types, facility sizes, and levels of technology present within the surveyed firms. Parenteral manufacturers

References 1. Annex 1, EU GMP Directive, “Manufacture of Sterile Medicinal Products,” (1996). 2. ISO/DIS 13048-1, “Aseptic Processing of Health Care Products–Part 1: General Requirements,” (1996). 3. Guideline on Sterile Drug Products Produced by Aseptic Processing, CDER and ORA, Food and Drug Administration, (1987). 4. Technical Report No. 22, “Process Simulation Testing for Aseptically Filled Products,” PDA J. Pharm. Sci. Technol., Vol. 50, No. S1, PDA, (1996).


worldwide continue to have considerable latitude in the design of their aseptic processing validation program. Acknowledgments This survey would have been impossible without the respondents who spent a great deal of time in answering the questions, and developing their comments. Pamela Jones, CreaTech, provided invaluable support in performing the tedious task of data entry.

5. Korczynski, M., “Validation of Aseptic Process by Media Fills—Survey Report and Discussion,” in Proceedings of the Second PMA Seminar Program on Validation of Sterile Manufacturing Processes: Aseptic Processing, PMA (1979). 6. Agalloco, J. and Gordon, B., “Current Practices in the Use of Media Fills for the Validation of Aseptic Processing,” J. Parent. Sci. Tech., Vol. 41, No. 4, PDA (1987). 7. Technical Report No. 17, “Current Practices in the Validation of Aseptic Processing–1992,” J. Parent. Sci. Tech., Vol. 47, No. 2, (S1), PDA (1993). 8.

Technical Report No. 24, “Current Practices in the Validation of Aseptic Processing,” PDA J. Pharm. Sci. Technol., Vol. 51, No. S2, PDA (1997).

35

PDA Journal of Pharmaceutical Science and Technology Supplement TR36 May/June 2002

Volume 56 No. 3

EDITOR: Lee Kirsch c/o The University of Iowa Pharmacy Building, S223 Iowa City, IA 52242, USA (319) 384-4408 [email protected] Editorial Assistant: Madhu Gokhale

CIRCULATION OFFICE: PDA 3 Bethesda Metro Center, Suite 1500 Bethesda, MD 20814 Phone: (301) 986-0293 www.pda.org ADVERTISING/CIRCULATION Nahid Kiani Phone: (301) 986-0293 x128 ADVISORY BOARD Michael Akers Frederick J. Carleton Patrick DeLuca, University of Kentucky Barry Garfinkle, Merck Sharp & Dohme Michael Groves, University of Illinois Joseph Robinson, University of Wisconsin Theodore Roseman, Baxter Healthcare 2002 OFFICERS AND DIRECTORS Chair: Floyd Benjamin Chair-Elect: Nikki V. Mehringer Secretary: Jennie Allewell Treasurer: Richard V. Levy, Ph.D. Immediate Past Chair: Robert B. Myers Vince R. Anicetti Robert L. Dana Kathleen S. Greene Suzanne Levesque Robert J. Mello, Ph.D. Lisa M. Skeens, Ph.D.

Joyce A. Aydlett Stephanie R. Gray Henry K. Kwan, Ph.D. Tim R. Marten, D.Phil. Taiichi Mizuta, Ph.D. Glenn E. Wright

European Steering and Development Committee Chair: Georg Roessling, Ph.D. President: Edmund M. Fry

PDA Journal of Pharmaceutical Science and Technology (ISSN 1079-7440) is published bimonthly by the PDA, Inc., 3 Bethesda Metro Center, Suite 1500, Bethesda, MD 20814. Subscriptions – PDA membership dues include an annual subscription to the PDA Journal of Pharmaceutical Science and Technology. For an application form and information regarding membership, address the Association. Industrial, university, and public libraries, as well as government agencies, may subscribe at the rate of $195 per year. Back issues are available from the Association at the rate of $ 55 members/$75 nonmembers plus shipping. Copies of individual articles are available at a cost of $20 members /$40 nonmembers, plus shipping (please specify volume number, issue, and title of article: this information may be referenced at www.pda.org). Claims – Issues lost in transit will not be replaced if claim is received more than 90 days from date of issue or if loss was due to failure to give notice of change of address. The Association cannot accept responsibility for delivery outside the United States when shipment has been made by first-class mail. Periodicals postage paid at Bethesda, Maryland and additional mailing offices. Postmaster: Send address changes to the PDA Journal of Pharmaceutical Science and Technology, 7500 Old Georgetown Road, Suite 620, Bethesda, MD 20814 Printed in the USA.

Copyright © PDA, Inc. 2002 ISSN 0277-3046 Copyediting, typesetting, and other production services provided by Davis Horwood Int’l Publishing, Ltd. Raleigh, NC, USA Godalming, Surrey, UK

Technical Report No. 36


Current Practices in the Validation of Aseptic Processing—2001

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

TR 36 2002 Current Practices of Aseptic Processing - 2001

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