Technical Report No. 17 One eer NCO a ey Journal of Parenteral Science and Technology LT) ra A STCL Ua OePDA PARENTERAL DRUG ASSOCIATION, INC. President: | “James E Akers, PhD. ‘er Kenedy & Asis President-Elect: ‘Clarence A. Kemper,Ph.D. Kemper-Massan, tn. Secretary “JoyeeL- DeYoung, Ph.D. MeN Pumice ‘Treasurer: Raymond Shaw,Jr4PhD. Marck & C0 Directors: ‘James Agalloco Joyce Aydlett Floyd Benjamin Peter T.Bigelow Site Beet Pharacestials Doris Conrad ‘SmbKline Beech | Robert Garnick, Ph.D. Geert, Ie John Geigert,Ph.D. imines Manafatring Com, Frederick A.Gustafson Abbot Lateton, Is Michael S. Korezynski, Ph.D. ‘At Laborer, Ine Jean A.LaDouceur ‘pled iimane Scenes. le Russell. Madsen Balers Squib Co Robert B. Myers Bavard J.Smith, PhD. Executive Vice President: ‘Edmund M.Fry General Counsel: ‘Carl Roberts Editor, Journal of Parenteral Seience and Technology: ‘Joseph B. Schwartz, Ph.D. Pada Coleg of Pharmacy & Founded 1946 April 12, 1993 NOTICE OF CORRECTION: PDA Technical Report No.17, Current Practices in the Validation of Aseptic Processing - 1992 Dear Subscriber/Member, We have identified the following correction to Technical Report No.17: The "Comments" in question No. 55 actually apply to question No. 56, "What acceptance criteria do you employ for solution products?" There are no comments that apply to question No. 55. We suggest you make a notation of this correction on your copy of the technical report for future reference. PDA regrets the error. / ns / Levine. CY geten... ames C. iigay’ Director of Bxterhal and Regulatory Affairs hs\te\eorrect.2e 7500 Old Georgetown Road Suite 920 @ Bethesda, MD 20814 Tel: (301) 986-0293 Fax: (301) 986-0296Current Practices in the Validation of Aseptic Processing-1992 James Agalloco, Agalloco & Associates, Princeton, NJ and James Akers, Akers Kennedy & Associates, Cary, NC Introduction The validation of aseptic processing has been the focus of considerable discussion within the pharmaceuti- cal industry since the publication of PDA’s Technical Monograph #2-Validation of Aseptic Filling for Solu- tion Drug Products in 1980. The specific methods, practices and limits employed by industry have evolved considerably over the intervening years. The PMA [in 1979] and the PDA {in 1986] conducted surveys on this subject in the past which have helped the industry understand the ways in which our peers have addressed this important area. With the passage of time, the state of the art has changed, regulatory positions have become more explicit, and technological advances have been made. To better assess current practice in the validation of aseptic, processes in light of the changes evidenced, the PDA. Science and Technology Committee decided in 1991 to stirvey the industry to identify how the passage of time [5 years since the previous PDA survey] has modified industry approaches. Media fill questionnaires were sent to individuals listed in the 1991 PDA membership directory at over 450. sites worldwide. A total of seventy seven [77] responses were received representing both US and Non-US loca- tions. The data was tabulated to provide both raw ‘umerical and percentage of total respondents for US facilities, Non-US facilities and all facilities. Where the respondents provided comments, whether solicited or voluntarily, they are provided after the question. Where ‘more than one respondent provided essentially the same response selection and comment, they have been consol- jdated and a number appears next to the response indi- cating the number of comments of that type. The nature and extent of the comments received was extensive and for this reason, the authors have chosen to combine similar responses to shorten the document somewhat. ‘As can be seen in question No. 1, three firms did not specify US or Non-US status. As a result, totals in the column AU! Finns may sometimes be slightly larger than the sum of US and Non-US firms. Further, readers are reminded that the column totals for each question will often not equal the sum of the responses. Many firms selected multiple responses, and many firms provided a response other than the choices presented. Where relevant, such responses have been shown as comments. 1, Inwhat country, or state is your Aseptic Processing Area [APA] located? ‘Number of responses, US firms: 45 Number of responses, overseas firms: 29 Number of responses, unspecified: 3 Total number of responses: 1 ‘Vol. 47, Supplement 1983 Non-US countries represented: Austria, Canada, England, France, Germany, India, Israel, Italy, Japan, Netherlands, Pakistan, Portugal, Slovenia, Spain, Sweden 2. Does your firm have APA operations in other countries? US Firms Non-US Firms All Firms a)No 19 432% 10 345% 29 38.7% by Yes 25 568% 18 621% 45 60.0% Total 4 2B 4 3. What types of sterile products do you manufacture at this site? Please check all that apply. US Firms Non-US Firms All Firms ayLvp’s 6 133% 4 138% 10 130% b)SVP's Solutions 19 422% 14 483% 35 455% Suspensions 4 89% 6 WI% ML 143% Freeze Dried 6 133% 10 345% 17 21% Poveder Fills 3 111% 7 241% 13 169% ©) Ophthalmics M1 264% 15 517% 26 33.8% 4) Inbatations 4 89% 1 34% 5 65% ¢) Ointments 8 178% 3 103% 1 43% 1) Biologicals 5 333% 6 2.1% 2 WHR g) Veterinary 15 333% 10 34.5% 27 35.1% h) Other 5 11% 3 103% 8 10.4% Total 45 2 n Comments Injectable biodegradable implant; ternary mix- ture pouches; oral liquids for diagnostics; con- tact Jens solutions; cell culture products; ani- ‘mal sera, media, medical devices; bone cement; bulk sterile powder; culture media; solution- doviee. 4, How many different sterile product presentations do you manufacture at this site? US Firms Non-US Firms All Firms ayo-s 18 400% 7 241% 26 33.8% b)6-49 17 378% 16 55.2% 35 45.5% ) 50-99 4 89% 3 103% 7 91% 4) 100-149, 1 22% 2 69% 3 39% ©) >150 S 11% 1 34% 6 7.8% Total 45 2» n 5. What percentage of your sterile products are ‘manufactured using aseptic processing? USFirms Non-US Firms All Firms a) Less than 25% 6 133% 2 69% 8 104% b) 25% 050% 2 44% 5 172% 7 9.1% st51% 107 8) More than 75% | 22% 2 9% 3 39% 3 RDO% 20 69.0% $9 76.6% Total 45 » n 6, Is this number an increase or a decrease from five (5) years ago? USFirms Non-US Firms All Firms a) Increase 1b ALI 8 276% 23 2996 byDecrease 367% 3 103% 6 78% ©) Same 2B 622 18 62.15 48 62.3% Total 45 » n 7. At your site are products which could employ a terminal sterilization process produced using asep- tic processing? USFirms Non-US Firms All Firms a) Yes 5S 333% 7 25.0% 22 28.9% b)No 30 66.7% 21 75.0% 54 TIT Total 45 8 1% yes, what percentage of the aseptically pro- duced products does this represent? Average % 39% B% 8, What pereentage of your aseptically filled products contain an anti-microbial preservative? US Firms Non-US Firms All Firms a)Lessthan 25% 25 6% 20 69.0% 47 61.0% b)25% 10 50% 3 67% 0 4 5.2% ©) 51% to 75% 3 67% 6 207% 9 ILI G)More than 75% 14 MA% =—-3 10.3% 17-22% Total 45 2» 7 Comments © Antibiotics are not considered as anti-micro- bial preserved, @ Consider our antibiotic ophthalmic ointments preserved, 9, What percentage of your aseptically filled products are single-use containers? US Firms Non-US Firms All Firms a)Lesthan 25% 19 42.2% 4 L8G 23. 29.9% b) 25% 0 50% 2 44% 4 BE 6 78% 51% 10 75% 122% 7 9.1% )More than 75% 23. SLL% 41 53.2% Total 45 7 10. What percentage of your aseptically filled products, have inherent anti-microbial activity such that they ‘would pass the USP preservative efficacy test? US Firms Non-US Firms All Firms a)Lesthan 25% 22 S12% 1S $8.6% 38 S2.1% 1) 25% 10 50% 9 29% 5 185% 14 19.2% ©) 51% to 750% 247% 1 RIM 3 dm 82 @)Morethan 78% 10 -28.3% «IG IS NIG Total a ” B Comments @ Aatibiotis 11, What percentage of your aseptically filled products have neither an anti-microbial preservative nor inherent anti-microbial activity such that they ‘would pass the USP preservative efficacy test? US Firms Non-US Firms All Firms a)Lessthan 25% 31 705% 14 50.0% 46 622% b) 25% 10 50% 2 45% 4 143% 6 81% ©) 51% 1075 3 68% 1 36% 4 5.4% d)More than 75% 8 182% 9 321% 18 243%. Total “4 8 " Comments ib) Antibiotics and diluents without preservatives. Noanswer Unknown, have not tested 12, What criteria are employed to determine the adequacy of the preservative system or anti- ‘microbial properties of your sterile formulations? Please check all that apply. USFirms Non-US Firms All Firms a) USP 35 833% 21 913% 57 85.1% b)BP 12 286% 8 348% 20 29.9% OrIP 2 48% 0 2 30% d) Other 8 19.0% 6 26.1% 15 224% Total 2 2 o Comments @ If we did the tes. @ Failed European Pharmacopeia. (ab) Preservative efficacy test. (aa) Japan Pharmacopeia and minimum require- ‘ments for antibioties products of Japan, (aa) Organisms isolated from APA are used to challenge, (aba) EC and active preservative testing by stability (abd) rman and French Pharmacopeia. (aba) Australia requires 14 day test. (abd) Code of Federal Regulations. @P No preservatives in the products. @BI Not applicable. @ 9 CER limitation on the use of antibiotics and other preservatives. No response Contract manufacturer. Release/Quarantine Practices. 13. If a media fill action level is exceeded on a line, what action do you take with regard to products processed on the line prior to the media-fill fail- US Firms Non-US Firms All Firms a) Release 3 10% 2 69% 5 6.1% b) Investigation 27 628% 25 96.2% $5 733% Journal of Parenteral Science & Technology©) Other action Total Comments 13) (b) (b) [6] ©) ) ) ©) bo) © © © o © ©. © © (9B) © (2) No response 13 302% 3 103% 48 9 5 16 213% Pending outcome of investigation. ‘Quarantine products. Inform Corporate Qual- ity Control about batch sterility results, investi- gations and recommendations for release of batches. May be rejected. If possible-if investigation not isolated with hold release and reject. Media fils are for training only! Provided repeat media fills pass. Tf assignable cause can be determined and a date assigned. Repeat media fill after correc- tive action must yield failure rate less than 10- Thorough investigation. No releases until con- clusions are made and/or repeat of media fil “Look back” period applicable to batches not yet released only. This happened only one time in the site’s history and all product was rejected or with- held from market. Investigation results would determine product release or not as well as product testing results Investigation would be performed to ascertain contamination source. A quarantine would not be placed on any lots filled prior unless a lot either failed a sterility test or experienced an environmental test response level during the filling operation. Has never happened have not execeded limit on a media fill. Product disposition will con: tinue to be solely dependent upon product and ‘component release testing. Release after satisfactory media fils. Thorough investigation involving isolating con- taminant and challenging preservative system Cf product with isolates if necessary. Extra sterility testing and 3 media fills in order toccheck for a systematic failure. ‘Quarantine batch prior to failure, double sterl- ity test batch prior to failure, repeat media fill, investigate sterility test and process for batch prior to failuze, review environmental results ‘on batch prior to failure. Investigate-then decide disposition of batch. Fail will not sel Suspend release of product not yet released pending investigation. Has never happened 14, Ifa media fill action level is exceeded on a line, what action do you take with regard to products processed on the line subsequent to the media-fill failure? a) Release ») Investigation ©) Other action Total USFirms Non-US Firms All Firms 2 47% 0 2 27% 24 S58% 15 $36% 40 S4.1% 19 4.2% 13 464% 34 45.9% 6 28 4 Vol. 47, Supplement 1983 Comments @ (b) (6) ) (b) (b) [2] (bey (be) ©) (©) 2] ©15) (©) [4] © (©) © © OB) © © © © OB) No response If possible-if investigation not isolated with hold release and reject halt production and will do 3 media runs before restarting production, Pending outcome of investigation. Quarantine products. Inform Corporate Qual- ity Control about batch sterility results, nvesti- gations and recommendations for release of batches. Provided repeat media fills pas. Double sterility to subsequent lots. Release if results are acceptable. Repeat media fil and assure compliance prior to re-initiating produc- tion, Depending on the outcome of the investiga tion, further product fills may be suspended until a satisfactory media fil(sis/are_per- formed, Release after investigation or conduct addi tonal media fils A successful media fil Investigate. Production not allowed to start until a media filis acceptable. Release after successful media fill and accept- able product release testing results. Production not restarted until conclusions with regard to cause and corrective action are made. Batches not yet released will be quarantined ‘and their disposition is only determined after conclusions are made. Running at [east two more media fills, ia order to achieve 99.00% sterility. Would depend on results of investigation and corrective measures taken as a result of the failed media fill ‘Quarantine, double sterility tests, repeat me- ia fil, investigate sterility ests and processes, Review environmental results for all batches produced subsequent to failure. Perform investigation, Not less than 3 accept- able media fill prior to resuming production. No product will be processed unless three successful consecutive media fills have been done. assignable cause, eg, environmental monitor- ing failure, line shutdown and restart w/o sterilization or other gross cause can be attrib- uted to the individual failure and a repeat media fill following corrective action passes- release, If repeat media fill fails or assignable ‘cause can be determined all lots are rejected. Rejection unless investigation provides insur- mountable proof of an isolated incident, Re~ Tease only after a successful media fill, We interrupt the filling process as soon as possible after such excessive result of the ‘media fill. Batches filled after the media fill- will be quarantined until reason of the devia tion has been identified. Depending on these results a release decision about products pro- cesses ete. will be taken. Immediate “hold” status pending outcome of investigation; typical action would be rejection. Depending upon the investigation results 3media fills would be executed and then possi- bile the lots may be have to be reprocessed, No response No batch will be manufactured Noresponse Suspend release of all products filled after media fill pending investigation. If enhanced ‘media fills are successful and speciation and other investigation indicates non-systemic prob- lem then product is released. Operator train- ing is emphasized. 15. Is positive action taken against a certain number of lots or over a certain time period in the event of a failure? US Fics Non-US Firms All Firms a) Yes-lots 9 22.0% 12 46.2% 21 b)Yestimeperiod 37.3% «7 -6.9% 10 No 15 366% 6 21% 23 4) Other 15 366% 5 19.2% 20 200% Total a 2% ° Comments @ Adjacent batches, @ Lot immediately prior 10 and all lots subse- quent to failure, @ All lots after failure. (@) All ots after failure, Lots before failure de pend on investigation results. @) 10 batches before, no fll after. @) One. @ All @) Given campaign, (@) All the lots produced since the previous accept ‘able media fil, @ Variable, none produced. (ab) Batches not yet released approximately 2 weeks before and 2-4 weeks after media fil (ab) 4) 20, b) 1 month. (ab) ) Adjacent or if they have something in common b) 2 weeks before and 2 weeks after (ab) 8) about 3b) about 2 (b) All associated fils (with common equipment setups, etc) () 1) Back to previous successful media fills) All lots, () Al lots processed since media fill and all lots processed since last successful media fill ) Evaluation of period between last successful run and present failure. © Not for sterility tes failures. (a) Not defined. (a) Positive action will be taken when such need @ ‘No manufacturing until satisfactory media fill. (a) Has never occurred. @ Dependson the nature or source ofthe contam- inant (a This would be determined as a result of the investigation of the specific problem, @ Yes. Time-lots determined by investigation and any processing changes. @P Action pending investigation and interpreta tion of data, ® Repeat media fill, Determine an assignable 8a cause. Product lots manufactured subsequent to the repeat are held pending outcome of repeat and investigation, isl No lot may be released until a successful qualification of the system is run, No response Every lot after failure and depending upon the results of the investigation multiple lots manu- factured prior to the media fill. Noresponse No media fill has ever failed 16, 1s positive action taken on production during a set period of time before and after failure? USFirms Non-US Firms All Firms a) Yes 8 20.0% 10 40.0% 18 26.9% b)No 16 400% 7 280% 25 37.3% ©) Other 16 400% 8 320% 24 35.8% Total 40 2% oa Comments (a) One week, we work Monday to Friday. (a) ‘One day. (a) Repeat of media fil, extensive training. (a) ‘weeks before and 2 weeks after. (a) Lots produced after held in quarantine until 2 successful media fils pass. (a) To last test. (@) Investigation of batches between media fil 22] Depending on investigation results. (a) ‘After-no production until investigation com- pleted and media fills successfully repeated. @ Production is stopped. @ Logging and sanitizing immediately before and after. (@) I month, @ On line all aseptic processing suspended until successful media il (a) Prior to resuming production 0) Investigation must reveal an assignable cause ‘or complete revalidation of filling. and HVAC is required prior to re-initiation of production, ©) Depends on investigation, (b) ‘How can a failure be predicted? © Positive action will be taken when such need arises. wor Production continues with ongoing investiga- tion 0 Dependent on investigation of failure, could involve increased environmental monitoring, etc 0 No production or product not released is held until investigation i satisfactorily completed. wor Action dictated after investigation is con- cluded on ease by case wr No production until completion of three sue- cessful media fils © Not defined. © Microbiological media runs with sterility test- ing. No response No batch failures. Noresponse Depending on actual situation 17. In the event of an unsuccessful media trial, how many consecutive satisfactory trials must be con- Journal of Parenteral Sclence & Technologyducted before acceptance of the line or proce- dure? US Firms Non-US Firms All Firms a) None 0 1 36% 1 13% b)One 8 182% 2 71% 10 133% o)Tw0 12 213% 7 250% 19 253% a) Three 2 523% 17 60.7% 43 573% ©) Other 2 45% 2 11% 4 53% Total “4 28 15 Comments ©) ‘One more per procedure and review data 0) But depends on the situation © Number of failures (percentage contaminated may increase numberof retests required). (ea) ‘Two or three depending on the results. @ If investigation provides no explanation for sedi trial filure @ Minimum of 3 @ Or four. © Ifassignable cause and corrective action taken, otherwise not less than 3 consecutive runs. © To be decided by validation committee usvally one. © One retrial, if fails then three trials after investigation. © Three separate media fill runs plus revalida- tion of maximum aseptic processing. ‘Time limit (1-3 runs). © ‘Until production integrity ssatisied. Frequency 18, Do you routinely monitor each filling line or machine by media fill? US Firms Non-US Firms All Firms a) Yes 42 933% 29 100.0% 74 96.1% b)No 3 67% 0 3 39% Total 45 2» 7 19. If yes” how often? US Firms Non-US Firms All Firms a) Weekly 0 0 0 ’b) Monthly 2 49% 2 69% 4 55% ©) Semi-mmonthly 0 0 0 4) Quarterly 2 49% 3 13% 5 68% e)Semiannually 35. «85.4% 24 82.8% 61 83.50% 1) Annually 2 49% 0 4 55% 8) Other 0 0 0 Total 41 9 B Comments © (Or more often, 20, Are different lines or container types subjected to different frequencies of media fill monitoring? Vol. 47, Supplement 1983 USFirms Non-US Firms All Firms a) Yes 3 186% 4 138% 12 16.0% b)No 35 814% 25 86.2% 63 84.0% Total 43 » 5 Comments @) One container type is monitored each time. @ Complete media fils only on big fines. Powder fills have no media fills. (a Aseptic twice per year; terminal once per year. @) Unique filling areas and containers. (a) Small lot fills annually (sterility sampling is so high it provides a good check). @ Each filing line. Each container type twice per year. May mean some filing lines are only {ested once per year. @ Ampule line annually since no aseptic process- ing is done on that line. (@ Certain types of processes require media fills at completion of each production batch. @ Only limited as practical @ More often for sensitive processes. @) Different lines but same frequency. ©) 2) Only one size. 21. Ifa sterility test failure occurs, will this initiate a media fill on that line or for that operation? USFirms Non-US Fiems All Firms a) Yes 9 214% 6 2.1% 1S 23% b)No 15 35.7% 11 379% 27 365% )Sometimes 18 429% 12 414% 32 43.2% Total 2 9 % Comments @ Dependant on results of sterility test failure investigation; if problems determined with en- vironmental controls, viable monitoring data, or filling operation, media fils may be neces- sary once problems corrected. @ ‘At least one media fil, @ Unless sterility test media is contaminated or an isolation cabinet environmental monitoring failure. ole When, after investigation, the conclusion is a processing problem. © If multiple sterility failures were experienced, itmight. Would depend on results of investiga- tion. 02) Depending on the result ofthe investigation. © Investigation first, extra media fill Link with investigation. on It depends on the type of contaminant. © Only if failure cannot be explained. © Only if multiple failure-has not occurred to date. © If after investigation evidence is available that the product is non sterile, then additional actions are taken in production, one of these could be a media fill, © After multiple failures. © Depends on environmental monitoring data. $5© © © No response No response No Tine testing if problem is related to bulk product tanks. Reviewed by validation committee. If environ- ‘mental problem will usually request media fill Depends on results of investigation. If the ‘process is at fault @ requalification (3 media fl tials) would be initiated. Ifthe aseptic production environment had high microbial counts (appeared to be out of control microbiologically) media fills may be per- formed before the Line is used again. After cause of sterility feilure is determined, consideration would be given (0 appropriate corrective actions, possibly including media fills 22. How are your media fills distributed among differ- ent shifts? a) Equally b) Volume No Total Comments @ ©N9 © © © © No response (2) 23. Are all gram? USEirms Non-US Firms All Firms 2% 634% 13 448% 41 56.2% 4 98% 6 20.7% 10 13.7% 1 268% 11 379% 23. 315% 41 2» B ‘We match the production of a product with @ media fil ‘There is only one shift. By random, Not all operations are run on more than one shift. Ifa filling operation is run on different shifts, a medi fill wil be run on each shift Just one shift filling operation, When we go to ‘multi-shift operation we will revert to a) Completely random: human access to aseptic filling area is not permitted, Not applicable. Only one shift personnel included in the media fill pro- US Firms Non-US Firms All Firms a) Annual basis 25 568% 17 S8O% 45 59.2% b)Yes-Frequency 1S 341% 6 20.7% 21 27.6% No 491% 6 20.7% 10 13.2% Total “4 2» 6 Comments (a) Aseptic processing area personnel only. ) Quarterly ©) (9) Semi 21 ‘Annually. (b) Every 18 months ©) (2) Bi-annual, (b) With every media fil, ©) 22) By normal rotation. (b) Initially for training, qualification. o Except on lines where human access is permis- sible: © Although no one is excluded from the sterile challenge program. Personnel who would nor- 86 mally by utilized in a product fil are utilized in a challenge. Absences, vacations, ete. some- times prevent every operator from taking part in a challenge, © (Only personnel involved in aseptic filling. © We try to rotate at each media fill incorporat- ing “worst ease” scenarios every 6 mont. 24, Are personnel qualified to operate in the aseptic processing area [APA] through participation in a ‘media fill trial? Firms Non-US Firms All Firms a) Yes 33 75.0% 17 63.0% 52 703% b)No 11 25.0% 10 37.0% 22 29.7% Total 44 n ” Comments @) ‘That is part of the training/qualification. ) All pertinent APA employees must show asep- tic skill proficieney by participating annually in ‘ aseptic skills test, (a modified hand fill sterile challenge), as well as undergoing normal per- sonnel monitoring, ) Not yet ) Except on lines where human access is permis- sible. No response Not applicable. We have a dedicated certiica- tion program, 25. If different filling setups and/or closure systems are utilized on a filling line, will your media fill program address all permutations? USFirms Non-US Firms All Firms a) Yes 38 864% 16 571% 57 76.0% b)No 6 136% 12 429% 18 240% Total “4 28 5 Comments @) In liquid filling suite only @) But staggered from fill to il @) By rotation @) Initial validation, Then rotation or worst case chosen, ) ‘Only the systems which are determined to be worst case are utilized. (b) Only the filling operations. 26. Does your firm employ a minimum time duration for media fill runs? a)No b) Yes-NLT 1 hour ©) Yes-NLT?2 hour ) Yes-NLT3 hour ©) Yes-2>-4 hours Total “4 28 75 Journal of Parenteral Science & TechnologyComments @ Media fill run 3000 time in accordance with speed equipment, @ Run by number. (a) However, media fill will last as long as the aseptic processing process we are validating (usually not less than 3 hours), @ This point is being re-evaluated. @) Time not a variable. Production of atleast 5000 vials required. @ Lines are run at normal operating speeds. (a) Minimum batch size of 1000; however, this batch size requires 4 hours or more to com: plete filling. @) ‘Same time production lot takes. (b) Generally we like to stress the system with “worst case” situations and long fills with media. @ By procedure approximately 4 hours, ©) 8-10 hours. © In yophilizer for lyophilized products Norresponse Yes-not less than 30 minutes. Norresponse Yes-after a routine production fil Methods 27. Is the fill volume of media employed the same as that utilized in production? USFirms Non-US Firms All Firms a) Yes 22 50.0% 20 690% 44 579% 'b) No-Vial large 5 114% 4 138% 9 118% No 17 386% 5 172% 23 303% Total 4 » 6 Comments @ Except for one vial size that is too large. @ Very often, @) Up to 10 ce; greater than 10 cc media fill ‘employs half volume. © ‘We use approximately 60% of the normal fill volume. © Only one fil volume utilized. ©), 40%. © Use half fil volume, © Sufficient to cover entire interior surface area of val. 28. Do you utilize the same filing line speed for media fills as utilized in production for that container? USFirms Non-US Firms All Firms a) Yes 31 689% 22 759% 54 70.1% b)Slowest speed 12 26.7% +7 21% +20 26.0% No 2 44% 0 3 39% Total 4s » n Comments @ Intermittent filling is applied for media fils. @ Itpossible. @ ‘Alternating with slow speeds. @ Generally Vol. 47, Supplement 1993 or Media fils are performed at a slower line speed than slowest normal production, © We use slow, medium and fast il speeds. 29. Do your media fill trials include inert gassing if used in production? US Firms Non-US Firms All Firms )FIM&Ny 5 119% 1 37% 6 83% b) SCDM & Air 14 333% 7 25.9% 23 31.9% ©) Other 5 119% 7 259% 12 167% No 18 429% 12 444% 31 43.1% Total 2 1 n Comments ) Where applicable oll Soybean Casein Digest Medium [SCDM or ‘TSB] and nitrogen, OB) All vials are purged with nitrogen. © Using SCDM and nitrogen. Such challenge containers have been demonstrated to support the growth of low numbers of Micrococcus luteus, a strict aerobe. © ‘We have never substituted air for nitrogen but ‘we do use a nitrogen gas overlay for almost all of our aseptically manufactured products. © Alternative thioglycollate medium and nitro- gen, (@){12]—_Noinert gassing in use. «@ Use compressed air to replace inert ga, or use same equipment. @ Only compressed gas. @ Only SCDM. «@) Only one product requires No «@ SCDM is used, air is not used because it would not blanket product as nitrogen does. @ Because of aerobic growth, @ “Transport to lyophilizer and pulling of vacuum is included in media fill, but sterile air rather than N; overlay is used to release vacuum. @ SCDM and air @ Inhibits aerobic microorganisms. No response No gassing used. 30, Will the number of samples used in a media fill vary from line to line? US Firms Non-US Firms All Firms a) Yes 10 222% 6 20.7% 16 208% b)No 35 718% 23 793% 61 79.2% Total 45 29 7 Comments @ Normally 3000 containers are filled, However if batch size is smaller, full batch is taken as representative. @ According to number of filling needles. (@) 3] Related to tine speed. Output line isnot equal (@) 2] Manual fils would reflect actual batch size. @) High speed lines will have more units filled, but all ines must fil 5,000 units. Number is dependant on container type being filled (a) [2] s73) Depending on batch size of usual filling pro ) ‘Only one line (b) Only one size and line media fill performed ) 3000 per media fill run, b) Same product all lines. 31, Please state the minimum number of units that are filled with a single medium when conducting @ media fil 2) 1000 or less ') 1001-2000 ©) 2001-3000 4) 3001-5000 €)5001-10,000 1) 10,001 or more 1) Other Total Comments (ad) 8) pouches d) powder in vials. te) 9000 minimum-target 11000. ®) Not less than 3000, () 500 per month per filling ine. 32. Which media do you utilize for media fill trials ona regular basis? fon-US Firms All Firms a)SCDM 28 803% 71 934% b) FIM 0 7 9.2% ©) Other 4 43% 5 6.6% Total 45 2% 1 Comments (@) 2) 30 g/liter. (ae) SCDM for liquids, lactose for powder filling © Alternative thioglycollate USP XXII. © Heart infusion broth (similar to product con- tem. © Both a) andb), No response SCDM 3%. 32a, Please indicate approximate percentage of use for cach media, US Firms Non-US Firms All Firms )SCDM 12-87% 5 100% 17 b)FTM 6 21% 6 Other 1 10% 1 Total 19 5 m 33, What equipment is utilized for media fll trials? Yon-US Firms All Firms a)Allproduction 36. 80.0% 22 75.9% 59 76.6% b) Production fillonly 14 31.1% 8 276% 23 29.9%. ©) Other 122% 0 2 26% Total 45 2» n Comments: (aby a) solution filling line b) sterile dry powder filling line, (ab) A combination of these two are often used. «) Stainless steel containers and production equip- © Simulated production tank (smaller capacity). 34. When performing media fill trials do you retain sterile media in bulk tanks to simulate holding times prior to filling? USFirms Non-USFirms All Firms ay Yes 22 489% 19 65.5% 43 55.8% byNo 2B 511% 10 345% 3M 442% Total 45 » n Comments OB) Not a part of standard operations. tb) We follow manufacturing procedures used in aseptic processing. There is no “hold time” which takes place during production which we need 10 simulate with a media fill process validation run, Growth Promotion Studies 35. Are growth promotion studies conducted on each medium used? Please check all that apply. USFirms Non-US Firms All Firms )Before filling 12 273% 9 31.0% 21 27.6% b) After filling 30 682% 17 58.6% 49 68.5% ©)Alterineubation 19 43.2% 10 345% 31 40.8%. Total 4 2» 6 Comments (ab) [2] Done on media before fil 36. What organisms are used for growth promotion studies? Please check all that apply. USFirms Non-US Firms. All Bioburden studies 2) Spore formers S 14% 1 36% 6 80% b)Nonsporeformers. S$ 114% 2 71% 7 93% Environmental monitoring ©) Spore formers 9 25% $ 179% 15 20% )Nonspore formers. 8 182% 3 10.7% 12 16.0% ©) USP Growth AL 32% 25 893% 69 92.0% Sterility test contaminants 9 Spore formers 123% 1 36% 2 27% g)Nonsporeformers 1 23% 1 36% 2 27% Less common ‘organisms th) Molds 1 36% 9 120% i) Yeasts 4 143% 10 133% i) Fungi 0 4 53% Total 44 8 1% Journal of Parenteral Sclence & TechnologyComments (ach) ) Non-spore formers, f) and g) Not applica- ble. (ce) S. epidermidis, (ede) Except P. aeruginosa. (caleshi) —-Molds/yeasts: always use () 1.5. aureus 2. C. albicans 3.S. pyogenes. ©) And others: B. subtilis, E. coli, S. Aureus, C. albicans, A. niger, Pseudomonas species. ei) And European Pharmacopcia, 37. Are both Gram negative and Gram positive micro- organisms used? USFirms Non-US Firms All Firms ay Yes 27 65.9% 15 57.7% 44 62.9% b)No 14 341% 11 423% 26 37.1% Total 4 6 0 Comments ©) 15] ‘Only Gram positive microorganisms. ©) [5] Based on USP growth promotion test for SCDM, ©) 1] ‘Yeast, Gram-positive rod/sporeformer. ©) [4] B. subtilis and C. albicans. ©) Is) ‘No gram negative in USP panel for SCDM. 38. Do you use an anaerobic microorganism in media growth promotion studies? JS Firms Ne All Firms a) Yes 8 195% 12 44.4% 21 29.6% b)No 33 805% 15 55.6% 50 704% Total a an n Comments (@) Regular growth promotion not for media fills. @) Clostridium sporogenics grows well under acr- ‘bic conditions. (8) Only USP organisms are used. ©) 2) [No anaerobic media is used in growth promo- tion studies as well as in monitoring activities. 15] Periodic survey of anaerobic microorganisms indicates none present in filling area, ©) Only for anaerobic fils. (b){10}——- SCDM does not promote anaerobic growth, 38a. If yes, do you prepare and incubate these units anaerobically? US Firms {S Firms All Firms a Yes 7 636% 5 417% 14 538% b)No 3 273% 7 583% 1 423% Total un 2 26 Comments (21 Thiogiycollate medium is used for anaerobics. @) Regular growth promotion not for media fil. (@) Preparation is ot anaerobic. ©) (21 Not applicable, \Vol. 47, Supplement 1983 Incubi 39. What temperatures do you use to incubate media fill samples? If more than one temperature is utilized, please check all that apply and explain your practice. US Firms Non-US Firms All Firms a 2-2c 21 477% 13 448% 34 44.7% b) 26-2 2 43% 1 34% 3 39% €)30-35C 5 WSK W IM 3 89% )3539C 4 91% "0 4 53% ©) 40-4°C ° 0 0 Total “4 2» 76 Comments oe) 30-35°C first week, 20-25°C second week. (@.e)[3] 7 days at 20-25°C, then 7 days at 30-35°C. (2)2] Total sample number split half at zoom temper- ature, half at 35°C. (ao) 2) for SCDM media, c) for FTM. (ao) First for 14 days then for 7 days. ©) 25-30°C. (oo) Media held @ 30-35°C for 7 days, then trans- ferred to 20-25°C for 7 days. © 30°C is used. 40. How fong do you incubate media filled containers? US Firms Non-US Firms All Firms a) < 7days 1 23% 0 1 13% b) 7aays, 2 45% 1 34% 3 39% OBB days, ° 1 34% 1 13% 4) 14 days 41 932% 23 793% 67 882% ©) 15-20 days 0 0 0 1)21 days 0 1 34% 1 13% 2) > 21 days 0 2 69% 2 26% hh) Other 0 1 34% 1 13% Total 4 6 Comments ©) At each temperature. @P) 7 days at 20-25°C; 7 days at 30-35°C. @ Calculated based on when media reaches incu- bation temperature. @ ‘Also check on day 21 and day 28. th) 7 days at 34°C followed by; 7 days at 22°C. 41, How do you insure the interior surfaces of the container are contacted with media? 179% 13 178% a) Switl 8 19.0% 5 b) Invert 2 524% 8 6% 32 438% )Onside 3 71% $ 179% 8 11.0% «d) Upside down 5 119% 4 143% 10 137% ©)Noaction 7 16.7% 10 35.7% 17 23.3% Total 2 8 B Comments @ t-side up”).() One is incubated inverted due to the nature of the package. (b) ‘Also half containers incubated upside down, (ba) Do both-it is container closure specific. (bs) Mixture, ay Items are examined three times which provides sufficient handling for majority contact. «© ‘Simulates production conditions. No response Swirl incubate right side up then up side down, No response Swirl and incubate at random in large contain- No response 7 days right side up. 7 days upside down. 42. What is the most frequent type of microorganism isolated from contaminated media fills? US Firms Non-US Firms All Firms )Gram positive rod 16 42.1% 10 38.5% 26 38.89% 'b) Gram positive coceus ey 1S ST.7% 38 56.7% ©)Gram negative rod 2 138% 3 4.5% d) Gram negative coccus 0 ° 0 ©) Other 3 132% 2 17% 7 104% Total 38 % 67 Comments (a) Mold. (b) Only 1 failure, (e) Mold. (6) [6] Have never had a contaminated media fil No response (6) None 43. What do you feel is the most likely source of contamination? TB8% 20 69.0% 54 73.0% 4) Personnel 3 b) Airsystem 0 134% 1 14% ©) Sanitization 4 95% 2 69% 6 BI% «d) Unknown 4 95% 6 20.7% 10 135% 2) Other S 119% 4 138% 9 12.2% Total 2 » " Comments © I61 Have never had a contaminated media fill. () Laboratory procedures, (©) Usually attributable to mechanical failures of filling equipment. Personne! Monitoring 44, Are personnel involved in media runs monitored for surface microbial load” US Firms Non-US Firms All Firms a) Yes 36 818% 26 89.7% 65 85.5% b)No B 182% 3 103% 1 145% Total “4 » % sto Comments «®) Gloves only. «@) Fingerprints only 45. Ifyes, which surfaces are monitored? A. Hands US Firms Non-US Firms All Firms a)Uponentering 20 7 280% 27 415% b) During Run 7 16 640% 34 523% ) After Run a 14 560% 39 60.0% 4) Not tested 1 0 113% Total 38 25 65 Comments (abe) Other personnel surfaces are not monitored because product is dispensed in an enclosed alovebox, B. Arms USFirms Nos a)Uponentering 13 371% +2 80% 13 24.2% ) During Run. 9 257% 6 240% 15 24.2% ©) After Run 16 45.7% 11 440% 28 45.2% 4) Not tested 9 257% 8 320% 18 290% Total 35 25 oe CC. Face-masks US Firm: a) Upon entering 5 152% 0 5 86% ) During Run 3 91% 1 43% 4 69% ©) After Run 5 152% 3 130% 8 138% ) Not tested 2 66.1% 19 826% 43 74.1% Total 3 B 58 D. Chest USFirms Non-US Firms All Firms a)Uponentering «15 40.5% 2 83% 17 270% ) Daring Run 10 270% 4 16.7% 14 22.2% ©) After Run 18 48.6% 9 375% 28 44.4% <) Not tested 8 216% 11 458% 20 31.7% Total 37 m 3 E. Other gown surfaces USFirms Non-US Firms All Firms a) Upon emtering 7 0% 1 48% 8 138% ) During Run 6 171% 2 95% 8 138% ©) After Run M 314% 2 95% 16 24.1% A)Not tested 1B 514% 16 76.2% 38 60.3% Total 35 a 38 Comments @ Use of media on gowns prior to entering APA. seems a bit risky. Bottom and top of zipper. @ Sleeve, goggles, gown zipper. Journal of Parenteral Science & Technology@ Neck, sleeves. No response No human intervention F. Foot covering US Firms Non-US Firms All Firms a) Upon entering 5 186% 0 5 93% ») During Run 1 31% 0 1 19% ©) After Run 4 125% 1 50% 5 93% 4) Not tested 25 T8i% 19 95.0% 46 85.2% Total 22 20 54 Other personnel surfaces are not monitored because product is dispensed in an enclosed glovebox; use of media on gowns prior to entering APA seems a bit risky; bottom and top of zipper; sleeve, goggles, gown zipper; neck, sleeves; no human intervention. 46. Do you routinely video tape media fill operations? US Firms Non-US Firms All Firms 2) Yes 6 140% 1 36% 7 95% b)No 37 860% 27 96.4% 67 905% Total 4 28 ™ Comments 0) Visual monitoring by QA personnel. ) But some operations have been taped. ©) But under consideration. ©) Only if media fil fails. Will video repeats, also new processes. Environmental Monitoring 47, What environmental monitoring methods do you utilize routinely in the filling room environment? If ‘more than one method is utilized, please check all that apply. US Firms Non-US Firms All Firms A. Microbiological Monitoring Methods a) Settle plates 30 66.7% 20 69.0% 53 68.8% b) Swabs 18 400% 18 621% 37 481% ©)STA 19 422% 10 345% 30 39.0% A)RODACplates 37 822% 23 793% 62 805% ) Electrostatic 122% 0 1 13% 1 Centrifugal 2 644% 18 621% 49 63.6% 1) Sieve-type 4 89% 1 34% $3 65% h) Other 3 67% 2 69% 6 78% Total 45 2» n Comments (bn) RCS. (bh) Sartorius air sampler. (a.b.d) SAS sampler. (@bch) —_ Metone particle counter. (hy GMF- gelatine membrane filtration 21 Swinnex filter for critical air Vol. 47, Supplement 1993 B. Particulate Monitoring Methods Firms Non-US Firms All Firms Continuous, 1S 349% 7 269% 23 324% Intermittent 30 69.8% 22 846% 53 74.6% Total 8 6 m 48. Are the microbial results obtained from media fills, used to establish the alert and/or action level during routine production? US Firms Non-US Firms All Firms a) Yes 1S 341% 8 276% 24 31.6% b)No 22 50.0% 19 65.5% 42 55.3% )Inpart 7 159% 2 69% 10 13.2% Total “4 2 16 Comments ) Only historical data is used. 0) Daring validation. © Reaction time too long. Ol Media fill results along with historical data are both used to establish alert levels. © Media fils done quarteriy. © ‘Use ongoing statistical trending 49. To what extent are environmental isolates from media fill runs identified? USFirms Non-US Firms All Firms 8) Morphology 3 61% 2 19% 35 68% )Gramstain 8 178% 7 269% 15 203% ©)Genus 16 356% 9 346% 27 365% 4) Species 32 711% 16 61.5% 50 67.6% Total 45 26 " Comments (abed) Where possible. (ba) ») routinely d) if exceed action limit, (bed) Species when staphylococcus. ©. ‘Sometimes. (€.4)[2]___ Genus and species where possible. @BI ‘Whenever possible Not done as routine. Not applicable. No response No response 50. Are the particulate results obtained from media fills used to establish the alert and/or action level during routine production? US Firms Non-US Firms All Firms a) Yes 9 2.0% 5 185% 15 20.0% b)No 31 68.9% 21 77.8% 53 70.7% o)Inpart 3 M1% 1 37% 7 93% Total 45 2 8 Comments () Only historical data is used, (b) Established by FDA guideline, Ola) Coupled with historical fill data sitoO) May trigger HEPA filter replacements, © Used for alert limits as part of statistical trending but not as sole data source No response Not applicable. 51. How frequently do you monitor your APA for the presence of anaerobic organisms? a)Daily b) Weekly 3 68% 2 69% 5 6.6% ©) Monthly 3 68% 0 3 3.9% ) Quarterly 7 1S9% 1 34% BR 10.5% ) Semi-annually 3 68% 2 69% 6 79% 1) Annually 2 43% 1 34% 4 5.3% 25 S68% 23 79.3% 49 64.5% 4 » 18 Comments fae) LVP during each run/ SVP is done semi annually (ag) 4) facultative g) obligative. () 2times weekly. ©) And media runs. © FDA thinks we should do it at least with every ‘media fil @ Not at all-testing was discontinued based on historical data @ Validation program supported not needed. 52. How frequently do you monitor your APA for the presence of molds and yeasts? US Firms Non-US Firms All Firms a)Daily 23 S615 IT S86% 41 56.9% ) Weekly 10 244% 8 27.6% 19 26.4% ©) Monthly 5 122% 0 6 83% ¢) Quarterly 2 49% 1 34% 4 5.6% )Semi-annually 1 24% 1 34% «2 28% ) Annually o 0 0 ) Notat al 2 49% 3 03% 5 69% Total 41 » n Comments @e2) During use, @ TSA incubated at 22-25°C. @ STA sampler: PDA-agar. SCDM will support growth of some molds and yeasts. (ab) Daily (with RCS method) Weekly (with con- tact method), ) Or every production run, (ed) Every time there isa fill, which varies. © But using same techniques as bacterial aer- bes. @ However, molds and yeast have been isolated from our trypticase soy agar [TSA] rodac and settling plates. (hy Not speciticaly No response 8) Not specifically Solution Products: Ifyou do not produce this type of product, at this site, please skip to the next section, siz 53. What percentage of your aseptically filled products are solutions? USFirms Non-US Firms All Firms a) > 75% 27 615% 10 476% 37 S87% b)50-759% 6 150% 4 19.0% 10 15.9% ©) 25-5066 5 125% 2 95% 8 12.7% 4) <28% 3 75% 5 28% 9 14.3% Total 40 2 63 54, What is the minimum number of units filled for solution products? USFirms Non-US Firms All Firms a) < 1000 3 75% 7 333% 10 15.9% ') 1000-1999 4 100% 0 4 63% ©) 2000-2999 3 15% 2 95% 5 79% <4) 3000-3999 9 25% 7 333% 17 270% 2) 4000-4999 125% 1 48% 2 32% 15000 oF more 20 500% 5 238% 2% 413% 8) Other 0 0 0 Total 0 a cy Comments (ac) Depends on product. @ Media ils. 55. Has this number increased in the last three years? USFirms Non-US Firms All Firms ayYes 9 225% 5 238% 14 22.2% byNo 31 775% 16 76.2% 49 778% Total 40 2 6 Comments © Atp = 0.95, © Actually 0; based upon sample size versus batch size, © For media fils 0 for production © ‘At the 95% confidence level; 0/3000. oO 0.25%, No response (6) Acceptance criteria for what? Media fill? Steri ity test? No response No retest went in effect January, 1992, ‘56. What acceptance criteria do you employ for solu- tion products? Firms Non-US Firms All Firms a) <0.05% 5 15.2% 2 14% 7 13.2% b)0.05-0.09% 1 30% 3 167% 5 94% ©)0.10% 22 66.7% 13 722% 36 67.9% )O1-9.14% ° 0 0 e)OUS-0.2% 1 30% 0 1 19% 021-03 4 121% 1 56% 5 9.4% 9) 03% 0 0 0 Total 3 18 33 57. Has the acceptance criterion for contamination been reduced in the last 5 years? ‘Jovinal of Parenteral Science & TechnologyUS Firms Non-US Firms All Firms a) Yes 6 182% 10 526% 16 29.6% b)No 27 818% 9 474% 38 70.4% Total 3 19 34 Comments (a) Lower percentage. No response Not applicable. Noresponse For what topic? Suspension Products: If you do not produce this type of product at this sit, please skip to the next section. 58. What percentage of your aseptically filled products are suspensions? a) > 18% o b) 50-75% 1 67% 0 1 34% ©) 25-50% 1 67% 1 83% 3 103% 4d) <23% 12 800% 10 833% 22 759% Total 15 2 » 59. What is the minimum number of units filled for suspension products? USFirms Non-US Firms All Firms a) <1000 f 1 83% 1 34% ') 1000-1999 0 0 1 34% .) 2000-2959 1 67% 0 1 34% 4)3000-3999 5 333% 4 23% 9 31.0% 2) 4000-2999 0 183% 1 3.4% 1) 53000 oF more 8 533% 6 900% 15 517% ) Other 1 67% 0 134% Total 1s 2 2» 60. Has this number increased in the last three years? USFirms Non-US Firms All Firms a) Yes 3 0% 4 333% 7 2.1% b)No 12 80.0% 8 66.7% 22 75.9% Total 15 2 » 61. What acceptance criteria do you employ for suspen- sion products? US Firms Non-U 2) <0.05% 0 2 20% 2 1) 005-0008 0 1 100% 2 60.10% 11 846% 7 70% 19 ayoutt-014% a ° 0 €) 05-02% 00 a )0.21-0.3% 2 154% 0 2 8.0% 2) >03% 0 ° a Total B 0 2 Comments () At the 95% confidence level. Noresponse No retest allowed went into effect January, 1992 Vol. 47, Supplement 1993 No response No media fill requirements for one product that isa suspension No response Not applicable. 62. Has the acceptance criterion for contamination been reduced in the last 5 years? USFirms Non-US Firms All Firms a) Yes 3 214% 3 273% 6 22.2% byNo il 786% 8 727% 2 718% Total 4 n 2 Sterile Semi-solid Products: If you do not produce this type of product at this site, please skip to the next section. 63. What percentage of your sterile products are semi-solids? US Firms Non-US Firms All Firms a) >75% 2 0% 0 2 154% by 50-75% 0 1 333% 1 7.7% ©) 25-50% 0 0 0 &) <25% 7 70.0% 2 66.9% 9 69.2% Total 0 3 1B Comments @ All terminally sterilized 64. What is the minimum number of units filled for semi-solids? US Firms Non-US Firms All Firms 3) <1000 00 ° 1) 1000-1999 0 ° 0 ©) 2000-2999 0 0 0 4) 3060-3999 3 300% 1 33% 4 308% ) 4000-8559 ° ° a £) S000 or more 5 500% 1 333% 6 46.2% 2) Other 1 100% 1 333% 2 154% Total 0 3 1b Comments © Replacement line will be capable of perform ing challenges with liquid medium and clear tubes so results will be comparable to other challenges being performed ® None. 65. Has this number increased in the last three years? US Firms Non-US Firms All Firms a) Yes 1 111% 1 500% 2 182% b)No 7 718% 1 500% 8 127% Total ° 2 " 66. What acceptance criteria do you employ for semi- solids? US Firms Non-US Firms All Firms a) <0.05% ° 0 0 )005-0.09% 0 a 0 00% 8B 88.9% 2 100.0% 10 90.9% S13,)0.L-014% 0 0 0 e)0.1S-0.2% 0 0 0 02-03 0 0 0 a) 203% 0 0 0 Total 9 2 n Comments © For media, 0 for production © At the 95% confidence level, 0/3000 No response Not applicable. 67, Has the acceptance criterion for contamination been reduced in the last 5 years? US Firms Non-US Firms All Firms a) Yes I iis 0 1 9% >) No 7 T18% 2 1000% 9 81.8% Total 9 2 u Freeze Dried Products: If you do not produce this type of product at this site, please skip tothe next section. 68. What percentage of your aseptically filled products are lyophilized? US Firms Non-US Firms All Fiems a) > 18% 1 83% 6 353% 9 29.0% 50-75% 1 83% 3 176% 4 129% 25-50% 8 66.9% 3 126% 38.8% 4) <25% 1 83% $294 6 19.4% Total 2 7 31 Comments © ‘These are APHIS biologicals. Not applicable to FDA regulations. 69. What is the minimum number of units filled for lyophilized products? USFirms Non-US Firms All Firms a) < 1000 ° 2 8% 26.7% ) 1000-1999 0 1 59% 2 6.7% ©) 2000-2999 0 425% 4 133% «d) 3000-3099 3.273% 6 353% 10 33.3% €) 4000-4999 1 91% 1 S9% 2 6.7% 1) 5000 oF more 5S 458% 3 176% 8 26.7% 8) Other 1 91% 0 133% Total u 0 30 Comments @) If a double challenge is performed (refer 10 question 75), minimum of 6000 units are filled: if a single challenge is performed the ‘miniraum is 3.000 units No response 19,000, 70, Has this number increased in the last three years? USFirms Non-US Firms All a) Yes 3 250% 4 235% 7 26% b)No 8 66.7% 13 765% 23 74.2% Total 12 ” eT sta 71, What acceptance criteria do you employ for lyoph- ilized products? US Firms Non-US Firms All Firms a) <0.08% 1 83% 2 125% 3 10.0% by 0.05-0.09¢% 0 4 250% 4 133% €)0.10% 8 66.7% 10 625% 20 66.1% ayOu-o1s% 0 0 0 ©) 015-0.2% 0 0 0 1 0.21-03% 2 67% 0 2 61% 2) 0.3% 0 0 0 Total R 16 Comments © Atp = 035. © Atte 95% confidence level, 0/3000, 72. Has the acceptance criterion for contamination been reduced in the last S years? US Firms Non-US Firms All Firms a)Yes 1 83% 5 313% 6 200% byNo- 10 833% 11 688% 23 76.7% Total R 16 30 73. In the course of the validation, what level of vacutum do you pull on the lyophilizer chamber? S Firms No a) None 0 17% ) <20in. Hy 2 182% 6 429% -28in, He 5 4s 0 d) > 28in, He 3% 7 $0.0% Total n 4 a Comments No response 750 mbar absolute No response Do not validate freeze dryers. 74, How long do the media filled vials remain in the Iyophilizer under vacuum? USFirms Non-US Firms All Firms a) <2 hr. 4 368% 14 878% 19 65.5% b)2-8hr. 191% 1 63% 3 10.3% 0) 924 hr, 2 182% 0 2 69% )Fulldryingtime «2 «182% «1 63% 3 103%, Total n 16 29 75. Do you freeze the media filled vials at any time during the simulation procedure? 167% 3 126% 8 16.1% ) Growth Study 2 b)NoGrowthstudly 216.7% 1 59% 3 9.7% No 7 S83% 13 765% 22 71.0% Total 2 7 a Comments ao) When double challenges are performed on Journal of Parenteral Science & Technologylyophilization lines: 3,000 units are frozen in a freozer prior to placement into an ambient Iyophilizer, and another 3,000 units are placed {nto ambient lyophilizer without pre-freezing, Separate growth promotion studies are per- formed, No response Not at all, Sterile Dry Powder Products: Ifyou do not produce ths type of product at this site, please skip tothe next section. 76. What percentage of your aseptically filled products are sterile dry powders? Yon-US Firms All Firms a) >75% 30.0% 6 25.0% b) 50-75% 1 42% 25-50% 30.0% 5 20.89% 0) <25% 40.0% 11 45.89% Total 2 10 a US Firms Non-US Firms All Firms a) Yes 2 167% 0 2 83% b)No, 9 75.0% 10 100.0% 21 875% Total 2 10 4 81. What is the acceptance criteria employed for dry powder filling? 77. Does your site validate the filling of sterile pow- ders using a media fill procedure? US Firms Non-US Firms All Firms Firms. All Firms 2) <0.05% 2 91% 5) 005-009 ° 1% 2 91% 30.10 8 2.7% 8 89% 17 713% d)0.11-0.14% 0 0 0 €)015-02% ° ° ° 021-03% ° ° 0 9 >03% ° 0 0 Total u 9 2 Comments © For media, 0 for production. ORI tthe 95% confidence level Noresponse Not sre what criteria and reject types looking for here, a) Yes 10 833% 9 90.0% 21 875% b)No 1 83% 1 100% 2 83% Total 2 10 mw 78. How is the media fill conducted? USFirms Non-US Firms All Firms Sequence of steps a)Pon, Loft 0 3 300% 3 125% b) Pon, Lon 5 41.7% 2 20.0% 8 333% ©)Lon, Pon 3 250% 4 40.0% 8 333% 4) Lofi,Pon 0 1 100% 1 42% e) Other 2 167% 0 2 83% Total 2 10 a Comments © Currenily performing liquid media fill only. Scheduled to begin liquid and powder on-line 7192. ©) (Currently-tiquid only. Evaluation of liquid and powder media fill in on-going. rms All Firms a) < 1000 ° 1 100% 1 42% ) 1000-1999 0 0 ° ) 2000-2999 0 0 0 6) 3000-3999 5 41.7% 4 400% 10 41.7% ) 4000-4999 1 83% 0 1 42% 1 5000 or more 3 417% 5 300% 11 45.8% Total 2 10 m 80. Has this number increased in the last three years? Vol. 47, Supplement 1993 82. Has the acceptance criterion for contamination been reduced in the last S years? USFirms Non-US Firms All Firms a Yes 2 16.7% 2 0% 4 16.7% byNo 9 75.0% 8 80.0% 19 79.2% Total 2 10 4 83. Does your powder media process include the following steps in the manufacturing process? Please check all that apply. US Firms Non-US Firms All Firms «) Filtration 6 462% 1 11% 8 33.3% b) Crystallization 2 154% 0 3 125% ©) Drying 3 21% 0 4 167% @)Blending 6 46.2% 2 222% 9 315% ) Subdivision 3 BIZ 2 DIM 6 25.0% 1) Filling 1 846% 9 100.0% 22 91.7% Total B 9 mw Comments © Routinely during inital validation. 84. Do you use a placebo material in lieu of filling the actual product? US Firms Non-US Firms All Firms ay Yes 8 61S% 9 900% 19 760% b)No 3 Bl% 1 100% 4 16.0% Total 1B 10 25 Comments ® Scheduled to begin use of placebo 7/92. 85, How is this placebo powder sterilized? sis,USEirms Non-US Firms All Firms a) Iradiation 6 548% — 9 000% 17-7736 b)EthyleneOxide 1 1 4see ©) Dry Heat 191% 0 ase «d) Moist Heat 0 0 0 €) Other 1 91% 0 1 4s¢ Total u 9 2 Comments © Sterile filtered and then lyophilized. No response Customer specific. 86. What placebo material do you use? US Firms Non-US Firms All Firms a) Mannitol 2 182% 1 UI% 3 13.60% b) Lactose 3.273% 7 TTR 11 50.0% ©) PEG 4 304% 1 ILI% © 27.35% 4) Diatomaceous Earth 0 ° ° ©) Other 2 IR2% 0 2 9% Total nL 9 2 Comments © SCDM, e) Sodium Chloride. Noresponse Customer specific. 87. To what extent do you monitor non-viable particu- lates during sterile powder operations? Please check all that apply. US Firms Non-US Firms All Firms 2) Prior to fill 9 75.0% 1 10.0% 12. 50.0% ) During fil 5 417% 3 300% 8 33.3% )End of fill 4.23% 0 4 16.7% 4) Not tall 183% 7 moe 8 33% ) Media runs 6 90.0% — 1 10.0% — 7 29.2% Other 1 83% 0 14.2% Total 2 to 4 Comments 0 ‘Once a week when not in use Research & Development—If you do not produce clinical supplies at this site, please skip (0 the next section, 8. Does you perform media fill trials in support of clinical trial production? US Firms Non-US Firms All Fiems ay Yes 16 800% § S56% 22 73.3% b)No 2 WO% 3 3S 8I Total 0 ° 30 Comments (a) Standard fills. (a) Sometimes, process and product dependant, si6 @ In the majority of cases 3.000 or more units are filled. In certain cases. if the normal produc: tion batch size is significantly less than 3.000 units. a smaller statistically significant number will be filled (b) Unless the production process is different than any products we have already validated, 88a. If yes, what is the minimum number of units filled? US Firms Non-US Firms All Firms a) Actual lot size 3 167% 2 40.0% 5 208% b) > than lo size 2 1% 1 200% 3 125% ©) >3000 13 72.2% 2 400% 16 66.7% 4) Other 1 35% 0 142% Total 18 5 um robial Levels for Controlled Areas 89. Does your site have quantitative airborne micro- bial levels for its primary APA? US Firms Non-US Firms All Firms a) Media ill data 3 10% 0 3 40% bb)Production data «818.6% 6 20.7% 15 20.0%. ©) Media & Produc. tion data 18 419% 7 241% 27 36.0% 4)Publshed data 16 37.2% 11 37.9% 28 37.3% ©) Arbitrary level S 16% 2 69% 7 9.3% Other 0 4 BR 4 53% Total 8 2» 6 Comments @ Federal Standard 209, oO Yes, wp] Published data and previous environmental data, 0 Corporate standards media fill and production data, 90. Does the same level apply to all portions of your APA which are of the same environmental classifi- cation? e.g, Class 100, Class 10,000 US Firms Non-US Firms All Firms ay Yes 38 884% 22 75.9% 63 84.0% b)No S$ 16% 7 21% 12 16.0% Total 4B 2» % Comments a) Only | APA. ©) European GMP class A/ class B, 91. Does the same level apply to other APA’s on this, site which are of the same environmental classifica- tion’? ay Yes 31 795% 18 75.0% 51 785% b)No 7 179% 6 25.0% 13 200% Total 9 4 6 Journal of Parenteral Science & TechnologyComments ©) Does not apply to sterility test bench. 92, Does your site have quantitative surface microbial level for its primary APA‘ US Firms Non-US Firms All Firms 8) Media fill data 3 11% 0 3 41% b)Productiondata 11 262% © 6 20.7% 18 24.3% ©) Media & production daa 20 476% 6 20.7% 28 37.8% 4)Published data —«'10.«238% 10: 345% 20 27.0% ) Arbitrary level 6 143% 2 69% 8 108% Other 3 11% «5 172% 8 10.8% Total a2 » ” Comments OB) ‘Yes, according to internal standards. © Published data and previous environmental data, or ‘Area is sterilized before production, No hu- ‘man intervention, No surface testing, © Group standards and c), o Form fil process with no surface to test. 93, Does the same level apply to all surfaces within your APA which are of the same environmental Classification? e.g, Class 100, Class 10,000 US Firms Non-US Firms All a) Yes 34 81.0% 24 828% 61 824% b)No 8B 19.0% S$ 172% 13 176% Total 2 9 ™ Comments © Does not apply o sterility test bench, 94, Does the same level apply to similar surfaces in other APA’s on the same site which are of the same environmental classification? US Firms Non-US Firms AlIFi a) Yes 27 711% 18 750% 47 73.4% b)No 10 263% 6 250% 16 25.0% Total 38 ™ 64 95. Does your site have quantitative personnel moni- toring microbial levels for its primary APA? US Firms Non-US Firms All Firms a) Media fll data 1 25% 0 1 14% b)Productiondata 8 2000% 7 (25.0% 15 21.1% ©) Media & production data 18 450% 4 143% 24 33.8% ) Published data = «8 2000% © 6 21.4% 14 19.7% ©) Arbitrary level 5 125% 7 250% 12 169% 1) Other 5 125% 4 143% 10 14.1% Total 40 28 1 Comments (ea) Hands only. Vol, 47, Supplement 1989 Op) Yes, according to internal standards. o No, for information only. © Based on statistical analysis. OL] No personnel intervention, no monitoring. 0 Dependant on environmental results. 0 Corporate standards, media fill and production data. o No; principal APAs do not permit human 96. Does the same level apply to all personnel within your APA who work in areas of the same environ- ‘mental classification? e.g, Class 100, Class 10,000 US Finns Non: $A Firms a) Yes 35 875% 23 821% 61 85.9% b)No 3 125% 5 179% 10 141% Total 40 28 1 Comments ©) Only monitor people in class 100 area, ©) Dependant upon process, 97. Does the same level apply to personnel in similar activities in other APA’s at this site which are of the same environmental classification? us Non-US Firms All Firms a) Yes 27 73.0% 19 826% 48 77.4% b)No 9 243% 4 174% 13 21.0% Total 37 2 62 Comments ) Dependant upon process. 98. The USP has drafted an information chapter on Microbiological Clean Rooms and Zones that supports uniform criteria for microbial levels de- pending upon the classification of the area. Do you believe that such an information chapter can be useful at your location? USFirms Non-US Firms All Firms a) Yes 30 698% 25 926% 57 781% b) No 13 30.2% 2 74% 16 219% Total a a B Comments ) Helpful as long as information only and not minimum requirement. ) As drafted, Terminal Sterilization and Aseptic Processing 99, Does your site employ the following types of heat sterilization processes for its current sterile prod- ucts after aseptic processing? Please check all that apply. si7US Firms Non-US Firms All Firms 8) Overkill 13 419% 12 63.2% 26 SL.O% ) Sub-everkil 2 63% 15% 4 78% «) Bioburden 397% 1 S53 4 78% 4) Sub-bioburden 1 32% 0 1 20% ©) Other 1B 419% 6 316% 19 37.3% Total 31 wo st 100. Is your site evaluating the following types of heat sterilization processes for its future sterile prod- ucts after aseptic processing? Please check all that apply. US Firms Non-US Firms ll Fis 2) Overkill IS 441% 1D Sk8% 25 49.0% ) Suboverki 8 235% 3 ITe% ML 216% «Biren 8 Rs% 3 176% 20% @Subbioburden 418% 478% ¢) Other 12% 4 25% 17 I Total xu 0 si Comments (©) ‘Not at this site at this time. © Not posible with products curentyilled (00) None © None, all but one of our aseptically manufac- tured products lyopilized. Lyophilized prod ucts cannot be subjected toa steam striioa- tn process (©)[2]—__Fornow products the application of pos filing hea treatment is investigated, © Done by parent company © Never validate by bioburden kil Noresponse No, products heat able 101, Is your site evaluating the following types of alternative sterilization processes for its future sterile products? Please check all that apply. Firms Non-US Firms All Firms a)Gammaradiation 17 620% 8 66.7% 25 64.1% b)X-rayradiaton = 3 LIS 1 BB 410.3%, Microwave 4 148% 2 167% 6 18.4% 6) Plasma 2 14% 0 2 5.1% ©) Other 9 3 3 28.0% 12 30.8% Total 2 R 9 ‘Comments @ Components only. (aa) Electron Beam, I None. © Parenteral production at this site is being phased out. No future products planned. No response [6]Not applicable. 102. Ifthe FDA were to mandate that firms must review all current aseptically filled products to determine whether they can be subjected to a post-fill heat treatment, how long would it take your site to complete this evaluation? sie USFirms Non-US Firms All Firms a) < 6months 14 308% S$ 25.0% 19 32.2% b)6-12 months BUM 4 20% 12 2wI% ©) F-2years BoOMI% 4 20.0% 13 22.0% 4) 2-3years 4 105% 3 150% 7 11.9% ) > 3years 45% 4 20% 8 136% Total 38 20 59 Comments @ All have phenol preservative which won't toler- ate heat sterilization, o 6 month to 1 year-assuming the FDA specifica- tion defines a target assurance level «) Stability studies reformulations Noresponse Not known, No response Already completed. No response Job of our customer. No response Products cannot be heat treated past fl, No response Our antibiotic products would be exempt lines. they are heat labile 103. Ifas a result of an FDA mandate you must subject current aseptic filled products to post-fill heat treatments, how long would it take your site to have the necessary equipment in operation? US Firms Non-US Firms All Firms a) < 6months 8 235% 2 10.0% 10 18.2% )6-12 months 1 29% 5 250% 6 109% ©) k-2years 12 353% 4 20.0% 17 30.9%¢ 9 265% 4 20.0% 13 23.6% ©) > 3years 4 118% 5 25.0% 9 16.4% Total 34 2» 55 Comments (a) But, not applicable. @ Compressed gas. ro) Product could not take it. No response RI Cannot be done with current products. All are heat sensitive, No response BI Not possible No response Ql Not applicable. Noresponse Already completed. Norresponse Job of our customer. 104. Does your site support the concept of a grandfa- thering aseptically filled products with an accept- able sterility profile [acceptable media fil results, less than a 0.5% sterility retest rate, consistent control over microbial contamination in APA]? US Firms Non-US Firms All Firms a) Yes 29 163% 17 113% 48 T14% b)No 9 27% 6 23% IS 24.2% Total 38 2 a ‘Journal of Parenteral Science & TechnologyComments (a) 01%. (a) But not exclusively- case by case review. ©) Retest No response Don't know. Aseptic Processing Technology 105. Does your site employ the following technologies within the APA in the preparation of its aseptically filled products? Please check all that apply. USFirms Non-US Firms All Firms a) Bariers 2 55.6% 13 61.9% 34 57.69% »)SIP 20 55.6% 12 57.1% 33 55.9% ©) CIP 21 583% 13 61.9% 35 59.3% @) Robotics 6 167% 2 95% 9 153% ¢) Integrated 5 139% 7 333% 12 203% f)Hermeticgowns 0 2 95% 2 34% ) Forméillseal 9 250% 2 95% 11 186% 1) Electrophoretic HVAC 1 28% 0 117% Total 36 a1 so Comments @ Curtains gowning. Ask if sterile filtration of liquids would qualify here. @) Laminar airflow hoods. (a) For sterility testing only (eed) Primary barriers for power filling. (bce) Under validation No response 2 None of the above. 106. Does your site utilize any additional advanced technologies for the manufacture of aseptic prod- ucts? US Firms Ni jms All Firms a) Yes 0 1 38% 1 1.4% b)No 42 1000% 24 923% 68 97.1% Total 2 %6 ” 107. Which of the following technologies is your site evaluating for utilization in the preparation of its aseptically filled products? Please check all that apply US Firms Non-US Fins All Firms a) Barriers: 18 66.7% 10 50.0% 29 60.4% dsr 10 370% 10 300% 21 438% ©) CIP 7 25.9% 9 45.0% 17 35.4% Sd) Robots 11 407% 6 300% 17 384% e)imegeated 19 Tae 10 320% 29 oDaee DHemeicgows 274% 0 3 63% 8) Form-fill-seal 8 29.6% 3 15.0% I 22.9% Py Elecwophoretc HVAC 1am 0 L 21% Total n 2» 48 Vol. 47, Supplement 1993. Comments {abce) —_ Isolator Technology. No response (6) None. FDA Aseptic Processing Guideline 108, The FDA Guideline on Sterile Products Produced by Aseptic Processing was published in 1987. Much of the technology and concepts present in that guideline represent approaches that were more prevalent in the late 1970's. How closely does your site adhere to the guideline in the following areas? A Definitions US Firms Non-US Firms All Firms Follow closely 3S 875% 15 60.0% SI 77.3% Follow > % 3 15% 8 320% 11 167% Follow about 4 2 50% 1 40% 3 45% Follow about 4 0 0 0 Follow very litle 0 0 0 Total 40 25 66 b. Buildings and Facilities US Firms Non-US Firms All Firms Follow closely 29 70.7% 13 $4.2% 43 65.2% Follow > 44 8B 195% 6 250% 14 21.2% Follow about 4 3 73% 2 83% 5 76% Follow about % 1 24% 2 83% 3 45% Follow very litle 0 0 0 Total 4 um 66 c. Components [Actives & Raw Materials} US Firms Non-US Firms All Firms Follow closely 34 81.0% 17 708% $2 72.6% Follow > 4 95% 6 25.0% 10 149% Follow about 14 2 48% 0 2 3.0% Follow about 1 24% 0 1 15% Follow very little 1 24% 0 1 15% Total 2 a a 4. Containers/Closures US Firms Non-US Firms All Firms Follow closely 32 80.0% 16 66.7% 49 75.4% Follow > % 6 15.0% 7 29.2% 13 20.0% Follow about 4 1 25% 0 1 15% Follow about 4 0 0 o Follow very little 1 28% 0 1 15% Total 0 m 65 ¢. Time Limi USFirms Non-US Firms All Firms Follow closely 32 80.0% 12 480% 45 68.29% Follow > Ys 4 10.0% 10 40.0% 14 21.2% Follow about 4 4 100% 2 80% 6 91% Follow about 4 0 0 0 si9Follow very Title 0 poo Total 0 25 66 £. Aseptic Assembly Operations US Firms Non-US Firms All Firms Follow closely 32 780% 17 708% $0. 75.86 Follow > 's 5 122% 5 208% 10 15.2% Follow about 2 49% 1 42% 3 45% Follow about 1 24% 0 115% Follow very litle 1 24% 0 1 15% Total 41 m 6 2. Filtration Sterilization US Firms Non-US Firms All Firms Follow closely 34 82.9% 15 60.0% Follow > Ys 4 98% 7 280% 11 164% Follow about 2 49% 1 40% 3 45% Follow about 0 0 0 Follow very little 124% 1 40% 2 3.0% Total 4 25 67 h. Equipment Sterilization US Firms AlLFirms Follow closely 35 833% 15 60.0% 51 75.0% Follow > Ys 495% 4 160% 8 118 Follow about 1s 2 48% 4 160% 6 8B Follow about 1 24% 0 1 13% Follow very little 0 1 40% 1 15% Total 2 25 68 i, Laboratory Controls [Environmental Monitoring] US Firms Non-US Firms All Firms Follow closely Bd 85.0% 1S 60% 50 75.8% Follow > is 5 125% 7 280% 12 18.2% Follow about 1 25% 1 40% 2 3.0% Follow about 0 1 40% 1 15% Follow very litle 0 0 0 Total 40 2 66 j Sterility Testing US Firms Non-US Firms All Firms Follow closely 35 854% 17 708% 53 803% Follow > Ys 4 98% 5 208% 9 13.65% Follow about 1 24% 1 42% 2 30% Follow about 1 24% 0 1 15% Follow very little 0 0 0 Total 41 ™ 66 Other Issues 109. Please rank the following potential sources of contamination from most-likely to least-likely to cause problems in media fills? 1-Most Likely 10- Least Likely US Firms Non-US Firms All Firms ) Sterilization [8] 65 [6] 56 [7] 62 b) Sanitization 57 M) 47 a} sa 820 ©)Matcrals transfer [6] S85) is] 37 4) Assembly b) 44 Bl Bl 44 ) Routine Is] 65 [8] 1] 64 )Non-routine RB) 43 PB) 41 pp 43 2)Air [4] 57 [7] 59 fo} 58 hy Surface 7] 62 [9] 63 Is} 6: ') Personnel u) o31 Pp) 20 fy j) Other [io] 77 (10) 100 fio) 8S Total 4 n ” Comments Other: trained staff; inadequate laboratory handling; lyophilizer SIP failure; machine fil ‘contaminant flame seal; bulk material storage process interruptions; equipment manufactur- 110. What would you estimate the probability of non- sterility associated with aseptically filled products tobe? USFiems Non-USFirms All Firms a) < Lin 1,000 M 244% 8 320% 20 27.49% b) < 1in 5,000 5 1% 2 80% 8 11.0% ©) < Lin 10.000 15 333% 7 280% 22 30.1% @) < 1in50.000 489% 1 40% 5 68% e) < Lin 100.000 4 89% 2 80% 7 9.6% 1) > Lin 100,000 7 156% 4 160% 11 15.1% Total 4 2s B Comments No response Powder fil less than 1 in 1,000, Solutions; less than I in 5.000 to 10,000. Form-ill-seal: less than 1 in 100,000 111. Does your media fill program cover all aseptically produced sterile products at your facility? US Firms Non-US Firms All Fi a) Yes 39 867% 24 85.1% 65 855% b)No 6 133% 3 107% 10 13.2% Total 45 28 6 Comments ©) It covers all injection products in glass vials. Procedure for media fill, program for new Product requested from validation group for implementation, ©) Sterile semi-solid products; replacement line will be capable of performing challenges with liquid medium and clear tubes so challenge results are comparable to others currently done. ©) Not the APHIS regulated veterinary biologi- cals, () No powder production tested. co) Aseptic fill of components/blending proce- dures prior to aseptic fil. () Products not regulated by the FDA. (b) ‘Media fill only covers fill lines. Aseptic prepara tion of solutions used in production not cov cred by media fill program. Journal of Parenteral Science & Technology&) ‘Small seale production. 112. Have we overlooked a significant concern or fact regarding the validation of aseptic processing? US Firms Non-US Firms All Firms a) Yes 7 184% 8 320% 16 24.2% b)No 31 81.6% 16 64.0% 49 742% Total 38 25 6 Comments @ Some FDA guidelines do not directly apply to dry powder filling and this should be stated. (ie. particulate counts during filling). @ This questionnaire may result in tighter limits ‘on aseptic processing. So it's a preview of future FDA recommendations for terminal sterilization. @ Qualification of personnel prior to being al- lowed to work in the APA. @) ‘Trend analysis rather than single tests. Person- nel training. Robotics. Combined aseptic tech- ‘nique and minor heat treatment. @ Method of media preparation sterilization. @) Clean room performance qualification, filing operator qualification. @) Disinfection and sanitization validation, gown ing qualification, personnel training, product flows, bioburden (a) Limitation/restrievion of number of personal in APA at a given time. (@) Handling of equipment and tools, storage of equipment and tools, (a) Vials and stoppers washing validation, vials and stoppers sterilization validation, distilled water distribution validation, maintenance, HVAC gstem validation, (@) Personnel background and training. (a) Solution preparation prior to production, (a) Does simulated process deviate in any way from production run? Media filtered or ster ized? Any part treatment of media? Special time for media fills or following production? Our answers re-anaerobes assumes obligates. Is the search for obligative anacrobes relevant to pharmaceuticals? @ I think you have not gone sufficiently deep into the sterility testing and results. Evaluation of ‘Vol. 47, Supplement 1993, these test as far as aseptic procedures are concerned, @ ‘As part of your questionnaire, especially if published for FDA review, acomparison should be made of actual media fill failure frequency for the following types of processes: 1. Pro- cesses where no human intervention is permi ted, 2 Processes where human intervention limited to Jes than one postion per shift, 3. Processes involving human intervention(or par- Licipation) by more than one position per shift Also a summary of total media fil failures as a % of total media filled units run during the last 3 years could be useful Tine thought process involved inthe determina- tion of whether a product shouldbe aseptically processed or not. That i, how does one rule out terminal sterilization or the use of “sublethal” cycles? How far should one go to rule them out... if 1-2 log reduction of a bioburden is achievable, should this processing stopbe further developed? No response Conclusion ‘The survey results, like prior surveys, indicate the validation of aseptic processing remains an activity where firms are operating with much independence. ‘While certain areas demonstrate much uniformity across the industry, there are numerous areas of difference. ‘The variation in approach is largely indicative of the range of product types, facility size, and levels of technology present within the surveyed firms. A broad comparison of US and non-US data suggests general similarities in the responses. Parenteral manufacturers worldwide continue to have a wide range of choices in the methods they utilize for their aseptic process validation programs. Acknowledgements This survey would have been impossible without the dedication shown by the respondents who spent a great, deal of time in both answering the questions, and through their submission of the comments which pro- vided clearer insight into the responses. The assistance of Ms, Nina Fry in performing the task of data entry and, Mr. Edmund Fry in managing the distribution, retrieval and data reduction is gratefully acknowledged.