Sterile Drug Process Inspections ASQ Philadelphia Section

1、sterile drug process inspectionsfda anita r. michaelpharmaceutical investigator definitions aseptic conditions which are free of pathogenic organisms or their toxins pathogens- organisms often microorganisms that cause diseasebio-burden- total number of microorganisms on a specific item before steri

2、lization (on components such as containers)definitions contamination- on items or in sterile drugs the presence of unwanted microbes sterile- free from bacteria or other micro-contaminations. parenteral- medications that move through the body via intravenous or intramuscular injectioncommon processe

3、saseptic process and terminal sterilization common processesaseptic processing- often used when terminal sterilization cannot be used because of degradation. in aseptic processing the components and drug actives and drug products are sterilized separately, to remove bio-burden, and then put together

4、 in a class 100 environment. common processesterminal sterilization- the finished drug is placed into container (filled), sealed in approved containers under clean room conditions, and then terminally sterilized via autoclave or gamma irradiated. then labeled, packed for shipment. also the clean con

5、trolled environment is not sterile. classification of rooms class 100 less than 100 particles of 0.5 micron or greater per cubic foot of air.class 1000 less than 1000 particles of 0.5 micron or greater per cubic foot of air.class 10,000 less than 100 particles of 0.5 micron or greater per cubic foot

6、 of air. class 100,000 less than 100,000 particles of 0.5 micron or greater per cubic foot of air. hepa filter hepa filter high efficiency particulate air filter that is able to capture particles 0.3 micron or more with a 99.9% accuracy. hvac-firms heating, ventilation and air cooling systemsaseptic

7、 processing endotoxins- gram negatives we are always looking to prevent in products. cause serious adverse events in patients, such as, fevers, shock and even death. endospores- spore forming bacteria, they can survive heat, uv. if spores survive the aseptic process they can germinate and grow in fa

8、vorable conditions. fda sterile inspectionsvarious compliance programs nor ich q7a will provide guidance on the sterilization and aseptic processing of sterile apis (see q7a section 1.3). investigators are to use the finished product regulations (21 cfr 210 and 211) as guidance and follow cp 7356.00

9、2a, sterile drug process inspections, when inspecting the sterile processing of apis labeled as sterile. investigators are also to use fda guidance on aseptic processing, sterile drug products produced by aseptic processing current good manufacturing practice, in evaluating aseptic processing condit

10、ions for sterile apis. fda sterile inspections aseptic core is under the highest pressure to prevent air flow in from areas of lesser air quality. for example air flow from gowning area into the aseptic core. gowning-personnel is a critical area to control. people carry microbes and shed skin cells.

11、 appropriate gowning can prevent contaminants from entering your aseptic core. fda sterile inspectionsequipment and personnel should flow one way in a facility. the closer to the core the cleaner the flow. class 100,000 to 10,000 to 1000, to core 100. this is checked during inspections. fda sterile

12、inspectionshvac systems control the temperature, humidity, air pressurehepa controls the particulates and the microorganisms. hepa filters filter 99.97% capturing substances 0.3 micron or larger. clean air versus isoclass 100,000 iso 8class 10,000 iso 7class 1,000 iso 6class 100 iso 5micro settling

13、plates action levels (diam. 90mm; cfu/4hours) class 100- 1 cfu however samples from class 100 (iso 5) environments should normally yield no microbial contaminants.class 1,000- 3 cfu / 4 hoursclass 10,000- 5 cfu/ 4 hoursclass 100,000- 50 cfu/ 4 hours fda sterile inspectionssterile api sterile finishe

14、d drug determine if the manufacturer are in compliance with the fd&c act and are they operating in compliance with title 21 cfr parts 210 and 211 gmpsfda sterile inspectionscan conduct full inspection or abbreviated inspection. depending on the firms history and numerous other factors. can also depe

15、nd on the risk and what types of sterile products are produced by the facility. full inspection can cover all 6 systems, production, quality, labeling, facilities and equipment, materials and laboratoryif questionable practices are observed during an inspection a deeper, more advanced inspection is

16、likely to be initiated. in depth coverage of the firms manufacturing practices including process validation. fda sterile inspectionsreview of the firms aprrejectssterility failures trending capa systemsfda sterile inspectionswater systems wfihvac air handling systems environmental monitoring fda ste

17、rile inspectionsmedia fills clean room qualificationcomplaints product quality and adverse events fda sterile inspectionsregulatory actions for sterile products are focused on contamination such as objectionable microorganisms, toxic chemicals, or a reasonable potential for contamination such as con

18、tact with unclean equipment or airborne contamination (hepa, hvac system)fda sterile inspectionsmedia soybean casein digest for micro growth should be used. the media selected should demonstrate that it can promote growth of gram negatives and gram positives bacteria and also yeast and mold (usp ind

19、icator organisms) also firm should determine if the usp indicator organisms represent the production related isolates. growth promotion isolates should be inoculated with a 100cfu challenge. if growth promotion fails the origin of the contamination found during simulation should be investigated and

20、media fill repeated. fda sterile inspectionsmediaproduction process should accurately simulate conditions that optimize detection of any micro contamination. containers filled with media should be filled to accuracy and appropriate media, contact the inner container closure surfaces, and permit a vi

21、sual check for detection of the microbial growth. fda sterile inspectionsincubation and media filled unitsmedia units should be incubated under correct conditions for example the temperature should be suitable to recover the bio-burden and should not be out of the range of temperature 20-35c and be

22、maintained within 2.5c of the target temperature. incubation should not be less than 14 days. fda inspection will often inspect to assure that each media fill sample is examine by personnel who has the education, experience, training to detect media filled vials that are positive for growth. any con

23、taminated unit should be considered objectionable and investigated. the organism should be identified to species level. investigation should cover possible causes of the contamination. in the future if there are sterility failures for marketed drug products investigations conducted during media fill

24、s can provide valuable information. fda sterile inspectionsmedia fillsfilling fewer than 5,000 units, no contamination units should be detected. if 1 contaminated unit is detected this is cause for revalidation following an investigation. filling 5,000 to 10,000 units 1 contaminated unit should resu

25、lt in an investigation and quality should address repeating the media fill. 2 units should result in an investigation and cause for revalidation. filling more than 10,000 units 1 contaminated unit should result in investigation. 2 contaminated units should be cause for revalidation following investi

26、gations. also, if media fill runs no matter what the filling size units are show intermittent incidents of micro contamination in media fills runs this can show that there is a persistent low level contamination problem that should be investigated. fda sterile inspectionsmedia fillsmedia fills shoul

27、d be representative of the conditions under which are actual manufacturing conducted. also pay attention to number of employees involved in the media fills. quality should address this question. fda sterile inspectionsenvironmental monitoring criticala quality system driven environmental program sho

28、uld be established addressing the following:sop on sampling proceduresfrequency of monitoringtypes of monitoring sites to be monitored alert and action levels when situations are critical and actions should be taken environmental monitoring should identify the potential contaminants preventing adult

29、erated products from entering the market. em should cover the following: air quality, floors, walls, surfaces, equipment and product contact surfaces.fda sterile inspectionsenvironmental monitoring critical frequency of samples close to operations or places critical to operations also covering other

30、 areas such as gowning areas. focus on the product and areas of concern that should be sampled such as air and surfaces near critical process operations with increased activity. very important to keep trend reports even if everything appears ok. data should be evaluated by quality. locations to be s

31、ampled fda sterile inspectionsenvironmental monitoring criticaltypes of sampling equipment for air laser particle counters-count particles using a laser and know amount of air. viable particulates and non-viable particulates- can be counted on setting plates, incubated, counted. fda sterile inspecti

32、ons can seek action warning letters, recalls and injunctionfailure to assure each batch conforms to established specifications, for example the nda, usp or label claims. distribution of product that does not meet established specifications. test methods that are not adequate or validated. failure to

33、 assure that a batch is uniform in character and quality. fda sterile inspections can seek action warning letters, recalls and injunction failure to keep adequate records for example: date of manufacturer, quantity manufactured, lot number, test results and dates, labeling specimen, how the firm det

34、ermined yields, blending, following established manufacturing procedures, proper review of testing records and production records to authorize release for distribution. failure for prompt recall and not knowing all lots that have been distributed.not having appropriate stability program, protocol, s

35、tability testing inadequate to support expiration dates. fda sterile inspections 483sparenterals a) the firms investigation, completed on xxxx, into xxxxx injection 200 mg lot xxxxx, that was released to market 10/24/07 regarding foreign material floating in the product, did not extend to other drug

36、 products that may have been associated with this problem. it is also deficient for the following reasons:i) an outside company analyzed samples from this lot and noted that particles were combined with either xxxx , or its derivatives. no documentation in the investigation exists to show the firm r

37、eviewed other lots of this product or other lots of product potentially affected by this problem. 2) the firm did not conduct a review of their manufacturing equipment which may have caused the problems. in their product.3) deviation report dr # xxxxx indicates the cause of deviation: is process rel

38、ated, yet there is no documentation in the investigation explaining what portion of the process caused the deviation.4) does not take into account the safety or efficacy risks associated with the deviations. 5) additionally, the risk assessment concerning efficacy and safety of this product was not

39、made by a person qualified to make this determination.fda sterile inspections 483s wfi 1) the firms deviation investigation and report for oos results regarding high particulate counts for sterile wfi, usp, lots xxxxxx released to market xxxxx, xxxxxx released to market xxxxxx released to market xxx

40、xxx, did not extend to other batches of product manufactured that may have been associated with this problem.2) sterile wfi, usp, lots xxxxxxx, xxxxxxx, xxxxxxxx, xxxxx failed in house particulate testing, but only lot xxxxxx was sent to an outside laboratory for identification/confirmation. the sum

41、mary is incorrect in that it reads in part samples of the affected products were sent to * for positive identification/confirmation of the particulate material suspected to be xxxxxx. 3) the firm failed to address possible sources of contamination identified by an outside laboratory for sterile wfi,

42、 usp, lot xxxxxxxxx.fda sterile inspections fda 483s field alerts firm did not file a field alert within three working days of first becoming aware of information pertaining to product and manufacturing defects that may result in serious adverse drug events. this was not performed for the following:

43、 for example:1) a field alert report was not filed within three days for xxxxxx, lot xxxxx released to market xxxxxxx, which contained particulate matter. the problem was discovered on xxxxx. the form used to report this field alert to fda reads date report received xxxxxx and it was not reported to

44、 fda until xxxxxx. 2) additionally, the fda form 1932 was filled out incorrectly in that the year of xxxx recorded as date sent to fda appears to be incorrect in that it was actually sent in 2009 on january 15.3) a field alert report was not filed within three days for xxxxxxx, released to market xx

45、xxxxx, which contained particulate matter. the ods was discovered on xxxxxx. the form used to report this field alert to fda reads date report received xxxxxx and it was not reported to fda until xxxxxxx. this xxxxxxxxx date would have met the three business day requirement, however no justification

46、 could be provided for the use of this date.fda inspections 483s deviation files are incomplete. for example: for those deviations resulting from operator error, the deviation file did not contain documentation that the operators were re-trained or counseled as a corrective measure. for deviations w

47、here informal investigations were conducted, there was no documentation of the investigationfda inspections 483there is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. specifically, operational deviation report was not performed in ac

48、cordance with sop xxxx. the operational investigation report xxxxx, dated xxxx, had no assignable root cause for the chipped vial of injection 10mg/ml -100 mi lot xxxx b and had not eliminated other possibilities. this operational investigational report was closed xxx/08. (eliminating variables was

49、is not the root cause discussion)fda inspections 483sinvestigations of an unexplained discrepancy did not extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. specifically, the firm initiated investigation reports # xxxx, 00001, 00004, 00024, and 00097 in 2008 and 2009 in response to water found inside the vials during filling process. these 20 vials with w (b) (b) were discovered as they were e