1. Sterile Drug Process Inspections
FDA
Anita R. Michael
Pharmaceutical Investigator

2. Definitions
Aseptic – Conditions which are free of pathogenic organisms or their toxins
Pathogens- organisms often microorganisms that cause disease
Bio-burden- total number of microorganisms on a specific item before sterilization (on components such as containers)

3. 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 injection

4. Common Processes
Aseptic Process
and
Terminal Sterilization

5. Common Processes
Aseptic 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 in a class 100 environment.

6. Common Processes
Terminal 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 controlled environment is not sterile.

7. 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 of air.
Class 100,000 less than 100,000 particles of 0.5 micron or greater per cubic foot of air.

8. 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-Firm’s Heating, Ventilation and Air Cooling systems

9. Aseptic 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 favorable conditions.

10. FDA Sterile Inspections
Various 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 A, 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 conditions for sterile APIs.

11. 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. Appropriate gowning can prevent contaminants from entering your Aseptic Core.

12. FDA Sterile Inspections
Equipment 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.

13. FDA Sterile Inspections
HVAC systems control the temperature, humidity, air pressure
HEPA controls the particulates and the microorganisms. HEPA filters filter 99.97% capturing substances 0.3 micron or larger.

14. Clean Air versus ISO Class 100,000 ISO 8 Class 10,000 ISO 7
Micro Settling Plates Action Levels (diam. 90mm; cfu/4hours)
Class CFU however samples from class 100 (ISO 5) environments should normally yield no microbial contaminants.
Class 1, CFU / 4 hours
Class 10, CFU/ 4 hours
Class 100, CFU/ 4 hours

15. FDA Sterile Inspections
Sterile API
Sterile Finished 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 GMPs

16. FDA Sterile Inspections
Can conduct full inspection or abbreviated inspection. Depending on the firm’s history and numerous other factors.
Can also depend 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 laboratory
If questionable practices are observed during an inspection a deeper, more advanced inspection is likely to be initiated. In depth coverage of the firm’s manufacturing practices including process validation.

17. FDA Sterile Inspections
Review of the firm’s APR
Rejects
Sterility Failures
Trending CAPA Systems

18. FDA Sterile Inspections
Water systems WFI
HVAC Air Handling Systems
Environmental Monitoring

19. FDA Sterile Inspections
Media Fills
Clean room qualification
Complaints product quality and adverse events

20. FDA Sterile Inspections
Regulatory Actions for Sterile Products are focused on contamination such as objectionable microorganisms, toxic chemicals, or a reasonable potential for contamination such as contact with unclean equipment or airborne contamination (HEPA, HVAC system)

21. FDA Sterile Inspections
Media
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 indicator 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 media fill repeated.

22. FDA Sterile Inspections
Media
Production 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 visual check for detection of the microbial growth.

23. FDA Sterile Inspections
Incubation and Media Filled Units
Media 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 20-35°C and be maintained within ± 2.5°C 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 contaminated 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 fills can provide valuable information.

24. FDA Sterile Inspections
Media Fills
Filling 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 result 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 investigations.
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.

25. FDA Sterile Inspections
Media Fills
Media fills should 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.

26. FDA Sterile Inspections
Environmental Monitoring Critical
A Quality System driven environmental program should be established addressing the following:
SOP on sampling procedures
Frequency of monitoring
Types 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 adulterated products from entering the market.
EM should cover the following: air quality, floors, walls, surfaces, equipment and product contact surfaces.

27. FDA Sterile Inspections
Environmental Monitoring Critical
Frequency of samples close to operations or places critical to operations also covering other 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 sampled

28. FDA Sterile Inspections
Environmental Monitoring Critical
Types 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.

29. Distribution of product that does not meet established specifications.
FDA Sterile Inspections can Seek Action Warning Letters, Recalls and Injunction
Failure 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 assure that a batch is uniform in character and quality.

30. 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 determined 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, stability testing inadequate to support expiration dates.

31. FDA Sterile Inspections 483’s
Parenterals
A) The firm’s 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 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 reviewed 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 related, 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 made by a person qualified to make this determination.

32. FDA Sterile Inspections 483’s
WFI
1) The firm's 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 XXXXXX,, 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 summary 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, USP, lot XXXXXXXXX.

33. FDA Sterile Inspections FDA 483’s
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:
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 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 XXXXXXX, 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 could be provided for the use of this date.

34. FDA Inspections 483’s
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 where informal investigations were conducted, there was no documentation of the investigation

35. FDA Inspections 483
There 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 accordance 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 is not the root cause discussion)

36. FDA Inspections 483’s
Investigations 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 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 exiting the depyrogenatlon tunnel and prior to the filling machine on Line X Building X.

37. FDA Inspections 483’s
The quality control unit lacks authority to fully investigate errors that have occurred. The Quality Unit and Senior Management failed to assure all drug products distributed have the safety, identity, quality, and purity that they are represented to possess. The Quality Unit failed to: review electronic data as part of batch release, review computer audit trails in the System and provide adequate training to analytical chemists. These practices led to the Quality Unit releasing batches of drug products which failed to meet in-process, finished product and stability specifications. These practices also led to the submission of erroneous data in Annual Reports and Prior Approval Supplement XXXX, The lack of Quality oversight resulted in: the ceasing of manufacturing and distribution of all drug products. Also the recall of all batches (which were in the thousands) of drug products and the withdrawal of at least 10 Abbreviated New Drug Applications.

38. Popular FDA 483 Issued
§ (d) Responsibilities of quality control unit
§ (b) Written procedures; deviations
§ (a) Sampling and testing of in-process materials and drug products.

39. Popular FDA 483 Issued § 211.160(b) General Requirements Lab
§ (a) Written Procedures; Deviations
§ Production Record Review; Investigations

40. Popular FDA 483 Issued
§ (a) Testing and release for distribution
§ Batch production and control records
§ (a) Personnel qualifications
§ (b) Equipment cleaning and maintenance

41. Contact Information