sterile drug process inspections fda

8/10/2019 Sterile Drug Process Inspections FDA

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Sterile Drug ProcessInspections

FDA

Anita R. Michael

Pharmaceutical Investigator
http://www.fda.gov/default.htm


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Definitions

AsepticConditions which are freeof pathogenic organisms or theirtoxins

Pathogens- organisms oftenmicroorganisms that cause disease

Bio-burden- total number of

microorganisms on a specific itembefore sterilization (on componentssuch as containers)


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Definitions

Contamination- on items or insterile drugs the presence ofunwanted microbes

Sterile-Free from bacteria or othermicro-contaminations.

Parenteral-medications that move

through the body via intravenous orintramuscular injection


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Common Processes

Aseptic Process

and

Terminal Sterilization


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Common Processes

Aseptic Processing-Often used whenterminal sterilization cannot be usedbecause of degradation. In asepticprocessing the components anddrug actives and drug products aresterilized separately, to remove bio-

burden, and then put together in aclass 100 environment.


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Classification of Rooms

Class 100less than 100 particles of 0.5 micron or

greater per cubic foot of air.Class 1000less than 1000 particles of 0.5 micronor greater per cubic foot of air.Class 10,000less than 100 particles of 0.5 micronor greater per cubic foot of air.Class 100,000less than 100,000 particles of 0.5

micron or greater per cubic foot of air.


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Aseptic Processing

Endotoxins- gram negatives we arealways 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 survivethe Aseptic Process they can germinate

and grow in favorable conditions.


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FDA Sterile Inspections

Various Compliance Programs nor ICH Q7Awill provide guidance on the sterilization andaseptic processing of sterile APIs (see Q7ASection 1.3). Investigators are to use thefinished product regulations (21 CFR 210

and 211) as guidance and follow CP7356.002A, Sterile Drug ProcessInspections, when inspecting the sterileprocessing of APIs labeled as sterile.Investigators are also to use FDA guidanceon aseptic processing, Sterile Drug Products

Produced by Aseptic Processing

CurrentGood Manufacturing Practice, in evaluatingaseptic processing conditions for sterileAPIs.


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Aseptic core is under the highest pressureto prevent air flow in from areas of lesserair quality. For example air flow from

gowning area into the aseptic core. Gowning-personnel is a critical area to

control. People carry microbes and shedskin cells. Appropriate gowning can

prevent contaminants from entering yourAseptic Core.


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Equipment and personnel should flowone way in a facility. The closer tothe core the cleaner the flow. Class100,000 to 10,000 to 1000, to core100. This is checked duringinspections.


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Clean Air versus ISO

Class 100,000 ISO 8

Class 10,000 ISO 7

Class 1,000 ISO 6 Class 100 ISO 5Micro Settling 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 hours

Class 10,000-5 CFU/ 4 hours

Class 100,000-50 CFU/ 4 hours


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Sterile API

Sterile Finished Drug

Determine if the manufacturer arein compliance with the FD&C act

and are they operating incompliance with Title 21 CFR parts210 and 211 GMPs


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Can conduct full inspection or abbreviatedinspection. Depending on the firms history andnumerous 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 andequipment, materials and laboratory

If questionable practices are observed during an

inspection a deeper, more advanced inspection islikely to be initiated. In depth coverage of thefirms manufacturing practices including processvalidation.


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Review of the firms APR

Rejects

Sterility Failures

Trending CAPA Systems


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Water systems WFI

HVAC Air Handling Systems

Environmental Monitoring


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Media Fills

Clean room qualification

Complaints product quality and

adverse events


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Media

Production process should accuratelysimulate conditions that optimize

detection of any micro contamination.Containers filled with media should befilled to accuracy and appropriate media,contact the inner container closure

surfaces, and permit a visual check fordetection of the microbial growth.


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Incubation and Media Filled Units Media units should be incubated under correct conditions for

example the temperature should be suitable to recover thebio-burden and should not be out of the range of temperature20-35C and be maintained within 2.5C of the targettemperature.

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 arepositive for growth.

Any contaminated unit should be considered objectionableand investigated. The organism should be identified to

species level. Investigation should cover possible causes ofthe contamination. In the future if there are sterility failuresfor marketed drug products investigations conducted duringmedia fills can provide valuable information.


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Media Fills Filling fewer than 5,000 units, no contamination units should be

detected. If 1 contaminated unit is detected this is cause forrevalidation 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. 2units should result in an investigation and cause for revalidation.

Filling more than 10,000 units 1 contaminated unit should result ininvestigation. 2 contaminated units should be cause for revalidationfollowing investigations.

Also, if media fill runs no matter what the filling size units are show

intermittent incidents of micro contamination in media fills runs thiscan show that there is a persistent low level contamination problemthat should be investigated.


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Environmental Monitoring CriticalA 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 potentialcontaminants preventing adulterated products fromentering the market.

EM should cover the following: air quality, floors, walls,surfaces, equipment and product contact surfaces.


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Environmental Monitoring Critical

Frequency of samples close to operations orplaces critical to operations also covering otherareas such as gowning areas.

Focus on the product and areas of concern thatshould be sampled such as air and surfaces nearcritical process operations with increased activity.

VERY IMPORTANT TO KEEP TREND REPORTSEVEN IF EVERYTHING APPEARS OK. Data should

be evaluated by quality. Locations to be sampled


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Environmental Monitoring Critical

Types of sampling equipment for air

Laser particle counters-count particlesusing a laser and know amount ofair.

Viable particulates and non-viableparticulates- can be counted onsetting plates, incubated, counted.


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FDA Sterile Inspections can Seek Action Warning

Letters, Recalls and Injunction

Failure to assure each batch conforms toestablished specifications, for examplethe NDA, USP or Label Claims.

Distribution of product that does not meetestablished specifications.

Test methods that are not adequate orvalidated.

Failure to assure that a batch is uniformin character and quality.


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FDA Sterile Inspections can Seek Action

Warning Letters, Recalls and Injunction

Failure to keep adequate records for example:date of manufacturer, quantity manufactured, lotnumber, test results and dates, labelingspecimen, how the firm determined yields,blending, following established manufacturing

procedures, proper review of testing records andproduction records to authorize release fordistribution.

Failure for prompt recall and not knowing all lotsthat have been distributed.

Not having appropriate stability program,protocol, stability testing inadequate to supportexpiration dates.


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FDA Sterile Inspections 483s

Parenterals

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 theproduct, did not extend to other drug products that may have been associated with thisproblem. 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 investigationexists to show the firm reviewed other lots of this product or other lots of productpotentially affected by this problem.

2) The firm did not conduct a review of their manufacturing equipment which may havecaused 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 wasnot made by a person qualified to make this determination.


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FDA Sterile Inspections 483s

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 tomarket XXXXXX released to market XXXXXX,, did not extendto 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 lotXXXXXX was sent to an outside laboratory foridentification/confirmation. The summary is incorrect in that itreads 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 ofcontamination identified by an outside laboratory for SterileWFI, USP, lot XXXXXXXXX.


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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 seriousadverse 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 discoveredon 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 in2009 on January 15.

3) A Field Alert report was not filed within three days for XXXXXXX, released to marketXXXXXXX, 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 metthe three business day requirement, however no justification could be provided for theuse of this date.


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FDA Inspections 483s

Deviation files are incomplete. Forexample: For those deviations resultingfrom operator error, the deviation file did

not contain documentation that theoperators were re-trained or counseled asa corrective measure.

For deviations where informal

investigations were conducted, there wasno documentation of the investigation


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FDA Inspections 483

There is a failure to thoroughly review anyunexplained discrepancy whether or not the batchhas been already distributed. Specifically,Operational Deviation Report was not performed

in accordance with SOP XXXX. The OperationalInvestigation Report XXXXX, dated XXXX, had noassignable root cause for the chipped vial ofInjection 10mg/ml -100 mI lot XXXX B and hadnot eliminated other possibilities. This OperationalInvestigational Report was closed xxx/08.

(eliminating variables was is not the root causediscussion)


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Investigations of an unexplained discrepancy didnot extend to other batches of the same drugproduct and other drug products that may havebeen associated with the specific failure or

discrepancy. Specifically, the firm initiatedinvestigation reports # XXXX, 00001, 00004,00024, and 00097 in 2008 and 2009 in responseto "water found inside the vials during fillingprocess". These 20 vials with w (b) (b) werediscovered as they were exiting the

depyrogenatlon tunnel and prior to the fillingmachine on Line X Building X.


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The quality control unit lacks authority to fully investigateerrors that have occurred. The Quality Unit and SeniorManagement failed to assure all drug products distributedhave the safety, identity, quality, and purity that they arerepresented to possess. The Quality Unit failed to: reviewelectronic data as part of batch release, review computer

audit trails in the System and provide adequate training toanalytical chemists. These practices led to the Quality Unitreleasing batches of drug products which failed to meet in-process, finished product and stability specifications. Thesepractices also led to the submission of erroneous data inAnnual Reports and Prior Approval Supplement XXXX, Thelack of Quality oversight resulted in: the ceasing ofmanufacturing and distribution of all drug products. Also the

recall of all batches (which were in the thousands) of drugproducts and the withdrawal of at least 10 Abbreviated NewDrug Applications.


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Popular FDA 483 Issued

211.22(d) Responsibilities ofquality control unit

211.100(b) Written procedures;deviations

211.110(a) Sampling and testingof in-process materials and drugproducts.


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211.160(b) General RequirementsLab

211.100(a) Written Procedures;Deviations

211.192 Production RecordReview; Investigations


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211.165(a) Testing and release fordistribution

211.188 Batch production and controlrecords

211.25(a) Personnel qualifications

211.67(b) Equipment cleaning andmaintenance


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