Sterile Drug Process

Inspections
FDA
Anita R. Michael
Pharmaceutical Investigator

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)

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

Common Processes
Aseptic Process
and
Terminal Sterilization

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 bioburden, and then put together in a
class 100 environment.

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.

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.

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 systems

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.

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
7356.002A, 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.

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.

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.

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.

Clean Air versus ISO

Class
Class
Class
Class

100,000
10,000
1,000
100

ISO
ISO
ISO
ISO

8
7
6
5

Micro 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

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

FDA Sterile Inspections

Can conduct full inspection or abbreviated

inspection. Depending on the firms 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
firms manufacturing practices including process
validation.

FDA Sterile Inspections

Review of the firms APR

Rejects

Sterility Failures

Trending CAPA Systems

FDA Sterile Inspections

Water systems WFI

HVAC Air Handling Systems

Environmental Monitoring

FDA Sterile Inspections

Media Fills

Clean room qualification

Complaints product quality and

adverse events

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)

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.

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.

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
20-35C and be 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 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.

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.

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.

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.

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

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.

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.

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.

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 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.

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 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.

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:

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.

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 where informal
investigations were conducted, there was
no documentation of the investigation

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)

FDA Inspections 483s

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 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 exiting the
depyrogenatlon tunnel and prior to the filling
machine on Line X Building X.

FDA Inspections 483s

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 inprocess, 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.

Popular FDA 483 Issued

211.22(d) Responsibilities of
quality control unit
211.100(b) Written procedures;
deviations
211.110(a) Sampling and testing
of in-process materials and drug
products.

Popular FDA 483 Issued

211.160(b) General Requirements

Lab
211.100(a) Written Procedures;
Deviations
211.192 Production Record
Review; Investigations

Popular FDA 483 Issued

211.165(a) Testing and release for

distribution
211.188 Batch production and control
records
211.25(a) Personnel qualifications
211.67(b) Equipment cleaning and
maintenance

Contact Information
Email
anita.michael@fda.hhs.gov