FDA Inspections

Back to Basics
(FOI Releasable 10/6/2003)

Robert Darius, Microbiologist

Center for Biologics Evaluation & Research
Office of Compliance & Biologics Quality
Division of Manufacturing & Product Quality

(301) 827-3031
DARIUS@CBER.FDA.GOV

The views expressed during this

presentation are my own and may
not be those of the FDA.

Overview
Regulatory Toolbox
Applicable Documents and Links

Inspection Stories for Engineers

The Importance of Being Engineer, by Oscar
Wilde

Summary Points and Parting Thoughts

Questions

Regulatory Toolbox - ORA

Pre-Approval Inspections/Investigations, 7346.832
www.fda.gov/cder/dmpq/7346-832CDER.pdf
Post-Approval Audit Inspections, 7346.843
www.fda.gov/cder/dmpq/7346-843CDER.pdf
Drug Manufacturing Inspections, 7356.002
www.fda.gov/cder/dmpq/compliance_g
uide.htm

Regulatory Toolbox - ORA

Sterile Products Manufacture, 7356.002A
www.fda.gov/cder/dmpq/7356002a-CDER.pdf
Bulk Pharmaceutical Chemicals, 7356.002F
www.fda.gov/cder/dmpq/7356002f-CDER.pdf

Regulatory Tool Box

The Preamble to the GMPs
Detailed discussion by the Commissioner
on the GMP regulations in Title 21 CFR
211.
www.fda.gov/cder/dmpq/preamble.txt

Regulatory Toolbox
Barr Decision
United States v. Barr Laboratories, Inc.
February 4, 1993, Decided
Civil Action No. 92-1744
812 F. Supp. 458; 1993 U.S. Dist. LEXIS 1932
www.gmp1st.com/barr1.htm
Includes discussion on:
9 Failures & Failure Investigations;
9 Sampling Sites and Sizes;
9 Cleaning & Methods Validations;
9 Mixing Times; and
9 Much, Much More

Who will you see on inspection?

CBER Regulated Products:
DMPQ Reviewers lead Pre-Approval
Inspections (PAIs) with Product Office
Specialist Participation. ORA representatives
invited per protocol.

CDER Regulated Products:

ORA Inspectors perform and lead PAIs. CDER
staff may not participate.

Who performs biennial

inspections?
CBER Regulated Products:
Team Biologics and Product Office Specialists

CDER Regulated Products:

ORA Inspectors
New Risked-Based Approach to determine whether
inspection will be performed (biennial / PAI).
Field Offices given greater flexibility on whether to
perform PAI or biennial inspections.

New Language on the FDA 483

(4/03)
This document lists observations made by the FDA
representatives during the inspection of your facility.
They are inspectional observations and do not represent a
final Agency determination regarding your compliance.
If you have any objection regarding an observation, or
have implemented, or plan to implement, corrective action
in response to an observation, you may discuss the
objection or act with the FDA representatives during the
inspection or submit this information to FDA at the
address above.
If you have any questions, please contact the FDA.

War Stories

War Stories

Inspection Stories for Engineers

High Purity Water Systems

Integrity testing of sterilizing grade vent
filters not performed post-use.
Dead legs.
Non-draining tubing on drops and
equipment.
Sampling ports located before use ports.
Collection procedures not identical to use
procedures.

High Purity Water Systems

Isometric drawings of as-builts should be
available.
Dead legs should not exist.
Valve types (threaded v. sanitary).
All sampling ports and drops should be included
in monitoring program.
Sampling methods should reflect actual use
conditions (i.e., sanitization, hoses, rinse/flush
times).

Equipment Suitability
(Suitability for Intended Use)
Spalling of silicone tubing used during
purification process.
Suitability studies not performed with solvent
system prior to determining acceptability for
intended use.
Impact on tubing of lengthy processing times
not evaluated.
Silicone particulates found in final purified
bulk.

HVAC Systems
Inability to balance rooms in classified
areas during OQ. Construction staff
added additional supply line to
supervisors office which was not accounted
for in the design specifications.
Pressure inversions of environmentally
classified areas (filling to capping areas).

HEPA Filters
SOP for integrity testing (performed by
contractor) not approved, nor available inhouse.
No specification to perform smoke studies
after repairs to HEPAs in Class 100 areas
have been made.
No specified life-spans for the HEPA filters.

Aseptic Filling Areas

Relative humidity and temperature monitoring not
performed in Class 100 aseptic filling areas.
Pressure differentials not monitored, or recorded,
in critical areas.
Must demonstrate that areas can maintain specified
pressure cascade.
Risk of pressure inversions.

Non-specific SOPs for room sanitization.

Isolator Design
Plywood mock-up model of isolators
Verifies suitability of design geometries.
Allows staff to try unit prior to construction of
actual unit and offer recommendations for changes.

Eliminates need for major retrofits once

installed.

Isolators
Environmental classification surrounding
isolator.
Purpose of the isolator:
Total or Negligible Containment.
Live viral processing or sterility testing.

Class 100,000 environment surrounding

isolators may be acceptable based on
successful media fill results.

Isolator Observations
Operator standing on stool to reach half-suite fell
during sterility test, damaging isolator.
No method to remove accumulated empty vials
from inside isolator after a five-day filling
operation. Vials blocked air return grills.
Paper edged HEPA filters installed, which
deteriorated after several VHP sterilization cycles.
HEPA filter integrity testing not performed after
unit was installed.

Equipment/Vial Washers
Improperly balanced washer spray arm
scratched internal stainless steel surface of
washer, resulting in stainless steel
particulates in final product.
Spray coverage studies performed as part of
FAT were not available, nor included in
validation package.

Equipment/Vial Washers
Filters installed in WFI fluid path on vial
washer. Microbial growth noted in filters.
Fiber and glue accumulated in equipment
washer from paper labels, resulting in fibers
and particulates in bulk and final product.
No evaluation for cleanliness of internal
surfaces performed prior to use.

Autoclaves
Incorrect Hz (50 v. 60) solenoid installed on
autoclave, resulting in delivery of variable
sterilization times.
Integrity testing of sterilizing grade vent filters not
performed after removal.
Inadequate steam supply delivered, unable to
successfully validate.
Accumulation of debris in steam traps resulting in
inability to re-validate.

Autoclaves
Gravity v. Pre-Vacuum Pulse Units.
Drains not protected (screened) or cleaned post-use.
No preventative maintenance program. Cracked
gaskets noted.

Master Site [you should have one].

The intent of the sterilization cycle is to validate
sterilization of the load, not the chamber.
The hardest to heat location (object) in the load should
be used to establish the cycle.
Artificial cold spots are acceptable, but not required
(silicone oil filled pipe with controlling RTD).

Sterilization Validation Studies

Choice of Overkill v. Probability of Survival
Approach (depends on what is to be sterilized).
Terminally sterilized product.
Product contact equipment (durable goods).
Surge vessels, manifolds, and filling needles.
Stoppers (closures).

Upstream processing equipment.

Fermenters / Bioreactors.
Transfer piping, manifolds, and vent filters.

Sterilization Validation Studies

(The most important validation you will perform...)

Objective of the Sterilization Process is to kill the bugs.

Objective of Validation Study is to provide quantifiable evidence that the bugs
are killed.

Physical

Bugs

Variable Type

Independent
(Controlled)

Dependent
(Outcome)

Variables

Fo

D-value & Spore

population

Proof

Variables were
controlled

Kill

Evidence (that
process objectives
were met)

Indirect

Direct

Sterilization Validation Studies

The Bugs Dont Lie
Fo values are only as good as the locations
monitored and the thermocouples used.
Fo values do not indicate steam saturation.
Fo, time and pressure are needed to determine steam
saturation, but may not disclose localized air pockets.

The bugs dont lie (Pflug), but Fos may.

Time and storage conditions BIs experience postexposure prior to inoculation are critical factors.
USP <55> Biological Indicators

Sterilization Validation Studies

Issues with Probability of Survival Method:
Periodically monitor bioburden and do not rely
solely on results from Certificate of Analysis.
Know the D-value of the normal bioburden.

Audit suppliers of components, containers,

closures, etc.

Process Design Flaws

Pressurization of a sterile filtered final bulk
tank (used for filling) with non-sterile filtered
nitrogen gas.
Aseptic connections (post-filtration) to filling
equipment made in Class 100,000 area.
Opening some sterilized filling equipment in
Class B areas during fill line set-up.

Media Fills
Do not remove filled vials for weight checks or inprocess testing culling vials.
The intent of a media fill is to demonstrate the ability to
aseptically fill the product, not validate weight checks
or fill volumes, which should be done during OQ.
Removal of filled units diminishes the power of a media fill.
Non-integral (damaged) filled vials should be documented &
removed prior to incubation.
When non-integral vials are found during incubation and
exhibit growth, the organism/s should be identified,
documented and investigated.
Do not use filled units for Growth Promotion testing prior to
conclusion of incubation.

Media Fills
Not capturing first flush of media through
lines.
Inert gas (nitrogen) used during media fills.
Residual moisture (water) in sterilized
tubing of filling lines.
Define the number of units to be filled and
incubate that number of units.

Filling Equipment
Inability to validate a time/pressure filling system
due to vibrations from nearby railway tracks.
Weight dosage system installed after unsuccessful
validations.
Remote Particle Counters:
Tubing length exceeded manufacturers
recommendation.
Samplers not covered during sanitization of filling line,
resulting in damage to laser/mirror units.

Filling Equipment
Filling line barrier frames not grounded, causing
static discharge resulting in particulate excursions.
Accumulator table too close to wall. High volume
of personnel movement over open vials
interrupting first flush HEPA filtered air.
Stopper hopper at waist height, not protected by
barrier, or microbially monitored.

Lyophilizers
No vent filter installed, vented to Class
100,000 area.
Lyophilizer loading door opens and
obstructs laminar flow curtained barrier.
Class 100 zone surrounding door broken
during loading.
Lyophilizer chamber & condenser not
cleaned or sterilized.

Lyophilizers
Clean chamber with WFI and alcohol and
validate or qualify cleaning procedure.
Monitor chamber and condenser for residual
products and cleaning agents (CIP v.
Manual Cleaning).
Remember that the longest time that a
product is exposed unstoppered is in the
lyophilizer, not the filling line.

Lyophilizers
Margin testing of allowable ramp rates
not evaluated during PQ studies.
Method to detect thermal transfer fluid
leaks (silicone, Lexsol).
Chamber leak rate testing (real v. virtual).
Preventative maintenance program.

Impellers
Sediment noted in filtered bulk product.
Testing revealed sediment to be composed of
tungsten & nickel.
Bottom mounted impeller contained a worn
tungsten carbide bearing.
Changed to a top mounted external impeller.

Bioreactors / Fermenters
To minimize contamination risk, consider
performing integrity testing of filters used to
supply buffers and media.
Consider utilizing block and bleed valves
on sample collection ports to minimize false
positives during microbial sampling.

Centrifuges
Typical Centrifuges cooled by:
Potable, purified, or reverse osmosis water
Glycol

Monitor bioburden levels of product stream

before and after centrifugation.
Monitor for the presence of glycol (or other
cooling fluids) in the process stream (or
final product).

Centrifuges
Sanitary design and have the diagrams
available in-house.
Perform periodic integrity testing of the
cooling jacket.
Rotor sanitization/sterilization and storage
conditions.

Jacketed Vessels & Tanks

Manufacturers diagrams should be
available in-house.
Pressure hold studies should be performed,
both initially and routinely.
Methods should be available to monitoring
for presence of cooling fluids in product.

Vent Filters
Perform integrity testing before and after use.
Life-spans should be based on conditions of use
and historical data.
Establish conservative life-spans initially, then increase
them as data/comfort levels increase.

Use the correct integrity testing method and

specifications for filters (hydrophobic vs.
hydrophilic).

Back-Up Generators

Back-Up Generators
Preventative maintenance schedule
procedurally based and documented.
Periodic testing of the generators.

Risk-Based Approach
When you know your:

Product
Flow-path
Equipment and how it works
Potential in-process and process impurities
Validation studies and their weaknesses
Readily available technologies at your disposal

Then, you can make intelligent, science-based

decisions on your process, validations, and
product, and support them during an inspection!

Parting Thoughts
Risk-based approach to validation, production, inprocess testing, and maintenance.
Know the process, equipment and human
capabilities.

System suitability
Process capabilities
Personnel and Training
Clear/detailed SOPs
No matter how hard you try, you cannot inspect quality into a
product

Parting Thoughts
Processes drift - Small changes over time
may result in significant changes in the
process and final product.
In-process and final release specifications
should be specific and narrow enough to
capture potential drift.
Validations and preventative maintenance
should assist in assuring that the process is in a
state of control.

Parting Thoughts
The most frequently issued observations
begin with:
There are no data available to support

Real Solutions for Real People

Questions