FDA InspectionsBack to Basics

(FOI Releasable 10/6/2003)

Robert Darius, MicrobiologistCenter for Biologics Evaluation & Research

Office of Compliance & Biologics QualityDivision of Manufacturing & Product Quality

(301) 827-3031DARIUS@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/7346-832-CDER.pdf

• Post-Approval Audit Inspections, 7346.843www.fda.gov/cder/dmpq/7346-843-CDER.pdf

• Drug Manufacturing Inspections, 7356.002www.fda.gov/cder/dmpq/compliance_guide.htm

Regulatory Toolbox - ORA

• Sterile Products Manufacture, 7356.002Awww.fda.gov/cder/dmpq/7356-002a-CDER.pdf

• Bulk Pharmaceutical Chemicals, 7356.002Fwww.fda.gov/cder/dmpq/7356-002f-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, DecidedCivil Action No. 92-1744 812 F. Supp. 458; 1993 U.S. Dist. LEXIS 1932www.gmp1st.com/barr1.htm

Includes discussion on:Failures & Failure Investigations;Sampling Sites and Sizes;Cleaning & Methods Validations;Mixing Times; andMuch, 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 StoriesWar Stories

War StoriesWar Stories

Inspection Stories for EngineersInspection 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 supervisor’s 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 in-house.

• 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.

DirectIndirectEvidence (that process objectives were met)

KillVariables were controlled

Proof

D-value & Spore population

FoVariables

Dependent (Outcome)

Independent (Controlled)

Variable Type

“Bugs”Physical

Sterilization Validation Studies“The Bugs Don’t 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 don’t lie” (Pflug), but Fos may.– Time and storage conditions BIs “experience” post-

exposure 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 in-process 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 manufacturer’s

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

• Manufacturer’s 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, in-

process 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