Regulatory & Compliance Perspectives on

Aseptic ProcessingIIR Aseptic Filling Conference, Philadelphia, PA November 4, 2004

FOI Releasable 11/2004

Robert DariusInspector & Review Microbiologist

FDA/CBEROffice of Compliance & Biologics Quality

Division of Manufacturing & Product QualityDarius@cber.fda.gov

301-827-4471

The views expressed during this presentation are my own and may

not be those of the FDA.

Overview

• Regulatory Tool Box– Revised Guidance & Link– Applicable Regulations

• Objectives of Aseptic Processing & Validation

• FDA 483 Inspection Observations• Conclusions

Revised Guidance for IndustrySterile Drug Products Produced by

Aseptic Processing

• Released September 30, 2004•http://www.fda.gov/cder/guidance/5882fnl.htm

21 CFR 10.115 (d)(1)

• Are you or FDA required to follow a guidance document?– No. Guidance documents do not establish

legally enforceable rights or responsibilities. They do not legally bind the public or FDA.

– Alternate approaches are acceptable if they apply to the relevant statutes and regulations.

– Guidance documents represent current thinking.

21 CFR 211.113 (b) Control of microbial

contamination

• Appropriate written procedures, designed to prevent objectionable microorganisms in drug products purporting to be sterile, shall be established and followed.

• Such procedures shall include validation of any sterilization process.

Barr Decision

• USA v. Barr Laboratories, Inc.February 4, 1993, DecidedCivil Action No. 92-1744812 F. Supp. 458; 1993 U.S. Dist. LEXIS 1932www.gmp1st.com/barr1.htm

Includes discussion on:-Failures & Failure Investigations;-Sampling Sites & Sizes;-Cleaning & Methods Validation; and-Mixing Times.

Objectives of Aseptic Processing (or, What’s Really Important)

• What is the fundamental objective of aseptic processing?– To keep sterile “things” sterile.

• What are the fundamental objectives of validating an aseptic process?– To demonstrate that the process, environment,

and personnel are capable of maintaining sterility of the final “assembled” product.

Selected FDA 483 Observations on

Aseptic Processing

Design

• The filling machine hopper is located outside the Class 100 curtained area in the filling room. Sterilized stoppers are charged into an unsterilized stopper hopper located in a Class 10,000 environment.

Design

• Design & construction of the facility did not prevent ingress of rainwater into the aseptic processing areas.

• Steam condensate back-up from the double door autoclave supporting the aseptic filling suite repeatedly flooded the Class 100 aseptic filling area.

Design & Personnel• Personnel interrupt first flush laminar flow HEPA

filtered air directly over unprotected vials on unscrambler table. a. Gowned personnel were viewed brushing against vial

unscrambler table on numerous occasions while moving to the other side of the filling equipment to perform fill line maintenance, view non-viable monitoring devices, and exchange microbiological sampling plates.

b. Vial unscrambler is not protected by barrier and area around unscrambler is too narrow to allow for minimization of personnel contact with table edges.

Design & Personnel

• Fill line operator entered the stopper bowl cabinet several times using tools that were non-sanitized, nor sterilized, prior to use. No requirements specifying sterilization/sanitization of tools prior to use.

• Autoclave wrap covering the sterilized stopper bowl was dislodged during set-up, exposing the stopper bowl to gowned operator’s arm and unsanitized tools.

Qualification

• Velocity testing and smoke studies have not been performed to demonstrate laminarity of the air supplying the curtained Class 100 filling areas.

Sterilizing Grade Filters

• Concerning Sterilizing Grade Filters:a. Post-use integrity testing of 0.2 µm vent filters on

autoclaves, WFI holding tanks, purified water systems, and product flowpath assemblies have never been assessed, nor performed.

b. There are no data available to support the 12-month replacement frequency for the sterilizing grade vent filters on the WFI holding tanks maintained at 80 °C. The same filters installed on purified water systems have a six-month replacement frequency.

Equipment Suitability

• Malfunction of the stopper feed system required numerous entries into the stopper bowl cabinet by fill line operators and engineers. Stopper bowl was alternately either partially covered with sterile paper sheets or left entirely uncovered during repairs performed prior to aseptic filling operation.

Training(Believe it or Not!)

• House fly (Musca domestica) in Class 100 filling room was not gowned per procedure.

Filling Room Tools

• Non-sterilized tools and lyophilizer loading trays stored in Class 100 areas used fill line set-up,repairs and vial transport have not been microbially assessed.

Equipment Transport

• Climet data loggers are transported between Class 100 and unclassified areas to the QC Microbiology department for data downloading. These Climets are wiped down with alcohol prior to their return to the Class 100 areas but the potential impact of this practice has not been assessed microbiologically.

Fill Line Set-Up Operations• Concerning Fill Line Set-Up Activities:

a. Procedure does not specify how to perform set-up of the filling line. Variability in aseptic technique was noted between different personnel performing fill line set-up.

b. Sterilized filling equipment (stoppering tubes and pins) are completely unwrapped in Class B areas during fill line set-up operations and transferred to the Class A areas for line set-up.

c. Non-sterilized tools are used during fill line set-up and have never been microbiologically evaluated, or monitored.

d. Viable microbial monitoring has not been evaluated, nor performed, during fill line set-up.

Aseptic Technique

• Personnel were observed having lengthy discussions while holding the door to the cleanroom fully open.

• Personnel were viewed speaking to each other across the room in close proximity to the aseptic operations near open vials.

Aseptic Technique

• Personnel were observed righting unfilled sterilized vials that were inverted and had contacted the sanitized surface of the unscrambler table prior to filling. These vials were filled, not discarded.

• Operators loading depyrogenated vials onto the unscrambler table were observed sanitizing hands with 70% alcohol in spray bottle directly over the the open, sterilized vials.

Aseptic Technique

• Personnel filling the stopper hopper allowed the exterior of the stopper bag to contact the sterilized surfaces of the stopper hopper. Equipment described has not been evaluated during the environmental monitoring qualifications performed.

Personnel Monitoring

• Microbial evaluation of thumbs has not been considered, nor monitored, as part of the personnel monitoring program.

Personnel Monitoring

• Personnel monitoring procedures direct filling personnel to perform microbial monitoring on themselves during aseptic filling operations. Additionally, QA oversight of personnel monitoring is not specified.

Air Flow Dynamics

• Smoke studies performed did not clearly demonstrate laminarity of air flow over the exposed product pathway in that the direction of air flow swept over the operators and downwards toward the filling equipment when the Lexan doors at the filling needles were opened.

Air Flow Dynamics

• Smoke studies were not conducted under dynamic conditions following the addition of a Lexan barrier to improve airflow laminarity.

Air Flow Dynamics

• Dynamic smoke studies demonstrated that swirling and turbulence were observed in front of the dry heat sterilizer supplying the Class 100 aseptic filling area and vial accumulator table.

Time Limits

• Maximum allowable time limits for aseptic filling operations have not been established. Media fills do not duplicate the longest time used in production for aseptic filling.

Sterility Testing

• Sterility samples were stored at – 40 °C prior to testing. In addition, suitability of the containers & closures to maintain integrity at – 40 °C has not been assessed.

Procedures

• The batch production record and associated procedures are not available to operators in the aseptic filling areas where processing occurs and manufacturing data are recorded. Operators must leave the room to record data in the batch record.

Change Control

• Incorrectly sized parts were installed on the filling line pump which resulted in rubbing of metal filling pistons against the metal support blocks during filling operations. Metallic particles were noted in final filled product. QC/QA departments did not assess potential impact of the changes made.

Environmental Monitoring

• Viable air monitoring is performed by sampling one-half the volume of air and multiplying by two in the Class 10,000 and 100,000 areas.

Environmental Monitoring

• Microbial monitoring of the stopper hopper and stopper feed tracks are not performed. This equipment is sanitized, not sterilized prior to use.

• Non-viable particulate monitoring is not performed in the area near the stopper bowl, where operators manually charge the bowl with sterile stoppers from breather bags.

HEPA Filters

• Integrity testing of the HEPA filters in the Class 100 aseptic filling area have never been performed.

HEPA Filters

• 85% of HEPA filters in the aseptic filling suite were determined to be non-integral during the scheduled six month HEPA filter integrity testing performed by an outside contractor.

Culling of Media Fill Units

• Visual inspection personnel remove media filled bottles which are damaged or defective after the incubation period is completed. The turbidity status of these bottles is not always recorded in the batch record and the damaged or defective bottles are not sent to QC Microbiology for evaluation prior to destruction.

Media Fills

• Not all filled units are incubated in that eight units per batch are removed and inoculated as positive controls.

Media Fills

• Media fill operations have not used container/closure systems representative of those used routinely during aseptic filling operations.

Media Fills

• Media fills do not include simulations of all aseptic operations such as aseptic additions of buffers and formulation components transferred into the mixing vessels supplying the filling line.

Media Fills

• There is no assurance that adequate volumes of media have been filled into each bottle to assure that it contacts all interior surfaces of the filled containers.

Media Fills

• Growth promotion testing of media used for aseptic media fill simulations has not been evaluated or performed.

Particulate Monitoring

• Non-viable particulate monitoring performed is not representative of actual conditions in that the monitoring probes are located in the return air ducts of the Class 100 aseptic filling area.

Particulate Monitoring

• Non-viable particulate monitoring is not performed during performance of aseptic connections made for the sterile filtration step of buffer solutions.

QA/QC Oversight

• Non-sterile filtered nitrogen is used to pressurize the sterile formulated bulk tank supplying the aseptic filling line. – Both the QA and QC Microbiology units

approved the process and deemed the practice acceptable.

– Anaerobic monitoring of the process has not been evaluated or performed.

Isolators

• Operator standing on stool in order to reach half-suite fell during performance of a sterility test and damaged isolator.

• No method available to remove accumulated empty vials from inside isolator after a five-day filling operation. Vials blocked air return grills.

• Paper edged HEPA filters installed in isolator deteriorated after several VHP sterilization cycles.

Lyophilization

• Product pathways for partially stoppered, and unprotected, vials conveyed from the filling area to the lyophilizers are monitored according to Class 10,000 rather than Class 100 environmental standards.

Lyophilization

• Lyophilizer chamber is vented directly to a Class 100,000 environment. A sterilizing grade vent filter was not installed to protect the chamber. In addition, there are no data available to support the maximum allowable seven day hold on the sterilized lyophilizer prior to use.

Lyophilization

• Non-viable particulate monitoring is performed at a location eight inches below the ceiling HEPA filter face (or four feet above the vial traying operations) for laminar flow air supplying the accumulator table where partially stoppered vials are loaded onto trays prior to lyophilization.

Novel Approach for Determination of Media Fill & Sterility Failures

Parting Thought

• The most frequently issued observations begin with:

There are no data available to support…

Conclusions• Understand your process and its limitations.

– Be alert to the practical realities of people and the process. Strive to minimize identified or perceived risks.

• Maintain a science-based evaluation of the processes to develop validation approaches that can be scientifically defended.– Question “why?” and “how?” to stimulate internal

dialogue on the process, risks, and validation approaches.• There are solutions to all problems.

– The solutions are waiting to be discovered.• Apply good common sense.

“The obscure we see eventually.

The completely apparent takes longer.”

E.R. Murrow

Robert Darius, FDA/CBERDarius@cber.fda.gov

301-827-4471