Sterile Drugs: The Benefits of Risk Analysis

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Sterile Drugs The Benefits of Risk Analysis

• Richard L. Friedman, M.S.
• Center for Drug Evaluation Research
• Office of Compliance

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TOPICS

• Risk Analysis
• Revision of Guidance entitled Sterile Drug
  Products Produced by Aseptic Processing
• Advisory Committee and PQRI Workgroup
• Risk-based Approaches
• Latitude Innovation
• Current Sterile Drug Issues
• Case studies, Modernization

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Risk

• With few exceptions, formal, systematic
  approaches are just beginning to be routinely
  used in manufacturing context
• Most risk methods share these similarities
• Estimation of Severity of Risk and Probability of
  Risk
• Work best when good quality information is
  available, and it is assessed in
  multi-disciplinary, science-based, practical
  manner
• Great advancement for an Agency and Industry
  making difficult public health decisions often
  characterized by complexity and uncertainty

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Risk

• Risk Analysis Output An Estimate
• Objective/Subjective Aspects
• Oversold?
• No. Risk Analysis is invaluable.
• Even if it can be considered a process that
  becomes more semiquantitative as the system under
  study becomes more complex, good risk analysis
  still clarifies the picture and promotes
  development of sound rationales.
• The value of risk analysis is the systematic
  approach to evaluation of
• a facility and its overall operation
• a process
• a method
• etc.

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Risk
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Clinical Effects of Drug Contamination

• The most serious outbreaks of infection have
  often occurred when contaminated products are
  injected into bloodstream of patients whose
  immunity is already compromised by their
  underlying disease or therapy.
• Disinfection, Sterilization, and
  Preservation, Ed. by S. Block, 2001
• Aging of our population and increasingly
  aggressive medical and surgical interventions,
  including implanted foreign bodies, organ
  transplantations, and xenotransplantation, create
  a cohort of particularly susceptible persons.
• Weinstein, Robert A., Nosocomial Infection
  Update, Emerging Infectious Diseases, CDC,
  1998(4)3. Nosocomial Infection Update

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Intended UseMight drug be used in patient
populations that are compromised?

• Some Higher Risk Hosts include
• Elderly
• Very Young
• Pregnant
• Shock or Trauma
• Immunocompromised
• Chronic Disease

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Ophthalmic Infections

• Pseudomonas aeruginosa, the notorious
  contaminant of eyedrops has caused serious
  ophthalmic infections, including loss of sight in
  some cases. The problem is compounded when the
  eye is damaged after trauma or ophthalmic
  surgery.
• In Sweden an outbreak where a hydrocortisone
  eye ointment caused eight cases of P. aeruginosa
  infection, resulting in impaired vision in five
  of the patients and necessitating enucleation of
  the eye in one.
• Ointment contained from 20 to 2000
  microorganisms/g
• Disinfection, Sterilization, and Preservation,
  Ed. by S. Block, 2001

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Pathogenic

• Acutely pathogenic
• Opportunistically pathogenic
• virulence of the microbe, and host susceptibility
  influence pathogenesis

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Why Processes Must be Designed to Prevent
Contamination (21 CFR 211.113)

• The infection dose of microorganisms is not only
  largely unknown but variable
• ...furthermore, it varies not only between and
  within species but between individual patients.
• The symptoms and outcome of medicament-borne
  infection may be diverse.
• Clinical reactions may range from local
  infection of wounds or broken skin after contact
  with a contaminated cream, to serious systemic
  infection such as bacteremia or septicemia from
  contaminated parenteral products.
• Disinfection, Sterilization, and
  Preservation, Ed. by S. Block, 2001

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Microbiological Adaptability and Survivability

• Apollo 12
• Camera retrieved from moon landing over 2.5 years
  earlier. Was found to contain bacteria, IDd by
  CDC as Streptococcus mitis. Had withstood the
  intense radiation, desiccation, and cold of
  space.
• Bottle of Beer rescued from 1825 shipwreck opened
  under sterile conditions
• Living yeast cells recovered
• 50,000 bottles of beer were then sold using that
  yeast
• Disinfection,
  Sterilization, and Preservation, Ed. by S. Block,
  2001

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Importance of Validation and Control

• End product microbiological testing, while
  providing some information should not be relied
  upon as the sole justification for the release of
  the drug product. The limitations of
  microbiological sampling and testing should be
  recognized.
• High Purity Water
  Systems Inspection Guide, FDA, 1993

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21 CFR 211.113

Sec. 211.113 Control of microbiological
contamination.   (a) Appropriate written
procedures, designed to prevent objectionable
microorganisms in drug products not required to
be sterile, shall be established and followed.
(b) Appropriate written procedures, designed to
prevent microbiological contamination of drug
products purporting to be sterile, shall be
established and followed. Such procedures shall
include validation of any sterilization process.
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Aseptic Processing Line

• Process
• personnel flow
• material flow
• layout

Facility Room
Personnel
HVAC/ Utilities
Daily Sterility Assurance
Media Fills
QA/QC
Deviations Environmental Control Trends
Disinfection Practices

• Includes both design and maintenance

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Aseptic Processing Guidance Revision
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Updating the Aseptic Processing Guidance

• CDER/CBER/ORA Concept Paper issued
• posted at www.fda.gov/cder/dmpq on 9/27/02
• unprecedented preview of GMP thinking before
  publishing a draft guidance
• Advisory Committee Meeting - Oct. 22, 2002
• significant input provided
• revisions made based on input from meeting

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Updating the Aseptic Processing Guidance

• PQRI Aseptic Processing Working Group
• revised following final PQRI recommendations
  received on 3/19/03
• Advisory Committee Meeting - May 19, 2003
• Updated manufacturing subcommittee on PQRI
  process and conclusions
• Regulatory/Policy Review
• Draft for Public Comment - Sept 3, 2003
• http//www.fda.gov/cder/guidance/1874dft.htm
• Review and assess comments
• Final Guidance

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Updating the Aseptic Processing Guidance

• Innovation
• Draft Guidance acknowledges process improvement
  and risk mitigation through use of
• Modern facility/equipment design
• Well-conceived (e.g., airlocks, appropriate
  ergonomics/layout)
• Automation
• Other Technological advancements Including
  reduction of direct personnel involvement in
  aseptic operations via isolation technology and
  barrier concepts
• Latitude
• Liberalizing some old standards
• e.g., velocity (FPM) BFS microbial air quality
  stressed

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Updating the Aseptic Processing Guidance

• Advantages to those
• Enhancing product protection and safety, through
  use of automation and aseptic process
  barrier/isolation concepts, as well as other
  beneficial innovations
• Following sound CGMP operating procedures
  defining good process metrics
• Predictability and Consistency
• Quality/Business Synergies

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Updating the Aseptic Processing Guidance

• Persistent CGMP issues can be resolved and
  averted
• proactive prevention of hazards
• Risk-Based CGMP Guidance
• Contaminated drug poses an unacceptable risk to a
  patient
• Sterile drugs are top priority of our risk-based
  inspection program
• Risk-based approaches in guidance
• e.g., environmental monitoring, design, media
  fills, personnel

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Sterile Drug Risk Analysis by FMEA

• Reducing Risk Severity Factor
• Process changes or product redesign including
  development of an aseptically produced product
  into one with terminal sterilization
• Reducing Probability of Occurrence of Risk
• Process automation projects, tighter controls
  upstream in the process, and new technologies
  such as isolators
• Probability of Detecting Failures
• Validation is intensified monitoring which
  should detect flaws or weaknesses, which may not
  be normally observable. A media fill is a good
  example of a validation test.
• Noble, P., PDA Journal of Pharmaceutical
  Science and Technology, July/August 2001.

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Whats New?
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Draft Guidance for Public Comment

• Format Improved
• More user friendly
• Table of Contents, Headings
• Easier to read and follow
• New Definitions Added
• air lock, components, colony forming unit,
  dynamic, endotoxin, gowning qualification,
  barrier, isolator, etc.
• Old Sections
• Updated old sections (e.g., sterilization)
• New Sections
• e.g., personnel, isolators, early processing

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Draft Guidance for Public CommentLimits vs.
Levels

• Action Limits
• Action Levels

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Draft Guidance for Public Comment Isolators

• A well-designed positive pressure isolator,
  supported by adequate procedures for its
  maintenance, monitoring, and control, offers
  tangible advantages over classical aseptic
  processing, including fewer opportunities for
  microbial contamination during processing.

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Draft Guidance for Public Comment Material Flow

• It is critical to adequately control material
  (e.g., in-process supplies, equipment, utensils)
  as it
• transfers from lesser to higher controlled clean
  areas to prevent the influx of contaminants. For
  example, written procedures should address how
  materials should be introduced into the aseptic
  processing room to ensure that room conditions
  are not compromised. In this regard, materials
  should be disinfected in accord with appropriate
  procedures.

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Draft Guidance for Public Comment Alternate Test
Methods

• New Section entitled Alternate Microbiological
  Test Methods
• Only new section added since Concept Paper
• States that Other suitable microbiological test
  methods (e.g., rapid test methods) can be
  considered for in-process control testing and
  finished product release testing.
• Recommends tests demonstrating increased
  accuracy, sensitivity, and reproducibility
• Investigations Nucleic acid-based methods
  recommended for microbial ID purposes.

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Draft Guidance for Public Comment Airflow

• Turbulent?
• Unidirectional?
• Laminar?
• Unidirectional replaces Laminar flow
• Acceptable uses of turbulent flow now discussed
  in Isolator section

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PQRI Survey on Media Fills Percentage of Media
Fills with Contamination (total of 606 Media
Fills)
9 Contaminated
91 No Contamination
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PQRI Recommendation on EM

• The document should be standardized to the ISO
  designations.
• The air classification table should only use
  metric units for the microbial action levels.
• Replace the term limits in the table with
  Action Levels.
• Add Microbial Settling Plates to Harmonize with
  EU Annex
• Remedial action when exceeding actions levels in
  all room classes should be taken based on
  unfavorable (intra and inter day) trends as
  opposed to individual data point excursions. A
  Class 100 action level may not require a
  corrective action after review of EM trend data
  for the area.

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PQRI Recommendation on EM
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Current IssuesCase Studies and Modernization
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1 Media Fill FailureControl of the Critical
(Class 100) Environment

• Media Fill Failures Same recurring fungal
  isolate common to each of them
• EM systems did not recover this particular
  microbe before the initial media fill failure
• Subsequent investigation and extended sampling
  plan identified many instances of this
  microorganism on multiple locations of the
  aseptic processing equipment.
• Investigation traced media fill contamination to
  the failure to adequately clean/sanitize aseptic
  filling line equipment. 

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2 Media Fill Inspection Inspection Reliability
/ Inadequate Investigation

• Data did not support the acceptability of Media
  Fill Lot ----. Initial examination of vials at
  end of incubation period found 4 contaminated
  vials out of the 7,800 incubated. Ten days
  later, 600 vials from this media fill were
  re-inspected. A fifth contaminated vial was
  found. All five vials had same isolate,
  Micrococcus luteus.
• No explanation why all contaminated vials were
  not removed during first inspection or why the
  remainder of the lot (the remaining approx. 7200
  vials) was not re-inspected to determine if
  additional contaminated vials were present.
  Quality and Production units did not investigate
  the fifth positive vial and concluded that the
  media fill was acceptable.

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Modernization Laboratory Tests (TGA on Sterility
Testing)

• If contamination is to be unequivocally ascribed
  to adventitious source and a sterility test
  invalidated
• It is necessary to employ sensitive typing
  techniques to demonstrate that a microorganism
  isolated from the product test is identical to a
  microorganism isolated from the materials and/or
  the environment. While routine biochemical/phenoty
  pical identification techniques can demonstrate
  that two isolates are not identical these methods
  are not sufficiently sensitive or reliable enough
  to provide unequivocal evidence that two isolates
  are from the same source.
• Suitably sensitive tests (for example, molecular
  typing with RNA/DNA homology) are those accepted
  by microbiologists conducting epidemiological
  studies to determine that microorganisms are
  clonally related and have a common origin.
  Repeat testing based on the biochemical or
  phenotypical characterisation of environmental
  and/or product isolates should not be permitted.
  
• TGA Guidelines for Sterility Testing for
  Therapeutic Goods, 2002

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Modernization Contaminated Media Fill Units are
Missed

• Study Visual Examination vs. Automated Method
• Automatic inspection of media fill using laser
  technology
• Microorganisms
• Staphylococcus aureus ATCC 6538
• Micrococcus luteus ATCC
• Aspergillus niger ATCC 16404
• Automated inspection sorts into two types
• Units without growth
• Units with possible growth only this subset is
  manually inspected by microbiology lab
• False acceptance (during manual inspection) of
  positive units was demonstrated in the study
• Christensen, A., PDA Annual Meeting, 1999,
  Washington, DC

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Modernization Study on Media Fill Examination
Accuracy
Note First percentage is Manual Detection
Second percentage is Automated Detection Conventi
onal manual inspection did not detect any of the
units inoculated with this microbe.
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Summary

• Weve been listening
• Pharmaceutical CGMPs in the 21st Century
• Latitude, Innovation, Risk-based Approaches
• Automation and Product Protection
• e.g., Isolator Technology
• Revised Guidance Reflects Uniformity Between
• Drug and Biologic Centers (CDER and CBER)
• ORA (co-sponsoring document)
• Will Promote Inspectional uniformity

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References

• CGMPs in 21st Century (Aug., 2002) and FDA
  Strategic Plan (Aug., 2003) Commissioners link
  at www.fda.gov
• Disinfection, Sterilization and Preservation, 5th
  Edition, 2001, edited by Seymour Block
• Claycamp, H.G., A Perspective on Risk Analysis
  for the GMP Initiative, April, 2003, PQRI
  Workshop - A Drug Quality System for the 21st
  Century
• Weinstein, Robert A., Nosocomial Infection
  Update, Emerging Infectious Diseases, Center for
  Disease Control 1998(4)3.
• Sundlof, S., FDA Science Forum, April 2003

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For More CGMP Information...

• Center for Drug Evaluation Research,
• Office of Compliance
• Division of Manufacturing Product Quality
  (HFD-320)
• Friedmanr_at_cder.fda.gov 301-827-9042
• Uratanib_at_cder.fda.gov 301-827-9024
• Melendeze_at_cder.fda.gov 301-827-9006
• Hirshfieldk_at_cder.fda.gov 301-827-9029