PAT Subcommittee Closing Report 12 March 2003

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PAT SubcommitteeClosing Report12 March 2003

• Tom Layloff
• Acting Chair

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50 mg API in a 275 mg IR Tablet
Component Wt per Tab (mg) Weight for 1 Million Tab
Active 50 18 50 kg 5g 1 pp 10,000
Diluent(s) 200 72 200 kg 200 g 1 ppt
Disintegrant 25 9 25 kg 25 g 1 ppt
Lubricant 0.3 0.1 300 g 0.3 g 1 ppt

•    

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Currently the API Serves As the Process Quality
Surrogate Marker

• Uni-variate handle on a poly-variate process
• Focus on API with little regard for excipients
  and process
• Poor surrogate marker for many components and the
  process

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PAT

• Optimal applications of process analytical
  chemistry tools,
• feedback process control strategies,
• information management tools and/or
• product/process optimization strategies to the
  manufacture of pharmaceuticals

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• 1978 21 CFR 210, 211 Preamble
• There is no prohibition in the regulations
  against the manufacturing of drug products
• using better, more efficient, and innovative
  methods.
• USP
• Compliance may be determined also by the use of
  
• alternative methods, chosen for advantages in
  accuracy, sensitivity, precision, selectivity, or
  adaptability to automation or computerized data
  reduction or in other special circumstances.

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Charges to the Process Analysis Technology (PAT)
Sub-Committee

• What is to be gained by embracing the technology?
• What is the state-of-the-art?
• What are the problems, hurdles, and solutions?
• How should the new technologies be regulated?
• How should FDA be prepared to adapt to dealing
  with the new technologies?
• What are the staff educational issues and how
  should competencies be assessed?

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PAT Subcommittee Meetings

• 25-26 February
• Applications and Benefits,
• Process and Analytical Validation, and
• Chemometrics.
• 12-13 June
• Product-Process-Development,
• Process and Analytical Validation, and
• Proposed PAT Training and Certification Program
• 23 October
• Computer systems validation--21 CFR 11 PAT
  issues,
• PAT case study, and
• Rapid microbiology testing.

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How?

• General guidance
• Conceptual framework
• Regulatory position, process and incentives
• PATRIOT
• Science and risk based approaches
• Integrated systems approach

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Proposed/Draft
NOT An NIR Guidance!
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Tools?

• The Assessment Tools, Data Support Systems And
  Technologies Are Available
• To
• Improve Product Consistency
• And
• Reduce Bad Production And Recalls

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USP Content Uniformity Test Issues USP Content Uniformity Test Issues USP Content Uniformity Test Issues
of tablets with drug content outside of of tablets with drug content outside of
RSD 75 - 125 85 -115
6.0 30 12,419
7.0 360 32,124
7.8 1,350 54,470
Assumptions One Million Tablet Batch, Normal Distribution, Mean 100, RSD Relative Standard Deviation. USP Limit for compliance NMT 1/30 Assumptions One Million Tablet Batch, Normal Distribution, Mean 100, RSD Relative Standard Deviation. USP Limit for compliance NMT 1/30 Assumptions One Million Tablet Batch, Normal Distribution, Mean 100, RSD Relative Standard Deviation. USP Limit for compliance NMT 1/30
Stella Machado, Ph.D., Meiyu Shen, Ph.D., Charles Anello, Sc.D., CDER/FDA Stella Machado, Ph.D., Meiyu Shen, Ph.D., Charles Anello, Sc.D., CDER/FDA Stella Machado, Ph.D., Meiyu Shen, Ph.D., Charles Anello, Sc.D., CDER/FDA
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Agencys Perspectives

• Use existing knowledge, experience, and guidances
  from other FDA components, NIST, ASTM, ANSI, etc.
• Design Control Guidance for Medical Device
  Manufacturers March 11, 1997
• Provide framework to manufacturers with
  flexibility needed to develop design controls to
  comply with regulations, and also appropriate for
  their own design and development of processes and
  Standard Operating Procedures (SOPs).

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Future Issues

• Validation Data and Retention
• In-Process End-Point Detection and Data
  Acquisition and Storage.
• Documentation and E-Sig Closure of Decision
  Points
• Incoming Material Stream Consistency Robustness
  Assessments

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Regulatory Incentives

• Not a requirement
• Regulatory support and flexibility during
  development implementation
• Eliminate the fear of delayed approval
• Dispute avoidance/resolution
• Science Risk based regulatory approach
• Low risk categorization based on a higher level
  of process understanding
• Research exemption
• Continuous improvement without the fear of being
  considered non-compliant

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Whats Missing?

• Industry Political Will
• FDA Is/Has Been Encouraging

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How To Move Forward.Dont Try to Eat the
Elephant in One Bite.Evolution not Revolution.

• Bring on Stream Validated PAT Systems Piecemeal.
• Incoming materials id, moisture, particle size,
  etc., are straightforward.
• In process moisture assessments.
• Blender consistency assessments.

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Acknowledgements FDA CDER Ajaz Hussain,
Rajendra Uppoor, Colleagues at the DPA,
DPQRColleagues On, and Presenters To the
Process Analytical Technology Sub-Committee

• Compilation of Reports and Activities
  http//www.fda.gov/cder/OPS/PAT.htm
• Comments, suggestions, etc. to
• PAT_at_cder.fda.gov