Process Analytical Technologies

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Process Analytical Technologies
February 2002 FDA Subcommittee Meeting

• Process and Method
• Validation

Leon Lachman, Ph.D. President Lachman Consultant
Services, Inc.
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Validation

• Establishing documented evidence which provides
  a high degree of assurance that a specific
  process will consistently produce a product
  meeting its pre-determined specifications and
  quality attributes.

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Qualification / Validation of Pharmaceutical
Processes

• IQ and OQ and Calibrations need to be performed
  prior to use of equipment for process validation.

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European Agency Guidance for Process Validation

• Validation is the act of demonstrating and
  documenting that a procedure operates
  effectively.
• Process validation is the means of ensuring and
  providing documentary evidence that processes
  (within their specified design parameters) are
  capable of consistently producing a finished
  product of the required quality.

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European Agency Guidance for Process Validation

• Change Control Clearly defined procedures are
  needed to control changes proposed in production
  processes. Such procedures should tightly
  control planned changes, ensure that sufficient
  supporting data are generated to demonstrate that
  the revised process will result in a product of
  the desired quality, consistent with the
  approved specification and ensure that all
  aspects are thoroughly documented and approved.

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Representative Dosage Forms

• Solids Tablets Capsules
• Liquids Solution
• Suspensions
• Emulsions
• Lyophilized
• Ointments / Creams

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Solids Tablets Capsules

• Size Reduction
• Blending
• Granulating

• Compressing
• Encapsulation
• Coating

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Powder Blending Operation

• Equipment Blender geometry use of intensifier
  bars operating principle size recommended
  powder capacity for efficient blending
• Blend Order of addition of ingredients volume
• Parameters RPMs time
• Homogeneity Blender post-discharge
  post-storage sampling (number location size)

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Liquids - Solution

• Solution Studies of
  
  Ingredients
• Fill Uniformity
• Filter Compatibility
• Product Tubing Interaction
• Flush Volumes

• Cleaning / Sanitization
• Inert Gas Effectiveness
• Bioburden
• Pyroburden

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Suspensions

• Milling
• Mixing
• Viscosity
• Resuspendability
• Agglomeration
• Caking

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Emulsions

• Homogenation / Emulsification
• Viscosity
• Creaming
• Reemulsify
• Coalesce
• Globule Growth

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Lyophilized

• Freezing
• Temperature
• Rate
• Drying
• Temperature
• Vacuum

• Cake Appearance
• Dissolution
• Melt Back

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Ointments / Creams

• Active Distribution
• Particle Size
• Mixing
• Emulsification
• Viscosity

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Method Validation

• Method validation is the process of demonstrating
  that analytical procedures are suitable for their
  intended use and that they support the identity,
  strength, quality, purity and potency of the drug
  substances and drug products.

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Method Validation

• Published Guidances
• ICH-Q2A Text on Validation of Analytical
  Procedure(1994)
• ICH-Q2B Validation on Analytical Procedures
  Methodology (1995)
• CDER Reviewer Guidance Validation of
  Chromatographic Method (1994)
• CDER Submitting Samples and Analytical Data for
  Method Validations (1987)
• CDER Draft Analytical Procedures and Method
  Validation (2000)
• CDER Bioanalytical Method Validation for Human
  Studies (1999)
• USPlt1225gt Validation of Compendial Methods
  (current revision)

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ICH Topic Q2BValidation of Analytical Procedures

• The main objective of validation of an analytical
  procedure is to demonstrate that the procedure is
  suitable for its intended purpose.
• In practice, it is usually possible to design the
  experimental work so that appropriate validation
  characteristics can be considered simultaneously
  to provide a sound, overall knowledge of the
  capabilities of the analytical procedure, for
  instance specificity, linearity, range, accuracy
  and precision.
• Well-characterized reference materials, with
  documented purity, should be used throughout the
  validation study.

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Considerations Prior to Method Validation

• Suitability of Instrument
• Status of Qualification and Calibration
• Suitability of Materials
• Status of Reference Standards, Reagents, Placebo
  Lots
• Suitability of Analyst
• Status of Training and Qualification Records
• Suitability of Documentation
• Written analytical procedure and proper approved
  protocol with pre-established acceptance criteria

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Examples of Methods That Require Validation
Documentation

• Chromatographic Methods HPLC, GC, TLC, GC/MS,
  etc.
• Pharmaceutical Analysis In support of CMC.
• Bioanalytical Analysis In support of
  PK/PD/Clinical Studies.
• Spectrophotometric Methods UV-VIS, IR, NIR, AA,
  NMR, XRD, MS, etc.
• Capillary Electrophoresis Methods Zone,
  Isoelectric Focusing, Isotachophoresis, etc.
• Particle Sizer Analysis Methods Laser,
  Microscopic, Photozone, Sieving, SEC, etc.
• Dissolution Methods Method of Analysis HPLC,
  UV, Automated, etc.
• Titration Methods.
• Automated Analytical Methods Robots, Automated
  Analysis.

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Method Characteristics to Be Considered for
Validation

• Specificity (Selectivity)
• Linearity
• Range
• Accuracy
• Precision
• Repeatability
• Intermediate Precision
• Reproducibility (Ruggedness)

• Detection Limit
• Quantitation Limit
• Robustness
• System Suitability Testing

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Specificity

• Specificity is the ability to assess
  unequivocally the analyte in the presence of
  components which may be expected to be present.
  Typically these might include impurities,
  degradants, matrix, etc.

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Specificity

• It is not always possible to demonstrate that an
  analytical procedure is specific for a particular
  analyte (complete discrimination). In this case
  a combination of two or more analytical
  procedures is recommended to achieve the
  necessary level of discrimination.

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Linearity

• The linearity of an analytical procedure is its
  ability (within a given range) to obtain test
  results which are directly proportional to the
  concentration (amount) of analyte in the sample.

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Range

• The range of an analytical procedure is the
  interval between the upper and lower
  concentration (amounts) of analyte in the sample
  for which it has been demonstrated that the
  analytical procedure has a suitable level of
  precision, accuracy and linearity.

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Accuracy

• The accuracy of an analytical procedure expresses
  the closeness of agreement between the value
  which is accepted either as a conventional true
  value or an accepted reference value and the
  value found.

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Precision

• Repeatability expresses the precision under the
  same operating conditions over a short interval
  of time. Repeatability is also termed
  intra-assay precision.
• Intermediate Precision expresses
  within-laboratories variations different days,
  different analysts, different equipment, etc.
• Reproducibility expresses the precision between
  laboratories (collaborative studies, usually
  applied to standardization of methodology).

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Detection Limit

• The detection limit of an individual analytical
  procedure is the lowest amount of analyte in a
  sample which can be detected but not necessarily
  quantitated as an exact value.

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Quantitation Limit

• The quantitation limit of an individual
  analytical procedure is the lowest amount of
  analyte in a sample which can be quantitatively
  determined with suitable precision and accuracy.
  The quantitation limit is a parameter of
  quantitative assays for low levels of compounds
  in sample matrices, and is used particularly for
  the determination of impurities and/or
  degradation products.

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Impurities (Quantitation)

• Accuracy should be assessed on samples (substance
  / product) spiked with known amounts of
  impurities.

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Robustness

• The robustness of an analytical procedure is a
  measure of its capacity to remain unaffected by
  small, but deliberate variations in method
  parameters and provides an indication of its
  reliability during normal usage.

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System Suitability Testing

• System suitability testing is an integral part of
  many analytical procedures. The tests are based
  on the concept that the equipment, electronics,
  analytical operations and samples to be analyzed
  constitute an integral system that can be
  evaluated as such. System suitability test
  parameters to be established for a particular
  procedure depend on the type of procedure being
  validated.

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Regulatory Approaches

• Compendial Analytical Procedures
• Noncompendial Analytical Procedures and
  Validation Requirements

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Compendial Analytical Procedures

• The Analytical procedures in the USP 25/NF 20 are
  legally recognized under section 501(b) of the
  Federal Food, Drug and Cosmetic Act as the
  regulatory analytical procedures for the
  compendial items. The suitability of these
  procedures must be verified under actual
  conditions of use. When using USP 25/NF 20
  analytical procedures, the guidance recommends
  that information be provided for the following
  characteristics
• Specificity of the procedure
• Stability of the sample solution
• Intermediate precision

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Compendial Analytical Procedures

• Compendial analytical procedures may not be
  stability indicating, and this concern must be
  addressed when developing a drug product
  specification because formulation-based
  interference may not be considered in the
  monograph specifications.

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Appropriate Automation Can.

• Reduce variability associated with human
  interaction
• Increase knowledge of process
• Improve monitoring, control and decisions

• Improve process and product consistency
• Improve documentation reporting capabilities
• Reduce costs

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AdvantagesProcess Validation

• Expanded real time monitoring and adjustment of
  process
• Enhanced ability to statistically evaluate
  process performance and product variables
• e.g., individuals mean range control limits
• Enhanced data and evaluation capabilities and
  increased confidence about process
  reproducibility and product quality
• Improved ability to set target parameters and
  control limits for routine production,
  correlating with validation results
• Enhanced reporting capability

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Consequences of Inadequate Automation

• Acquired data may not be complete, accurate
  and/or representative
• Improper evaluation
• Process assurance and adjustments based on
  inadequate information
• Process deviations

• Product quality problems
• Avoidable costs
• downtime
• rejection of in-process and finished product
• product recalls
• eroded goodwill

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Calibration and Maintenance

• Sensors must be calibrated
• e.g., time temperature pressure wattage
  humidity weight force dimensions
• Controllers must be qualified, calibrated and
  maintained at appropriate intervals
• Environmental requirements for the computerized
  system must be defined, maintained and documented

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Compliance Issuesautomated equipment

• System for reporting and evaluating deviations
• hardware
• software
• security
• life cycle management
• Equipment Maintenance
• Calibration
• Target and Control Limits
• versus validated parameters
• versus historical process performance

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Compliance Issuesautomated equipment(continued)

• Operating Environment
• defined controlled documented
• In-Process Control Datause and retention
• SOPs and Training
• Data Integrity
• Legacy Systems

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Closed System Controls

• Validation
• Electronic and Human readable formats
• Protection to ensure accurate and ready retrieval
• Authorized access only

• Audit trails
• Device checks to determine validity of input
• Operational system checks, as appropriate

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Closed System Controls(continued)

• Written policies procedures
• Controls over system documentation
• Operational system checks, as appropriate
• Controls over access to system operation and
  maintenance

• Revision and change control procedures
• Documented evolution of changes
• Qualified personnel