Analytical requirements of Clinical Trial Materials

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Analytical requirements of Clinical Trial
Materials
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Topics

• Setting Specifications for
• Clinical materials
• Cleaning Validations
• Method Transfer

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International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH) Reference
documents

• Recommendations concerning test procedures,
  setting and justification of acceptance criteria
  for new active pharmaceutical ingredients (API)
  and the new drug products produced from them
• Q6A Specifications Test Procedures and
  Acceptance Criteria for New Drug Substances and
  New Drug Products
• Q3A Impurities in New Drug Substances
• Q3B Impurities in New Drug Products
• Q3C Impurities Residual Solvents
• Q6B Specifications Test Procedures and
  Acceptance Criteria for Biotechnological/Biologica
  l Products
• Q5A Quality of Biotechnological/Biological
  Products Viral Safety Evaluation of
  Biotechnology Products Derived from Cell Lines of
  Human or Animal Origin
• Q5D Quality of Biotechnological/Biological
  Products Derivation and Characterization of Cell
  Substrates Used for Production of
  Biotechnological/Biological Products

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Specification

• Consists of
• List of tests
• References to analytical procedures
• Acceptance criteria

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Types of Specifications

• Compendial (USP, EP, JP)
• if harmonized this will be stated
• if not, expert review of all applicable compendia
  to ensure appropriate tests and specifications
  are met
• In process controls (IPC)
• Intended for process parameter adjustment
• If same or similar to release specification, IPC
  can also be used for release, however, approach
  must be validated

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Types of Specifications (contd)

• Release
• Tests and criteria to establish batch disposition
• Must stipulate tests that are not required to be
  performed for every lot (skip lot)
• Shelf life or stability
• Allow for loss of parent within range to maintain
  potency
• Allow for growth of degradation products below
  limits established as safe based on toxicological
  data
• Establish expiry
• Differences between API and Drug Product
• Typically not necessary to monitor the product
  for synthetic related substances that are already
  controlled in the release of the API unless also
  shown to be potential degradation products

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Setting Specifications

• Purpose Confirm the quality of the drug
  substance and drug product rather than to
  establish full characterization
• Focus on characteristics that will ensure
  acceptable for intended use
• Safety
• Purity
• Potency
• Effectiveness

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Setting Specifications

• Justification for Each Test
• Why included (or excluded)
• Rationale for associated criterion
• Supporting development data
• Pharmacopeial standards
• Clinical and toxicological data
• Accelerated and long term stability data

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Development is all about Change!

• Experience accumulated during the development
  forms the basis for the setting of specifications
  
• Specifications can be either tightened or
  loosened
• Possible to propose excluding or replacing
  certain tests
• N1 is not a pattern for batch manufacture
• Again - safety, potency, purity and efficacy are
  the focus
• Specs can change beyond registration based on
  experience
• Modifications to specifications after approval of
  the application may need prior approval of the
  regulatory authority

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Tests

• Universal
• Generally applicable to ALL new APIs and Drug
  Products
• Specific
• Designed for the specific API or Drug Product
• Considered on a case by case basis as they are
  demonstrated to impact batch quality of either
  API or Drug Product
• Not an exhaustive list

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Universal Tests

• Generally applicable to ALL new API and Drug
  Product
• Description (visual appearance)
• Identification
• Assay
• Impurities

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Specific Tests API

• Physicochemical properties (i.e.. pH of aqueous
  solution, melting point)
• Particle Size
• Polymorphism (i.e. PXRD, DSC, TGA, IR . . . )
• Enantiomeric Purity
• Water Content
• Inorganic Impurities
• Microbial Limits

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Specific Tests Drug Product

• Solids Tablets, Hard Shell Capsules, Soft Shell
  Capsules and Granules
• Oral Liquids
• Parenterals
• Inhalation

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Specific Tests Solids

• Dissolution
• Disintegration
• Hardness/Friability
• Uniformity
• Water Content
• Microbial Limits

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Specific Tests Oral Liquids

• Uniformity of Dosage Units
• pH
• Microbial Limits
• Antimicrobial Preservative Content
• Antioxidant Preservative Content
• Extractables
• Alcohol Content
• Dissolution
• Particle Size Distribution
• Redispersibility (for suspensions that settle on
  storage)
• Reconstitution Time (for suspensions that require
  reconstitution)
• Water Content (for products requiring
  reconstitution)
• Total Delivered Volume

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Specific Tests Parenterals

• Uniformity of Dosage Units
• pH
• Sterility
• Endotoxins/Pyrogens
• Particulate Matter
• Water Content (for non-aqueous parenterals)
• Antimicrobial Preservative Content
• Extractables
• Functionality of Delivery Systems
• Osmolality
• Particle size distribution (injectable
  suspensions)
• Redispersibility (for parenterals that settle on
  storage)
• Reconstitution Time (for parenterals that require
  reconstitution)

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Specific Tests Inhalation

• Particle Size Distribution
• Respirable Fraction
• Delivered Dose
• Total Doses
• Plume Geometry
• Loss of Priming
• Redispersibility (for suspensions that settle on
  storage)

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Biologics Proteins and Polypeptides

• Similar principles and tests to synthetic
  molecules
• Additionally
• Need to assess physicochemical properties
  including primary and higher order structural
  conformations as they pertain to biological
  activity
• Biological Activity
• Animal based
• Cell culture based
• Biochemical assay
• Ligand or receptor binding
• Biophysical conformation
• Immunological Properties when antibody is desired
  product
• Cell or cell based contaminants

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A Few More Items

• When should specifications be reviewed for
  potential modifications
• Synthetic route
• Formulation
• Change to manufacturing process or site
• Review of IPC and release trends
• Stability findings
• Selection of API batches for use in toxicology
  studies
• Combination device/drug products eg. Drug coated
  stents
• Experts from both device and drug side to
  contribute to the design as well as establishment
  of specifications

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Comparator Products

• Innovator product to be used in clinical trial to
  compare performance against experimental

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Consider Degree of Product Manipulation

• Category 1 Use of innovator product in
  innovator package (open label study)
• Category 2 Innovator repackaged
• Category 3 Overencapsulation of innovator
• Category 4 Overcoating of innovator
• Category 5 Grind innovator and fill/compression

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Method Considerations

• Compendial methods are considered validated.
• Unless specified, compendial methods are not
  stability indicating.
• Compendial methods available
• Utilize compendial methods
• Evaluate whether assay is stability indicating
• If yes, document evidence and use
• If no, develop stability indicating assay method
  then validate
• Compendial methods not available
• Develop and validate stability indicating assay
  and dissolution methods
• Use a validated, stability indicating assay and
  dissolution methods for the generic product of
  same active and similar strength.

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Specification Approaches

• If a pharmacopoeial monograph for the innovator
  product is available, the specification stated in
  the pharmacopoeia should be applied to the
  modified innovator product unless it is
  demonstrated that this is not feasible.
• If a pharmacopoeial monograph for the innovator
  product is not available, use FOI, and develop
  specifications and/or Alert Limits for modified
  innovator product

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Other Specification Considerations

• IdentificationTest - Use a visual test, if
  possible. Shape and logo Color of the product
  color and consistency of the contents
• Assay 90.0 - 110.0 or range specified in the
  pharmacopoeia
• Related Substances
• Compare differences in the impurity profile of
  modified vs reference product of the same lot
  stored identically

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Cleaning Verification Considerations

• Methods
• Non-selective
• Examples total organic carbon (TOC), pH
• Advantages speed of analysis
• Disadvantages Non-conforming results difficult
  to investigate
• Selective
• Examples HPLC, IMS
• Advantages Direct correlation to presence or
  absence of specific active
• Disadvantages speed of analysis
• Development/Validation
• Method development using coupons representative
  of each contact surface
• Demonstrate at least 70 recovery of the limit
  concentration from each surface

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Setting Cleaning Verification Specifications

• Consideration of potency, toxicity (NOEL or
  NOAEL) and exposed equipment surface
• Many ways to calculate
• 1/1000 of either the NOEL or the lowest strength
  allowed to carry over into a single unit of a
  worst case follow on batch, whichever is more
  restrictive

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Method Transfer Considerations

• Approaches
• Comparison testing
• Perform experiment on authentic lots
• Variability of batch may obscure actually method
  performance
• Mini-Validation
• Spiked placebo recovery
• Variability associated with batch can be divorced
  from method perfomance
• Recommended Approach
• Spiked recovery (n6) demonstrating method
  performance independent of batch variability
• Analysis of well characterized lot (n6)
  demonstrating suitability of method for authentic
  material

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Method Transfer Setting Specifications

• For validation like exercises use the same
  criteria as outlined in the validation protocol
  for the method
• For comparison samples, must take into
  consideration the variability of the method plus
  the variability of the batch itself in order as
  well as the criteria established for release of
  the material

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Summary

• Specifications
• When setting specifications consider
• Intended purpose (Phase of development)
• Supportive development data
• Safety, Purity, Potency, Efficacy
• Cleaning Verification
• Selective methods provide greater visibility for
  cleaning verification
• Method Transfer
• Dont confuse batch variability with method
  variability

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Thank you