Functionalityrelated Characteristics

1
Functionality-related Characteristics

• R. Christian Moreton, Ph.D.
• Immediate Past Chair, IPEC-Americas
• IPEC-Americas 15th Anniversary Conference
• Orlando, FL, January 26 27, 2006

2
Presentation Outline

• TriPECs Position
• TriPECs concerns
• The European Pharmacopoeia statement
• Background
• The Objective
• Pharmcopeia Mission Statements
• Definitions
• TriPECs Thinking
• Identifying the Problem
• Key questions
• Answers with examples
• Conclusions

3
TriPECs Position

• Functionality-related characteristics (FRCs) do
  not belong in pharmacopeia monographs, even in a
  non-mandatory Labeling Section.
• The pharmacopeias can provide harmonized methods
  as General Information Chapters.
• There should be a harmonized General Information
  Chapter on how to assess the FRCs for a
  particular application.
• Certain tests, particularly those relating to
  identity and/or safety should remain in the body
  of the monograph.
• The adopted policy should be harmonized within
  the three pharmacopeias (Ph Eur, JP and USP).

4
2. TriPECs Concerns
5
The European Pharmacopoeia Statement

• The following tests are not mandatory
  requirements, but in view of their importance for
  achieving consistency in manufacture, quality and
  performance of medicinal products, it is
  recommended that suppliers should verify these
  characteristics and provide information on the
  results, and the analytical methods applied, to
  users.

6
3. Background
7
Objective

• The objective is to produce a formulation that
  will
• Deliver the drug to the patient
• conveniently
• in the required amount
• at the required rate
• Perform consistently
• within a batch
• from batch to batch
• over the shelf-life of the product

8
United States Pharmacopeia Convention Mission

• To promote the public health and benefit
  practitioners and patients by disseminating
  authoritative standards and information developed
  by its volunteers for medicines, other health
  care technologies, and related practices used to
  maintain and improve health and promote optimal
  health care delivery.
• Working with many constituencies and
  stakeholders around the world, USP's compendial
  activities support the availability of safe,
  effective good quality therapeutic products for
  consumers everywhere.
• USP 28-NF 23, 2006

9
Purpose of the European Pharmacopoeia

• To promote public health by the provision of
  recognized common standards for use by
  health-care professionals and others concerned
  with the quality of medicines. Such standards are
  to be of appropriate quality as a basis for the
  safe use of medicines by patients and consumers.
  Their existence
• facilitates the free movement of medicinal
  products in Europe
• ensures the quality of medicinal products
  exported from Europe.
• European Pharmacopoeia monographs and other
  texts are designed to be appropriate to the needs
  of
• regulatory authorities
• those engaged in the control of quality
• manufacturers of starting materials and medicinal
  products.
• European Pharmacopoeia, 5th Edition

10
Definitions

• Functionality A desirable property of an
  excipient that aids manufacturing and improves
  the manufacture, quality or performance of the
  drug product. (IPEC Draft Excipient
  Qualification Guide)
• Functionality-related characteristic (FRC)
  Physical and/or physicochemical characteristics
  that are critical to the typical uses of an
  excipient.
• (From European Pharmacopoeia)
• (Performance may include manufacturing
  performance, stability performance or product
  (i.e. dissolution) performance.)

11
Why are Functionality-related Characteristics an
Issue?

• Probably three main reasons
• A belief that the specification defines the
  excipient.
• Process Analytical Technologies (PAT) reduce
  variability in the input parameters, and thereby
  reduce variability in the output parameters.
• Quality by Design (QbD) reduce variability and
  thereby develop more robust formulations and
  processes.
• All the above arguments are flawed!
• A suggestion that pharmacopeial excipient
  monographs may not be sufficiently defined for
  todays (and tomorrows) needs.
• A desire to fix the apparent problem(s).

12
4. TriPECs Thinking
13
Why Drugs Are Formulated

• Convenience
• Accuracy of dose/consistency of dosing
• Improved bioavailability
• Taste masking/improvement of palatability
• Reduction of side effects
• Controlled dissolution/release

14
Components of a Medicinal Product
15
How does functionality arise?

• Derives from the chemical and physical make-up of
  the materials in question (API or excipient)
• Derives also from the fact that most excipients
  are quite complex systems, and contain other
  components that help bring about the
  functionality so-called functional components
• Precise details will depend on the application
  and formulation

16
What is the real problem?

• Variability
• Variability of materials
• Variability of process
• Variability of product
• Manufacturing
• In-vitro testing
• In-vivo release
• Stability

17
Understanding Product Variability
18
Key Questions

• What is our (lack of?) understanding of
  functionality and FRCs?
• How far do we need to go in establishing and
  setting specifications for an excipient?
• What is the economic impact of including FRCs in
  monograph specifications?
• What is the technological impact of including
  FRCs in monographs?

19
What do we know about Excipients?

• Certain excipients are available in different
  grades, usually differentiated using physical
  tests.
• But are these differences related to
  functionality in a given formulation?
• Do we need to go beyond grade differentiation?
• Do we need those tests to be in the monograph or
  in General Information Chapters?
• Some customers may be able to correlate product
  performance with a particular characteristic of
  an excipient, and will ask their supplier for an
  agreed specification.
• Will such tests apply to all applications?
• Do such tests need to be in the pharmacopeia
  monograph? Would the user want them to be?

20
What is the potential impact of introducing FRCs
into pharmacopeial monographs?

• Economic
• Increased cost of testing
• Increased purchase price
• More incentive for excipient manufacturers to
  abandon manufacture to pharmacopeial standards
• Technical
• Stifling of innovation

21
Example - Microcrystalline Cellulose

• Labeling section includes Degree of
  Polymerization test.
• Test originally introduced as an i.d. test to
  help distinguish Microcrystalline Cellulose from
  Powdered Cellulose.
• Degree of Polymerization will give some
  rudimentary information about the type of pulp
  used.
• However, the source of pulp does not correlate
  with functionality so much as the extent of
  hydrolysis.
• Degree of Polymerization is not a reliable FRC.
• Inclusion of the test in the Labeling section of
  the monograph has given the test far more
  emphasis than is necessary

22
Example Lactose Monohydrate

• Particle size testing is included in the
  monograph.
• This test may be important for some applications
  of lactose, but not all of them!
• For Lactose Monohydrate used in film coating
  compositions, it is dissolved during the
  preparation of the coating solution or
  suspension.
• For film coating applications, the particle size
  of the Lactose Monohydrate is largely irrelevant.
• in this case, particle size analysis is an
  example whereby including a FRC in the monograph
  leads to unnecessary testing.

23
5. Conclusions
24
TriPECs Position

• Functionality-related characteristics (FRCs) do
  not belong in pharmacopeia monographs, even in a
  non-mandatory Labeling Section.
• The pharmacopeias can provide harmonized methods
  as General Information Chapters.
• There should be a harmonized General Information
  Chapter on how to assess the FRCs for a
  particular application.
• Certain tests, particularly those relating to
  identity and/or safety should remain in the body
  of the monograph.
• The adopted policy should be harmonized within
  the three pharmacopeias (Ph Eur, JP and USP).

25
Thank you!Any Questions?