Transcript Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007 Slide.

Pharmaceutical Development
Training Workshop on
Pharmaceutical Development with
focus on Paediatric Formulations
Protea Hotel
Victoria Junction, Waterfront
Cape Town, South Africa
Date: 16 to 20 April 2007
Slide 1
Walters
April 2007
Pharmaceutical Development
Quality Specifications & Testing of the
Finished Pharmaceutical Product
(FPP)
Presenter:
Susan Walters
Email:
[email protected]
Slide 2
Walters
April 2007
Quality Specifications & Testing of the FPP
My background
Pharmacist
PhD Pharmaceutical Chemistry
2.5 years pharmaceutical manufacturing
27 years regulation of prescription medicines (TGA Australia)
Now:
Teaching pharmaceutical development of medicines (UNSW)
Ad hoc consultancies for WHO and others
Slide 3
Walters
April 2007
Quality Specifications & Testing of the FPP
Outline of presentation
We will:
 Discuss the meaning of ‘quality’ in the context of FPPs
 Define key terminology
 List relevant pharmacopoeias & guidelines, & discuss their roles
 Outline typical tests for finished products
 Discuss the development & validation of dissolution test
methods & acceptance criteria
Slide 4
Walters
April 2007
What does ‘quality’ mean in the context of FPPs? - 1
“Quality:
The suitability of either a drug substance [=API] or drug
product [=FPP] for its intended purpose”
ICH Q6A (1999)
Some of the elements of FPP quality:
 Meets suitable criteria for content of active(s)
 Meets suitable criteria for content of impurities
 Does not contain toxic excipients or unexpected
contaminants
Slide 5
Walters
April 2007
What does ‘quality’ mean in the context of FPPs? - 2
The product:
 Is reproducible from batch to batch in terms of all characteristics
that may affect the patient
 Has container labelling & prescribing information that is clear,
contains all the necessary information, & accurately represents
the FPP’s efficacy & safety profile
 For FPPs containing new APIs: Has the same efficacy & safety
profile as the batches used in pivotal clinical studies
 For generics: Has the same plasma concentration/time profile as
the innovator whose efficacy & safety profile is known
Slide 6
Walters
April 2007
Quality Specifications & Testing of the FPP
How to ensure the quality of FPPs
ICH:
are
– Ensure you “Specifications
have the results of pharmaceutical
development studies
part of a total quality
 Validate:
strategy… designed
– Manufacturing
toprocedures
ensure product
– Test methodology
quality &
– Acceptance criteria
consistency”
The message:
 Implement Good Manufacturing Practice at all
sites of manufacture
End-product
testing
is one element of the
 Undertake appropriate end-product testing for conformance to specifications
quality package
 Know your API!
 Conduct stability studies on the FPP exactly as it is to be marketed
 Validate any subsequent variations
Slide 7
Walters
April 2007
Quality Specifications & Testing of the FPP
Some terminology
Slide 8
Walters
April 2007
“Specification” - 1
 “A list of tests, references to analytical procedures, ranges
or other criteria for the tests described”.
 “[The specification] establishes the set of criteria to which
[an API or FPP] should conform to be considered
acceptable for its intended use.”
– [and for excipients, containers, intermediates & others]
 “ ‘Conformance to specifications’ means that the [API or
FPP], when tested according to the listed analytical
procedures, will meet the listed acceptance criteria”.
ICH Q6a (1999)
Slide 9
Walters
April 2007
“Specification” - 2
 “Specifications are critical quality standards that are
proposed & justified by the manufacturer & approved
by regulatory authorities”.
 “Specifications are chosen to confirm the quality of
the [API or FPP] rather than to establish full
characterization, & should focus on those
characteristics found to be useful in ensuring …
safety & efficacy”.
ICH Q6a (1999)
Slide 10
Walters
April 2007
“Acceptance criteria”
“Numerical limits, ranges or other suitable
measures for acceptance of the results of
analytical procedures”
ICH Q6a (1999)
Quantitative acceptance criteria are sometimes
referred to as ‘limits’.
Slide 11
Walters
April 2007
A typical monograph for an FPP might
include: - 1
• Description
• Eg size, shape, colour
• Identity tests for API(s)
• Assay of API(s)
• Purity tests
• API-related impurities
• Solvents (often water)
• Physicochemical properties as appropriate to the dosage
form (includes performance/functionality testing)
• Eg particle size of API(s) in suspensions
• Dissolution rate of tablets
Slide 12
Walters
April 2007
A typical monograph for an FPP might
include: - 2
• Identification & assay of any critical excipients
• Eg antimicrobial preservatives, antioxidants
• Uniformity of dosage units for solid dosage
forms
• Eg uniformity of weight (high dose tablets)
• Content uniformity (low dose tablets)
• Microbiology
• Eg sterility (injections etc)
• Microbial load (non-sterile oral products &
others)
Slide 13
Walters
April 2007
The monograph as a whole
“A product is not of
pharmacopoeial quality unless it
complies with all the
requirements stated in the
[relevant monograph]” my emphasis
WHO TRS 908 (2003)
Slide 14
Walters
April 2007
Sources of guidance as to the content of
monographs for FPPs
• Pharmacopoeias
• General monographs
• Eg for parenteral products, capsules
• Specific monographs
• Eg dapsone tablets, artemether injection
• Guidelines
• WHO PQP
• Especially p16/26 Control of the FPP
• ICH
• Technically ICH guidelines apply only to new APIs. In practice
regulators apply them more widely (eg PQP)
Slide 15
Walters
April 2007
Internationally recognised pharmacopoeias
• International Pharmacopoeia (Ph Int)
• Published by WHO
• United States Pharmacopeia (USP)
• Japanese Pharmacopoeia (JP)
• European Pharmacopoeia (EP)
• British Pharmacopoeia (BP)
Slide 16
Walters
April 2007
Pharmacopoeias – PQP’s view?
• PQP has not published a formal decision
as to acceptable pharmacopoeial
monographs for FPPs
• But precedents suggest that monographs
of all of the preceding pharmacopoeias
would be acceptable, with the caveat that
monographs in Japanese are not easily
understood outside Japan
Slide 17
Walters
April 2007
ICH guidelines & FPP specifications
 From ICH’s early days, there have been working groups that focussed on
harmonisation of pharmacopoeial requirements among the three ICH regions
 But to date no harmonised monographs have been published on the ICH
website
 These are the three relevant topics that appear on the ICH website
– Q4 Pharmacopoeias
– Q4A Pharmacopoeial Harmonisation
– Q4B Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria
(RAAPAC)
 Of these, only Q4B has published a draft consensus guideline. It deals with
bureaucratic processing of documentation.
– Keep an eye on the ICH website for updates
Slide 18
Walters
April 2007
An important ICH guideline
 Q6A: Specifications: Test procedures & acceptance criteria for
new [APIs] & new [FPPs]: Chemical substances
 Applies to products containing synthetic APIs (including
antibiotics), semi-synthetic antibiotics, & synthetic peptides of
low molecular weight, but not to higher molecular weight
peptides, & complex biotechnological or biological APIs.
 This ICH guideline is referenced by PQP in its guidelines for
generics, & is a key guideline for this training course.
 I recommend that you read it in detail !
Slide 19
Walters
April 2007
Other relevant ICH guidelines
 Q3A(R2) Impurities in new [APIs] (2006) Q3B(R2)
Impurities in new [FPPs] (2006)
 Q3C Impurities: Guideline for residual solvents (1997)
 Impurities in non-new APIs
– Pharmacopoeial monographs
– Review route of synthesis
– Compare chromatographic profiles with those of innovator
Slide 20
Walters
April 2007
Impurities in non-new FPPs
“Generally specifications for impurities in an existing API
&/or an associated finished product are acceptable if
one or more of the following criteria are met:
– Levels of impurities are below ICH qualification thresholds
– Nature of impurities & their limits match those of a
transparent [pharmacopoeial] monograph
– The new product does not contain impurities in
concentrations that exceed those in a market leader
(normally the innovator)”
TGA (2004)
Slide 21
Walters
April 2007
Deciding acceptance criteria
 The justification (for acceptance criteria) should refer
to relevant development data, pharmacopoeial
standards, test data for [APIs & FPPs] used in
toxicology & clinical studies, & results from long term
stability studies, as appropriate.
 Additionally a reasonable range of expected
analytical & manufacturing variability should be
considered.
Adapted from ICH Q6A (1999)
Slide 22
Walters
April 2007
Parametric release & end product testing
 Sterility testing is probably the most well known example
of the parametric release option
 Q6A describes it as “an operational alternative to routine
release testing”
 In the case of sterility, “release of each batch is based on
satisfactory results from monitoring specific parameters,
eg temperature, pressure & time during the terminal
sterilization phases of...” manufacturing (Q6A)
 In principle parametric release can be substituted for
other end product testing, but there are few examples
 All batches must nevertheless meet the full product
specification if tested
Slide 23
Walters
April 2007
Periodic & skip testing - 1
 “Periodic or skip testing is the performance of specified tests
at release on preselected batches &/or at predetermined
intervals, rather than on a batch-to-batch bases”
 All batches must nevertheless meet the full product
specification if tested
 Once a manufacturer has developed confidence in the
manufacturing process & a number of consecutive batches
have passed the test in question, testing may be reduced to
one in every x batches, or once every x months, where x is a
number that varies with the test in question
Slide 24
Walters
April 2007
Periodic & skip testing - 2
 Certain tests are considered ‘critical’ in terms of GMP,
& must be conducted on every batch. Examples
include identification & assay of the active(s).
 Regulatory approval must be obtained (on a productspecific basis) before periodic testing may be
implemented
 In the event that a batch is tested & fails to meet
acceptance criteria, regulatory authorities must be
immediately informed. The batch may be recalled. The
reason for the failure must be identified in order to
assess the consequences for other batches.
Slide 25
Walters
April 2007
Release & expiry limits
 Manufacturers (almost always) have separate release & expiry limits
for tests that have a quantitative result. The main reasons are:
– To allow for any observed deterioration of the measurement during
stability studies
– To incorporate a safety margin so that batches are less likely to be
recalled in the event of testing by a regulatory laboratory
• Effect on product image
 Immediately after a batch has been released, the expiry limits
apply.
 Some regulatory authorities consider this ‘in-house’ information & do
not require disclosure of the release limits. Most do.
 PQP seeks both sets of limits.
Slide 26
Walters
April 2007
Alternative test procedures
 Pharmacopoeias & regulators allow manufacturers to use
alternative test methodology
 In the event of a dispute, the approved methodology must be
used.
 Why?
– Science moves on ! Methodology improves. Regulators should not
discourage improvements.
– Alternative methodology may be simpler &/or cheaper to conduct, but
equally effective. For example if the product has been shown not to
degrade during manufacture, a titration method may be more
accurate, precise & cheaper to perform than HPLC/MS, although less
specific for the target analyte.
Slide 27
Walters
April 2007
Dissolution
testing
Slide 28
Walters
April 2007
Dissolution test methods & acceptance criteria:
Available guidelines
– “Dissolution Testing of Immediate Release Solid Oral Dosage
Forms”
• FDA, CDER (1997)
– <1092> “The Dissolution Procedure: Development & Validation “
• USP
– “Dissolution testing of solid oral dosage forms”
• BP, Supplementary Chapter E
– “FIP Guidelines for Dissolution Testing of Solid Oral Products”
• http://www.fip.org/www2/statements/index.php
– “Dissolution testing”
• WHO PQP: Guideline on Submission of Documentation for
Prequalification of Multisource (Generic) FPPs: Supplement 1.
Slide 29
Walters
April 2007
For what purposes are dissolution studies
conducted?
– During product development, selecting formulations for further
development
– During end-product quality control, determining whether each batch
meets predetermined in vitro release criteria
– During stability studies, determining whether in vitro release rate
changes with product age
– In the context of bioequivalence studies, to determine the extent to
which in vitro dissolution results mirror in vivo results.
– During the product’s market lifetime, determining whether variations
affect in vitro release rate
• Eg change of manufacturing site or equipment
Slide 30
Walters
April 2007
What constitutes a good dissolution test?
– Repeatability
• Within & between equipment, analysts, labs etc
• Over time (eg this year vs next year)
– Discriminatory power
• Discriminates between batches that perform well in
vivo & those that do not
Slide 31
Walters
April 2007
Formal ‘validation’ of dissolution test
methodology
Examples:
 Repeatability studies
 System suitability tests
– Eg using USP dissolution calibrators
 Manual vs automated procedures
 Analytical methodology
Slide 32
Walters
April 2007
What should we take into account when choosing
dissolution test methods & acceptance criteria? - 1
– The APIs in question & their characteristics
• Especially solubility in aqueous media
• Known history of dissolution &/or bioavailability problems
• Biopharmaceutical classification (see FDA’s Waiver of In Vivo
Bioavailability & Bioequivalence Studies for Immediate-Release Solid Oral Dosage
Forms Based on a Biopharmaceutics Classification System, 2000)
– The purpose for which the test is being conducted [this affects
acceptance criteria]
• Routine batch release
• Stability testing
• For registration purposes
• To support results of a bioequivalence study
• To justify a waiver of in vivo BE data
Slide 33
Walters
April 2007
What information should we take into account when choosing
dissolution test methods & acceptance criteria? - 2
– Recommendations made by FIP, by pharmacopoeias & in regulatory
guidelines
– Regulatory requirements for registration
• Eg those of WHO’s PQP
– Whether an in vivo/in vitro correlation (of any type) has been
established
• May or may not have been published
• See especially the website for the FIP Special Interest Group for BABE at
http://www.fip.nl/www2/sciences/index.php?page=pharmacy_sciences&pharmacy_scienc
es=sciences_bioavail_groupbcs
– Precedents
• Concerning the API in question, related APIs or related dosage forms
– Published
– Or known only to you
• But only if there are facts/data that you can cite in support
Slide 34
Walters
April 2007
Dissolution testing: Decisions to make
– Apparatus
– Medium (solvent)
– Sampling times
– Acceptance criteria
Slide 35
Walters
April 2007
Dissolution test methods: Apparatus - 1
Options (all described in the Ph Int, BP & USP):
• Stirred methods
• Rotating paddle
• Rotating basket
• Modifications
– For floating dosage forms, especially capsules
– May need to change medium during the test, eg pH for enteric coated products
• Flow through methods
• Reciprocating cylinder (USP only)
• Useful for modelling media changes & predicting in vivo profiles of modified
release products (Personal Communication David Elder 2007)
Slide 36
Walters
April 2007
Dissolution test methods: Apparatus - 2
In general milder agitation conditions are
preferred
– More likely to be able to discriminate
between good & bad batches
– May have to increase speed in some cases
in the event of coning due to insoluble
excipients
Slide 37
Walters
April 2007
Dissolution test methods: Apparatus - 3
• Recommendations by PQP for immediate
release products:
• Paddle (USP Apparatus 2) usually at 50 or 75
rpm
• Basket (USP Apparatus 1) usually at 100 rpm
Slide 38
Walters
April 2007
Dissolution test methods: Medium/solvent
Prefer media that are:
– Not dissimilar to physiological conditions
• Eg avoid 50% acetone!
– Discussed in pharmacopoeias
– Defined in regulatory requirements
• Eg WHO’s PQP Dissolution testing: Guideline on Submission
of Documentation for Prequalification of Multisource
(Generic) FPPs: Supplement 1.
• FDA/CDER’s Dissolution Testing of Immediate Release Solid
Oral Dosage Forms
– Water is now out of favour because pH is uncontrolled
Slide 39
Walters
April 2007
Dissolution test methods: Sampling times - 1
Prefer sampling times that are:
– Recommended in pharmacopoeias
– Defined in regulatory requirements
Prefer:
– Profiles (multipoint) vs one or two point tests
• Profiles are more discrimating than one or two point tests
• Formulation comparisons should normally be profiles
• One or two point tests may be adequate for routine batch release if fully
justified
Slide 40
Walters
April 2007
Dissolution test methods: Sampling times - 2
Some relatively recent (but non-official) nonnumerical terminology:
• ‘Very rapidly dissolving’
≥ 85% in 15 minutes
• ‘Rapidly dissolving’
≥ 85% in 30 minutes
Slide 41
Walters
April 2007
Dissolution test methods: Sampling times - 3
The FDA guidance describes three categories
of dissolution test:
– Single-point specifications
– Two-point specifications
– Dissolution profile comparison
From: Dissolution Testing of Immediate Release
Solid Oral Dosage Forms FDA (1997)
Slide 42
Walters
April 2007
Dissolution test methods: Sampling times - 4
• Single-point specifications. Can be used:
– As a routine quality control test for highly soluble and rapidly
dissolving drug products
• Definition of rapidly dissolving?
• Recently defined as >85% in 30 minutes but the FDA dissolution guideline did
not define the termSingle-point specifications. Can be used:
– As a routine quality control test for highly soluble and rapidly
dissolving drug products
• Definition of rapidly dissolving?
• Recently defined as >85% in 30 minutes but the FDA dissolution guideline did
not define the term
Slide 43
Walters
April 2007
Dissolution test methods: Sampling times - 5
• Two-point specifications. Can be used:
– For characterizing the quality of the drug product.
– As a routine quality control test for products that contain
slowly dissolving or poorly water soluble APIs such as
carbamazepine.
• Dissolution profile comparison. Can be used:
– For accepting product sameness in the context of variations.
– To waive bioequivalence requirements for lower strengths of
a dosage form.
– To support waivers for other bioequivalence requirements,
especially for BCS #1 APIs.
Slide 44
Walters
April 2007
Dissolution test methods: Sampling times - 6
• So for routine quality control of immediate release products:
Either specify a dissolution profile
Acceptable for most types of product
Or specify a two point dissolution test
Acceptable for most immediate release products
Or specify a single point dissolution test
Acceptable for most immediate release products that contain highly soluble &
rapidly dissolving APIs
 But each case must be considered individually
Slide 45
Walters
April 2007
Deciding acceptance criteria - 1
 Approaches for setting dissolution
specifications for a new chemical entity
 Approaches for setting dissolution
specifications for generic products
From: Dissolution Testing of Immediate Release
Solid Oral Dosage Forms FDA (1997)
Slide 46
Walters
April 2007
Deciding acceptance criteria - 2
 Considerations when setting dissolution
specifications for a new chemical entity:
–
–
–
–
pH solubility profile
pKa of active
GI permeability or octanol/water partition
Dissolution characteristics of batches used in pivotal
clinical trials and/or in confirmatory bioavailability
studies.
– If the formulation intended for marketing differs
significantly from the drug product used in pivotal
clinical trials, dissolution and bioequivalence testing
between the two formulations are recommended.
From: Dissolution Testing of Immediate Release
Solid Oral Dosage Forms FDA (1997)
Slide 47
Walters
April 2007
Deciding acceptance criteria - 3
 Considerations when setting dissolution
specifications for a generic product:
– Has a pharmacopoeial dissolution test been
published?
– Is a dissolution test publicly available for a reference
listed drug product?
– Conduct comparative dissolution testing using test &
reference products under a variety of test conditions
Slide 48
Walters
April 2007
Comparing dissolution profiles
When comparing two immediate release products:
 If both are >85% dissolved in 15 minutes, the profiles
may be considered similar. Statistical calculation is not
required.
PQP (2005 )
 Calculate the similarity
factor f2 where………


– Need minimum
of 3 points
Slide 49
Walters
April 2007
f2



 





100
1
 tn

 t 1
R ( t )  T ( t ) 

n
2









Summary and conclusion
 It is important to understand the place of end-product
testing in the total quality context
 Monographs for FPPs should be based on:
– Pharmacopoeial general monographs
– Pharmacopoeial precedents
– ICH & PQP guidelines
– Characteristics of the API & FPP in question
 The bottom line is safety, efficacy & reproducibility for
the patient
Slide 50
Walters
April 2007