API and Product

Specifications as applied to
stability evaluation

David Edmonds
Principal
CMC Regulatory
 Overview of Stability
Materials are inherently stable or unstable
depending upon their chemistry/formulation,
packaging (sealing) and environment

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 Overview of Stability
Materials are inherently stable or unstable
depending upon their chemistry/formulation,
packaging (sealing) and environment

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 Overview of Stability

Same specifications for both:

Built for immortality; no change to structure.

Different outcome over time

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 Overview of Stability

Products can fall out of specification over time

owing to imperfect formulation, and/or packaging
and/or storage/environmental conditions.

ie Specifications are fixed; performance is

(potentially or actually) variable.

Products must be designed to prevent or minimise

variation over time.

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 Overview of Stability
cGMP para 6.4

The purpose of the on-going stability

programme is to monitor the product over its
shelf life and to determine that the product
remains, and can be expected to remain,
within specifications under the labelled
storage conditions.

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 Overview of Stability

Product stability and its evaluation is dependant all

the various contributing technologies at R&D and
commercial phases
– raw materials
– formulation
– manufacturing processes
– packaging

all above have requisite specifications and

test methodologies
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 Overview of Specifications
Specifications are a critical parameter of
“Control Strategy” systems and outcomes.
also of
“Critical Quality Attributes” in ensuring
safety, efficacy and consistency of product
performance across batches and throughout
their shelf lives.

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 Overview of Specifications
Term “Specifications” is defined in ICH Q6
as:

A specification is defined as a list of tests,

references to analytical procedures, and
appropriate acceptance criteria which are
numerical limits, ranges, or other criteria
for the tests described.

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 Overview of Specifications
Specifications define those test
parameters and their limits, leading to
and maintaining safety and efficacy of
raw materials and dose form pre and
post product registration within the
Product shelf life.
(Specifications also define existing
process control and set criteria/potential
limits for down-stream processes.)
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 Overview of Specifications
Term “Critical Quality Attributes” for API is
defined in ICH Q11 as:

“A CQA is a physical, chemical, biological,

or microbiological property or characteristic
that should be within an appropriate limit,
range, or distribution to ensure the desired
product quality.”

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 Overview of Specifications
As well as specifications, CQA cover
non-routine characteristics and properties,
which are critical parameters of “Control
Strategy” eg NMR & MS identification,
crystallography etc.
“Specifications” are used for routine batch
test requirements, although the other
characteristics are still expected to be
consistent and compliant.
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 Overview of Specifications
Consequently other characteristics and
properties may be necessary to review and
include in specifications, both for API and
formulated product manufacture and
subsequent stability evaluation purposes.
This applies especially to Products in
development.

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 Overview of Specifications
Safety – unacceptable impurities and/or impurity
levels (chemical and microbiological)
and/or unacceptable (Product)
performance

Efficacy – unit/dose or concentration of API(s)

and/or Product performance
(Product only)

Process – Conformance with specifications

demonstration that processes are within
acceptable parameters/tolerances
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(at in-process and completion stages)
 Specification Structure
API/excipients

Identification
Physical and physico-chemical
properties
Purity (never more than 100%)
(but assay may be more than 100%)
Impurities
(Chemical, microbiological)

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 Specification Structure
API/excipients

Packaging design
Packaging integrity
Weights and measures (after packaging)
Storage temperatures
Shelf life
Manufacturer(s)

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 Physical Properties
API/Excipient
Appearance (Colour, particle description
etc)
Solubility (Detailed)
Hygroscopicity
Crystal properties (Polymorphic forms,
different crystalline forms, solvation or
hydration products and amorphous forms)
Particle size, type & distribution

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 Physico-chemical Purity Indicators
API/Excipients

– Appearance and description

– pH
– Chiral Properties - Specific Optical Rotation
– Melting/Boiling Points
– Liquids - Refractive Index
– Liquids – Density/Relative Density/Specific
Gravity (be aware of differences between
definitions of the same characteristic)
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 API/Excipient
Physical Properties
These have a direct effect on Formulated
Product at one or more of manufacturing steps,
active rate of release from Product and (later)
stability parameters.

eg in manufacture:
– Preparation steps of solutions
– Wet and dry granulations

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 API/Excipient
Physical Properties
and in subsequent product performance:
– change in dissolution profiles of
tablets and capsules
– emulsion characteristics & performance
– suspension characteristics &
performance
– change of solubilising characteristics in
lyophilised injections for reconstitution

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 API/Excipient
Physical Properties
USP 35 General Notices 4.10
“Because monographs may not provide
standards for all relevant characteristics, some
official substances may conform to the USP or
NF standard but differ with regards to
nonstandardized properties that are
relevant to their use in specific
preparations. To assure interchangeability in
such instances, users may wish to ascertain
functional equivalence or determine such
characteristics before use.”
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 API/Excipient
Physical Properties

These physico-chemical characteristics

are not normally described in specific
material specifications from Authorities
but likely to be required in Application to
Market to Authorities.

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 Specifications
Formulated Product
Specifications cover product API content
dosage unit or concentration, and, where
applicable, Product performance
parameters.

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 Specification structure
Formulated Product
Batch “Release for Supply” & “Shelf Life”
Physical and chemical identification
Physical parameters
Concentration/unit dosage
Uniformity of dosage (not a stability
parameter)
Impurities (chemical and microbiological)
(in-vitro) Performance eg dissolution
Sterility assurance (where applicable)

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 Specification structure
Formulated Product
Batch “Release for Supply” & “Shelf Life”

Packaging design
Packaging integrity
Weights and measures (after packaging)
Storage temperatures
Shelf life
Manufacturer(s)

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 Formulated Product Shelf Life
Usually test similar parameters as for
Product Release.

Shelf life specifications may recognise

allowed changes from specifications at
batch release stage, broadening some test
parameter limits.
eg
- permitted active ingredient degradation
after formulated overages eg (vitamins)
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 Formulated Product Shelf Life

Concentration unit dosage content and

Uniformity of Dosage specifications,
determinations and calculations must
allow for permitted formulation overages.

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 Formulated Product Shelf Life
Many parameters, apart from measured
chemical degradation can change over the
shelf life of a formulated product.

eg Description failure:
- colouring of colourless solutions
- change of colour of tablets and liquids
- emulsion separation
- development of hard particles in
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solutions and emulsions
 Formulated Product Shelf Life
Other potential non-chemical changes
examples:

- tablet hardness and friability

- tablet/capsule disintegration and
dissolution
- permeation of moisture through
packaging/moisture intake or loss
- bioburden levels

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 Specifications
Packaging

Packaging design (specifications &

testing) and performance must be robust
to protect product in the packaging
process handling and subsequent
transport.

Packaging must also be appropriate and

practical for use by the Product user.

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 Specifications
Packaging
Packaging must ensure sealing integrity
throughout shelf life ie be impermeable
and perform and protect the Product under
storage in low and high humidity,
especially under bathroom and
refrigerated conditions.

Specifications of packaging materials and

packaging design must enable fulfilment of
these objectives.
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 Specifications
Relationship with Test Methods

Test Specifications and results are reliant on

specific test methods and equipment from a
lesser to total extent:
– Lesser: Content, Uniformity of Dosage
– Intermediate: Impurities
– Absolute: Physical tests, dissolution,
microbiological
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 Specifications
Relationship with Test Methods

Test methods must be stability

indicating when developing comparative
time/temperature data.

Stability protocol design and data

assessment must include an
understanding of the Test Method used.

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 Specifications
Relationship with Test Methods

Knowledge of duplication (or not) of sample

preparation and/or HPLC/GLC injections
(and similar test equipment) is critical in
applying test methodology and assessing
test results for compliance with
specifications.

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 Specifications
Relationship with Test Methods

BP and USP General Notices (7.20)

describe application of significant figures
and rounding-off of data. Also see TGA
ARG Appendix 18; Impurities ...
This and if and/or when averaging is
applied, is particularly important in the time
point and comparative (statistical)
assessment and presentation of stability
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data.
 Specifications
Relationship with Test Methods
BP 2012 General Notices

Tests and Assays

Limits. The limits stated in monographs are
based on data obtained in normal analytical
practice; they take account of normal analytical
errors, of acceptable variations in manufacture
and of deterioration to an extent considered
acceptable.
No further tolerances are to be applied............
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 Impurities

Impurities may or may not be toxic; may or

may not contribute to degradation
Impurities may or may not be known or
identified; therefore not necessarily
determined
HPLC impurities; are these calculated
simply from whole HPLC run or against
major peak.

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 Impurities

Highly desirable to be able to be able to

predict degradation products and more so
to distinguish these from impurities at
manufacture of API, excipients (synthesis)
and Formulated Product (from ingredients
or introduced).

This enhances the ability to set

appropriate stability specifications.

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 Impurities

Specifications do not necessarily cover all

contingencies.
BP2012 General Notices
Material found to contain an impurity
not detectable by means of the
prescribed tests is not of
Pharmacopoeial quality if the nature or
amount of the impurity found is
incompatible with good pharmaceutical
practice.
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 Impurities
API/Excipients

– Related Substances
(synthesis, degradation -
identified & unidentified;
individual and total)
– Known potential process impurities
(reactants, solvents, metal catalysts)
– Inorganic salts
– Heavy Metals
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(from metal catalysts)
 Impurities
API/Excipients

– Microbiological
– Viral
– Transmissible Animal Spongiform
Encephalopathy Agents (TSE)

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 Impurities
Formulated Product
Impurities from API and excipients
Impurities introduced during
manufacturing process (solvent, water, air-
borne air particulates, microbiological)
Subsequent Product degradation
impurities – individual and total
(including interaction with packaging
and/or any exposure to the
environment)
All to be covered by specifications.
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 Impurities
Formulated Product
Degradation products

See ICH Guideline Q3B(R2)

Impurities in New Drug Products for
threshold guidelines and required actions
and evaluations, including degradation
products requiring specifications.

http://www.ich.org/fileadmin/Public_Web_
Site/ICH_Products/Guidelines/Quality/Q3B
_R2/Step4/Q3B_R2__Guideline.pdf
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 Shelf Life “Loss of Content”
Calculation
“Degradation products should be reported,
identified and/or qualified if they are present
at levels above those described in the
CHMP/ICH guidelines on impurities in new
active substances and medicines or
(TGA ARG) Appendix 18” (Impurities in
active pharmaceutical ingredients and
finished products).
TGA Australian regulatory guidelines for prescription
medicines
Appendix 14: Stability testing
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 Shelf Life “Loss of Content”
Calculation
The ICH impurity requirements (indirectly)
give far less latitude in the calculation of
shelf life than the regression 95%
intersection “content” calculation, also
referenced in the TGA guidelines.

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 Shelf Life calculation
Linear Regression and
Lower 95% Confidence

110
108
106
104
Contnet (mg)

102
100
98
96
94
92
90
0 10 20 30 40 50 60
Time (Months)

Y-Data
Predicted Y

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 Shelf Life “Loss of Content”
Calculation

See Sections 3.3, 5 and Annex 2 Point 11

for further guidance.

TGA Australian regulatory guidelines for

prescription medicines
Appendix 14: Stability testing
http://www.tga.gov.au/pdf/pm-argpm-ap14.pdf

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 Change Control
It is taken as given that changes of source of
materials will be within specification and
changes of processes will result in Products
within specification.
Nevertheless assessments of changes
should include a comprehensive review of
all characteristics, particularly physical
and not necessarily currently specified, to
prevent subsequent adverse “unforeseen
consequences” of Product performance.

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 Conclusion – Setting of Specifications

Specifications must be “fit for purpose” of

the ingredients, packaging materials and
Formulated Product; ie beyond mere
“numerical description” which ensures
consistency but not necessarily
effectiveness.

eg packaging plastics and laminates

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 Conclusion – Setting of Specifications
In setting “at release” and “shelf life”
specifications, anticipate those parameters
likely to change and those remaining static
and confirm with stability testing.

How much latitude is there ? eg should a

liquid be described as “colourless” or
“colourless to pale yellow” or a cream
“white to off-white” rather than “white”.
(Colour and pH changes can be more
sensitive and indicative of degradation
than an HPLC impurity run.)
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 Conclusion – Setting of Specifications

No broadening of shelf life

specifications is allowed to
compromise the safety and efficacy of
the Product.

Specification parameters and limits

must be justified to enable API and
Product registration and continued
API/Product manufacture and supply to
market.
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 Sources of Specifications and Related
Test Methods

Common Technical Document;

Module 3 Quality
Pharmacopoeias
(structure and likely precedent parameters)
ICH guidelines; Quality series
TGA Australian regulatory guidelines for
prescription medicines
Appendix 14: Stability testing
Raw material suppliers
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 Sources of Specifications and Related
Test Methods

Leading to API and Dose Form manufacturers’

product and process development,
development specifications and test data
through to Authority approval and marketing.

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