IABS Reference Standards for

Therapeutic Proteins
Essential Reference Standard Program Questions
Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
For what purposes are reference standards used?
One purpose of a reference standard is to demonstrate through
biological and physicochemical tests that a product lot accurately
represents the intended product and is of acceptable strength,
identity, purity, and potency.
Additionally, reference standards have particular uses for method
development and validation, calibrating equipment and continuity of
reference standards themselves.
As they relate to product, reference standards are obviously critical in
the demonstration that each lot of material is suitable for release
and patient use.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
For what purposes are reference standards used?
Reference standards also demonstrate consistency in the process
between lots, for comparability after process changes, technology
transfer and aid in the identification of drift in quality attributes over
time.
A carefully managed reference standard program establishes a link in
the material through the product lifecycle, from the early stage
clinical trials to the commercial product following licensure,
ensuring that quality attributes are tracked throughout the product
lifecycle.
Reference standards are necessary to qualify future primary and
working reference standards. They protect against drift in a quality
attribute between current and candidate standards and to
demonstrate the long-term stability of other reference standards.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How are reference standards used in analytical methods?
As they relate to analytical methods, reference standards are used in
trending programs to ensure that method performance is consistent
over time as well as being used to validate the assays themselves.
Reference standards are also used in analytical methods for the direct
calculation of a test sample result or as a component of system
suitability and/or assay acceptance criteria.
A reference standard may be used to directly quantitate a quality
attribute. The most obvious example of such a use is the
determination of relative potency, in which the biological activity of
a test sample is calculated by direct comparison to the reference
standard response.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How are reference standards used in analytical methods?
Reference standards are also used to generate a test sample
response through the qualitative comparison of a quality attribute.
Gel methods (e.g. SDS-PAGE) can be used to aid in the
determination of product purity by demonstrating that the banding
pattern of the test sample is sufficiently similar to that of the
reference standard, or conforms to standard.
Similarly the chromatograms from methods such as HPLC are
compared between reference and test sample if conforms to
standard or no new peaks are part of the acceptance criteria.
Reference standards, therefore, are used in both a quantitative and
qualitative capacity to determine the quality attributes of a product
lot.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How are reference standards used in analytical methods?
Standards have an even wider use in various analytical methodologies
as a component of the system suitability. When used for this
purpose, the reference standard is intended to verify performance
of an analytical method in accordance with validated parameters
each time that it is performed.
For example, HPLC purity assays (cation exchange, reversed phase,
and size exclusion) include multiple criteria that establish, through
the reference standard chromatogram, that the assay demonstrates
precision, efficiency, recovery and resolution that is sufficiently
similar to the historical behavior of the method.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How are reference standards used in analytical methods?
A separate type of material can be prepared solely for verifying the
capabilities of an assay (e.g. to show it can detect stability related
moieties) termed a Reference Material.
These additional reference materials may be required to ensure
identity, accuracy and precision of different sample types (e.g.
product in various process streams).
This material does not necessarily have to be derived from the primary
or working reference standard and may not need to be compared to
them depending on use, but this should be justified.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How are reference standards used in analytical methods?
Therefore, one can use the primary reference or working standard for
all of the aspects of assays described, but reference materials can
be used instead for certain aspects of analytical
development/validation and control.
Reference materials may be used in certain aspects of the routine QC
lot release/stability program (especially those where quantitation or
direct qualitative comparison occur). For example, stressed product
samples may be used for identification of expected impurities.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How should one select a reference standard?
Core considerations for initial and subsequent reference standards
include production schedule, material availability, the quantity
required as well as its intended use. For the identification of the
initial (or interim) reference standard, the selection may be
restricted due to time constraints and limited production.
Because of limited product knowledge at the time of selection and
qualification of the initial standard, the production schedule is likely
to act as the primary input in standard selection.
At all stages of product development, the reference standard should
be representative of production and clinical materials (ICH Q6B).
The concept of representative will change as product knowledge
increases; however, the quality attributes of the standard should
represent the desired characteristics of the production lots as
understood at each development stage.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How should one select a reference standard?
For example, a reference standard should not demonstrate an impurity
profile that is substantially different, either in identity or quantity of
impurities, than the lots for which it is intended to support release
and stability testing.
While there may be exceptions to this guidance, such as the use of a
separate lot of material as a potency standard, in general the
quality attributes of the standard should reflect the product that is
intended for patient use.
For a potency reference standard, within a particular bioassay, the
reference standard must have a biological activity that is identical to
the biological activity of the test sample (i.e. shows parallelism). It
should be free from substances that may interfere with the assay.
Links to the material used in clinical material is essential.
The reference standard must be evaluated to ensure it is a
homogeneous preparation (i.e. minimal vial-to-vial variation).
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How should one select an immunogenicity standard?
The use of an immunogenicity standard is different from that for most
assays. In general, it is agreed that antibody standards are not that
helpful in attempting to quantitate immunogenicity, and thus a titer
assay readout is recommended
Different antibody preparations can have very different properties
(avidity, affinity etc.) that can give different readouts in an assay
(e.g. non parallel dilution curves).
Obviously polyclonal antibody preparations suffer more from this
variability when compared to a monoclonal antibody, but then a
MAb will not represent the attributes of a polyclonal human
antibody response.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How should one select an immunogenicity standard?
A MAb or well characterized (usually purified) polyclonal can be used
to compare the sensitivity between assays to illustrate how well
antibody assays perform and/or useful to show changes in assay
sensitivity during assay development
If reagents are available for both high and low affinity antibodies, these
can be used during assay development and compare different
assays.
A medium affinity would be best if only a single reagent is available.
However, what is clinically relevant should be considered.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How should one select an immunogenicity standard?
In the clinical diagnostics arena, large collaborative studies have been
used to select antibody standards for diagnosis and/or prognosis of
disease (e.g. in diabetes).
However, these studies illustrate the complexity of identifying an
antibody preparation that would work in different assays to the
same extent (even be detected in all assays) whereby hundreds of
sera are included in such studies and one (if any) is shown to have
utility as a standard.
Standardization of the assay across laboratories is essential if an
immunogenicity reference preparation is going to have its
maximum impact and to have the ability to compare between
clinical studies run by different sponsors.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How do the intended uses of primary and working
reference standards compare?
The principal difference between the primary and working reference
standards are their uses in qualifying and monitoring other
reference standards and frequency of use day to day. The primary
reference standard should be used to qualify new primary or
working reference standards.
The primary standard is also used in the stability monitoring of working
reference standards and is critical in establishing product
consistency over long periods of time, both within and between
working reference standards.
In order to maintain a consistent product history, sufficient quantities of
the primary standard should be qualified for usage over a period of
at least ten to twenty years.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
How do the intended uses of primary and working
reference standards compare?
The working reference standard is used for lot release and stability
testing, as well as other quality activities such as investigations and
method transfers/validations and thus the working reference
standard is depleted much faster than the primary standard.
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Session 1 Questions:Understanding the attributes
required for reference standards and the purpose of
their use
When is drug substance or drug product suitable for use
as a reference standard?
Drug substance may be suitable for use as a reference standard for
multiple reasons. First, some products may not be stable enough
to serve as a long term reference standard in the final formulation
(i.e. frozen).
The formulation and/or concentration of drug substance may lend
greater stability to the molecule, such that it may be used for an
extended period of time as a reference standard.
In addition, drug substance may be better suited to illustrate the
presence of impurities if final product goes through additional
purification steps.
However, there may be the need to have both DS and DP reference
standards depending on how they react in assays.
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Session 2 Questions: Reference
standard qualification
What are the essential qualification parameters for a
Reference standard and from where are the acceptance
limits for qualification derived?
As described, the type of qualification carried out is closely linked to
the use of the reference standard.
There is a phase specific approach to the level of qualification during
the product lifecycle in both the number of tests and their limits.
Often the first standard (interim RS), derived from either tox material or
the first GMP run, would simply be compared to specifications in
place at that time and results provided as a report of the test
result.
As product development proceeds, acceptance criteria for selection of
the standard can be set on manufacturing history and exposure in
the clinic to provide assurance the standard is representative of
clinically qualified material.
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Session 2 Questions: Reference
standard qualification
What are the essential qualification parameters for a
Reference standard and from where are the acceptance
limits for qualification derived?
Meeting specifications (both the test and limits) alone is often not
enough to ensure the reference standard fully represents the
product - additional characterization tests are usually employed for
defining the first primary reference standard and occurs late or post
Phase III, preferably creating the primary reference standard from
commercial scale material.
Tests may be included or removed during development dependent
upon the structure/function and development history of the
molecule and especially as use of the standard is more closely
defined.
Regardless, the rationale for the selection of qualification tests and the
accompanying acceptance criteria must be detailed in the
qualification protocol for the first reference standard.
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Session 2 Questions: Reference
standard qualification
What are the essential qualification parameters for a
Reference standard and from where are the acceptance
limits for qualification derived?
Qualification tests generally include determination of some or all of the
following: potency, concentration (strength), mass, primary
structure, secondary structure, tertiary structure, disulfide structure,
carbohydrate structure, impurity profile, and thermal stability.
Because product concentration and potency are determined by direct
comparison to the reference standard, these parameters must be
precisely defined during reference standard qualification.
When comparing directly to a standard profile (e.g. compares to
reference, no new impurities) then having a representative profile
is desirable (centered quantities of the attributes) however, the
use of both a ref std and impurity std may be useful.
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Session 2 Questions: Reference
standard qualification
What are the essential qualification parameters for a
Reference standard and from where are the acceptance
limits for qualification derived?
For certain characterization tests used for the first primary reference
standards, such as secondary or tertiary structure methods,
reporting the value is satisfactory although acceptance criteria for
all test results should be established when utilizing a protocol for
replacing a standard after licensure.
For quality attributes that are known to be critical, it is more likely that
acceptance criteria for selection of the first primary reference
standard should be predefined to ensure the standard represents
attributes similar to those used in pivotal clinical studies and have
been clinically qualified.
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Session 2 Questions: Reference
standard qualification
What are the essential qualification parameters for a
Reference standard and from where are the acceptance
limits for qualification derived?
Regardless of what was in the protocol to define the acceptance
criteria for the first primary reference standard, looking at the
results of the qualification assays and comparing them to clinically
qualified material and commercial material and assessing how
representative the standard is can be valuable (and what the
regulators do!)
The number of determinations required to generate a final result
during qualification is dependent upon method capability, such that
sufficient statistical power is obtained in assigning the reported
result.
For critical quantitative product attributes such as potency, there must
be sufficient agreement between replicate results to assign a final
value (e.g. CV 5%, or using a tolerance interval approach).
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Session 2 Questions: Reference
standard qualification
Should the intended use of the reference standard
(potency determination vs. assay system suitability
criteria) dictate the qualification requirements?
Yes because the level of qualification depends on the sue of the
standard. For example, if one is never going to use a particular
reference standard to test for secondary/tertiary structure (in say
comparability studies) then adding those tests to qualification would
not be necessary.
A potency standard that is separate from a physicochemical standard
may not need the same level of physicochemical analysis,
especially if potency impacting quality attributes are well
understood as well as those that dont.
If a reference standard is not going to be used for quantitative analysis
but only for system suitability (e.g. is a band or peak there or not)
then relative levels of different variants may not be relevant.
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Session 2 Questions: Reference
standard qualification
Should the intended use of the reference standard
(potency determination vs. assay system suitability
criteria) dictate the qualification requirements?
Regardless of use, a reference standard qualification protocol should
be written prior to the selection of material for a reference standard.
The use of the reference standard/s in different assays should be
included in the protocol with justifications for what is and isnt
tested.
In addition, the use of the standard can impact the level of
comparability or equivalence required to prevent drift or if drift in
an attribute is even a concern (e.g. in levels of an impurity to which
a comparative quantitation is not required).
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Session 2 Questions: Reference
standard qualification
Should the intended use of the reference standard
(potency determination vs. assay system suitability
criteria) dictate the qualification requirements?
It is more likely a potency (or quantitation) standard should be the
gold material stored in a stable manner to which all future
replacement standards are used.
This is likely not necessary for physicochemical standards that are
qualitative in nature where changes to its profile are likely to be
more acceptable over time, mainly because physicochemical
profiles can be visualized more easily and can be manipulated if
necessary.
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Session 2 Questions: Reference
standard qualification
Should primary and working reference standards be
qualified to the same extent?
Primary reference standards should be qualified to the fullest extent
possible for the use of the standard as previously described.
Current guidance does not adequately address the qualification of
working reference standards, specifically how (and if) the approach
should differ from that used for primary reference standards.
In the absence of available guidance, qualification of working
reference standards should consist minimally of several activities
but should be justified on the product type and the use of the
working standard as well as how the working standard is derived
- the more manipulation from the primary standard, the more study
is required to ensure attributes have not changed.
Full specification testing should be performed at a minimum.
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Session 2 Questions: Reference
standard qualification
Should primary and working reference standards be
qualified to the same extent?
Additional levels of testing of all product quality attributes that are
calculated by direct comparison to the working reference standard,
such as protein concentration and potency, should be performed.
The minimum requirements for working reference standard
qualification should therefore sufficiently demonstrate that the
material is representative of the intended product to which it is
being compared and/or to illustrate that the working standard is fit
for purpose for its particular use.
Qualification against the primary reference standard with the full range
of assays does establish the necessary link to the product
development history if the working standard is not directly derived
from the primary standard.
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Session 2 Questions: Reference
standard qualification
Should more than one testing laboratory participate in
qualification activities?
When calibrating a standard, method variability should be reduced as
much as possible and since side by side analysis occurs, the
concern for any analyst bias is not relevant the number of repeats
to ensure the most precise estimate is the vital factor.
However it depends on the use of the study estimating a true value
of an attribute is one type of study and requires the least variability
(best analyst, best machine).
Another study would be to use more than one analyst/machine etc. to
confirm if the calibration carried out by a single analyst is actually
correct how can you confirm your true value is true!
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Session 2 Questions: Reference
standard qualification
Should more than one testing laboratory participate in
qualification activities?
An additional type of study is one to assure that the qualification
assays used to calibrate or qualify the standard adequately
represent the inherent variability of the analytical methods and that
method transfers will be successful, whereby qualification should
be performed by more than one laboratory.
This is accomplished by varying the days, analysts, equipment, and
critical reagents used to complete the required testing.
These measures help to ensure that the reference standard
qualification represents the actual conditions of use following
implementation.
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Session 2 Questions: Reference
standard qualification
What differences are required for selecting and qualifying
a vaccine, protein particle or host cell reference standard?
Compared to well characterized products, vaccines, protein particles
and HCPs are inherently more complex and heterogeneous.
As for any product, an understanding of what the purpose of the
reference standard is for is critical to its qualification.
For protein particles, the properties of the particles have to be
considered - and we are at the stage of simply trying to understand
which attributes are impactful for their detection in the different
assays available ( size dispersion, refractive index/contrast,
diffraction, shape etc.). Prior to the development of a suitable
standard the methods themselves need to be better characterized
and standardized.
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Session 2 Questions: Reference
standard qualification
What differences are required for selecting and qualifying
a vaccine, protein particle or host cell reference standard?
For HCPs, one is dealing with a very complex mixture of proteins. On
top of that, the mixtures can be cell line and process specific.
Thus there are potential issues with creating an HCP mixture
standard depending on how it is prepared and its relevance to
HCPs in product produced by actual manufacturing.
Plus manufacturing changes can impact the type of HCPs in product.
Thorough characterization of the HCP protein profile allows
confidence in the representativeness of the standard (e.g. 2D
gels) and the need for, or not, a change.
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Session 2 Questions: Reference
standard qualification
What differences are required for selecting and qualifying
a vaccine, protein particle or host cell reference standard?
Antibodies raised to the HCP mixture then add to complexity in the
assay. Use of 2-D gel western blotting should be used to illustrate
the immunoreactivity of the antibodies. Showing such coverage is
essential to understand the readouts of the assays.
One needs to understand whether the HCP mix represent the
proteome of the cell line used and does the antibody preparation
recognize that appropriately?
Over representation against a few proteins can be as bad as
antibodies to many (but not all) the proteins limiting signals thus a
medium coverage appears most desirable.
The comparison of HCP levels between manufacturing runs can
illustrate the run to run differences in HCP reactivity to assess the
cross product utility of a single HCP/antibody preparation.
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Session 2 Questions: Reference
standard qualification
What differences are required for selecting and qualifying
a vaccine, protein particle or host cell reference standard?
For vaccines, one is also dealing with a complex of proteins. Plus,
there are combination and adjuvanted vaccines.
Old physiological activity has been replaced by either absolute
quantities (e.g. CFUs for live vaccines) for potency standards or
titers of antibody production for clinical serology tests as well as in
potency assays that test the immunogenicity of the vaccine.
Vaccine standards are usually used quantitatively to create a standard
curve but can also be used as assay controls as for other biotech
products.
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Session 2 Questions: Reference
standard qualification
What differences are required for selecting and qualifying
a vaccine, protein particle or host cell reference standard?
Basic qualification of a vaccine reference standard is similar to other
biotech products.
However, when qualifying anti-vaccine antibody standards, other
factors have to be considered as described for anti-drug antibody
reagents,.
This can involve the use of different species, considering the age of
subject providing the antibodies, immunizing protocol etc. Multiple
standards are often created.
For vaccines, as for many other products, IUs are often not
transferrable between assay types (e.g. functional versus ELISA)
unless confirmed by a collaborative study.
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Session 3 Questions: Reference standards
and their replacement
What are the main considerations when replacing a
reference standard?
It is clear that minimizing drift is the most essential consideration when
moving from one reference standard to another.
When to replace a reference standard is critical to ensure:
1. You dont run out of the first reference standard (one should try to
always have enough primary reference standard to calibrate.
against regardless of how many standards have been made after it)
2. You have enough of the appropriate material to create a new
standard.
3. You know how to create the new standard for example, changing
formulations between standards can dramatically alter the stability
of a standard and this needs to be assessed (snap freezing etc.),
understand volume requirement, numbers of vials etc.
4. Give yourself enough time to do all the necessary work.
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Session 3 Questions: Reference standards
and their replacement
What are the main considerations when replacing a
reference standard?
5. Have a plan including justification for the need to replace a
reference standard (as this may influence your activities) and an
appropriate protocol with acceptance criteria are essential.
6. Investigate the availability of an international standard and if there
isnt one, consider working with a public standards organization to
create one.
7. Plan ahead to track the performance of assays and their results in
your trending program to ensure subtle changes arent missed
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Session 3 Questions: Reference standards
and their replacement
How do you prevent drift when implementing a new
potency standard?
The accurate determination of the relative potency of a candidate
reference standard is a critical component in maintaining a
consistent product linkage for potency throughout the development
lifecycle.
The relative potency testing design and acceptance criterion in the
qualification protocol must be such (e.g. tight enough) that any
difference in the potency between the current and candidate
reference standards can be shown to be due to either a real
difference or the characterized variability of the analytical method,
which should be minimized as much as possible.
Other signals beyond the actual potency result (such as slopes,
asymptotes etc.) can be tracked as well to illustrate if there are
subtle differences between standards.
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Session 3 Questions: Reference standards
and their replacement
How do you prevent drift when implementing a new
potency standard?
Keeping the first primary reference standard as the calibrator each
time another standard is developed (ensuring it is stable) as A-B,
A-C, A-D and not A-B-C-D.
A sample size should be such that there is sufficient statistical power
to demonstrate equivalency in potency between the standards.
The equivalency acceptance criterion (EAC) must also be
established in relation to the intermediate precision of the potency
method. In general, it appears FDA recommend around 30
individual estimates of potency.
One also needs to take into consideration physicochemical tests as
indicators of potential drift as well. In vitro bioassays do not
necessarily detect all aspects of biological activity.
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Session 3 Questions: Reference standards
and their replacement
How do you prevent drift when implementing a new
potency standard?
To further aid in demonstrating a lack of potency drift between
standards, the internal control lot should not be changed at the
same time as the reference standard lot.
An overlap in the internal control potency data over time provides
further evidence that there is no change in the activity of the
reference standard.
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Session 3 Questions: Reference standards
and their replacement
How should the impact to method trending be evaluated
when implementing a new standard?
Analytical parameters are trended for quantitative methods that use a
reference standard or internal control to test the purity, potency, or
integrity of active product or the formulation of placebo.
As described, the reference standard usually has direct consequence
on only very few trended parameters, such as the protein
concentration and relative potency of the internal control.
If stringent selection and qualification practices are executed, there
should be minimal impact to trended parameters that are directly
influenced by the reference standard.
Nonetheless, all trended parameters that are derived from the
reference standard should be evaluated for a shift in the assay
results following the implementation of a new reference standard
lot.
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Session 3 Questions: Reference standards
and their replacement
How should the impact to method trending be evaluated
when implementing a new standard?
In the event that a shift in a trended parameter should occur directly
following the implementation of a new standard, the consequence
to the program and the impact in relation to the current trending
limits must be determined.
The decision to reset trending limits must be fully evaluated and
justified when a change in a parameter is identified.
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Session 3 Questions: Reference standards
and their replacement
Under what circumstances does a process change require
the implementation of a new standard?
A change in the manufacturing process does not necessarily
automatically require the implementation of a new reference
standard.
One has to consider what the effect of the process change has on the
critical quality attributes of the product In addition, the intended use
of the reference standard in question also dictates if it needs
replacing or not.
A reference standard should ensure that the product's properties are
representative of the clinical trial material not production processes
that make a comparable product.
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Session 3 Questions: Reference standards
and their replacement
Under what circumstances does a process change require
the implementation of a new standard?
However, a new reference standard is not necessary if a process
improvement slightly alters the impurity profile without an
accompanying impact on potency nor the ability to compare to the
impurity profile of the existing standard i.e. no new impurities or
total loss of an impurity.
Therefore, even if the reference standard is no longer entirely
representative of the product delivered by the process, but does not
impact any of its uses, a new reference standard may not be
necessary following process changes.
In fact, a new reference standard lot should be implemented only
when absolutely necessary in order to ensure that the historical link
to the clinical material is maintained without disruption.
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Session 4: The role of Public Reference
Standards
How should public reference standards be utilized in the
reference standard program?
Public reference standards can be used to augment the reference
standard program because they represent an independent and
externally available material that is widely assumed to be stable for
long periods of time.
The continued stability of an internal primary reference standard can
be supported by periodic calibration against the international
reference standard. ICH guidelines stipulate that an internal
primary reference standard must be periodically compared to the
international standard, when available (ICH Q5C, Q6B).
The comparison to an international potency standard should minimally
consist of potency determination with a relative potency method
and a sufficient number of replicates to ensure an accurate
comparison.
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Session 4: The role of Public Reference
Standards
How should public reference standards be utilized in the
reference standard program?
However, the frequency with which this comparison is required, as
well as the necessary or preferred analytical tests, are not specified
in the guidelines.
Unless there are data to suggest that the primary reference standard
is not stable long-term, it is generally sufficient to calibrate against
the international standard on an annual basis or longer.
This frequency can align with the reference standard stability program,
for example, where the reference standard stability time points
occur annually after the second year of the study.
How often one is required to compare to a pharmacopoeial standard
remains obscure.
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Session 4: The role of Public Reference
Standards
How should public reference standards be utilized in the
reference standard program?
Beyond being a stable reference point to which in house reference
standard stability can be compared, if a product is labeled and
dosed in units, an International Standard is also intended to ensure
similar products manufactured by different companies that can be
used interchangeably have the same unitage and thus no efficacy
impact when switching.
Thus the establishment of a continuous unitage when replacing an IS
is essential.
However, one has to be sure that every product responds the same
way when compared to the IS and there is a need to define a
specific assay unless it has been proved that the IS performs
similarly in different bioassay systems.
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Session 4: The role of Public Reference
Standards
How should public reference standards be utilized in the
reference standard program?
Interim public standards or reference reagents can be created early on
in the development of products to aid research and product
development.
Pharmacopoeia standards are also used for compliance purposes to
state that your product meets compendial requirements (which
does have legal implications for things like the use by pharmacies
and for reimbursement) and thus can be labeled USP or EP
compliant.
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Session 4: The role of Public Reference
Standards
How do/should public standards (NIST, WHO,
Pharmacopoeia) inter relate to one another?
In order to prevent drift, the relationship between one public standard
and another must be carefully controlled.
A proliferation of standards, especially potency standards, can cause
issues for pharmaceutical companies.
A best practice is to create WHO and pharmacopeia standards at the
same time (e.g. endotoxin standard), with greatly increased
volumes of material, to reduce the need to continuously change
standards as they run out.
Pharmacopeias do collaborate to try to harmonize monographs
through the PDG (but it takes for ever) and efforts are
made to harmonize standards across organizations.
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Session 4: The role of Public Reference
Standards
Should public standards be established for all commercial
products?
International standards are established by the World Health
Organization (WHO) as are other reference standards such as
those from the Pharmacopoeias or specific scientific/government
organizations such as NIST, ISICR or the Diabetes Foundation.
These materials are intended to establish standards for efficacy,
quality, purity and safety of a biological material, and allow for
activity to be reported consistently throughout the world as
International Units (IU) or other units defined by the standard.
Public standards are usually established through a collaborative study
that involves candidate preparations independently tested with the
analytical methodologies of participating laboratories.
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Session 4: The role of Public Reference
Standards
Should public standards be established for all commercial
products?
One potential hurdle to the establishment of public standards for
proprietary molecules is the potential for intellectual property risk. It
could be argued that a public standard, as a globally recognized
quality standard, only makes it easier for competitors to infringe
upon intellectual property. However, because the product is
already available commercially, the public standard does not
represent the only means of acquiring the molecule in question.
In fact, because public standards are commonly lyophilized in sealed
glass ampoules, a combination of product formulation and primary
packaging that is not utilized in any innovator product, a better
representation of innovator drug products is the commercially
available material, although drug substance provided may still be
easier to analyze than re-engineering publicly available drug
product.
49
Session 4: The role of Public Reference
Standards
Should public standards be established for all commercial
products?
Although the provision of drug substance might be seen as improving
the ability to analyze the material, a greater inherent risk is the
possibility that a similar molecule could be designated as the public
standard should the innovator choose not to lead or participate in
the collaborative study.
This could result in a scenario whereby the innovator would need to
compare in-house primary reference standards to a public
reference standard that was established from a biosimilar.
50
Session 4: The role of Public Reference
Standards
Should public standards be established for all commercial
products?
Given these considerations, it is advisable that the innovator lead or
participate in collaborative studies, when feasible, to establish
public standards for their products at a time when patents are about
to expire and yet give enough time for the standard to be created.
This approach will ensure that an innovators own molecules are
recognized as the global standard.
An additional benefit is that it establishes an independent material to
which the in-house primary reference standards can be periodically
calibrated without the concern that there may be subtle differences
between the two preparations.
51