Copenhagen Workshop May 2014
Quality assessment
principles
Part I
L. Paleshnuik
Lead Quality Assessor
PQP
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Lynda Paleshnuik | May 2014
Overview
Elements of the assessment process
Approaches to assessment
 Using QRM principles
Issues of outstanding importance
Factors that add complexity
Low-importance sections
Reviewing the API – 2 common issues
The assessment report
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Elements of assessment
Assessors must:
Review the dossier
Write the assessment
report (AR)
These are equally important aspects.
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Assessment report (AR)
Understanding the dossier, the QOS and the AR.
The QOS is a template (next slide), filled in by the
applicant with a summary of information on the product.
The filled QOS becomes the basis for the AR.
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≈25 pages
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≈100 pages

The assessor reviews the data in the dossier,
confirming the QOS is summarized correctly, and
adds their comments, questions, discussions.
Dossier
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+
QOS-PD
=
AR
Brute force method (zero QRM)
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Brute force method
In this model the reviewer:
Jumps into the review without forethought
Reviews every section fully and in depth
Assigns equal importance to each section
Assigns equal importance to each dossier
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Applying zero QRM
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Don’t read every page of every dossier
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The importance of critical thinking
Critical thinking, if it is applied throughout the process,
allows for the greatest use of time to result in the highest
quality of the review process.
Quality risk management is an aspect of critical thinking.
Critical analysis is most important when starting a
review.
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Understanding quality risk management
QRM: the overall and continuing process of managing
risks to product quality
QRM can be applied to the assessment process (TRS
981 Annex 2, section 5.4, 2013)
For quality assessment, major risks include not making
the most of limited capacity (excessive resources on lower
risk dossiers), and delaying the availability of important
products on the market
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Finite capacity
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Decisions during the process
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Brute force method versus using QRM principles
You jump into the review without forethought
Significant aspects of the dossier are identified
(FDC? Solid oral or more complex? Immediate
release? Sterile?)
You review every section
Non-critical, non-important sections are identified
You assign equal importance to each section
Critical sections are identified to focus attention on
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Making QRM choices
The ability to make QRM choices comes from
experience.
However, there are some basic considerations.
1. Understanding issues of outstanding importance
2. Recognizing factors that add complexity
3. Understanding low-importance sections
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Issues of outstanding importance
The dossier and report are in CTD format
BUT
Some primary issues should be checked first
These issues may result in DELAY or
TERMINATION of the assessment
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Issues of outstanding importance
Primary issues: these may result in termination of
the assessment:
Issues of the biostudy
Biobatch size
Correct comparator
Acceptable biostudy or biowaiver
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Issues of outstanding importance
Primary issues: these may result in termination of the
assessment:
Issues of the stability studies (without getting into the data):
acceptable conditions (“room temperature” vs 30±2ºC, 75±5%),
packaging (representing proposed), batches (sufficient number,
size).
If no evidence of stability or bioavailability, can decide to stop
the assessment.
Note that a good screening process is helpful here.
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When beginning the review:
It is important to understand:
1. the solubility of the API
This topic is covered later in this talk
Consideration of the API solubility is necessary
throughout the assessment process
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When beginning the review:
It is important to know:
2.If there are related dossiers that have been
reviewed.
This is important both for consistency of approach,
and to minimize duplication of effort.
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Dossier screening process
Examines the completeness of a dossier
Checks for key data
Only dossiers meeting the minimum standards are
accepted for assessment
Without a (good) screening process, lower quality
dossiers are submitted/assessed, increasing assessment
time. One of the largest factors for assessment time is
the quality of the dossier.
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Absolute relationship
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Factors that add complexity
Unfamiliar or less common dosage form
Complex API synthesis or complex dosage form (e.g.
inhalation products)
FPPs with additional safety issues (e.g. sterile products)
Combination products (especially where the APIs are
incompatible)
Forms with modified release (EC, transdermals, ER)
Novel excipients
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Understanding low-importance sections
Not all data is of equal importance.
When capacity is limited, agencies can decide on areas to spend
less time on. (This should be defined, or each assessor will make
their own decisions.)
General low-importance sections:
Batch packaging records (most solid orals)
Compendial excipient specifications and COAs
Validation of GC methods for common solvents
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Understanding low-importance sections
Examples of agency-specific low-importance sections:
Less/no assessment of validation of methods
for companies with a good track record
No review of batch records when there is a strong
inspectorate
The decision is based on the capacities of the NMRA,
including laboratories, assessors and inspectors
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Examples approaches to method validation

Applicant is new to stringent requirements: review
their validation data in detail; check their calculations
for precision, linearity, etc; review their chromatograms,
review SST

Applicant is not new but errors have been identified
in the past: review their validation summary, spotcheck raw data, review chromatograms, review SST

Applicant is established: review their validation
summary, review impurity/assay chromatograms for
separation, review SST
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System suitability testing
Unlike validation, SST is part of the running of the
method.
Regardless of the approach to assessment of method
validation, SST should always be reviewed as part of the
method review for purity, assay, dissolution, residual
solvent methods.
This is important due to the inherent variability of
columns, column aging, variation in MP and eluting
solvent, instrumentation, etc.
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SST criteria – non-compendial methods
HPLC assay: precision (RSD ≤ 1% (API) or ≤ 2% (FPP))
and: either peak asymmetry/tailing factor (≤ 2) or
theoretical plates (≥ 2000) or resolution (≥ 2)
HPLC/GC purity: precision (RSD ≤ 5%*, up to 10% at
LOQ) and resolution (≥ 2)
TLC purity: limit of detection and specificity
(API/FPP/placebo spiked with impurities at their specified
limits)
*30 May
consider up to 10% for 0.2-0.5% level
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API – applicants must…
Applicants must demonstrate:

They have a valid source of the API

They have adequate understanding of the API (physicochemical properties, impurities, etc) Common issue #1

They can adequately control the quality of the API
(specifications, validated methods, reference standards)
Common issue #2

The API is sufficiently stable
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Elements of API sections
Applicants must:
Provide data on the API according to one of the 4 options
(PQ’d API, CEP, APIMF, full data).
Regardless of the option used, the dossier should include
sufficient info to show their understanding of the API
(solubility profile and hygroscopicity are critical, as well as
the impurity profile)
The elements that must be demonstrated by the
applicant,
must be understood and discussed by the
assessor in the
AR.
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Factors that add complexity: API

API is a product of fermentation – an understanding of
fermentation processes is required

API is sterile – understanding of sterilization processes is
required

API is low solubility – common issue with additional
considerations (covered next)

API is hygroscopic or moisture sensitive – considerations for
manufacture (e.g. avoid wet granulation) and packaging to
ensure stability; one standard test = BP = EP 5.11
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Low solubility API
The solubility of the API over the physiological pH should be
determined for every API
The dose solubility volume (DSV) should be calculated:
DSV =
largest dosage strength (mg)
Minimum concentration of API (mg/mL)*
DSV > 250 mL is a low solubility API
* Lowest solubility determined over pH 1.2-6.8 at 37◦C
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Low solubility API
Polymorphism must be investigated and controlled if necessary, and
particle size is critical.
These parameters are critical for any API with DSV > 250 mL, i.e.
any low solubility API.
An exception can be made when the manufacture of the FPP
involves fully dissolving the API. This is common with
reproductive health products, where an organic solvent is often used
for this purpose. In this case neither PSD nor polymorphism is
relevant.
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Low solubility API
Identifying critical issues:
Eg. Dossier where polymorphism is critical (BCS low solubility, different
polymorphs observed). Recent report correctly states it is critical, but
does not deal with it.
This is not meaningful unless you understand the
implications/necessary considerations and include them in the report.
Polymorphism: are there various forms? is one preferred? Is there a test in
specs? Does it ensure that form (e.g. XRD, DSC, IR)? What was the form
of the API lot used in the BE study? Confirm the reference standard has
the same form. Ensure the specs include the validated test/limits
(validated to show it can distinguish possible forms).
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API Solubility categories

BCS high solubility: the API soluble over the entire
physiological pH range (DSV < 250 mL)

BCS low solubility: The DSV is calculated based on the
lowest solubility over the physiological pH range. The
API is often still soluble at other pH(s) in that range.
(DSV > 250 mL)

Critically low solubility: The API is insoluble over the
entire phys pH range. (DSV > 250 mL)

An example follows regarding the change in an API
supplier.
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PSD and solubility
There are three situations:
API is BCS high solubility i.e. soluble over the physiological pH range
PSD is not critical
API is BCS low solubility (DSV > 250 mL) but is soluble at some phys pH
PSD is critical, a test/limits must be in API specifications (based on BE
profile)
API is critically low soluble (API is insoluble over the physiological pH
range)
PSD is critical, a test/limits must be in API specifications (based on BE
profile)
PSD should be in the retest parameters
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PSD and solubility
API is critically low soluble (API is insoluble over the physiological pH
range)
PSD is critical, a test/limits must be in API specifications (based on BE
profile)
PSD should be in the retest parameters
Note that PSD should be carefully considered, case-by-case.
Normal PSD limits are:
d10 NMT x
d50 xx-xxx
d90 NMT xxxx
For critically low soluble, consider the need for a range for d90.
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Low solubility API
QRM approach to low solubility APIs
The API has been found to have low solubility
What should be checked next (far ahead in the CTD
dossier), before getting into PSD and polymorphism?
Is it fully dissolved during manufacture. If so, you have
saved time reviewing PSD/polymorphism data (no longer
important considerations). (in 21 QOS subsections)
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Common API Issues
 Multiple suppliers or change in
supplier
 FPP manufacturer’s use of API
supplier’s methods
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Common API issue #1 – multiple API suppliers or
change in API supplier

It is acceptable to have more than one supplier of an API
as long as the quality of the API is adequately controlled
for each supplier.

When it is a low solubility API, the PSD and
polymorphic form (if relevant) should be representative
of the lot(s) used in the BE study, for API from each
supplier.
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Change in API supplier

A common FPP manufacturer complaint: they have
conducted the BE study with API from supplier A, but that
supplier is no longer available (or will not provide sufficient
info on the API).

Can they change the API supplier?


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Can they change the supplier without having to repeat the
BE studies using the new source?
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Change in API supplier

Full information is required on API from the new supplier, AND

The quality of the API must be adequately controlled for each
supplier.

This does not mean they must have the same impurity profile, but they
must have adequate controls based on their impurity profile (according
to potential impurities, residual solvents, etc)

When it is a low solubility API, the PSD and polymorphic form (if
relevant) should be representative of the lot(s) used in the BE study,
for API from each supplier. (See details for PSD, next slides)

If the above is established, new BE studies are not required and no
new stability data is required on the FPP, beyond the commitment for
studying of future batches
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Change in API supplier
PSD
The generally accepted variations from BE lot PSD results are:

D10 ± 45%

D50 ± 30%

D90 ± 45%
Where the values are < 10 μm, the values are doubled.
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Change in API supplier
PSD change
There are three situations:
API is soluble over the physiological pH range
PSD is not critical
API is low solubility (DSV > 250 mL) but is soluble at some phys pH
PSD is critical, a change must be within the tolerances, OR
Comparative dissolution may support differences outside these tolerances
API is critically low soluble (API is insoluble over the physiological pH
range)
PSD is critical, a change must be within the tolerances
Change outside these tolerances may require a new biostudy
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PSD change supported by dissolution data
For the low solubility API, where it is soluble at some phys pH:
 Comparative dissolution profiles can be used to justify a
change in PSD outside the tolerances:
 Multipoint dissolution profiles in 3 media (pH 1.2 or 0.1N HCl,
pH 4.5 and 6.8) without surfactant for:
One FPP batch made with the API with the new PSD profile
One FPP batch made with the API with PSD within the
tolerances of the BE lot
Dissolution profile data on the BE lot
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Common API issue #2
The applicant’s use of the API supplier’s methodology

The applicant must be able to adequately control the
quality of the API

Often the applicant adopts the supplier’s methods

How much verification and/or assessment is required for
the validation?
There are three basic scenarios, and in each case we are
assuming we have the full validation from the originating
site
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The applicant’s use of the API methodology:
Validation required
1) When analytical methods have been developed
in a GMP compliant facility and the original site
included intermediate precision, pursuit of
method transfer data is not required.
2) When both sites are within the same
corporation, method transfer data isn't usually
required. If there is a concern, the applicant should
confirm that a transfer report is available.
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The applicant’s use of the API methodology:
Validation required
3) For methods that come from a facility for
which GMP compliance hasn't been
established (e.g. APIMF holder), the applicant
is required to provide:
• complete validation, or,
• method transfer (specificity and
intermediate precision), or,
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The applicant’s use of the API methodology:
Validation required
Equivalency:
for
Results of NLT 2 batches at each test site.
For assay methods: e.g. COAs by both sites
the same two batches.
For impurity methods, results (both sites)
for samples spiked with the specified
impurities at their specification limits.
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Final assessment report (AR)
The AR is a very important document. The quality of the AR is
one of the biggest factors of the success of the assessment process.
That AR will be used throughout the rounds of assessment of the
dossier, and beyond:
In the review of variations
As a reference document for other dossiers
A good AR is useful as a training tool
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Absolute relationship
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Data we need in the first assessment report/round
Characterization of API lot used in the BE study
specially PSD/polymorphism of low solubility API
FPP dissolution data (biolot) in media over the
physiological pH range
Discriminatory data for dissolution method when
required (CR products, critically low soluble API)
This data should be requested as soon as possible.
Lynda Paleshnuik | May 2014
Final assessment report (AR)
Wrapping up the report will be covered in the
second talk on quality assessment principles.
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Summary
Elements of the assessment process
Approaches to assessment

Using QRM principles
Issues of outstanding importance
Factors that add complexity
Low-importance sections
Reviewing the API – 2 common issues
The assessment report
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