API Development - PANalytical · 2019-12-20 · ICH Q6A –Decision Tree 4 ... Sources of Elemental...
Transcript of API Development - PANalytical · 2019-12-20 · ICH Q6A –Decision Tree 4 ... Sources of Elemental...
© Malvern Panalytical 2017
API DevelopmentPurity and Stability
Dr Michael Caves
© Malvern Panalytical 2017
API?
• Active Pharmaceutical Ingredient (API) – Any
substance or combination of substances….intended
to furnish pharmacological activity (WHO)
• DMF – Drug Master File, a submission to the FDA
providing confidential detail about the manufacturing,
processing, packaging, and storage• ASMF – EU equivalent
• DMFs are created for API and follow the API
(whether used in house or sold to a 3rd party)
• Responsibility of Regulatory Head
19 August 20192
Generally refers to the active ingredient in chemical drugs
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Scientific Terminology
• Polymorphs: Different crystalline forms of the same API.• Considered the same APIs
• Pseudopolymorphs: Differently Solvation/hydration
forms of the same API• Considered the same API
• Salts: Any of numerous compounds that result from
replacement of part or all of the acid hydrogen of an acid
by a metal or a radical acting like a metal• Considered different APIs.
• Co-crystals: Crystalline materials composed of two or
more different molecules• one of these is the API
19 August 20193
Important for patents etc.
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API Chemical Development
19 August 20194
Control the Crystal form to ensure good yield and
processability
Discovery Formulation
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API Chemical Development
19 August 20195
Control the Crystal form to ensure good yield and
processability
Discovery Formulation
XRD
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API Chemical Development
19 August 20196
Control the Crystal form to ensure good yield and
processability
Discovery Formulation
XRD
Particle
Size
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API Chemical Development
19 August 20197
Control the Crystal form to ensure good yield and
processability
Discovery Formulation
Elemental Analysis
XRD
Particle
Size
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What parameters can be considered CMAs?
International Conference on Harmonization
Guidance on Q6A Specifications:
Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products:
Chemical Substances
• Specific tests and criteria:
• Physiochemical properties (pH, melting point, RI)
• Particle size
• Polymorphic forms / amorphous content
• Chiral identity tests
• Water content
• Inorganic impurities, based on process knowledge
• Microbial Limits
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Same Reg. Issues as Finished Product
• Poor API design and manufacturing leads to
poor finished product
• Regulation of API manufacturing as stringent
as that of finished product (GMP principles)
• Fallout can be worse, with API sold to 3rd
parties being used in multiple finished products
19 August 20199
Fallout often worse
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Polymorph Selection and CrystallizationSolubility optimisation
& Patentability
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When is solid form considered a CMA?
Do the forms have different
properties (e.g. stability, solubility)
Characterise the forms (e.g. XRD,
DSC, Spectroscopy, Microscopy)
No further test or acceptance
criterion for drug substance
No
Yes
Yes
Yes No
No
Can different polymorphs be
formed?No further actionConduct polymorph screening
Is the drug product safety,
performance or efficacy affected?
ICH Q6A – Decision Tree 4 (1&2) – Drug Substances
Set acceptance criterion for
polymorphic content in drug
substance
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When is solid form considered a CMA?ICH Q6A – Decision Tree 4 (3) – Drug Product
Does drug product performance
testing adequately control if polymorph
ratio changes (e.g. dissolution)?
No
Monitor polymorphic form during
stability of drug product
Does a change occur which could
affect safety or efficacy?
Yes
No need to set acceptance criteria
for polymorph change in drug
product
No
Yes
Establish product acceptance criteria
which control safety / efficacy
Establish acceptance criteria for
relevant performance tests
Need to specify polymorphs due to differential solubility
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Why is Polymorphic Form a CMA?
• Changing polymorph can alter bulk properties of API➢dissolution rate and solubility
➢bioavailability
➢chemical and physical stability
• Can have a direct effect on the ability to process and/or
manufacture the drug substance and the drug product• Polymorph monitoring used to improve production efficiency
• Knowledge of the complete set of possible polymorphs is
also important for patent protection. • A new crystalline form can be patented as a new
pharmaceutical product
• Polymorphic contamination can infringe on existing patents
Polymorphism can affect the quality, safety, and efficacy of
the drug product
✓ It is desired to produce and
characterize all accessible
polymorphs of a given drug
substance
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Poorly Soluble Drugs
• Polymorphic form modification optimises solubility• 70 % of API under development practically insoluble
• Amorphous forms more soluble but less stable
• Problems with API stability can arise• Soluble amorphous forms may rapidly transform to the
less soluble crystalline form during storage
• Polymorphism must be controlled to ensure
reproducible bioavailability after administration also
19 August 201914
What would once have been considered poorly soluble API
now dominate pharma development
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Developing Poorly Soluble API
• “~50% of drug candidates that
enter clinical trials fail due to
efficacy and safety concerns,
and the remaining 40% fizzle
due to patent concerns and
issues like solubility and drug
interaction” GSK CEO
• Available data suggest a 20 %
chance of costly solubility
problems during development
• Most stable polymorph not
observed in 15-45 % of API – post-
development stability risk19 August 201915
Polymorph Control Essential
Rotonavir (Norvir®)
Low Stability
High Solubility
High Stability
Low Solubility
Storage
at RT
6 months stop-
production
100s of M USD
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API Development. Polymorophism
• Rotonavir (Norvir®) capsules for treatment of AIDS• Selection of a less stable polymorph led to dissolution problems 2 years into production
• Disruption of production for 6 months, costing hundreds of millions of dollars
• Rotigotine (Neupro®), a transdermal medicine used to treat Parkinson’s disease• ‘Snowflake’ crystals appeared during storage due to formation of less soluble polymorph
• Led to product requiring reformulation in order to return to USA market – took 5 years
• Mebandazole• Form A is more stable but inneffective, whilst Form C is soluble and preffered as the active form
• Traces of form A in final formulation reduced shelf-life to a month in 4 cases – all failed to win
FDA authorisation
• Carbamazepine (Tegretol®)• Transition to thin anhydrous particles, with smaller particle size actually leads to slower
dissolution, due to the narrow shape of the small particles enabling conversion to the dihydrate
19 August 2019Title of the presentation16
(Brazilian Journal of Pharmaceutical Sciences vol. 50, n.1, jan./mar., 2014)
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Polymorph Identification Methods
• XRPD provides unequivocal proof of
polymorphism
• Other methods are helpful to further characterize
polymorphic forms
17
FDA Guidance
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Compound/form selection and characterization
• Automated polymorph, hydrates/solvates, co-crystals, salts screening
• Structural stability and phase transition determination under elevated temperature/humidity/light
• Highly sensitive Structural/polymorphic purity determination
19 August 2019Title of the presentation18
API Chemical development
19 August 201919 August 2019
Empyrean and Aeris
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Case study: oral solid dose products
Success
• Pfizer patented Atorvastatin (Lipitor)
polymorphs at the turn of the century• In 2003, Ranbaxy patented a new polymorph
• Pfizer claimed infringement of 2 of their patents
• Patent expiry in 2016-17
• Generic version sold in parallel since 2011
• Value of first-to-file: $600M (Dec 11 – May 12)
19 August 201919
Using a different (unpatented) polymorph as a generic
Failure
• In 1984, Glaxo released Zantac using Form
2 Ranitidine API (3.4 B USD sales by 1992)• In 1998, TorPharm applied for approval for a
generic version of Zantac, using polymorphic
Form 1 of the API (Ranitidine), the 1978
Glaxo patent for which had expired
• GSK demonstrated the existence of 0.5 %
Form 2 (still under patent) in the generic and
successfully barred entry of this until 2002
• GSK sales: ~$1.5 billion annually in 1997
• Loss to generics: ~$115M per annum• Assumes 25% market penetration and a 70%
price reduction
Sector Training: Complex Generics
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Elemental AnalysisCatalytic Residues
Toxic elements
Process-wear
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API Chemical Development
19 August 201921
Control the Crystal form to ensure good yield and
processability
Discovery Formulation
Elemental Analysis
XRD
Particle
Size
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Sources of Elemental Impurities in Developed API
19 August 201922
Adapted from ICH Q3D
Manufacturing
Equipment
Elemental
Impurities in
API
Catalyst
Residues
Container
Closure System
Drug
Substance
Water
• Impurities come from reactor vessels and from catalysts
used in reactors
• Main Toxic Elemental Impurities are the ‘The big four’:
As, Cd, Hg, Pb
• Further other elements possible (used in the process)
like Cr, Ni, V, Mo, Ir, Pt, Os, Rh, Ru, Cu
• Concentration levels are a few µg/g (few ppm)
• Even at this level, may be toxic for human consumption
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ICH Q3D
• Control strategy – if the risk
assessment concludes that elemental
impurities are below 30% of PDE, it
should be acceptable to rely on cGMPs
without regular testing of each batch
Heavy metal permissible limits
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ICH Q3D
• Transition metals frequently used:• Platinum
• Osmium
• Iridium
• Ruthenium
• Rhodium
• Palladium
• Catalysts intentionally added –
always require measurement
19 August 201924
Catalytic Residues
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USP chapters <232/233>
• New chapters to replace USP<231> Heavy metals
• <232> Elemental impurities – Limits• Drug product analysis and summation options
• Specifies Permissible Daily Exposure (PDEs) limits for different drug delivery routes
• NOW covers same elements and limits as ICH Q3D
• <233> Elemental impurities – Procedures• Describes two analytical procedures (ICP-OES & ICP-MS) + the criteria for acceptable alternatives
• Defines validation requirements for Accuracy, Precision, and Specificity
• <735> X-ray Fluorescence for metal impurities testing• Describes the use of Wavelength Dispersive XRF & Energy Dispersive XRF as qualitative and
quantitative method for heavy metal impurity analysis in
• Liquids
• Powders
• Solid Materials25
From 1st January 2018 onwards
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XRF not sensitive enough to replace ICP
• ICP-MS/OES - late stage development• Highly sensitive
• Methods already set
• Why take the risk
• XRF - API development stage• API, and impurities, undiluted here
• Good enough for people to predict what
the levels will be after formulation
• Production support – rapid response
time allows efficient optimisation of
manufacturing processes
19 August 201927
Works for API Development Assessment however
Technology LOD, typical
Drug impurities,
(ppt)
ICP-MS 1
ICP-OES 1000
XRF - General 1000,000
XRF – E4 100,000
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Case Study
• Optimisation of Palladium scavenging process to bring down to USP acceptable levels
19 August 201928
E1 – Pilot Plant for API Production Process Development
Method Feedback time Development Time
ICP-MS 1 week 6 months
Epsilon XRF 1 hour 2 months
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Summary
• Sensitivity• Detect trace differences
• Feedback time and ease of continuous operation• Reduced Development time
19 August 201929
API Development
Produce High Quality Drugs more efficiently and with less financial risk
© Malvern Panalytical 2017
API DevelopmentMorphological Characterisation
Dr Michael Caves
© Malvern Panalytical 2017
API Chemical Development
19 August 201931
Control the Crystal form to ensure good yield and
processability
Discovery Formulation
Elemental Analysis
XRD
Particle
Size
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Why API Particle Sizing?
19 August 201932
API SupplierAPI Development
Lab of an
integrated company
Contract
Manufacturer
(CMO)
API must be milled to a specific size
Tabletting
optimisationBioavailability Formulatability
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Is Particle Size critical to:
• Dissolution, solubility, or
bioavailability?
• Drug Product Processability?
• Drug Product Stability?
• Drug Product content uniformity?
• Maintaining Product appearance?
No drug substance particle size
acceptance criterion required for
solution dosage forms
When is Particle Size considered a CMA?ICH Q6A – Decision Tree 3 – Drug Substance
Is the Drug Product a solid dosage
form or liquid containing undissolved
drug substance
Yes
No
No Acceptance Criterion Required
No to
ALL
Yes to
ANYSet Acceptance Criterion
Drug Product Test
Decision Tree
ICH Q6A
Decision Tree 3
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Why Particle Size Matters
• Changing particle size can alter bulk properties➢dissolution rate and solubility
➢bioavailability
➢physical stability
• Can have a direct effect on the ability to process and/or
manufacture the drug substance and the drug product,
Particle Size affects bioavailability, processability and stability
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Processability
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Processability and particle size and shapeTabletting – Problems associated with direct compression
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• Particle size• Reducing the size of the particles increases the strength of the tablet
• However, greater adhesion can lead to voiding, cracking and breakage
• Affects flowability of powder into the die
• Particle size distribution• Close overlap between actives, excipients and binders
• Narrow distributions improve content uniformity
• Wider distributions increase packing density
• Particle shape• Affects the way particle pack together (max packing fraction)
• Affects flowability
Processability and particle size and shapeTabletting
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Size / m
1 10 100
Vo
lum
e (
%)
0
1
2
3
4
5
6
7
Fine Material
Fines + 10% Coarse
Fines + 20% Coarse
Fines + x% Coarse
Fines + 30% Coarse
Processability and particle size and shapeTabletting – Controlling the Packing Fraction
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Processability and particle size and shape
Flowlac 100 InhaLac 230 SpheroLac 100
Predicting processability for excipient powders
Fu, X., et al. Effect of particle shape and size on flow properties of lactose powders.
Particuology (2012), doi:10.1016/j.partic.2011.11.003
Particle size Particle shape
Flowlac 100
InhaLac 230
Flowlac 100
InhaLac 230
SpheroLac
100
SpheroLac
100
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What is important for processability?Predicting processability for excipient powders
Fu, X., et al. Effect of particle shape and size on flow properties of lactose powders.
Particuology (2012), doi:10.1016/j.partic.2011.11.003
Flowlac 100 InhaLac 230 SpheroLac 100
Air Permeability / Compactability Shear stress / Flowability
Effect of shape
Effect of size
Effect
of size
Effect of shape
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“Should include, at a minimum, control of the critical process
parameters and material attributes”
“Control of input material attributes…based on an understanding
of their impact on processability or product quality”
“Controls for unit operations that have an impact on downstream
processing or product quality (e.g.…particle size distribution)”
Processability and particle size and shapeICH Q8 (R2) – QBD Control Strategy
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• Having determined the ideal size and shape of particles during discovery;• How are these parameters affected by production processes and excipients?
• Surface abrasion (chipping) or fragmentation affect the dissolution behaviour differently
• Morphologically Directed Raman Spectroscopy (MDRS) allows us to follow the size and
shape of the API• Through different process
• And with different excipients
August 19, 2019Title of the presentation43
How do production processes affect particle shape
Chipping
Fragmentation
Processability and particle size and shape
© Malvern Panalytical 2017 19 August 201944
Understanding the effects of processing using MDRS
––– initial AP (Active Pharmaceutical Ingredient);
– – – API with lactose,
+ + + API with lactose & MCC;
–– + –– API with MCC.
John Gamble et. al. International Journal of Pharmaceutics 470 (2014) 77–87
Chipping
Fragmentation
Processing
Tumble blended
Processability and particle size and shape
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––– = initial API; – – – – = API in lactose formulation; + + + = API in lactose and MCC formulation; –– + –– = API in MCC formulation.
Understanding the effects of processing using MDRS
Cone milled Roller compaction
Similar low level attrition seen with tumble blended and cone milled processes
More pronounced, high level attrition from the roller compaction process
Both excipients caused more attrition than API alone
MCC caused higher level of attrition than lactose
Processability and particle size and shape
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What is important for processability?
19 August 2019Resolving analytical challenges in the deformulation of complex generics46
Polymorph CPolymorph B
➢ Combination of Raman and
size + shape enables
polymorph detection.
➢ Polymorph B is more regular
in shape (not needles) so will
be easier to process (high
flowability, less propensity to
break,).
VoC
Kevin Dahl Associate Director, Particle Characterization Core Facility, KBI Biopharma
Very positive about the G3-ID and the M4-ID is clearly an improvement. The new laser and spectrometer
make it -5x more sensitive which is a significant improvement for small molecules and leads to a
reduction in run time of approximately 1/3rd”
Detecting the presence of different API polymorphs using
MDRS. M4-ID
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Bioavailability
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What is important for bioavailability?
Läkemedel och kristaller
Karin Lilltorp, Soren Lund Kristensen, Particle Analytical APS
Kemiivärlden Biotech, No. 9, September 2013
Xs = mass of solid drug
t = time
D = drug diffusion coefficient
S = surface area
Cs = drug concentration in diffusion layer
C = drug concentration in bulk
h = diffusion layer thickness
𝑑𝑋𝑠𝑑𝑡
=𝐷𝑆
ℎ𝐶𝑠 − 𝐶
Dissolution rate depends on particle size
Noyes-Whitney equation
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Controlling bioavailability
• If the particle shape is well understood and the production processes controlled• Then changing the dissolution behaviour can be a simple change in particle size distribution
Particle size distribution
0
1
2
3
4
5
6
7
8
9
10
0.01 0.1 1 10 100 1000
Vo
lum
e d
en
sit
y /
%
Size / um
Long Lasting
Fast Acting
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Controlling bioavailabilityHow does particle shape affect dissolution?
Particle size in
these 2 drugs is
the same
Why the different
dissolution
profiles?
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Bioavailability and particle surface area
High surface
roughness increases
particle surface area
and yields rapid
dissolution
Low surface
roughness decreases
particle surface area
and yields slow
dissolution
Convexity = Perimeter of circle with equivalent area
Perimeter of particle
Correlating dissolution performance with API particle shape from MDRS
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What is important for content uniformity?
August 19, 2019Title of the presentation53
Large particle size hinders uniform distribution of ingredients
XRPD data
RECALLS AND FIELD CORRECTIONS:
PRODUCT : Xactdose Phenytoin Oral Suspension, USP, 100 mg/4 mL unit dose cups, anticonvulsant. Recall #D-217-6.
CODE: Lot numbers: 508608 and 508613 EXP 2/97.DISTRIBUTION: NationwideQUANTITY: 1,947 cases were distributed; firm estimated that 10-15% of the product remained on the market at time of recall initiation.REASON: Due to large particle size, some of the unit doses may not meet potency specifications.
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Value of Joined-up Approach
Examples of physicochemical and biological properties that might need to be examined include
solubility, water content, particle size, crystal properties, biological activity, and permeability.
These properties could be interrelated and might need to be considered in combination.
• Polymorph testing and Particle sizing are the 2 most important factors in drug behaviour
characterisation (Critical Reviews™ in Therapeutic Drug Carrier Systems, 21(3):133–193 (2004))
19 August 201954
ICH Q8 (R2)
2.1.1 Drug Substance
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Data Integrity
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Data Integrity
• “The completeness, consistency, and
accuracy of data. Complete, consistent, and
accurate data should be attributable, legible,
contemporaneously recorded, original or a
true copy, and accurate (ALCOA)” – FDA
definition
• U.S. Code of Federal Regulations, Title 21
(Food and Drugs), part 11 (electronic records
and signatures).
19 August 2019Title of the presentation56
What is it?
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Data Integrity – Regulatory Focus
https://www.pharmaceuticalonline.com/doc/an-analysis-of-fda-fy-drug-gmp-warning-letters-0003
8/19/201957
Data-integrity associated with 60 % of FDA Warning Letters
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API Chemical Development
19 August 201958
Control the Crystal form to ensure good yield and
processability
Discovery Formulation
Elemental Analysis
XRD
Particle
Size
© Malvern Panalytical 2017
Key required Features
General Access Rights Audit Trail Electronic
Records
Electronic
Signature
Installed with
checklist (OQ) &
diagnostic testing
4+ configurable
User levels
Timestamps,
including user ID
and privileges
Records (inc Raw
Data) protected
from change
Cannot be edited,
deleted, copied or
transferred
Compatible with
Windows
Unique logins for
each user
Preserved
alongside data
Include User ID,
Equipment ID,
Sample ID, Time
Done using a
specific ID – no
collective IDs
Last test
recoverable after
a failure
Data can only be
modified by
authorised
Automatically
generated and
updated
Easily storable,
directly printable,
PDF format
Must involve
Password and ID,
with no replication
Allow the back-up
and archiving on
a network server
Use of Active
Directory
Cannot be
switched off
Simultaneous
Generation and
Storage of data
Different Sig. for
creation &
approval
19 August 2019Title of the presentation59
Based on previous questionnaires etc
© Malvern Panalytical 2017
General Access Rights Audit Trail Electronic
Records
Electronic
Signature
Installed with
checklist (OQ) &
diagnostic testing
4+ configurable
User levels
Timestamps,
including user ID
and privileges
Records (inc Raw
Data) protected
from change
Cannot be edited,
deleted, copied or
transferred
Compatible with
Windows
Unique logins for
each user
Preserved
alongside data
Include User ID,
Equipment ID,
Sample ID, Time
Done using a
specific ID – no
collective IDs
Last test
recoverable after
a failure
Data can only be
modified by
authorised
Automatically
generated and
updated
Easily storable,
directly printable,
PDF format
Must involve
Password and ID,
with no replication
Allow the back-up
and archiving on
a network server
Use of Active
Directory
Cannot be
switched off
Simultaneous
Generation and
Storage of data
Different Sig. for
creation &
approval
19 August 2019Title of the presentation60
Reason for
measurement
termination
given
Malvern Access
Configurator
Audit attached
to record,
separate from
system
Export
according to
SOP (flexible
template and
destination)
Measurer
cannot approve
Key required Features
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Cost of a Warning Letter
• Risk-based cost of warning letters is 1.8 million
USD per FDA-approved API Factory per year on
average• 4276 FDA-approved total manufacturing plants
receive Approx.76 Warning Letters associated with
data integrity per year, each costing approx. 100
million USD (a low-end estimate)
• A reduction in the probability of a FDA Warning
Letter by just 5 % would give a risk-based cost
saving of approx. 90,000 USD per facility per year
19 August 201961
Loss of revenue during stoppage, Remedial measures etc.
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Summary
• Sensitivity• Detect trace differences
• Feedback time and ease of continuous operation• Reduced Development time
• Versatility• Generate info on all components
• Software usability and compliance• Minimize Regulatory Risk
19 August 201962
API Development
Produce High Quality Drugs more efficiently and with less financial risk
© Malvern Panalytical 2017 Co
mp
any C
on
fidential
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Co
mp
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on
fidential