New EMA Guidance on Real Time Release Testing.

This presentation is compiled by “ Drug Regulations”
a non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
10/12/2015 1

This presentation is compiled from freely available
resource like the website EMA, specifically Draft
Annex 17 titled
“ Real Time release Testing”
“Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
10/12/2015 2
Drug Regulations : Online
Resource for Latest Information

 What is Real Time Release Testing
 Conventional Vs RTRT
 RTRT Control Strategy
 Process Monitoring
 Examples of RTRT
Specifications/ COA
 Submission Requirements
 Documentation
 Parametric Release & Sterilization
 ICH Case Studies.
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 A product must comply with the requirements stated in
the authorized specifications for release and shelf life.
 RTRT
◦ A system of release
◦ Gives assurance that the product is of intended quality, based
on
 The information collected during the manufacturing process,
 Product knowledge
 Process understanding and control.

RTRT
 Following combination may provide greater assurance
of product quality than end product testing
◦ Process controls (critical process parameters)
◦ Pre-defined material attributes
 The RTRT principle used in routine sterility testing
◦ Terminally sterilized in their final container
◦ i.e. parametric release.

www.drugragulations.org 6
Input
Fixed
Process
Output
Disturbance:
Variation
due to
materials or
process Several days latter QC
End Product Testing

Input
Adjustable
Process
Output
Disturbance:
Variation
due to
materials or
process
Immediate Feed back/
forward loop
Process analyzers used to
measure process
parameters and adjust the
process
NIR
Interface

8
Assay (HPLC)
Purity, related
impurities, ((HPLC)
Residual solvent (GC)
Moisture content (KF)
Heavy Metals
Etc…
ID, Assay, CU (HPLC)
Purity, ((HPLC)
Dissolution,
Appearance
Moisture content (KF)
Etc
NIR, at-line (id
raw materials)
NIR, on-line
(reaction id)
IR, on-line
(purity, assay)
FBRM, on-
line (PSD)
NIR, on-line
(Moisture, purity
NIR, at-line (id raw
materials)
NIR, on-line, blend
homogeneity
NIR, on-line
(assay, CU, ID)
NIR, on-line, blend
homogeneity
ConventionalTesting

 EMA is now providing RTRT platform for for other
application based on
◦ Enhanced product knowledge
◦ Process understanding
◦ Use of quality risk management principles
◦ Application of an appropriate pharmaceutical quality system
◦ For new products as well as established marketed products

 Release of a product can be a combination of
 A RTR approach for certain critical quality
attributes (CQAs) and
 A more conventional evaluation for other CQAs
(partial RTR).

◦ Active substances
◦ Intermediates
◦ Finished products.
◦ Requirements to be fulfilled
◦ Need for interaction between quality assessors and GMP
inspectors in the approval process.

 RTRT may be applied during different stages of
manufacture
◦ Chemical
◦ Biological products
 May result in the elimination of all, or certain,
specific tests in the specifications.
 Guideline not applicable to investigational
medicinal products.

 Application of RTRT may offer advantages to a manufacturer
 Enhanced knowledge is welcome from regulatory point of
view
 Potential benefits
◦ Enable real time control
◦ Process intervention (feed-back or feed-forward options),
◦ Assessment based on a larger set of data
◦ Reduced overall operational cycle times.
 RTRT is not a mandatory requirement.

 The introduction of RTRT requires pre-authorization.
 A new M A or a variation should address only those quality
aspects that are specific for the medicinal product.
 Site specific quality aspects not specific to the product fall
within the remit of GMPs.

 RTRT may be introduced as a part of
◦ Application that is based on an enhanced product understanding
◦ Introduced following a variation of an existing market
authorization when
 more Experience has been gained
 Sufficient product and process knowledge has been demonstrated.
 Adequate risk management should be
demonstrated for both.

 Assessment of applications: Primarily made by the assessors,
 However assessors will closely collaborate with inspectors
 Input from both will form the basis for the approval
 Assessors will focus on the product related issues
 Inspectors will focus on the system related ones
 Approval as well as withdrawal of RTR testing is at the discretion
of the Competent authority.
 A withdrawal may be based on the results of an inspection or on
the receipt of other information.
 After approval of RTRT wishes to return to end product testing, a
variation of the marketing authorization is required.

 QP considers amongst others conformance to specifications
before release of product.
 For RTRT this this does not happen.
 However a specification has to be established
 Each batch of a product should comply with it if tested.
 A specification is also necessary
◦ For stability studies, to establish shelf-life
◦ and
◦ For Official Medicines Control Laboratory (OMCL) controls.

 RTRT application should be supported with
◦ Adequate validation of the RTR test method
◦ Clear understanding of relationship between the RTR test
and the end product test
◦ Clear understanding of associated specification
◦ Substantial comparative data at commercial scale (parallel
testing).

 When approved use RTRT for routine batch release.
 If RTRT fails or tends toward failure, RTRT can not be
substituted by end product testing.
 Any failure should be investigated
 Trending should be followed up appropriately
 Batch release decisions should be based on
investigation outcome
 Must comply with MA and current GMP requirements.

Manual
Simple
Automated & Advanced

Every product MUST have a control strategy
Drug product quality
controlled primarily
by intermediates (in
process materials)
and end
product testing
Minimal
• Drug product quality
ensured by risk-based
control strategy for
well understood
product and process
• Quality controls
shifted upstream, with
the possibility of real-
time release testing or
reduced end-product
testing
Enhanced approach

 NIR can be used for RTRT of water determination
 Conventional lab-based NIR system
◦ Validated over range 1 – 6%
 Tablets dried and “spiked” to encompass historical
range and regulatory specification
 Prepare calibration curve
 In line NIR for water content determination

 CQA: CU, dissolution,
 Crystal size during formation - PSD
1. Focuses beam
reflectance
measurements can be
used to measure PSD
2. Measure crystal
diameter
3. Probe inserted into
reactor

 FBRM used to define the best cooling ramp
 FBRM used to measure PSD inline
 RTRT of PSD
 No sampling and
 QC test

Design Space
MockP2example

In line Monitoring of drying Process

28
API
Excipient
Excipient
Blend Screen
Pass
or
Fail
Blend Tablet
Sample
&
Test
Sample
&
Test
Sample
&
Test
Fixed processes
Quality Criteria met if:
• Meets specification(s) (off-line QC tests)
• GMP Procedures followed
John Berridge, Pfizer www.drugragulations.org

29
API
Excipient
Excipient
Blend Screen
100%
Pass
Blend Tablet
Characterise
Standards and acceptance criteria for a PAT/QbD approach are not
the same as a “Test to Document Quality” approach
PAT PAT
Real
time
release
Adaptive
processes
www.drugragulations.org

 Liquid product, used to determine mix time
 CQA related to mix uniformity
 CPP’s (Critical Process Parameters) included agitator speed, time after
addition of one ingredient until the addition of another, solution
temperature, and recirculation flow rate.
 Process analyzer used was a refractometer
 Resulted in cost savings and quality enhancement
Mix
Tank
Pump
RI
Sensor
SCADA,
User
Interface
Control
System
Data
Historian

 In case of Equipment Failure
◦ Manage under Deviation system.
◦ M A application should have a contingency plan
 Alternative testing or monitoring approaches on a
temporary basis.
 Could involve use of end-product testing or other
options
◦ Maintaining an acceptable level of quality is
important.

 Approach will depend on process requirements.
 Strategy may be based on following, at appropriate steps
throughout the process
◦ Control of process parameters,
◦ Monitoring of product attributes or
◦ On a combination of both.
 Critically of the strategy should be based on
◦ A firm understanding of the process and
◦ Relationship between process parameters, in-process material
attributes and product attributes.

 May be applied to various manufacturing steps or
unit operations
 This can be based on of appropriate testing at
various stages.
 Some parameters/attributes are usually checked
routinely at defined intervals
◦ Uniformity of mass,
◦ Crushing strength
◦ Disintegration

 Results of a comprehensive set of in process
tests and controls may
◦ Replace the end product testing
◦ Offer greater assurance of the finished tablet
meeting specification, without the tests being
repeated finished product
 This is so as the amount of data will be
substantially larger.

 Reaction developed and
understood during development –
typical tools are IR, NIR and
Raman.
 At commercial scale NIR is used to
control the reaction.
 Stop the reaction at Maximal API
Concentration
 Stopping time differs from Batch to
Batch
 Real time release measurement of
the API assay and bi-product
(impurity)
 No sampling for in-process control
or end-product testing for this
CQA

Holistic Control Strategy e.g.:
Content Uniformity = Blend uniformity + Drug
concentration + Weight control
RTRT
1 = Blend Uniformity
2 = Granule particle size
3 = Weight, Hardness, Potency, Drug
concentration, Identity, Rate–controlling
polymer concentration

Process Control Philosophy - Paradigm Shift
Obtain raw
materials
Mix active and
excipeints
Press tablets Package
End of phase testing of quality, to reduce the risk in
moving to the next stage
Conventional approach - lab based
Obtain raw
materials
Mix active and
excipeints
Press tablets Package
P.A.T approach - process based, at-line or on-line
Continuously or more frequently test quality during each
phase, to remove the risk in moving to the next stage

Unit Operations
Attributes
Controls
Content Uniformity NIR
Water Content – NIR
Particle size – FBRM
Dispensation
Blending
Fluidized Bed
Dryer
Packaging
Tableting
Identity-NIR
Blend Homogeneity -
NIR
Granulation
Extent of Wet
Massing - Power
Consumption
Air
Scale
Multivariate Model (predicts
Disintegration)
Raw Materials

 If testing of units is part of the RTRT,
define
◦ Sampling strategy
◦ Number of locations sampled throughout the
batch
◦ Number of dosage units tested at each location.

 RTRT comprises
 Combination of process controls with the control
of relevant material attributes.
 Process Controls :
◦ Utilizes process analytical technology (PAT) tools
◦ Near infrared spectroscopy (NIR) and
◦ Raman spectroscopy (usually in combination with
multivariate analysis),

 Material Attribute Controls
◦ Spectral data monitored on-line controlling
◦ Content of active substance,
◦ Polymorphism,
◦ Water content,
◦ Blending homogeneity,
◦ Particle/powder properties or
◦ Film thickness
 This could replace end-product testing
 e.g. uniformity of content, tablet strength and drug dissolution.

 Continuous manufacturing processes,
 Discrete unit operations such as
 Distillations,
 Hydrogenations
 Crystallizations
 All sorts of other chemical reactions or
separations

 When RTRT is applied, the attribute that is indirectly controlled
together with a reference to the associated test procedure,
should still be included in the specification as “Conforms if
tested”
 The relationship between end-product testing, material
attributes, process monitoring and acceptance criteria, should be
fully explained and justified.
 In addition, the use of any prediction models should be fully
explained, justified and verified at the commercial site.

 RTRT can be implemented for
biological/biotechnological product, if it can be
demonstrated that acceptable level would be
maintained in the final product level, if tested.
 Following can justify the replacement of end product
testing on a routine basis by RTRT.
◦ Product/process understanding,
◦ In-process parametric control
◦ Attribute testing at an earlier step in the process

 A combination of in-process tablet weight, blend
content uniformity measurement
◦ Use of NIR for drug substance purity and
◦ Particle size could serve as a control strategy for drug
content of a tablet if the relationship has been
demonstrated.
◦ Core tablet weight, blend uniformity, drug substance
purity and particle size in this example are the RTR
tests.

 Attributes relating to the properties of a tablet
granule such as porosity, particle size, surface area,
bulk/tapped density etc. if shown to have a predictive
relationship with dissolution behavior could serve as
RTR testing surrogates for dissolution testing.
 These dependencies would have to be confirmed on a
product-by-product basis.

 RTRT for impurities for an active substance may
be achieved through control of starting materials
and
 Process parameters which directly impact
impurity levels, supported by empirical and
mechanistic knowledge of impurity formation
and purging during processing.

 Products coming from third countries into the
EU each production batch is required to
undergo in a Member State
◦ A full qualitative analysis,
◦ A quantitative analysis of at least the active
substances and
◦ All the other tests or checks necessary to ensure
the quality of medicinal products

 This normally means a complete reanalysis of the
product according to the approved specification.
 When a company has approval for RTRT , this
retesting would not be considered necessary for tests
which are approved as RTRT.
 Therefore a relief from this testing will be accepted.
 Identification upon receipt of material as part of GMP
will apply even if this test subject to RTRT.

 For some substances and dosage forms, the different
stages of the manufacturing process will be discrete.
 Therefore critical parts of distinct stages of the process
can easily be sampled.
 For other substances and dosage forms, the
manufacturing process may be partially or wholly
continuous,
 This requires a more integrated process monitoring.
 Therefore EMA has not specified how RTRT can be applied.

 This must be assessed in each individual case verifying that the
requirements of in the guidance have been met.
 The authorization of the RTRT programme will be granted for specified
sites
 This will be on the basis of an assessment of the product and process
understanding together with the proposed control strategy
implemented in accordance with GMP.
 Monitoring of critical parameters/attributes must be capable of
demonstrating that pre-determined validated conditions have been
achieved throughout the batch.

 In addition, assessors will evaluate
 The choice and limits of the critical parameters in
relation to their effect on the technical
characteristics, and
 Their potential impact on stability and bioavailability
of the product and its packaging.
 Methods of controlling critical parameters will also be
assessed and adequacy of operations evaluated on
inspections.

 The approval of RTRT by the competent authority
will be based on an assessment of the regulatory
submission
 and
 Knowledge of sufficient experience with the
process
 and
 GMP compliance at the actual site.

 The application upon which an authorization may be granted should
demonstrate (not unique to a RTRT application):
 That the pharmaceutical development studies have identified the critical
quality attributes for the finished product;
 That a risk based development program has been carried out;
 That a scientifically based control strategy has been developed and
implemented;
 That the manufacturing process is, or will be, validated adequately (as
evaluated on inspection);
 That in process requirements chosen for approval/rejection are decided
on the basis of the acceptance criteria defined in the development
studies

 The relationship between end-product testing and RTRT, including
justification of acceptance criteria;
 That clear, specified procedures are in place describing the reporting
and actions to be taken on approval/rejection;
 That the applied technologies gives an acceptable quality;
 Comparative test results (parallel testing) supporting the relationship
between the end-product specification and the RTRT where applicable;
 That the RTRT approach is equivalent to or better than the end product
test;
 That a contingency plan is in place

 Parametric release is based on
◦ Evidence of successful validation of the manufacturing
process and
◦ Review of the documentation on process monitoring during
manufacturing, without direct measurement of quality
attributes.
◦ It can be used as an operational alternative to end product
testing for the drug product in certain cases when approved
by the competent authority.
◦ Sterility testing for terminally sterilized drug products is
one example.

 Parametric release is referred to in the European
Pharmacopoeia monograph ”Methods of preparation of
sterile products”
 This states ”When a fully validated terminal sterilization
method by steam, dry heat or ionizing radiation is used,
parametric release, may be carried out, subject to the
approval of the competent authority.”
 That is the release of a batch of sterilized items based
on process data rather than on the basis of submitting a
sample of the items to sterility testing.

 The statistical limitations of the sterility test
in predicting sterility assurance are well
known and based on
◦ The small number of samples required for testing
in relation to the batch size and
◦ The limited ability of the culture media to enable
growth of all potential microorganisms.

 Sterility test will only detect major deviations in the
process resulting in the contamination of a large
number of units.
 By accurately monitoring relevant sterilization
parameters
◦ e.g. for moist heat sterilization;
 Temperature, pressure and time, data derived from
in-process monitoring of a validated terminal
sterilization process can provide more accurate
information

 This is because the probability of product bio burden
surviving the process in any single unit can be
calculated to be less than one in a million.
 Approval for parametric release eliminates the
requirement for a finished product sterility test as a
condition for batch release.
 The release of each batch is dependent on the
successful demonstration that predetermined, validated
sterilizing conditions have been achieved throughout
the load.

 The sterilization process in an application for parametric
release of sterility must be in accordance with the
requirements of the European Pharmacopoeia.
 Parametric release can only be applied to products sterilized
in their final containers by moist heat, dry heat or radiation.
 The choice of a sterilization process must be well founded
considering both
◦ Knowledge of the stability of the product under relevant conditions
and
◦ Data gained in development studies where critical process parameters
are identified.

 Inspections based on Parametric Release Inspection
 Inspector checks that SOP’s for the various stages in the
manufacturing process that are of significance for product
sterility are in place.
 In particular, the procedures for quality control of starting
materials, packaging materials, process water, steam and
environmental monitoring are checked.

 Other aspects of importance are for example
 Filtration procedures,
 Equipment cleaning/sterilization procedures,
 Maximum holding times for bulk solutions
 Quality of the cooling medium used in heat sterilization
processes
 Physical arrangement to separate non-sterilized and
sterilized loads.

 When parametric release has been approved this should be
routinely used for batch release.
 In the event that the results fail or are trending toward failure,
parametric release may not be substituted by end product
sterility testing.
 Any failure should be investigated and trending should be
followed up appropriately.

 A sterilization process shall be validated in accordance with
GMP guidelines.
◦ Qualification of equipment and validation
◦ Process which is applied at a particular time
◦ Heat distribution and heat penetration studies with a given, established
load
◦ Calculation of heat equivalents

 The technical validation of a heat sterilization method should
be complemented by microbiological performance
qualification.
 Consideration should be given to the level and heat
resistance of the microorganisms associated with the
product.
 When the sterilization process has been defined, its
reproducibility shall be demonstrated.
 Compliance with specific GMP requirements as described in
the annex 17 to the EU-GMP2 should also be demonstrated.

 An example of such a requirement is the segregation of non-
sterile products from sterilised products.
 There should be a readily apparent system of identifying
sterilized and non sterilized products.
 The distinction may be enhanced when process monitors
(color indicators and tapes which change after being
subjected to the sterilization process) are used to indicate
sterilization.
 However, these devices are only process indicators and do
not constitute absolute proof that the correct process
parameters have been achieved.

 An application for parametric release of sterility should be
supported by
◦ A description of the sterilisation process including type of cycle, load
pattern, specifications for cycle parameters (time, temperature, pressure,
F0/FH-value) and chemical indicators (if applicable);
◦ Specifications and methods/procedures used for in-process controls e.g.
pre-sterilisation bioburden, monitoring of cycle parameters and
verification of load sterilisation;

supported by
◦ A process validation report should be prepared comprising of following
◦ Heat distribution and heat penetration studies for at least three runs for
each load pattern used,
◦ A microbiological performance qualification showing sufficient efficacy
(SAL) at the minimum level of the cycle
◦ Information on the biological indicators used (type, D-value, Z-value,
stability), and bioburden characteristics (number, type resistance) as
applicable;

supported by
◦ A process validation report should be prepared comprising of following
◦ Heat distribution and heat penetration studies for at least three runs for
each load pattern used,
◦ A microbiological performance qualification showing sufficient efficacy
(SAL) at the minimum level of the cycle
◦ Information on the biological indicators used (type, D-value, Z-value,
stability), and bioburden characteristics (number, type resistance) as
applicable;
◦ Package integrity data (if applicable).

 Typically the specific sterilisation process for the product
proposed for parametric release should be the same as the
process already approved in the original application and
reference could, where applicable, be made to the previously
submitted data.

 It is suggested that the risk assessment presented in the
application focus on the failure to achieve sterility in each
unit of every batch. The risk assessment should include:
 Consistency of performance of the sterilisation process within
validated limits;
 Experience with the product applied for and similar products;
 Risks associated with any changes made to the product, or
process or equipment since the first approval;
 Steps taken to assess and control identified risks.

 Parametric release can also be applied in the case of
sterilization by radiation. The minimum absorbed dose
should generally be 25 kGy.
 Lower doses can be acceptable if justified by routinely
collected bio burden data comprising both count and type of
microorganisms as well as adequate validation data.
 The same requirements regarding documentation as for
sterilization by heat must be met where applicable.
 The documentation shall comply with the guidelines defined
by the EU in regard to ionizing radiation.

Example from ICH case study
Blending Process Control Options
Decision on conventional vs. RTR testing
Key message: Both approaches to assure blend uniformity are valid in combination
with other GMP requirements

Example from ICH case study

RTRT of Assay and Content Uniformity
• Finished Product Specification – use for stability,
regulatory testing, site change, whenever RTR testing
is not possible
- Assay acceptance criteria: 95-105% of nominal amount
(30mg)
- Uniformity of Dosage Unit acceptance criteria
- Test method: HPLC
• Real Time Release Testing Controls
- Blend uniformity assured in blending step (online NIR
spectrometer for blending end-point)
- API assay is analysed in blend by HPLC
- Tablet weight control in compression step

RTRT of Assay and Content Uniformity
• No end product testing for Assay and Content Uniformity
(CU)
- Would pass finished product specification for Assay and Uniformity
of Dosage Units if tested because assay assured by combination of
blend uniformity assurance, API assay in blend and tablet weight
control (if blend is homogeneous then tablet weight will determine
content of API)

Investigation of the effect of API particle
size on Bioavailability and Dissolution
Drug Substance with particle size D90 of
100 microns has slower dissolution and
lower Cmax and AUC
In Vivo In Vitro correlation (IVIVC)
established at 20 minute timepoint
Early time points in the dissolution
profile are not as critical due to PK
results

Multifactorial DOE study of
variables affecting dissolution
 Factors:
◦ API particle size [API]
unit: log D90, microns
◦ Mg-Stearate Specific Surface Area
[MgSt]
unit: cm2/g
◦ Lubrication time [LubT] unit: min
◦ Tablet hardness [Hard] unit: N
 Response:
◦ % API dissolved at 20 min [Diss]
 DOE design:
◦ RSM design
◦ Reduced CCF (quadratic model)
◦ 20+3 center point runs
Exp No Run Order API MgSt LubT Hard Diss
1 1 0.5 3000 1 60 101.24
2 14 1.5 3000 1 60 87.99
3 22 0.5 12000 1 60 99.13
4 8 1.5 3000 10 60 86.03
5 18 0.5 12000 10 60 94.73
6 9 1.5 12000 10 60 83.04
7 15 0.5 3000 1 110 98.07
8 2 0.5 12000 1 110 97.68
9 6 1.5 12000 1 110 85.47
10 16 0.5 3000 10 110 95.81
11 20 1.5 3000 10 110 84.38
12 3 1.5 12000 10 110 81
13 10 0.5 7500 5.5 85 96.85
14 17 1.5 7500 5.5 85 85.13
15 19 1 3000 5.5 85 91.87
16 21 1 12000 5.5 85 90.72
17 7 1 7500 1 85 91.95
18 4 1 7500 10 85 88.9
19 5 1 7500 5.5 60 92.37
20 11 1 7500 5.5 110 90.95
21 12 1 7500 5.5 85 91.95
22 13 1 7500 5.5 85 90.86
23 23 1 7500 5.5 85 89
Note: A screening DoE may be used first to
identify which of the many variables have the
greatest effect

-6
-5
-4
-3
-2
-1
0
API
MgSt
LubT
Hard
MgSt*LubT
%
Scaled & Centered Coefficients for Diss at 60min
N=23 R2=0.986 R2 Adj.=0.982
DF=17 Q2=0.981 RSD=0.725 Conf. lev.=0.95
MODDE 8 - 2008-01-23 10:58:52
API
Particle
Size
Mg
Stearate
SSA
Lubricatio
n
Blending
time
Tablet
Hardness
Mg St*LubT
• Key factors
influencing in-vitro
dissolution:
- API particle size is
the dominating
factor (= CQA of
API)
- Lubrication time has
a small influence
(= low risk
parameter)
Acknowledgement: adapted from Paul Stott (AZ) – ISPE PQLI Team

 Prediction algorithm
◦ A mathematical representation of the design space
for dissolution
◦ Factors include: API PSD D90, magnesium stearate
specific surface area, lubrication time and tablet
hardness (linked to compression pressure)
Prediction algorithm:
Diss = 108.9 – 11.96 × API – 7.556×10-5 × MgSt – 0.1849 × LubT –
3.783×10-2 × Hard – 2.557×10-5 × MgSt × LubT

 Account for uncertainty
◦ Sources of variability (predictability, measurements)
 Confirmation of model
◦ compare model results vs. actual dissolution results for
batches
◦ continue model verification with dissolution testing of
production material, as needed
Batch 1 Batch 2 Batch 3
Model prediction 89.8 87.3 88.5
Dissolution testing
result
92.8
(88.4–94.2)
90.3
(89.0-102.5)
91.5
(90.5-93.5)

Diss (% at 20 min)
Area of potential
risk for dissolution
failure
Design
Space
 Response surface plot for effect of API
particle size and magnesium stearate specific
surface area (SSA) on dissolution
Graph shows interaction
between two of the variables:
API particle size and magnesium
stearate specific surface area
Acknowledgement: adapted from Paul Stott
(AZ)
API particle size (Log D90)

 Controls of input material CQAs
◦ API particle size distribution
 Control of crystallisation step
◦ Magnesium stearate specific surface area
 Specification for incoming material
 Controls of process parameter CPPs
◦ Lubrication step blending time
◦ Compression pressure (set for target tablet hardness)
 Tablet press force-feedback control system
 Prediction mathematical model
◦ Use in place of dissolution testing of finished drug product
◦ Potentially allows process to be adjusted for variation in API particle
size, for example, and assure dissolution performance

Impact on Assay and Content Uniformity CQAs
 QRA shows API particle size, moisture control, blending and
lubrication steps have potential to affect Assay and Content
Uniformity CQAs
◦ Moisture is controlled during manufacturing by facility HVAC control
of humidity (GMP control)
Drug
substance
particle size
Moisture
content in
manufacture
Blending Lubrication Compression Coating Packaging
- Low risk
- Medium risk
- High risk
Degradation
Content uniformity
Appearance
Friability
Stability-chemical
Stability-physical
in vivo performance
Dissolution
Assay

Decision on conventional vs. RTR testing

DOE for the Blending Process Parameter Assessment to
develop a Design Space
◦ Factors Investigated:
Blender type, Rotation speed, Blending time, API Particle size
DOEdesign
Experiment
No.
Run Condition
Blending time
(minutes)
Rotation speed
(rpm)
Blender
Particle size D90
(m)
1 2 varied 2 10 V type 5
5 6 varied 2 10 Drum type 40
9 3 standard 9 20 V type 20
10 12 standard 9 20 Drum type 20
11 9 standard 9 20 V type 20
12 4 standard 9 20 Drum type 20

Blend uniformity monitored using a process
analyzer
 Control Strategy to assure homogeneity of the blend
◦ Control of blending
end-point by NIR
and feedback control
of blender
◦ API particle size
In this case study, the
company chooses to use
online NIR to monitor blend
uniformity to provide
efficiency and more
flexibility

 On-line NIR spectrometer
used to confirm scale up of
blending
 Blending operation complete
when mean spectral std. dev.
reaches plateau region
◦ Plateau may be detected
using statistical test or rules
 Feedback control to turn off
blender
 Company verifies blend does
not segregate downstream
◦ Assays tablets to confirm
uniformity
◦ Conducts studies to try to
segregate API
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0.045
0 32 64 96 128
Revolution (block number)
meanspectralstandarddeviation
Pilot Scale
Full Scale
Plateau region
Number of Revolutions of Blender
Data analysis model will be provided
Plan for updating of model available
Acknowledgement: adapted from ISPE PQLI Team

Conventional automated control of Tablet Weight using
feedback loop:
Sample weights fed into weight control equipment which sends signal to
filling mechanism on tablet machine to adjust fill volume and therefore tablet
weight.

Tablet
Compression
Pan
Coating
Sifting
Roller
compaction
Blending
Raw materials &
API dispensing
• Specifications
based on product
NIR Monitoring
Blend Uniformity
Laser Diffraction
Particle Size
Dispensing
NIR Spectroscopy
(At-Line)
• Identity
• Assay
• API to Excipient
ratio

 Real Time Release Testing Controls
◦ Blend uniformity assured in blending step (on-line NIR spectrometer for blending
end-point)
◦ API assay is analysed in blend by HPLC
 API content could be determined by on-line NIR, if stated in filing
◦ Tablet weight control with feedback loop in compression step
 No end product testing for Assay and Content Uniformity
(CU)
◦ Would pass finished product specification for Assay and Uniformity of Dosage
Units if tested because assay assured by combination of blend uniformity
assurance, API assay in blend and tablet weight control (if blend is homogeneous
then tablet weight will determine content of API)

This presentation is compiled from freely available
resource like the website EMA, specifically Draft
Annex 17 titled
“ Real Time release Testing”
“Drug Regulations” is a non profit organization
which provides free online resource to the
Pharmaceutical Professional.
10/12/2015 97
Drug Regulations : Online
Resource for Latest Information

New EMA Guidance on Real Time Release Testing.

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