2.

3 Solid oral manufacturing-

common issues

8th CPH assessment

Wondiyfraw Worku training
Assessor May 2016

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 Some common issues related to solid orals

In this presentation,

- API attributes: Control of PSD and

polymorphism
- Dissolution profiling, selection of routine
method and limits
- Critical processing steps and parameters:
Granulation
- Hold time

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 API attributes- PSD

- Critical attribute when an API is insoluble according

to BCS solubility criteria
- Affects dissolution and bioavailability
- As well, could affect the FPP manufacturing
process (processability), e.g. flow properties and so
content uniformity of the FPP
- Particularly for direct compression or filling processes
and low dose products
- Distribution depends on method of sizing (e.g.
micronization) and method of size determination

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 Common analytical methods for determining PSD
in the area of solid orals
Sieve analysis Laser diffraction
provides weight distribution provides volume distribution

more suitable for larger particles suitable for wide range of particle sizes -micro
and millimeter range

Reproducibility problem uses instrument specific algorithm for size

determination- as a result different profiles
may be obtained, e.g. Malvern vs Sympatec,

With the two methods, different distributions are obtained unless particles are
truly spherical
Generally, laser diffraction preferred but according to USP <786> sieve analysis
may be used if at least 80% of particles are shown to have size larger than 75m

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How do we establish acceptable PSD limits for
routine control?
Tolerances used by PQ for laser diffraction method
(considering the inherit variability of the method):
Measured d10 d50 D90
size (result
for biobatch
API)
Size <= +/-90% +/- 60% +/-90%
10um

Size +/-45% +/-30% +/-45%

>10um

Usual format for defining limits

d10 d50 d90
Less than AA m Between YY-ZZ m Less than XX m

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Additional significant variations can also arise even when
same instrument is used at different testing sites or when
procedures for sample preparation are not consistently
followed
Example PSD by laser diffraction for a given API lot

d10 d50 d90

Test site 1, 10 15 19

Test site 2, Same 19 23 28

method as site 1

Therefore,
- Routine testing procedure should be applied consistently as was used for the biolot
API batch- to reduce factors that contribute to variations, e.g. sample preparation
steps should be applied consistently
- Results from another site can not be relied upon unless adequately validated based
experience on several batches to ensure minimal variations (as part of vendor
qualification)

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What are the reference values used to establish
routine limits?
We use results for the API batch used in the manufacture of the BE batch and
as obtained from testing performed by the FPP manufacturer

Example PSD by laser diffraction for biolot API batches

d10 d50 d90
Batch 1 (25% of the batch 9 19 25
quantity)
Batch 2 (75% of the batch 11 17 20
quantity)

Taking the extreme values of the two batches as reference:

- d10 limit: NMT 9m + (90%x9m)= NMT 17m
- d50 limit: 17m- (30%x17m) to 19m + (30%x19m)= 12m to 25m
- d90 limit: NMT 25m + (45%x25m)= NMT36m

If the difference between the two batches is significant: we can take the average values

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 Alternative API sources- Comparison of PSD

- Reference values: results for the API used in the biobatch

API from Tolerance API batch API batch

supplier A based on alternative alternative
(used in the biobatch source B (m) source C (m)
biobatch) (m) results (m)
d10 2 0.2-4 2 2
d50 39 27- 51 23 29
d90 125 68- 181 50 108

- Which alternative API has similar PSD as the biobatch

API?
- What is required to support the API with a different
PSD profile ? And what if the API is critically insoluble?

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 Common morphic forms and their importance

- Polymorphs, Solvates, Hydrates, Amorphous

- They may exhibit different
- hygroscopicity
- chemical and physical stability
- solubility and dissolution
- melting point
- And, so may affect
- bioavailability and bioequivalence of the FPP
- manufacturability of the FPP
- stability of the FPP

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 Control of morphic forms

- Common methods for routine control:

- X-ray powder diffraction (XRPD), most accurate method for
polymorphs
- DSC for polymorphs
- Spectroscopy (e.g., FT-IR, Raman) when demonstrated to
provide different spectra for known polymorphs, e.g.,
Rifampicin polymorphs;
- Solvent or water content, e.g. to differentiate between Darunavir
ethanolate and hydrated Darunavir which other wise show
similar XRPD pattern.

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 Routine polymorph identity test

- In general, when relevant for performance (i.e., when

at least one known form exhibits low BCS solubility).
However, the following scenarios may justify absence
of a routine test (based on ICHQ6A)
- all known polymorphs that are likely to be formed
demonstrate similar solubility
- when sufficient investigations of polymorphs that are likely
to form during manufacture or storage indicate that only one
single known form is expected under the mfg and storage
conditions
- however, usually such investigations are performed
inadequately and therefore we ask for routine control

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 Polymorph ID test- some times also required
in the FPP specifications
In most cases, polymorph ID test in the FPP is not required. However,
when
- thermodynamic unstable form is used
- the FPP manufacturing process involves change of the API form, for
example from crystalline to amorphous form,

- interconversion between hydrates and anhydrates (or solvates), due to

wet granulation is expected: water content, solvate content

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 Critically insoluble APIs
APIs which show DSV > 250 across the physiologic pH media
Example: Solubility DSV Example: Solubility DSV (highest dose
Nevirapine mg/ml (highest Efavirenz (mg/ml) strength= 600mg)
(mg/ml) dose
strength=
200mg)

pH 1.2 3.5 57 pH1.2 <0.1 60,000

pH 4.5 0.2 1000 pH 4.5 <0.1 60,000

pH 6.8 0.1 2000 pH 6.8 <0.1 60,000

Insoluble API Critically insoluble API

- Both APIs should be controlled for PSD at the time of release (and when multiple
forms are identified then for polymorph ID as well)
- Critically insoluble APIs should also be tested for PSD at the time of retesting and
during stability studies (and when multiple forms are identified then for polymorph
ID as well)

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Dissolution profile of biobatch- important reference profile
for process validation and future changes
Some of the critical aspects to check
- profile should be generated in the usual buffer media (pH 1.2,
4.5 and 6.8) as well as in the routine medium (e.g. water),
unless the API is demonstrated or known to be unstable in the
specific pH buffer
- usual time points- for immediate release products
- for very rapid release products (>=85% in 15 minutes) : 5, 10, 15, 20, 30
min
- for rapid release products (>=85% in 30 minutes ): 5, 10, 15, 20, 30, 45
- When >=85% is released between 30 and 45 minutes : 5, 15, 30, 45, 60
- Other cases- until at least 85% is achieved plus one more time point or
until asymptote is reached (which ever comes first)
- whether samples were immediately filtered using in line
(syringe filters) or online (at the end of sampling probe) filters
or both

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 Dissolution importance of appropriate sampling
times- example
Consider the following profiles that were submitted to
support a scale up in batch size:
5 min 10 min 15min 20 min 30 min 45 min
Biobatch Not 55 87 Not 100 100
available available
Biobatch 25 59 88 97 98 98
representative
Validation batch 17 42 74 91 97 97
(to support a
scale up)

-Can we use the biobatch profile as a reference to support the

scale up?
-And the biobatch representative profile?
-What does biobatch representative refers to?

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 Dissolution how do we determine whether a
proposed routine method is acceptable?
- Tests adopted from the following sources are usually
acceptable with out further justification
- Method described in a specific pharmacopoeial monograph
- USFDA dissolution database
- Other wise, the selected method should be justified
- Selection of medium, volume and rpm
- For example use of surfactants and amounts proposed, if
any, should be justified

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 Establishing routine dissolution limits
Whether the selected method is in-house or
pharmacopoeial, routine limits are considered product
specific and therefore should reflect the biobatch profile
as well as accelerated and stability data reported in the
dossier
It is preferred that the acceptable limit allows S1 pass.
Example: Model dossier
- Proposed method acceptable?
- Pharmacopoeial limit:
- Biobatch performance:
- Stability observations:
- Acceptable limit:

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 Critical processing steps

- Granulation, drying, sizing, blending and

compression/filling are generally considered
critical processing steps for all immediate
release solid orals- affect the most attributes of
a solid product
- Parameters for these unit operations should be
kept same or as close as possible to the
parameters used for biobatch

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Why do we demand that process parameters are kept same
or as close as possible to those used for biobatch?

Example: Granulation in high shear granulator

- amount of granulating fluid and addition rate
- Impeller and chopper mixing speed
- granulation time
Variations in the above parameters (and others e.g. API or
excipient properties), affect the granules in terms of
- granule size distribution
- flow properties
- density and porosity
- moisture content,
These in turn affect all characteristics of the final tablet,
including DT and dissolution.

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 Example: The effect of granulation time on mean granule
size at different binder quantities and at speeds of 200,
300 and 400rpm

Sima R, Fathollah F. Experimental studies on the effects of process parameters on granule properties in a conical high shear
granulator. Iran J. Chem. Eng. Vol 32, No. 3, 2013

Therefore, unless wide processing ranges are supported by a good design of

experiments/design space evaluation, parameters for production batches should
be established based on what were applied for the biobatch.

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Common critical process parameters to check
when reviewing granulation processes
Common Scale Key process parameters End point determination/control
granulation dependent
processes
Wet granulation in Yes Granulating fluid amt, addn rate, - Processing using exact same parameters
RMG, including impeller and chopper speeds, as was used for biobatch or as validated
spray granulation mixing times - Measuring current withdrawn or torque
- requires 8-15% developed by the chopper and impeller
granulating fluid Spraying rate, atomization air
pressure for spray granulation

Wet granulation: Yes Spray rate, atomization air - Processing using exact same parameters
FBD processor pressure, inlet temp, exhaust as was used for biobatch or as validated
- requires 15-30% temp - Measuring exhaust temp, product temp
granulating fluid and drying time

Melt extrusion No Feeder speed, melt/zone - Processing using exact same parameters
temperature, melt pressure as was used for biobatch or as validated
Dry granulation: No Roll gap, roller pressure, roller - Processing using exact same parameters
Compaction speed, horizontal and vertical as was used for biobatch or as validated
screw feed speed, number of
compaction cycle

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 Example: Comparison of granulation process as
described in BMR
Compare blank BMR with the executed biobatch BMR:
- Go to granulation steps (see the hand outs instead)
- Check if the granulation steps are adequately
described in the master BMR (see hand out 1)
- equipment type, capacity
- liquid addition parameters
- mixing parameters (speeds and durations)
- granulation end point determination
- Check whether these parameters are comparable
with those recorded for the biobatch (compare with
hand out 2)

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 Example contd
Comments to the applicant may include (given that the production
batch size is same as that was used for the biobatch).

- Remove the statement for subjective end point determination

- Since same scale is used, the granulation parameters should be set
to same values that were used for the BE batch(fluid amount,
mixing time, and speed)
- Remove the instruction for additional liquid (IPA) use and
granulation
- When production size is larger than biobatch size, we may allow
use of ampere/torque recording with better defined granulation
parameters

See hand out 3 for the applicants response (revised blank BMR)

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 Hold times
Holding intermediates, for a few to several days
during manufacturing, is a common practice

Commonly held intermediate materials Allowed period with out supporting

stability data

Final blend/granule 30 days

Compressed tablets 30 days
Coated tablets 30 days
Maximum cumulative time from the date of API-excipient mixing to primary
packaging should not exceed 90 days

Ideally batch processing is completed within 30 days from the first date
on which the API is mixed with excipients

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 Example: model dossier

Determine if hold times are proposed

- check BMR, section 3.2.P.3.4 and QIS section
2.3.P.3.4
- supporting data provided?
- are test parameters acceptable (are they stability
indicating)? Examples provided in TRS 992 Annex 4
can serve as reference
- proposed hold time acceptable?

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 When cumulative period of more than 90 days is
proposed- additional stability data is required
Sufficient amount of
Held for the proposed period Remaining amounts of
Granules of at least 2
(e.g. 60 days) and sampled and the granules are
production batches
tested at appropriate intervals compressed to tablets
stored in a representative
container and at the
routine storage
conditions

Tablets held for the

Remaining coated tablets
are packaged in to the FPP
primary package and
samples are subjected to
normal accelerated and long
term stability studies
covering the approved shelf
life (e.g. 24 months)
proposed period (e.g. 60
days) and sampled at
Coated tablets held for the appropriate intervals
proposed period (e.g. 60 days)
and sampled at appropriate
intervals
Remaining core tablets
are coated

With this study, the individual hold times and cumulative hold time of 180 days are justified
- Shelf life for the FPP remains 24 months

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 When statements for retesting are included
Example: Hold time 30 days. Retest if not used within 30 days.
Is this acceptable?
Note that:
- Intermediate product specifications usually do not contain all
important parameters applicable for hold time study.
- Retesting implies undefined individual intermediate product
and cumulative holding time beyond the period validated by
stability data.
Therefore, statements for retesting are not allowed in BMRs
- Exceptional deviations should rather be recorded and
investigated as any other deviations in line with GMP

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 Thank you

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