WHO PREQUALIFICATION TEAM
2.3 Solid oral manufacturing-
common issues
8th CPH assessment training
May 2016
Wondiyfraw Worku
Assessor
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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
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 75µm
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,
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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 size (result for biobatch API)
d10 d50 D90
Size <= 10um
+/-90% +/- 60% +/-90%
Size >10um
+/-45% +/-30% +/-45%
Usual format for defining limits
d10 d50 d90
Less than AA µm Between YY-ZZ µm Less than XX µm
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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
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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Example PSD by laser diffraction for a given API lot
d10 d50 d90
Test site 1, 10 15 19
Test site 2, Same method as site 1
19 23 28
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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 Taking the extreme values of the two batches as reference: - d10 limit: NMT 9µm + (90%x9µm)= NMT 17µm - d50 limit: 17µm- (30%x17µm) to 19µm + (30%x19µm)= 12µm to 25µm - d90 limit: NMT 25µm + (45%x25µm)= NMT36µm If the difference between the two batches is significant: we can take the average values
Example PSD by laser diffraction for biolot API batches
d10 d50 d90
Batch 1 (25% of the batch quantity)
9 19 25
Batch 2 (75% of the batch quantity)
11 17 20
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Alternative API sources- Comparison of PSD
- Reference values: results for the API used in the biobatch
API from supplier A (used in the biobatch) (µm)
Tolerance based on biobatch results (µm)
API batch alternative source B (µm)
API batch alternative source C (µm)
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 - 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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Example: Nevirapine
Solubility mg/ml (mg/ml)
DSV (highest dose strength= 200mg)
pH 1.2 3.5 57
pH 4.5 0.2 1000
pH 6.8 0.1 2000
Insoluble API
Example: Efavirenz
Solubility (mg/ml)
DSV (highest dose strength= 600mg)
pH1.2 <0.1 60,000
pH 4.5 <0.1 60,000
pH 6.8 <0.1 60,000
Critically insoluble API
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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: -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?
5 min 10 min 15min 20 min 30 min 45 min
Biobatch Not available
55 87 Not available
100 100
Biobatch representative
25 59 88 97 98 98
Validation batch (to support a scale up)
17 42 74 91 97 97
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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. 19
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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
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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.
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
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Common critical process parameters to check when reviewing granulation processes Common granulation processes
Scale dependent
Key process parameters End point determination/control
Wet granulation in RMG, including spray granulation - requires 8-15% granulating fluid
Yes Granulating fluid amt, addn rate, impeller and chopper speeds, mixing times Spraying rate, atomization air pressure for spray granulation
- Processing using exact same parameters as was used for biobatch or as validated
- Measuring current withdrawn or torque developed by the chopper and impeller
Wet granulation: FBD processor - requires 15-30% granulating fluid
Yes Spray rate, atomization air pressure, inlet temp, exhaust temp
- Processing using exact same parameters as was used for biobatch or as validated
- Measuring exhaust temp, product temp and drying time
Melt extrusion No Feeder speed, melt/zone temperature, melt pressure
- Processing using exact same parameters as was used for biobatch or as validated
Dry granulation: Compaction
No Roll gap, roller pressure, roller speed, horizontal and vertical screw feed speed, number of compaction cycle
- Processing using exact same parameters as was used for biobatch or as validated
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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 applicant’s response (revised blank BMR)
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Hold times Holding intermediates, for a few to several days during manufacturing, is a common practice Ideally batch processing is completed within 30 days from the first date on which the API is mixed with excipients
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
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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
With this study, the individual hold times and cumulative hold time of 180 days are justified - Shelf life for the FPP remains 24 months
Sufficient amount of Granules of at least 2 production batches stored in a representative container and at the routine storage conditions
Held for the proposed period (e.g. 60 days) and sampled and tested at appropriate intervals
Remaining amounts of the granules are
compressed to tablets
Tablets held for the proposed period (e.g. 60
days) and sampled at appropriate intervals
Remaining core tablets are coated
Coated tablets held for the proposed period (e.g. 60 days)
and sampled at appropriate intervals
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)
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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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