2.3 solid oral manufacturing- common issues · 2.3 solid oral manufacturing- common issues . 8th...

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


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


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


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

:

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


- Measuring exhaust temp, product temp and drying time

Melt extrusion No Feeder speed, melt/zone temperature, melt pressure


Dry granulation: Compaction

No Roll gap, roller pressure, roller speed, horizontal and vertical 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 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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2.3 solid oral manufacturing- common issues · 2.3 solid oral manufacturing- common issues . 8th...

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