common process related deficiencies · justification or adjust the amount of extra-granular...
TRANSCRIPT
Common Process Related
Deficiencies
Sharmista Chatterjee, Ph.D.
Division Director (Acting)
Division of Process Assessment II
Office of Process & Facilities (OPF)/OPQ/CDER/FDA
2016 GPhA CMC Workshop
May 18, 2016
Outline
• Overview of Process Review
• Some commonly seen deficiencies
– Focus: Solid oral dosage forms
• Submission expectations
• Conclusion
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Philosophy of Process Review • Begin with the ‘End in Mind’
– Evaluate adequacy of final commercial scale manufacturing
process
• Risk based review
– Focus on high risk unit operations
• Evaluation of proposed risk mitigation approaches
– In-process controls
– Setting of process parameter targets/ranges
• Integrate Process review with facility evaluation
– Identify any remaining issues for follow up during pre
approval inspection
– Assess outcome of process validation, if available
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Areas of focus in Process Review (typical solid oral dosage)
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1. Batch formula and commercial scale process flow diagram
2. Rationale for selection of manufacturing process
3. Identification of high risk unit operations
4. For high risk unit operations in depth evaluation of proposed mitigation
strategies (e.g. in-process controls, process parameter settings)
5. Scale up
6. Adequacy of manufacturing process description
7. Microbiological control
8. Comparability Protocols
Common Deficiencies: Batch Formula • No rationale provided for inclusion of overage You have proposed 2 % overage to compensate for manufacturing losses during commercial
manufacturing. However, you failed to provide any justification. Moreover, your assay value on
stability are all above 102% at all stability time points. You will need to reformulate your
formulation for the 100% target in case you fail to provide adequate justification with data.
• Possibility of variation in composition at commercial
scale The amount of extra-granular excipients (Croscarmellose Sodium and Magnesium Stearate) was
not adjusted based on yield of the milled granules. It is seen for the exhibit batches the yield of
the milling step after granulation varies from 96.5% to 98.1%, therefore, the composition of the
final blend changes according to the amount of available milled granules. Please provide
justification or adjust the amount of extra-granular excipients to ensure consistent batch
composition for commercial batches.
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Common Deficiencies: Defining
Manufacturing Process (I) • Difference in processing steps between exhibit/bio and
commercial batch
– No data provided to demonstrate intermediate critical material
attributes remain unchanged
For the exhibit batch wet granules were dried on trays by hot convection air in an oven.
Whereas, your proposed commercial batch for the drying of the wet granules uses
circulating hot water within the high-shear mixer granulator. Variation between these two
drying processes could lead to variation in granules porosity, density and particle size
distribution that could affect finished product CQA such as content uniformity, dissolution
Provide data to demonstrate that that intermediate material attributes of the granules
remains unchanged
• No rationale/data provided for proposed manufacturing
step(s) For the sifting/milling step you have emphasized the requirement of passing all the dried granules
through #40 mesh screen. However, no data is provided to support this requirement. Provide
data showing impact of this step on finished product CQA
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Common Deficiencies: Defining
Manufacturing Process (II) • Lack of adequate in-process controls to mitigate risk and
consistently assure quality Producing intermediate drug product material with consistent particle size distributions is critical
as it could impact blend uniformity, content uniformity and dissolution.
– Propose particle size acceptance criteria with upper and lower specifications for the base
granule PSD acceptance criteria, as justification for these limits include development data
which shows the proposed range would result in acceptable blend uniformity, content
uniformity, and dissolution.
• Proposed in-process controls not supported by provided
data Consistency of granulation is critical for assuring the consistency of the drug product with respect
to dissolution and homogeneity.
– Describe how the granulation end point was determined during development and for the
exhibit batches.
– Propose an end-point for commercial manufacturing and update the Master Batch
Records accordingly.
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Common Deficiencies: Defining
Manufacturing Process (III) • No measure of yield or reconciliation of intermediate
steps Measurement of yield is an estimation of robustness of the process, since deviation
investigations are typically performed if yield in the reconciliation section is outside of the
specification limits. In the commercial scale master batch record include yield limits.
• Potential of change in physical form of the active drug
substance during processing (e.g. polymorph conversion)
is not evaluated Active XX is known to exhibit polymorphism. Please provide any available data to show that there
is no potential for polymorphic transition during Active XX tablet manufacturing at commercial
scale and during stability.
• Hold time data not provided for high risk products
Given that API content is very low (500 µg) in this drug product and the drug product is
manufactured by direct compression, uniformity is a major quality concern. Indicate if the final
blend is stored prior to compression. Indicate what are the storage conditions and duration.
Provide available data to show that the storage conditions have no adverse impact on
homogeneity of the blend and compressed tablets.
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Common Deficiencies: Blend Uniformity
(BU) and Tablet Content Uniformity (CU) • Proposal to remove BU/CU testing without supporting data
Considering the low drug loading and potential for segregation, we believe the risk of non-
homogeneity in final product is very high. Hence, for routine commercial batches please perform
either blend uniformity testing (just before compression) or stratified content uniformity testing.
Upon obtaining data from statistically significant number of routine commercial scale batches to
demonstrate capability of the process to achieve consistent blend and/or content uniformity, if
needed you can then submit a supplement to the agency requesting removal of BU and/or CU in-
process tests with adequate justification.
• Setting of acceptance criteria for tablet content uniformity per the
withdrawn FDA draft guidance ’Powder Blends and Finished Dosage
Units—Stratified In-Process Dosage Unit Sampling and Assessment’
The acceptance criteria proposed for the stratified content uniformity testing for both validation
and commercial batches are not consistent with the current FDA standards. For guidance on
stratified CU testing see the Level II Q&A, at:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.ht
m#16. (Questions 15-18).
This document replaces the Agency’s draft guidance for industry – “Powder Blends and Finished
Dosage Units – Stratified in-process Dosage Unit Sampling and Assessment” which was
withdrawn as inconsistent with current Agency thinking. Please submit your sampling plan and
acceptance criteria for stratified CU test that conform to the new guidance.
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Common Deficiencies: Scale up
• Proposed process parameters for commercial scale not
supported by established scale up principles You have indicated that pre-lubrication and lubrication mixing time would be fixed at 15 and
5 minutes respectively, irrespective of the size of the double cone blender (5L, 25L, 100L,
200L and 750L) i.e. Lab, Exhibit and & proposed Commercial scale. Generally for scale-up
of blending operation in diffusion mixers, the total number of revolutions is maintained the
same among blenders irrespective of their sizes. Hence, mixing time should be higher for the
larger blender as its shaft speed decreases. Please explain the difference in your scale up
approach and provide a scientific rationale.
• Variation in equipment capacity utilization between exhibit
and commercial scale
– Risk not evaluated
– No in-process controls to mitigate risk
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Common Deficiencies: Manufacturing
Process Description • Process parameter ranges not provided
– Ranges listed as “To Be Determined/ Established”
Undefined manufacturing instructions and missing process parameters poses a risk to
product quality. While process parameters may be refined during Process Performance
Qualification (PV Stage 2), process parameters must be defined for manufacturing
operations to ensure consistency and quality.
Update the Master Batch Record to provide a product temperature setting or range. It
is currently listed as “to be established”.
• Inclusion of subjective operator dependent controls Granulation Step 7.2.2 states that extra kneading or extra purified water can be added “if
required”. Provide the criteria for these additional steps including how operators will assess
whether the material has reached the “required consistency of wet mass”.
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Common Deficiencies: Microbiological
control • Proposing to waive microbial detection without
supporting data Your proposal of waiving microbial limits release testing for your drug product may be acceptable if adequate
upstream controls are established and documented. More information on your process is needed. Address the
following points.
• Identify and justify critical control points in the manufacturing process that could affect microbial load of the
drug product.
• Define the maximum processing time for the wet granulation step.
• Define the maximum holding time for the coating solution(s).
• Describe microbiological monitoring and acceptance criteria for the critical control points that you have
identified. Conformance to the acceptance criteria established for each critical control point should be
documented in the batch record in accordance with 21 CFR 211.188.
• Describe activities taken when microbiological acceptance criteria are not met at control points.
• In addition to these points, address the following:
– Provide the results of microbial limits testing performed on exhibit or stability batches of the drug
product. Test method suitability should be verified (if compendial methods are used) or validated.
– You should minimally perform microbial limits testing at the initial stability testing time point. Provide an
updated stability schedule to reflect this testing.
12 Note: Above comment only asked when there is potential for higher risk of microbial growth
Submission Expectations (I)
• Providing rationale for selecting the process
Based on understanding of desired finished product CQA
Properties of the API and selected excipients
• Identification of high risk unit operations
• Control strategy considerations:
Data to support proposed process parameter ranges
Inclusion of in-process controls to enhance detectability and mitigate
risks
On-line monitoring (e.g. NIR) offer advantage of real time monitoring
Inclusion of a table comparing process parameters, equipment's, in-
process controls between batches manufactured across different scales
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Submission Expectations (II) • Scale up considerations:
Ensuring significant intermediate material attributes remain un-changed
across scale
Consider impact of variability of in‐coming material (e.g. due to change
in supplier)
Consider impact of change in equipment type, size and % utilization
Adopt scientifically valid scale up principles
Blend uniformity and tablet content uniformity
For guidance see the Level II Q&A, at:
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm#16
• Manufacturing Process Description
Include complete description of commercial scale manufacturing
process and flow chart
Provide commercial scale master batch
• No “ambiguous/subjective” steps
• Provide target/ranges for process parameters
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Conclusion • Goal is to implementation of a control strategy that mitigates
any scale up and technology transfer risks
– Assures consistent manufacture of desired quality product
• Regulators have been steadfast in encouraging industry to
adopt science and risk based principles for manufacturing
process development
• Providing necessary process related information in the
submission facilitates thorough evaluation of the proposed
manufacturing process and minimizes IR (Information Request)
cycles
• OPF process review is integrated with facility review that can
include pre-approval inspections, when appropriate
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Acknowledgements • OPF colleagues
– Rakhi Shah
– Bogdan Kurtyka
– Jennifer Maguire
– Masihuddin Jaigirdar
– Bob Iser
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