Common Process Related Deficiencies

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1 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

2 Outline Overview of Process Review Some commonly seen deficiencies Focus: Solid oral dosage forms Submission expectations Conclusion 2

3 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 3

4 Areas of focus in Process Review (typical solid oral dosage) 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 4

5 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. 5

6 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 6

7 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. 7

8 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. 8 Provide available data to show that the storage conditions have no adverse impact on

9 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 nonhomogeneity 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 inprocess 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: 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 9 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.

10 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 10

11 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 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. 11

12 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 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

13 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, inprocess controls between batches manufactured across different scales 13

14 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: 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 14

15 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 15

16 OPF colleagues Rakhi Shah Bogdan Kurtyka Jennifer Maguire Masihuddin Jaigirdar Bob Iser Acknowledgements 16

17 Thank you! Questions, comments, concerns: 17

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