1. In your experience, what are the critical success factors for ensuring regulatory approval when transitioning from batch to Continuous Manufacturing?

To transition from batch processing to continuous manufacturing, companies need extensive manufacturing knowledge and equip their facilities with competent production, engineering, maintenance, financial, quality, and safety staff who will play crucial roles in continuous manufacturing operations.

The dossier should disclose a comprehensive and complete description of the scientific approach used to develop the process and identify the process controls.

 

2. What kind of support or tools would benefit the CMC Regulatory Affairs team when working on Continuous Manufacturing projects?

Process analytical technology (PAT) is perceived as the main enabler for a robust control strategy with continuous manufacturing (CM) because it can help implement CM throughout the entire life cycle.

The Residence Time Distribution (RTD) is a fundamental chemical engineering concept. By definition, it is the probability distribution of time that solid or liquid materials stay inside one or more unit operations in a continuous flow system. It can be used to characterize the mixing and flow behavior of material within a unit operation. Currently,  pharmaceutical companies are going through a paradigm shift from conventional batch to Continuous Manufacturing (CM). RTD has been recognized as one of the most important tools with several novel applications in continuous pharmaceutical manufacturing (Singh, 2024).

 

3. How can we demonstrate the equivalence of product quality attributes (PQAs) between CM and batch processes in regulatory submissions?

A continuous manufacturing system, especially with RTR and an increased number of critical quality attributes (CQA), requires greater and more significant effort to monitor the process continuously than a batch system.

The testing strategy for a drug product manufactured by a continuous process does not necessarily need to differ from the testing strategy for the same drug product manufactured by a batch process.

In practice, however, implementing a continuous or batch process or totally replacing laboratory-based methods with online or real-time analysis is a tough hill to climb. A number of product quality attributes, such as associated impurities, elemental impurities, and microbiological content, are not conducive to online analysis. Further, the same laboratory-based methods that one might hope to avoid in product release testing are still required for product stability testing.

 

Development and Manufacturing (CTD Module 3 Sections 3.2.S and 3.2.P)

4. What specific information should be included in CTD Module 3, sections 3.2.S (Drug Substance) and 3.2.P (Drug Product), to demonstrate compliance in a CM environment?

 

CTD section Information and Data[1]
3.2.S.2.6

3.2.P.2.3

 Manufacturing Process Development

·    Summary of the overall process development

·    Summary and justification of the control strategy, with links or references to the CTD sections that contain comprehensive information on the control strategy elements, for example:

o   Strategy for system start-up, shutdown and pause

o   RTD and material traceability information

o   Disturbance management (e.g., material diversion and collection strategy)

o   Sampling strategy, including sampling frequency

o   Equipment design and system integration aspects that are shown to be critical to output material quality

o   Process controls such as feedforward and feedback process control based on a measured attribute, if used

o   Development and justification of models#[2] were used in the control strategy (e.g., process model used for feedforward control, model associated with a PAT analytical method used for in-process testing and/or real-time release)

o   Justification for a range of batch sizes, where claimed
 3.2.S.2.2

3.2.P.3.2

 Batch Definition

·     Batch size or range, and approach to achieving the intended batch size or range
 3.2.S.2.2

3.2.P.3.3

 Description of Manufacturing Process and Process Controls

·    Narrative description of the commercial manufacturing process and flow diagram as described in ICH M4Q, clearly indicating which portion of the manufacturing process is continuous

·    Examples of CM-specific aspects of the commercial manufacturing process to be described are:

o   Equipment design and system integration aspects when critical to the output material quality

o   CM-related process parameters, controls, and criteria (e.g., input rates/mass flow rates, relevant feeder operating ranges), and location points at which process controls or testing is conducted

o   Location of active process controls if used

o   Criteria for product collection, including strategy for diversion
 3.2.S.2.4

3.2.P.3.4

 Controls of Critical Steps and Intermediates

·     Critical process parameters

·     In-process testing (e.g., sampling frequency, sample size, analytical method)

·     Relevant information, parameters, and criteria associated with ensuring correct application of process models used as part of the control strategy2 including contingency plan when the model is not available

·     Relevant information on active process controls, when applicable (e.g., limits of acceptability for controls that ensure monitored critical process parameters and critical quality attributes stay within desired ranges)
 3.2.S.4

3.2.P.5

 Control of Drug Substance or Drug Product

·     When models are associated with the analytical procedures for release testing of the drug substance or the drug product (e.g., NIR model, dissolution model):

o   Summary and justification of the model and the sampling strategy

o   Contingency testing and monitoring plans instituted for when the model is not available (e.g., when gaps in PAT data occur or in case of PAT equipment failure)

o   Analytical model validation information
 3.2.R Regional Information

·     Validation data for high-impact process models, if used.

·     Continuous process verification scheme, if applicable.

5. What are the risk assessment and management documentation expectations within Module 3 for a CM process?

A comprehensive criticality analysis should be conducted to determine an appropriate control strategy for the drug product CQAs. Based on the development knowledge and using quality risk management tools as described in ICH Guideline Q9, the drug product manufacturing process should be systematically evaluated to determine which process parameters and material attributes can potentially impact the CQAs of the drug product.

The criticality of the process parameters and/or material attributes should be assigned based on their impact on the drug product CQAs within potential operating ranges. This impact assessment is based on the product’s process development and manufacturing data, and/or on prior knowledge from process platform experience, scientific insight, or regulatory expectations.

 

6. How do you approach the presentation and analysis of PAT (Process Analytical Technology) data in CTD submissions for Continuous Manufacturing?

Analytical Model: %Potency by In-Line NIR PAT: A NIR probe is positioned in the feed frame of the tablet press for the in-line analysis of the lubricated blend just before compression into core tablets (Sampling Point 1). This in-line NIR PAT tool enables the determination of the drug substance concentration in the blend as defined by the %potency CIPC in Section 3.2.P.3.4 Controls of Critical Steps and Intermediates.

The in-line NIR PAT tool allows real-time monitoring of the blend’s %potency at a high frequency (e.g., minimum once per 10 seconds) throughout the runtime. Manufacturing deviations (e.g., feeder deviations) resulting in a potency CIPC result outside the specified range will automatically initiate the diversion of core tablets at the outlet of the tablet press (Diversion Point 1) until results are again within the specified range.

 

This article and interview were written by:

Author:

Jimmy Gandhi

CM Specialist

ProductLife Group

 

Co-Authors:

Mélissa Bou Jaoudeh

Innovative Product Development Officer

Research & Innovation

ProductLife Group

 

Alaa Abdellatif, PhD

Innovation Product Development Officer

Research & Innovation

ProductLife Group

 

Supported by:

Fabio Pedna

Team Lead

ProductLife Group

 

The interview was conducted with and answered by Jimmy Gandhi.

 

Bibliography:

  1. Singh, R. (2024). Residence time distribution (RTD) model: Novel applications to continuous pharmaceutical manufacturing. Pharma Focus Asia, (56). Retrieved October 10, 2024, from https://www.pharmafocusasia.com/manufacturing/residence-time-distribution-model
  2. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2022). ICH Q13: Continuous manufacturing of drug substances and drug products. https://database.ich.org/sites/default/files/ICH_Q13_Step4_Guideline_2022_1116.pdf

[1] Note. Adapted from “ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products,” by International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), 2022, https://database.ich.org/sites/default/files/ICH_Q13_Step4_Guideline_2022_1116.pdf.

[2] # The purpose of a model may vary (e.g., testing the quality of in-process material, drug substance intermediate, drug substance or drug product, real-time release testing, process control). Not all categories are covered in this table; information relating to the models should be submitted in the appropriate CTD sections identified in ICH M4Q guideline for these categories. For example:

  • Models used for drug substance release testing in 3.2.S.4;
  • Models used for in-process testing in 3.2.S.2.4 or 3.2.P.3.4;
  • Model used for both in-process testing and real-time release testing in relevant 3.2.S.4 or 3.2.P.5 sections, and incorporated by reference into the applicable Control of Critical Steps and Intermediates section;
  • Models used only for process development in 3.2.S.2.6 and 3.2.P.2.3.

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Continuous Manufacturing in Pharmaceuticals: Critical Factors and Success Strategies Part 2