Process Validation in Context of Small Molecule DS and DP Continuous Manufacturing Processes

Authors: Carly Evans (Akebia Therapeutics), Katherine Giacoletti, (SynoloStats LLC), Declan Hurley (Lilly), Robert Ievers [Co-Lead] (Merck), Matthew McMenamin (GSK), Jonathan Wade [Co-Lead] (Lilly)

*The views expressed in this Discussion Paper by contributing authors represent their personal views and do not represent the official position of individual companies or regulatory authorities. This paper is not a regulatory guideline and the information in this paper does not reflect agreements among authors on content of process validation documentation.

1 Introduction

This Discussion Paper discusses considerations for process validation (PV) activities with a specific focus on elements unique to continuous manufacturing processes. The intent is to acknowledge differences or additional considerations for continuous manufacturing processes without creating new definitions. In some cases, the concepts discussed in this paper may apply universally; however, the intended focus is on small molecule drug substances and drug products that leverage continuous manufacturing processes, whether for a new product development or post-launch conversion from batch to continuous manufacturing.

For clarity, some key definitions relating to PV for continuous manufacturing are:

• A Continuous Process is a process where, during normal operation, raw materials are continuously fed into the system at the same time as acceptable product is continuously removed from the system [1].
• The term Continuous Process Verification [2] refers to “an alternative approach to traditional process validation in which manufacturing process performance is continuously monitored and evaluated (ICH Q8).” Continuous process verification can be used in addition to, or instead of, traditional process validation.
  The term Continuous Process Verification is not to be confused with the term Continued Process Verification, which is defined in Section 3. This paper will not focus on concepts associated with continuous process verification since it is not unique to continuous manufacturing; rather, attention will be called to a few Continuous Process Verification related aspects relevant to continuous manufacturing processes for illustration purposes.
• Continued Process Verification, assurance that the process remains in an ongoing state of control during routine production (Stage 3 in the FDA PV Guidance [3]), is performed via the collection and evaluation of commercial batch data. Continued Process Verification is referred to as Ongoing Process Verification (OPV) throughout this paper to prevent confusion, and is also the term used in EU Annex 15 [4].

The benefits of continuous manufacturing for pharmaceutical production include operational efficiencies, real-time quality monitoring, and product segregation for non-conforming material. The sample integration has the potential to be an efficient fit for continuous manufacturing processes.

Data collection and monitoring tools such as Process Analytical Technology (PAT) are used in traditional batch manufacturing and can also be applied for continuous manufacturing processes. The use of these tools enables the collection of large amounts of process and spectroscopic data that can be utilized for feedback and/or feed-forward control beyond the subsystem at which the data is acquired. Data can be collected continuously throughout manufacturing that can feed into process models; therefore, the detailed quality of the batch can be known.

With this high level of automation and real-time monitoring, small changes or shifts in the process are readily detected. thus, the statistical methodology and business processes for analyzing and trending data from a continuous manufacturing process may be different from those for a batch process.

This Discussion Paper consists of three sections that are aligned with the PV lifecycle approach stages, namely Stage 1 – Process Design, Stage 2 – Process Qualification, and Stage 3 – Ongoing Process Verification, with a focus on additional considerations needed during the development and validation of a continuous manufacturing process. A fictional case study is presented in the Appendix to provide additional context to the concepts described herein. The example is specific to a solid oral dosage form product; however, the concepts can be considered for other small molecule manufacturing processes.

2 Stage 1 – Process Design

In Stage 1 the commercial manufacturing process is defined based on knowledge gained through development and scale-up/scale-out activities. The control strategy is defined and refined to ensure that the process is ready to progress to Stage 2. One of the primary aims of Stage 1 is to develop a control strategy to make sure that the output consistently meets the expectations as described in the Quality Target Product Profile (QTPP). At a high level, the main science and risk-based steps completed in Stage 1 are the same for both batch and continuous manufacturing processes:

1. Define QTPP
2. Define/review product Critical Quality Attributes (CQAs)
3. Define Critical Process Parameters (CPPs) that impact the CQAs
4. Perform initial risk assessment of control strategy, linked to CQAs
5. Execute studies (as applicable) and evaluate product/process data to understand relationships/interactions between process parameters and CQAs
6. Develop/refine control strategy and process parameter ranges
7. Perform final (residual) risk assessment of the control strategy; summarize the final control strategy and expected product performance based on data from Stage 1

Several unique considerations exist for the development of continuous processes. Continuous Manufacturing within a controlled and reproducible operation may have periods of process disturbance, for example, raw material feed rate fluctuations during process start-up. The potential for these disturbances should be considered and criteria developed to define and maintain the process in a state of control. When process performance is deemed outside its state of control, a process pause or a decision to isolate material can be engaged.

Read more by downloading Process Validation in Context of Small Molecule DS and DP Continuous Mfg Processes Discussion Papers.

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