During the development cycle of a regulated therapeutic, the transfer of the manufacturing process is inevitable. The process will be transferred from the development lab to a pilot or small-scale manufacturing facility and, if the program is successful, to a facility for commercial manufacturing. With each transfer, important information needs to be readily available to the receiving party to ensure the required utilities, facilities, and equipment are available for the successful implementation of the manufacturing process. The tool used to transfer the information to the receiving party is called the manufacturing process description (MPD).

Definition of the manufacturing process description

The Parenteral Drug Association defines the MPD as:

A tool used to assist in execution of risk assessments, in the development of the Control Strategy, and for transfer of the process for commercial manufacturing. The manufacturing process is described as a series of constituent unit operations in a process description, block diagram, or process flow diagram that describes each unit operation, each with an accompanying process parameter table. Each unit operation in the manufacturing process is depicted with a similar level of detail . . .

The MPD is designed to capture and communicate information required to execute the phase-appropriate clinical or commercial manufacturing process. The varying groups that generate or summarize the information that comprises the MPD over the course of development are called the sending unit, and the group that utilizes the information to manufacture the drug substance or drug product is call the receiving unit. The MPD is a pivotal tech transfer document that facilitates a rapid and efficient transfer of process information and instructions from the sending unit (e.g., technical operations, product development or process development) to an internal or external receiving unit (e.g., clinical manufacturing, commercial manufacturing, or contract manufacturing organization).

Development of the manufacturing process description

The development of the MPD is an iterative process. The MPD is best created and controlled by a sponsor, rather than by a contract development and manufacturing organization (CDMO) assigned to perform the process and assay development.

Early development and first-in-human

In the early stages of drug development, process and chemistry, manufacturing, and controls (CMC) knowledge may be limited. Most of the available information at this point has been developed at the bench and pilot scale, and good manufacturing practice (GMP) is not introduced until the production of early clinical supplies. While it may be tempting to jump to GMP production after scale-up from the development lab, producing at least one non-GMP engineering batch at-scale allows the manufacturing facility to optimize the process and ensure that the newly developed process yields material meeting the critical quality attributes. Thus, a single GMP batch may be the extent of process knowledge at scale at the time of an Investigational New Drug application (IND) submission.

The MPD typically is organized by unit operation and, at this stage, includes:

• Process Flow Diagram or Process Flow Chart
• Brief description of the purpose of each process step
• Table of process parameters and set points or targets for each process step (process inputs)
• Chemical and reagent bill of materials (BOM), including Chemical Abstracts Service (CAS) number and grade, specific manufacturer, and part number if nonstandard material is required (i.e., growth media and chromatography media)
• Acceptable product contact materials
• Process solutions recipes, tests, and acceptance criteria
• Sample Map and drug substance or drug product testing plan, including instruments requirements (process outputs)

At this point in development, the set points and operating ranges should be considered estimates, since they have not been derived experimentally in most cases. In-process sampling during the early phase of development may be more extensive, as the process parameters have not been fully assessed for their impact of the critical quality attributes of the drug substance or drug product. It is important to specify the acceptable product contact materials for the in-process tubing and containers, as well as the final product storage containers, to ensure that the product is not lost during processing or storage.

Clinical development

As product development moves from the initial first-in-human trials to more advanced clinical stages, information pertaining to the process should also be increasing. Observation and small-scale experimentation should generate acceptable ranges for the process parameters, and a new version of the MPD must be created based on the increased process knowledge. These revisions to the MPD should be made under a change management process to ensure that process changes are adequately reviewed for product impact and process consistency. This can be especially important when a drug product or drug substance is manufactured at multiple sites.

An advanced MPD should include the following elements:

• Process Flow Diagram or Process Flow Chart
• Brief description of the purpose of each process step
• List of critical and noncritical process parameters and key performance indicators, with associated setpoints/targets and acceptable ranges
• List of critical and noncritical performance attributes with associated ranges, alert and action limits, and acceptance criteria
• Hold points and acceptable hold time
• Disposable BOM
• Chemicals BOM, including CAS number and grade
• Process solutions recipes, tests, and acceptance criteria
• Sample Map

Uses of the manufacturing process description

The information detailed in the MPD is useful in preparing requests for proposals and other necessary documents for determining if prospective manufacturing partners’ capabilities align with the process to be transferred. It may also be used for the development of sections 3.2.S and 3.2.P of an IND or other regulatory submission. In addition, during an investigation into a deviation during a manufacturing process, the MPD provides an important starting point in determining the root cause.

By creating and maintaining the MPD under change controls over the lifecycle of a product under development, a sponsor can ensure that the history of manufacturing changes and improvements to the process is readily assessable. This historic perspective can be invaluable when assessing product quality and its impact on patient safety and efficacy over the course of the preclinical and clinal development. Contact us to find out how Premier Consulting can help you prepare and maintain your MPD today.

Author:

Chris Hendry
Vice President, Technical Services

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