Drug Development and Manufacturing for PhDs

Simulation authors – Sophia Isis, PhD candidate at UT Austin
Job simulation vetted by professionals from CDMOs in the greater St. Louis area

Simulation Objective:

Evaluating Process Deviations

Associated Simulation Library:

Background

Within the pharmaceutical industry, a Contract Development and Manufacturing Organization (CDMO) is a biotechnology organization that provides clients with services such as drug development and drug manufacturing. For example, a cell culture development CDMO specifically focuses on the production of cell lines and media. This type of CDMO also commonly offers clients analytical services to analyze their cell environments to ensure optimal growth. 

Process engineers play an important role in CDMOs. The main function of a process engineer within this type of company is to oversee manufacturing protocols known as master batch records (MBR) to be used in manufacturing. An MBR documents the entire manufacturing process and the history of a product batch. MBRs provide detailed instruction on how a product is made (including equipment, product amount, temperature, time, etc), and records each step that happens for each batch. Utilization of the MBR helps to ensure that products are being produced safely, efficiently, and consistently by the scientists directly involved. MBRs are authored by the process engineers, which are reviewed by a cross functional team including quality assurance, quality control, manufacturing, process development, and the customer. These protocols are executed by manufacturing scientists who make the products. 

Process engineers then provide oversight of the manufacturing process, which typically involves the daily review of process data, review of MBRs  to determine that every step outlined is followed and identify areas for process improvement. When the paperwork reveals a deviation in the MBR, the event is documented and management is notified. A deviation is any unwanted event that differs from the approved processes, procedures, instructions, or specifications. A thorough investigation is completed to determine if the deviation resulted in any issues with product quality. Process engineers are a critical member of the investigative team to provide insight into how the deviation impacts the process and (if applicable) the product.At other times, deviations can be discovered through other paths such as changes in product quality. In situations such as this, a process engineer is asked to step in and investigate the manufacturing practices to determine the cause. 

Apart from a strong technical background and knowledge of regulatory guidelines, good communication skills are essential to be a process engineer. When deviations are the fault of personnel, it is their responsibility to discuss the problem and provide training. They are also the primary point of contact between the facility and its customers where they are involved in ensuring that stakeholder expectations are met while ensuring the manufacturability of the process.

The Process

  • Check documentation from standard operating procedures, MBRs, and logbooks to ensure consistent execution and manufacture of the drug substance

  • Identify and assist in remediating manufacturing challenges

  • Working in interdisciplinary teams and engage with external stakeholders

  • Identify source of deviation as man, machine (equipment), material, method, measurement or milieu (environment)

  • Determine the level of severity, assess changes in product quality and if is it still acceptable for client use

  • Develop a course of action to resolve the current problem and prevent the recurrence of similar issues (e.g., train relevant personnel)

  • Communicate with the customer during the investigative process, its findings, and possible remediative actions

Resources

The Exercise

For this exercise, you are a process engineer at a cell culture development CDMO. You will be evaluating two different manufacturing deviations and using the details to determine whether there was a product quality impact.

Task 1 - Deviation Discovery

Read the example of a deviation that could occur in cell culture manufacturing. Write a brief summary (4-5 sentences) describing how the deviation was discovered, what went wrong, and how the deviation may have impacted the product quality. Refer to the Resources section for more information on deviations and industry cell culture protocols.

Task 2 - Identify Performance Indicators

Using the deviations in the example, make a list of cell culture performance indicators that could be used to assess cell culture viability (and therefore product quality) in response to the deviations.

Task 3 - Determine Possible Personnel Actions

[Advanced]

Based on the problems that occurred during the deviation, determine what, if any, correct action would be suggested for the personnel and staff involved. Note: Corrective actions ensure proper training of personnel involved in the affected processes.

Deliverables

Task 1

Summary of deviations and possible impacts on product quality.

Deviation 1: During an informal check, you discover that the incubator logbooks indicate that the cleaning cycle was not properly documented. You go to the incubator event log and see that “auto-zero” was not completed there, either. Additionally, the red CO2 cap had not been removed prior to use. Lacking control of the level of CO2 in the incubator could have negatively affected cell culture growth.

Deviation 2: Manufacturing scientists noticed that cell cultures were exhibiting varying degrees of growth profile and metabolic trend differences. The source of these variations couldn’t be identified even after review of documentation, inspection of the gas expeller and a screen for the presence of contamination in the cultures. Inspection of the bioreactors indicated that the temperature transmitter was out of calibration. Further investigation revealed that the bioreactors had died after a power outage 9 months previous. When bringing the reactors back online, they had reverted to factory settings and the temperature during cell culturing was not maintained in line with key performance predictors (were running at 34.7°C outside of the acceptable range 35.7-37.3°C). This resulted in some cell culture lots produced with the bioreactor operating at a temperature that differed from approved specifications leading to the observed changes in cell culture performance.

Task 2

List indicators to assess cell culture performance and viability

  • growth curve

  • pH changes

  • viable cell density

  • metabolic profiles using metabolite concentrations

Task 3

Identify what corrective actions, if any, to address with personnel.

It was determined that neither deviation resulted in a severe product impact and product recall would not be necessary. However, in both deviations, corrective actions would be recommended to ensure proper training of personnel involved in the affected processes. In Deviation 1, possible actions: The scientist notified of issues upon detection. The standard operating procedure (SOP) re-reviewed and verbal training of pertinent sections of SOP were emphasized to mitigate any future problems with incubator operations. An instructor-led training plan was put in place.

In Deviation 2, possible actions: It was determined that the root cause for the calibration failures of temperature transmitters was due to a procedural gap. Several facilitative corrective actions were made to prevent recurrences in the future including training of personnel and updates to facility procedures.

Additional Tasks

A professional in the field of Drug Development and Manufacturing may also perform these activities:

  • Process validation (statistical evaluation of processes to ensure that the parameters deliver a consistent product)

  • Technology transfer (process scale-up and facility fit)

  • Equipment qualification and commissioning (identifying new equipment and ensuring that it is suitable/usable for manufacturing use)

  • Floor support (support the technicians from a technical/troubleshooting standpoint)

  • Project management (manage and drive projects – typically process improvement initiatives – apart from customer programs)

Skills Used to Perform this Task

  • Root cause analysis

  • Research

  • Problem solving

  • Critical thinking

Skills Used in the Field

  • Knowledge of Good Manufacturing Practice and regulatory guidelines

  • Attention to detail

  • Collaboration

  • Communication skills

  • Technical knowledge (statistics, bioprocessing, chemistry, cell biology)