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Essentials of Auditing in the Manufacturing of Cell and Gene Therapies

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Released By CCRM

Our previous posts on quality management systems and steps to ensure your cell and gene therapy (CGT) product is Good Manufacturing Practices (GMP) compliant alluded to auditing in the context of a larger manufacturing workflow. This post provides useful insights into auditing to help clients and contract manufacturing organizations (CMOs) understand this critical aspect.

What is the Goal of Auditing a GMP Facility?

Auditing is a process that ensures a manufacturer or service provider can operate according to a set of agreed-upon requirements set by the customer. These requirements can be an independent standard, e.g., ICH Q7, U.S. GMPs (USFDA 21 CFR Part 210/211), or Health Canada GMPs (Part C, Division 2). Broadly, an audit will determine if a facility or firm is suited for production, testing, or acting as a service provider for a product. Audits should allow for testing of quality systems and facilities, and an evaluation of the staff and expertise in a facility. Also, audits can be carried out by potential customers looking for a CMO, and/or regulators as part of maintaining compliance (routine monitoring) or as a result of an incident (“for cause” audits).

How do GMP Audits Drive Improvements?

While the audit process can seem onerous, the feedback that it generates is often invaluable to an organization as it drives continuous improvements in service standards to better meet the needs of the customer.

The following are usually outcomes of a site visit by auditors:

  • Auditors will offer observations, feedback and suggestions and indicate if they were critical or non-critical to the current processes or if they can be considered a potential improvement. An observation report can also provide general recommendations. The process of creating the observation report often includes sharing a draft report with the CMO to confirm accuracy of content before the auditor issues the final report.
  • The CMO will generate a plan to close-out the observations, feedback and suggestions in the observation report, which is agreed-upon by the audit teams of both parties. This plan includes details on how each task will be addressed, target dates for completion of identified tasks and the department responsible for the closure of the observations.
  • The CMO can generate an audit closure report to document all observations and resulting actions.
General Auditing Checklist:

An auditing checklist is designed to enable systematic audit of a manufacturing facility. It typically covers the following audit segments:

1. Facilities: A review of basic facility design and personnel and material flow parameters including, but not limited to, environmental monitoring and cleaning procedures, documentation of equipment qualification, and HVAC system performance.
2. Staffing and Team: A review of the team members, their qualifications, and the training they have received (e.g., do operators have the right training to produce a CGT product?).
3. Quality Assurance (QA) Procedures: Evaluation of QA processes from batch record review to product release using a Quality Management System (QMS). Auditors might like to know how quickly the QA team can conduct this process and a fast turn-around time could provide a competitive advantage.
4. Quality Control (QC) Procedures: Evaluation of in-process and release testing procedures. Auditing will determine if the CMO has appropriate QC capabilities to perform the required tests on-site, or if outsourcing to approved third parties is required.
5. Supply Chain Procedures: Examination of procedures in place for storage, shipping, vendor approval and inventory management. The auditor will want to assess how the supply chain team ensures quality of the raw materials coming into the facility and the final products leaving the facility.
6. Outsourcing Control: Determining what services a facility outsources (e.g., quality control testing, transportation) and whether external providers meet relevant standards.

A Successful Audit Requires Careful Planning

Preparing before hosting an audit is critically important. This is best carried out with the use of an agenda, which includes the name(s) of the auditor(s), the reference standard to be used during the audit, and a brief outline of the interests of the audit. Depending on the auditor and the intent to audit, preparing for an audit requires different levels of planning to ensure minimal disruption to the facility’s day-to-day operations and to staff, while still enabling the audit to access the areas of focus. Maintaining the confidentiality of customers’ information, products and processes is paramount during auditing, as many documents will need to be reviewed by external parties.

In a typical site visit lasting one-to-two days, the audit process covers the following steps:

1. Introduction: A presentation to introduce the facility and team to auditors.
2. Facility Tour: A tour of the facility where auditors typically review client safety, evacuation procedures, available resources and equipment.
3. Supply Chain: Review of standard operating procedures (SOPs) for material control, packaging and labeling control.
4. Manufacturing: Interviews of trained personnel, review of process knowledge and SOPs for carrying out critical clean room operations in order to manufacture GMP-grade CGT product.
5. Quality Control: Evaluation of QC facilities and capabilities, including SOPs for analytical testing and environmental monitoring.
6. Quality Assurance: Review of SOPs for all QA procedures including management of deviations, and change controls.

In summary, an audit is a quality system evaluation that involves controlling inputs into the supply chain and reinforcing the input-dependent output principle of manufacturing. Successful audits from potential clients and regulators enhance an organization’s reputation and its ability to deliver quality therapeutic products for patients’ benefit. From preparation, to execution, to implementation of audit findings, auditing plays an integral role in the continuous improvement of systems governing GMP manufacturing capabilities.

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