Chemistry, Manufacturing, and Controls (CMC) is a critical component of drug product development. As a Senior Consultant in Drug Development, I serve as a representative for sponsors with the Contract Development and Manufacturing Organization (CDMO). The CDMO manufactures drug substances or drug formulations for safety studies and investigational drugs for clinical trials. This is a long-term relationship.
But why you should audit the manufacturer? This is a question that often emerges when the sponsor intends to test the product in clinical trials.
Here I’ll expand on why sponsors should audit the CDMO as well as go into when and how to conduct this critical check in ensuring the quality and safety of your drug.
Why perform an audit of the drug manufacturer?
The short answer is: the sponsor of a clinical trial is ultimately responsible for the safety of the test subjects.
Thus, according to Good Clinical Practice (GCP), the sponsor of a clinical trial is obligated to ensure that patients are not put at risk. Also, the study drug and its constituent active pharmaceutical ingredient (API) must be proven to be manufactured according to Good Manufacturing Practice (GMP). This must be under the control of the sponsor.1
If I invested a lot of money and devoted myself to such a tough and expensive task as developing a drug, I would not want to compromise on safety, quality, or control! By performing an audit, you have the chance to uncover any shortcomings in the procedures, training, or equipment at the CDMO. This goes beyond a phone call — quality control cannot be assured without an audit.
Failing to ensure the quality of the product early on can result in its disqualification, and then you are left without a drug to test in your clinical trial.
In the early development phase, the sponsor may be unaware of the extent of their responsibilities or the benefits of performing an audit. Sponsors often refer to the fact that no guideline explicitly states that sponsors are required to audit the GMP suppliers for an investigational medicinal product (IMP). That may be so, but Sponsor Oversight says that the sponsor must ensure that the manufacturing and quality systems of your GMP suppliers for the IMP meet regulatory requirements.
According to the U.S. FDA “ICH E6(R2)” guideline for good clinical practice, Section 5.13 “Manufacturing, Packaging, Labeling, and Coding Investigational Product(s)”:
“The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labeling should comply with applicable regulatory requirement(s).”1
Additionally, there are chapters that deal with IMP manufacturing in EudraLex, Volume 4 “Good Manufacturing Practice (GMP) Guidelines”:
“The qualified person should determine that equivalent standards of good manufacturing practice apply through knowledge of the quality system employed at the manufacturer. This knowledge is normally acquired through audit of the manufacturer’s quality systems. In either case, the qualified person may then certify, on the basis of documentation supplied by the manufacturer in the third country, and document the rationale for certification.”2
And the qualified person (QP) certifying the IMP shall have access to “Audit reports concerning the quality system of the manufacturer.”2
While it is not stated that a sponsor is required to perform audits of the CDMOs, sponsor oversight states that the sponsor is obliged to ensure that the manufacturing and quality system of the contracted CDMOs comply with the guidelines.
If there is no audit report authored by a competent auditor available, the QP at the CDMO may not feel confident about the manufacturer’s quality systems. In other words, the QP may decline to release the IMP. Furthermore, the ICH E6(R2)1 stipulates that the sponsor ensures that the IMP is manufactured according to GMP and local regulations. The sponsor can only meet this requirement if the sponsor performs an audit at the manufacturing site.
Approaching the question from a GMP perspective, it can be concluded that, according to EudraLex Annex 13,2 the sponsor is responsible for the quality of the IMP and for the implementation of an effective quality management system (QMS).
When should a sponsor perform the audit?
Ideally, the audit should be performed before the GMP manufacture of the drug substance (or drug product) is initiated. However, in any case, it should at least be conducted before the drug substance is included in the drug product to be used in clinical trials (so that the use can be stopped if the CDMO does not qualify).
How should the sponsor conduct the audit?
A GMP audit of the contracted manufacturer is a way for the sponsor to understand that the drug substance supplier complies with the GMP requirements.
For this task, a qualified auditor is contracted, and it is not uncommon for a sponsor’s representative to accompany the auditor to the on-site audit.
Preparation for the qualified auditor to inspect the CDMO will likely take 1–2 days and the on-site audit normally involves an additional 1–2 days. The audit work encompasses the (preferably on-site) visit and the review of the quality management system.
The on-site audit will assess key areas related to the proper manufacturing procedure of the specific substance or product, control and release of API, and bulk drug product, respectively. The GMP audit (in accordance with GMP EudraLex, Volume 4,2 for active substances and medicinal products for human use) to qualify a CDMO reviews the following (or parts of):
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- Quality system
- Personnel
- Facilities and equipment
- Documentation and data
- Production
- Quality control
- Qualification and validation
The auditor compiles eventual findings and suggestions for improvement in an audit report, which is shared with the CDMO. The CDMO then follows up with Corrective and Preventive Actions (CAPA) based on the outcome of the auditor’s report. Once the auditor is satisfied with the CDMO’s comments and corrective actions, the auditor writes and signs a letter to this effect to close the audit.
Additional benefits of performing an audit
There are several other benefits gained by performing an audit.
The sponsor gets to know about the manufacturer’s equipment, laboratories, quality system, competence, and staff turnover. The visit allows time for comprehensive discussions about the project, which also improves cooperation.
I have accompanied many audits as a sponsor representative. Both consultants and sponsors get a deeper understanding of the manufacturer and their processes, which is mutually beneficial for the work and collaboration ahead.
Interested in learning more? Contact us!
Notes
1. U.S. Food & Drug Administration. (2018). E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1).
2. European Commission. (2017). The rules governing medicinal products in the European Union. Volume 4, Annex 13. “Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014.”
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