Inspection Readiness

Manufacturing is from Mars, Clinical is from Venus

Post by
Denise Lacey
Manufacturing is from Mars, Clinical is from Venus

Because we must make drugs before we test them, most young biotechs start their Quality Assurance departments with a leader experienced in manufacturing.  In small start-ups, that QA Head is often tasked with overseeing GCP quality in addition to GMP. A growing part of my consulting practice involves advising GMP QA heads on how to navigate the resulting “culture clash” (their description!) to improve communications with their GCP counterparts.  Below are the top five issues that GMP QA leaders find surprising:

In GCP, QA is viewed as consultative, not authoritative. For most sponsors, QA doesn’t approve clinical trial protocols or plans or have any kind of authority over GCP operations. The GCP QA representative may be expected to attend study team meetings, answer questions about regulations and Good Clinical Practice, and propose solutions to issues the team encounters. This “high-touch” approach can be a surprise to the GMP QA head who isn’t expecting GCP QA to be quite as resource-intensive.

GCP vendor relationships are complex. Manufacturing involves multiple vendors, but there are typically clear linear handoffs between drug substance, drug product, packaging, labeling, and distribution. GCP sponsors and multiple vendors, by contrast, are frequently enmeshed on a study team.  A data management CRO may interface with a monitoring CRO several times a day, for example, while the sponsor provides close oversight.  The sponsor may monitor sites in one region while another CRO handles a different region. Sometimes, one CRO oversees a laboratory or EDC vendor, but the sponsor holds the contract, or vice versa. Thus, when a quality issue occurs, the root cause typically involves the sponsor and may involve more than one vendor. The sponsor must play a significant role in coordinating GCP vendor activities and investigating GCP quality issues.

GCP audit programs are project-driven and, in start-ups, externally focused.  Site audits, Trial Master File audits, and in-process audits (which may span two or more vendors – see above) are the crux of the GCP audit program, while internal audits take a back seat. Vendor requalification audits are usually combined with in-process project-focused audits. Because of this, there are no hard-and-fast rules for developing a GCP audit program, such as a biennial requalification or annual review of internal systems. It’s a risk-based approach, and the clinical study team is accustomed to weighing in on how the risk is quantified.

GCP vendors’ quality departments are not typically active participants in the clinical study process. In CROs, QA’s function is primarily to give assurance that the CRO is following its SOPs.  Thus, complex quality issues that span multiple vendors are out of scope for the CRO’s QA group unless the CRO is specifically contracted to provide that service. CROs may audit clinical study sites or CRO processes associated with a sponsor’s study but typically do not share information gathered unless specifically compelled by a quality agreement. Most CRO SOPs also state that they will only notify the sponsor of a potential serious breach after they assess it internally, so the sponsor may not be alerted to a fraud accusation, for example, unless a quality agreement specifies otherwise.

GCP quality agreements are not standard and, when in place, do not address quality of services. GCP quality agreements are gaining traction, but when they are put into place, they rarely address key quality indicators for operational tasks. Instead, quality agreements are used to negotiate QA-to-QA interactions such as audit and inspection notifications, exchange of quality issue information, and serious breach processes. As noted above, CRO SOPs typically don't favor the sponsor on these topics, so the quality agreement is the place to negotiate better terms.

Good communication depends on common ground, which sometimes feels like building bridges between different planets.

Denise DeRenzo Lacey, RQAP-GCP, has over twenty years’ experience in clinical Quality Assurance and clinical development operations.  Her practice focuses on application of quality risk management techniques for clinical studies, including risk-based approaches to auditing, data quality and integrity, and SOP development.  She has provided consulting services to a wide range of pharmaceutical, medical device, biotech and CRO clients in the US and Europe and has held senior positions at Vertex Pharmaceuticals and Radius Health.