Just how connected are quality and the pharma-CMO relationship?
As the FDA begins to rein in the regulatory free-for-all that was the COVID-19 emergency use authorization (EUA) process, it has become clear that skyrocketing demand, truckloads of tax-free government funding, and an overwhelmed regulatory system can result in relaxation of the usual quality standards applied to pharmaceutical and medical device manufacturing. Forget a document or two here, use a small patient sample pool there, and – poof – you have an approved test/vaccine/drug that may or may not be up to pre-EUA standards.
Not surprisingly, the COVID-era EUA process has been roundly criticized for reducing the amount of validation testing and patient data required for most products to gain FDA authorization. And while most vaccines, tests, therapeutics and other medical products cleared for use have proven safe and effective, there are many others that have been pulled from the market amidst concerns about questionable results and patient safety.
Even well-established organizations are not immune. Astra Zeneca (AZ) and Johnson & Johnson (J&J) have recently been in the news thanks to patient safety and potential quality issues surrounding their respective vaccines. While both companies were quick to respond, the questions arising from the investigations center on not only the parent company, but the contract manufacturing organization (CMO) as well.
CMOs are standard practice in the pharmaceutical industry, allowing the parent organization to focus on drug discovery and marketing while the CMO handles everything from drug development to formulation to clinical trials and manufacturing. But if the CMO has a substandard quality management system and makes a mistake, the pharmaceutical company is ultimately responsible for the regulatory fallout.
It’s CMO, not CYA
Contract manufacturing organizations became an integral part of pharmaceutical manufacturing in 2008, following the financial crash in 2007. Funded largely by venture capitalists seeking new investment opportunities, these fast-growing manufacturing organizations offered comprehensive drug and device manufacturing services to big pharma companies trying to minimize their financial risk. The CMO took on the financial responsibility – and risk – for drug development, formulation, clinical trials, and production while big pharma focused on drug discovery and marketing. If the drug failed to reach the market, the CMO absorbed the loss, and the pharma company turned its attention to the next big thing.
However, working with a CMO still carries some element of risk. Pharma companies have no control over the project cost or schedule, and their intellectual property and other proprietary information flows freely between the company and the CMO, raising valid concerns about data security. If a CMO receives a warning letter for a regulatory deficiency, production grinds to a halt while the FDA swoops in to ensure the deficiency is properly addressed – and the pharma company must publicly tap dance around the delayed launch and/or reduced availability of the compromised drug.
Compliance is where the CMO rubber meets the road, and it is expected that these organizations adhere to good manufacturing practices (GMP) and implement a robust quality management system (QMS). But the responsibility for properly vetting a potential CMO and ensuring their suitability for partnership falls squarely on the pharmaceutical firm, as does the bad publicity when something goes wrong.
When the QMS Works, It Works Well
Johnson & Johnson is riding out a negative news cycle after their CMO – Emergent BioSolutions – found that a key ingredient in a recent batch of the much-anticipated, single-dose vaccine did not meet quality standards. What makes the story even more interesting is the fact that Emergent is also a CMO for Astra Zeneca, and some news reports have indicated that the ingredient mistakenly used in the J&J vaccine was intended and approved for use only in the AZ vaccine. A mix-up on the production floor led to the error, which Emergent identified, placing the batch – 15 million doses worth – into quarantine before it reached the vial filling stage. No patients were impacted, but it still caught the FDA’s attention, and now both J&J and the FDA are expected to send swarms of inspectors and GMP experts into Emergent’s Maryland facility to oversee vaccine production and audit the company’s QMS procedures.
Mistakes happen, even in carefully controlled environments such as this, and the good news here is that Emergent’s quality system caught the issue early on. One of the basic tenets of GMP is to prevent finished products from causing harm to customers, so Emergent’s detection of the error indicates that they do have a QMS system in place. And this is not J&J’s first rodeo, so they should have properly vetted Emergent BioSolutions before contracting with them for large-scale vaccine production. But because the potential for adverse events in the pharma industry is so high, companies need to remain vigilant, performing regular audits of their CMO’s quality system and documentation.
Keeping Bad Quality Out of Good Pharma
The FDA can audit pharmaceutical companies and CMOs at any time, without warning, to verify that a manufacturer fully complies with GMP and has full, documented control over their:
- Manufacturing Facility
- Raw Materials
- Operating Procedures (SOPs)
- Staff Training
- Quality of Finished Products
- Quality Management System
Regardless of how diligent the FDA may be in auditing contract manufacturers it remains the sole responsibility of the pharmaceutical company contracting with a CMO to verify that the manufacturer’s processes and analyses are in full compliance with all applicable regulations. Companies should perform audits of their CMO’s quality management system at least once per year to ensure that the manufacturer is following the most basic of GMP requirements – accurate and up-to-date documentation regarding their processes and procedures.
A shortage of written policies is a common deficiency noted in FDA warning letters, followed closely by a complete lack of evidence of a quality system at all. At a minimum, the CMO should be able to produce documented evidence of the following:
- Availability of written procedures
- Well-defined CAPA process
- Definitive product design controls
- Purchasing controls (including an Approved Supplier List)
- Process validation plan
- Production record review
- Testing and release plans, including stability testing of components, containers and closures
- Documented product complaint files
- Definition of the responsibilities of the quality unit
SOPs can make or break any audit of a CMO’s quality system, so pharma companies should carefully review all operating procedures to be sure they are accurate and show evidence of regular document control updates. SOPs should also reflect what is actually being done on the production floor, so a full, in-person facility inspection should be part of the CMO approval process. The expense of a thorough audit up front will produce plenty of investment return in the form of a quality product produced on time, on budget, and quarantine-free.
How Premier FDA Solutions Can Help
If a CMO doesn’t have a robust quality management system in place, the contracting pharma company can either work with the CMO to implement a quality program, or they can find another CMO. Most companies will probably opt to look elsewhere rather than incur the expense of implementing a QMS from scratch.
But if you’re a CMO looking to bolster your business, and need to strengthen your GMP and quality system, Premier FDA Solutions can help. We understand the importance of maintaining a proactive quality management system, and we have a range of right-sized audit services to meet your needs. We can assist you in preparing for GMP supplier audits, implement inspection readiness checks, and perform a gap analysis of your existing processes.
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