Lethal injection: the issues in sterility assurance

In October 2012, an outbreak of fungal meningitis in the US was traced back by the Centers for Disease Control and Prevention to contamination in three lots of medication used for aseptically processed epidural steroid injections, packaged and marketed by a Massachusetts-based compounding pharmacy called the New England Compounding Center.

The consequences have been severe for everyone involved. Unfortunately, doses from the contaminated batches had already been distributed to 75 medical facilities in 23 states across the US, and administered to approximately 14,000 patients. As of September this year, a total of 750 patients were identified as having been adversely affected, 64 of whom had died. Within three months, the New England Compounding Center had filed for Chapter 11 bankruptcy, following an investigation by the House of Representatives, the Senate and the FDA, as well as the receipt of more than 400 lawsuits against it.

This is, thankfully, an isolated case; however, it illustrates precisely why standards and regulations covering the manufacture of injectable sterile products need to be technically demanding, and why specialised facilities, processes, workflow, monitoring and expert staffing are necessary to consistently conduct the activity to the standards necessary for patient safety.

"Given the potentially life-threatening implications for patients in failing to consistently do this activity well - particularly where the product requires the use of aseptic manufacture - regulators would not be doing their job if they did not focus on this area," says Peter Murray, former quality director at GlaxoSmithKline, who is an expert on quality and compliance management, and the management of third-party contract manufacturers.

"The regulations are there to protect the patient. Consistent manufacture of injectable products by aseptic processes to the required standards is not easy, or cheap. Patients, of course, are at significant risk of severe - possibly fatal - consequences if the required standards of manufacture are not consistently met," he adds.

Tightened regulations

Effective manufacture of injectable products, Murray advises, necessarily relies on a mix of inherent plant design features and good aseptic techniques by operators to achieve sterility assurance.

Murray argues that, while the regulations themselves have not changed much in the past ten years, what has changed is the regulatory administrative interpretation of what an emphasis on the need to avoid "human intrusions into the grade A sterile zone where possible" can reasonably be construed to mean in terms of facilities and processes, and the balance between sterility assurance from design and the role of aseptic techniques.

"Regulatory expectations of what constitutes current best practice for the manufacture of injectable products have increased," he warns. "This is something pharmaceutical companies need to be very aware of if they are considering adding the GMP control and supply chain complexities inherent in any contract manufacture to the existing complexities of injectable product manufacture.

"The key change is that, when considering the impact of operator intrusion into critical filling zones for injectable products as a key potential source of contamination by micro-organisms, regulators are taking the view that a lot more is possible in terms of eliminating intrusion by plant design and workflow that has, in many cases, been done historically. Excessive reliance on aseptic technique to cover plant and workflow design flaws is increasingly not considered acceptable," he adds.

If one is considering outsourcing one's injectable product manufacture (or indeed any pharmaceutical manufacture), one needs to be clear on a range of broad questions. Murray argues that key among these are: "Why you are doing it? What are the benefits you expect to see? What activities do you understand the contract to cover? And what are the benefits going to be for the third party?

"As a manufacturing authorisation holder, your responsibility does not stop at placing the product with a third party. For example, the new source will need to be registered, validation and supply stability data will be required, complaints must be answered and so on, and the contract-giver needs appropriate expert staff to oversee the management of these activities," he explains.

Murray is also adamant that companies need to be clear on just what the outsourced manufacturer's intentions are in terms of production. There needs to be transparency as to what their involvement is in the chain. Even if you just receive the product from them and then sell it, the expectations of both parties need to be clearly communicated to one another.

Murray continues: "Clear communication of which activities the outsourced manufacturer is expected to be doing is critical: are they just going to be manufacturing the product or will they be packaging it as well? Who, for example, will perform, and who will pay for, technical transfer, validation, stability testing and registration? Clear definition, communication and agreement of both your own, and the third party's, expectations are critical to any successful contract manufacturing arrangement.

"Good business practice and GMP regulations require effective oversight of the contracted activity by the contract-giver, using appropriate expert resources, and the regulator will hold the company named on the licence fully responsible for the product produced. Therefore, the contract-giver needs to be very clear."

Increased accountability

As well as communicating expectations with regards to regulations and responsibilities, there is also the matter of cost, which is of high importance to businesses in the current financial climate. Outsourcing does not always come cheap and headline costs need to be identified, particularly those relating to the product unit quoted as this cost will not include additional management expenses.

"With large pharmaceutical companies, the drivers will often revolve around being able to access specialist capability," Murray says. "For example, if you wanted to manufacture a cartridge syringe injection presentation, in order to set up your own manufacturing facility, it would - depending on the capacity - cost tens of millions of pounds and take a minimum of two years to construct, validate, register and bring into commercial production.

"If it is a relatively low-volume product, are you really going to set up your own plant to run half a day a week, or are you going to approach an expert manufacturer that deals specifically in this dose form, which is approved by multiple regulators and has provided similar services for many pharmaceutical companies? The latter is, clearly, economically the best solution for everybody including, of course, the patient."

This is particularly applicable when operating within the parameters of manufacture of injectable products. Under conditions such as these, achieving an informed balance between workflow management, sterility assurance and the aseptic technique of the human beings, who are necessarily within the critical areas of the plant, is of paramount importance.

As traditional manufacturing plants may not be optimised for contract injectable manufacture, in terms of workflow or plant design, it would be rare to achieve a fully automated process in compliance with modern GMP.

Accepting responsibility

"Deciding whether a particular plant has an appropriate balance between design and aseptic technique in providing assurance of absence of micro-organisms is, essentially, an exercise in advanced risk analysis," Murray explains.

"There is no 'one size fits all' checklist for this risk analysis - for example, scale of manufacture, physical form and potency of the active ingredient product, and complexity of the assembled dose form are just some of the factors that may need to be considered. With third-party outsourcing of injectable products, one issue is have you got, or can you find, a facility with the capability and proven track record to meet the standards that regulators now require?" he asks.

Some governments, Murray points out, are increasingly taking the line 'If you do not make it here, you cannot sell it here' and this can potentially lead to ethical and reputational issues for a manufacturer that is considering supplying injectable products in these countries.

"The insistence by governments on country-based manufacture does mean you can end up with a scenario when you have the delicate task of going back to them and saying: 'For this product, could you reconsider because, currently, we cannot identify a source within your country with the capability to manufacture to the standard we believe is necessary for patient safety and apply to all manufacturing of this product,'" he says.

"Ultimately, however, you need to recognise that you are attaching your company's reputation among patients and regulators to products produced by your contractor. Outsourcing anything is a challenge as you are creating a more complex supply chain that requires active, expert management of the potential product safety, regulatory compliance and reputational issues.

"Manufacture of injectable products to a standard that consistently ensures patient safety and regulatory compliance is one of the most technically demanding specialist activities undertaken by the pharmaceutical industry.

"Added to this are the complexities of entrusting this activity to a third party: something that is not to be undertaken lightly. If you are a large pharmaceutical manufacturer, your reputation with both patients and regulators is dependent on a proven record of consistent supply of satisfactory product. This means that you are likely to partner with specialists that offer a particular expertise or capacity, or have facilities in appropriate locations, and which understand and are implementing current best practice standards in terms of plant, processes and workflow," Murray concludes.