Calculating risk

25 September 2018



Last year, the International Society for Pharmaceutical Engineering released the second edition of ‘Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products’, to help manage the risk of cross-contamination in shared facilities. What kind of strategies does the guide recommend and what challenges does cross-contamination still pose to the pharmaceutical industry? Patrick Kingsland asks guide co-author Stephanie Wilkins.


Around the world, demand for highly potent drugs is on the rise. By targeting diseased cells more selectively than other compounds, toxic APIs have proved particularly popular in the pharmaceutical industry, driven by increasing incidences of cancer and the need for anti-cancer drugs.

According to a report by Grand View Research, highly potent active pharmaceutical ingredients (HPAPIs) account for roughly 25% of drugs currently in development. The report estimates that the HPAPI market will be worth close to $26 billion by 2022.

Despite their popularity, the toxic properties of HPAPIs pose significant challenges for pharmaceutical companies that are manufacturing and handling them. In mixed or shared facility laboratories, the danger of cross-contamination between different drugs carries particularly serious implications for patient safety.

The issue of cross-contamination first started to appear on regulator’s radars in the early 2000s, as increasing amounts of highly hazardous drugs emerged in the industry. While cost-conscious companies were keen to manufacture these drugs in the same facilities as other, less potent products, the regulators were concerned.

“They wanted to know how other products that were not in this potent, highly hazardous category were being protected when manufactured alongside these drugs,” says Stephanie Wilkins, one of the lead authors of the International Society for Pharmaceutical Engineering’s (ISPE) second edition of ‘Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products’ (Risk-MaPP), which lays out a risk-based approach for reducing cross-contamination.

Initially, the US Federal Drug Agency (FDA) believed the best course of action was to follow the so-called ‘penicillin model’. According to the Code of Federal Regulations 21, anybody manufacturing, processing and packaging penicillin must do so in separate facilities with separate air-handling systems.

A new approach

But not everyone agreed this approach was best applied to the new generation of potent drugs. In 2005, at an ISPE conference attended by Edwin Melendez, then of FDA, a group of pharmaceutical professionals argued that it would make the cost of drugs too high.

The group then began researching how to use ‘risk-based approaches’ that could allow pharmaceutical companies to safely co-manufacture different products together. That research eventually produced the first edition of the ISPE’s Risk-MaPP in September 2010.

Based on the International Conference on Harmonisation’s Quality Risk Management Guideline (ICH Q9), which was adopted by FDA in 2006, the guide encouraged pharmaceutical manufacturers to adopt risk-control strategies for the four main sources of cross-contamination in shared facilities: mix-up (when the wrong drug is used), retention (when residues are left in equipment after it has been cleaned) mechanical transfer (where contaminants are passed from non-product contact surfaces) and airborne transfer, when contaminants move through the air.

“It was a new concept at the time,” reflects Wilkins. “We were working extensively with FDA as well as with a European Medicines Agency (EMA) representative. They were struggling with how to update their GMPs to handle this issue, and were unsure whether to just list different types of compounds and say they need to be manufactured in a dedicated facility. The Risk-MaPP guide was designed to educate the industry and the regulatory bodies that there was in fact a scientific riskbased approach to doing this.”

While the guideline helped educate the pharmaceutical industry, in July 2017 the ISPE decided to publish a new version of Risk- MaPP to respond to a series of regulatory changes introduced by the EMA and the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S).

“These changes were very much in line with what we had done in the original Risk-MaPP but there were some nuances in the EMA regulations, and we also had more people using the process and more understanding that we did when we wrote that first version,” says Wilkins.

“We therefore updated the guide to bring in the EMA’s perspective. We also added a case study that was more in line with what we were seeing in the industry and we moved things around in the guide to sit in the appropriate ICH Q9 category.”

The second edition of Risk-MaPP specifically looks at the EMA’s “guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”. It suggests permitted daily exposure (PDE) and states on how PDE levels are determined in pharmaceuticals.

“Whereas we in the ISPE and Risk-MaPP world called them acceptable daily exposures (ADE), the new guideline called them PDEs,” says Wilkins. “So in the second Risk-MaPP, we put together a table that described the factors involved in coming up with PDEs and ADEs and showing how they come together.”

The new Risk-MaPP also looks at changes to chapters three and five of volume four of EudraLex, the body of rules and regulations that govern medicinal products in the EU. These updates aimed to provide improved guidance on the prevention of cross-contamination.

Analysts say the revisions to chapter three demonstrate a particularly significant shift in thinking from the EU, which had old rules that caused confusion in the pharmaceutical industry and requested dedicated facilities for certain products, such as penicillin and those using live pathogenic microorganisms.

“In order to minimise the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitizsng materials (penicillins) or biological preparations (from live microorganisms),” said the EU’s old guide. “The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should not be conducted in the same facilities.”

In the updated version, this proscriptive policy has been replaced by a criteria-based approach that determines whether a company’s policies and procedures allow it to handle potent drugs in shared facilities.

“It says if you cannot control the risk with technical and organisational controls you need a dedicated facility; if you cannot get a toxicological or a safe limit you need a dedicated facility; and finally, if you do not have analytical methods that can detect to at least the required residue limits, you need a dedicated facility,” says Wilkins. Chapter five of the EU guideline was also revised, setting out a series of measures that pharmaceutical companies should use to mitigate risk.

“It says that you should use a risk management process that enables you to assess what your risks are and leads to the controls required to manage that risk,” says Wilkins. “There are then listings of typical technical controls and organisational controls.”

A clear picture of safety

To help the industry understand how to assess risk and determine where control strategies are needed, the new Risk-MaPP provides an updated logic diagram that walks manufacturers through the lengthy process.

“The logic diagram is not meant for somebody to sit at their desk and read through in a single day,” says Wilkins. “It actually could be quite a long process. It should also be a multidisciplinary process, because different areas of the organisation bring different outlooks and specific aspects to the assessment.”

The guide asks, for example, if manufacturers have calculated ADE levels for their compounds – something that can take a considerable amount of time depending on the number of compounds in consideration and the workload of the toxicologist being used.

If the manufacturer cannot get ADEss calculated then the guide says a dedicated facility is required. If they can, it moves on to the next big issue: determining whether the manufacturer has analytical methods that meet or are lower than the product residue levels required.

In a section on risk analysis, the guide asks whether the manufacturer has the right technical and organisational controls in place to manage risk. In particular, it focuses on the four modes of cross-contamination (mix-up, retention, mechanical transfer and airborne transfer) discussing likely triggers for each.

It also focuses on how to review risk in the event of a new product or equipment being introduced into a facility. The guide takes the reader through a number of risk management tools including a fishbone diagram, again tailored to each of the four modes of cross-contamination.

Since the first Risk-MaPP guide came out, Wilkins says awareness of cross-contamination has improved in the pharmaceutical industry.

“From the first edition to now, we have come a long way,” she says. “At first, people were making these products more and more hazardous but the industry did not necessarily understand. Today there is awareness that there are people in organisations who have information that can be really helpful, such as toxicologists or safety personnel. You can no longer just keep doing things the way you always did. You need to know why you are doing them.”

But the EMA also remains concerned about manufactures that lack in-house toxicologists and depend entirely on the services of third parties to prepare ADEs. And there is still work to be done, Wilkins adds, in improving understanding of crosscontamination among smaller and medium-sized pharmaceutical companies.

“I don’t think the industry is totally up-to-date and educated on this,” Wilkins says. “The regulators want them to understand what the issue is with each individual compound, but there are some who still don’t understand that they are dealing with highly hazardous products.”

While a third edition of Risk-MaPP is unlikely to be produced any time soon, Wilkins says future supplements may be needed as the pharmaceutical industry continues to rapidly evolve.

“There may be amendments, supplements and additional case studies. But the principles of Risk-MaPP are good. I don’t think there is much that we are going to see changing there,” concludes Wilkins.

Revisions to Risk-MaPP highlight the shift in thinking from the EU.
Although a third revision of Risk-MaPP is not currently on the cards, the pharmaeutical industry may require supplements as it rapidly evolves.


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