OsoBio Featured in Contract Pharma Article: “Risk-MaPP and Multi-Use Facilities” Contract Pharma
Mar 07, 2011 – No doubt that the Risk-MaPP approach is state-of-the-art thinking when it comes to managing the risk of cross-contamination. David Cockburn of the EMA declared as much at the launch of the new Baseline Guide in Washington, DC this past October. Although the EMA has some minor issues with the document, Mr. Cockburn acknowledged the International Society for Pharmaceutical Engineering (ISPE) for its efforts in translating a 2005 EMEA concept paper dealing with the need for updated GMP guidance concerning Dedicated Manufacturing Facilities in the Manufacture of Certain Medicinal Products into a practical reality.
ISPE recently launched its new Baseline Guide, Risk-Based Manufacture of Pharmaceutical Products, A Guide to Managing Risks Associated with Cross-Contamination (Risk-MaPP), in Europe and the U.S. both to acclaim and tough criticism. Hard questions indicated areas for improvement and areas that need further education and explanation. Let’s explore some of the questions and issues raised during the first two launch sessions.
The cornerstone of the Risk-MaPP document is the use of health-based limits, which are referenced as the acceptable daily exposure (ADE) to determine cleaning limits, cross-contamination limits and acceptable risk. The ADE is defined as the dose that is unlikely to cause an adverse effect if an individual is exposed by any route, at or below this dose every day for a lifetime. By the definition, the risk would be acceptable if the results of cleaning data and cross-contamination data indicated levels below the ADE.
One attendee felt the ADE was too conservative because it assumes that an individual would be exposed to the cross-contamination for a lifetime. This really isn’t feasible because a batch produces a finite amount of product. Other attendees disagreed because the root cause of the cross-contamination could be a systemic issue and not a batch only issue. In addition, the product receiving the ADE amount or lower of another product could be a drug that is taken daily for a lifetime such as insulin-lowering drugs or blood pressure medicines.
This dialogue is important because it does show that the development of the ADE includes some conservatism and that adding additional safety factors to cleaning limits, etc., without justification does not protect the patient any better and may cause manufacturers to employ more costly measures to meet the newly lowered limits. The guide discusses how route adjustments can be made to cleaning limits when there is appropriate scientific justification.
During the launch sessions the EMA indicated that updated wording for the revisions to the EU GMP clauses 3.6, 5.18 and 5.19 with regards to cross-contamination and the need for dedicated facilities may be available soon. The EMA is clear that input from toxicologists is required when using risk assessments to confirm that use of multi-product facilities is safe. They are currently debating the use of a toxicological tool to determine the health-based limits. While the ADE approach is outlined in Risk-MaPP and ICH Q3C outlines the PDE method for residual solvents, the EMA is considering providing a more prescriptive tool based on either of these methods that eliminates any room for interpretation. Specifically the EMA is considering dictating the use of safety (uncertainty) factors to eliminate the variability in the limits established by different toxicologists.
The danger in having the EMA dictate the safety factors is that manufacturers could bypass the toxicological input, since the variables for determining the health-based limit will already have been defined, leaving no room for the incorporation of the professional judgment of the toxicologist. This will perpetuate the status quo, where the cleaning validation department sets the limits without discussing the hazards with a toxicologist and not allowing the proper professionals to interpret the data and assist in the risk assessment and limit-setting activities. Ideally, if you allow the toxicologists to participate and use their professional knowledge, a better understanding of the compounds and the hazards will proliferate throughout the organization rather than leaving individuals to calculate formulas without truly understanding the impact of their actions.
As stated above, Risk-MaPP suggests using ADE values to determine cleaning limits. In essence the ADE value would replace the 1/1000th of a low clinical dose (LCD) or the 10 ppm in rinse water to calculate cleaning limits.
Change can be difficult and some attendees defended the use of 1/1000th of the LCD and the 10 ppm models. It is important to remember that these traditional methods may be over- or under-protective of patient health. To illustrate the point refer to the tablebelow. The first three compounds have the same lowest therapeutic dose at 1 mg but have varying levels of teratogenic activity. Using the 1/1000th of the LCD or 10 ppm to set cleaning limits does not address these varying teratogenic effects, whereas using the ADE method takes these effects into consideration, as can be seen in the table. The fourth compound in the table actually has a higher lowest therapeutic dose and therefore the cleaning limits based on the 1/1000th of the LCD would also be correspondingly higher. The compound is of much more concern due to the teratogenic effects that appear at a lower dosage. The ADE derived using the teratogenic effects as the critical effect is 10 times lower than 1/1000th of the LCD. In this case, using 1/1000th of the LCD to set the cleaning limits would not be adequately protective of patient health.
So to summarize this point, unless the health-based limits are obtained, it is unclear if the limits used are over- or under-protective of patient health.
Some manufacturers may select cleaning limits based on the lowest of the values obtained by using the ADE, 1/1000th of the LCD or 10 ppm methods, which is conservative and protective of patient health. But these manufacturers are losing the opportunity to be green and cost effective. It has been established that using the ADE to determine cleaning limits is safe and that setting the limits lower doesn’t provide additional safety to the patient. But this practice may drive the company to dedicated or disposable parts/equipment, to more rigorous cleaning than necessary, or even to more cleaning failures. To be clear, the guide is not advocating that manufacturers should clean just enough to pass the limits; this is where the safety threshold value (STV) concept is important (see below).
Another important distinction is that Risk-MaPP replaces the maximum allowable carryover (MAC) term with the STV. The reasoning for this change is twofold:
First, the STV is just that: a safety threshold. If your data shows you have exceeded the STV, your product is adulterated and cannot be sold. The MAC term has erroneously led some to believe that it is “acceptable” to carry over large amounts of a compound into the next process so long as the amount is at or below the calculated value. Some may believe that they can also carry over amounts up to the STV value, even when the value is quite large. Obviously this is not acceptable. This is where the GMP requirement for visually clean equipment surfaces plays an important role. As reinforced in the visual limits workshop at the launch sessions, even under less than ideal conditions, the human eye can see fairly low residue concentrations (less than 1 mcg/cm2). So in situations where the health-based limits are high, visual limits could be used to bring some sensibility to assessment of the amount that could be carried over to the next product.
Second it is necessary to know the STV so that the risk due to cleaning/retention can be quantified. This risk is quantified by determining the distance between the actual cleaning data and the calculated STV. This distance is the margin of safety the cleaning process achieves.
As cleaning data is gathered, statistical analysis should be used to set process control limits, including alert and action limits. By using a tiered limit scheme if the process starts to drift out of the normal/expected operating range, an alert can be sent so that more attention or an investigation can be given to the process with possible corrective action completed before the process exceeds the action limits or the limits that would require rejection of the product. By understanding the process capability of the cleaning process and setting the process control limits based on this capability, a manufacturer can have confidence and evidence in their ability to minimize the risk of cross-contamination due to cleaning.
Two case studies were presented during the launch sessions by Oso Biopharmaceuticals and élan Drug Technologies. The OsoBio case study was for a multi-product parenteral facility and the élan one was for a multi-product facility with various dosage forms. Both case studies used failure mode and effects analysis (FMEA) to thoroughly review their risk of cross-contamination, but to start they needed to get a firm handle on the compounds they process. A matrix of compounds was developed that included basic information such as product name, ADE (if known), batches processed per year, weight of the API per batch and doses per batch. This helped them determine where to focus the risk analysis efforts. When processing many compounds in a facility, it is not feasible to analyze each possible combination of compounds.
Both companies found that the matrix alone provided some valuable insight into their operations and coupled with an in-depth FMEA exercise gave the companies a thorough understanding of their products, processes and facilities. This understanding was perpetuated throughout the company via the risk assessment process. The return on the investment is now priceless, as staff truly understand why something is done a certain way and compliance to the procedures is improved. In addition, with a better understanding, better and quicker decisions can be made.
Quality Systems and the Product Lifecycle
Although Risk-MaPP mirrors the ICH Q9 document, aspects are also inline with both ICH Q8 and Q10. Two presentations were provided that discussed how Risk-MaPP principles can apply to the product lifecycle and be incorporated into the company’s quality system. Q8 discusses pharmaceutical development and how that information is used to provide a better understanding of the processes and products for reviewers and inspectors. It also discusses how, with better understanding of the products and processes, a manufacturer may have greater regulatory flexibility. Clearly the approach in Risk-MaPP, amplified through the case studies, providesa greater understanding of the facilities, processes and products produced in a multi-product facility. This knowledge should help a manufacturer safely produce medicines while allowing flexibility in the manner in which cross-contamination is controlled.
Q10 outlines a model for a pharmaceutical quality system. Quality risk management is a subset of the quality system. The quality system includes policies, standards, procedures and the organizational responsibilities. In the context of Risk-MaPP, the following may apply:
1.A manufacturer should have a policy that stateswhat acceptable risk is. Acceptable risk should not be determined by the project team or vary from site to siteor from phase to phase (e.g. R&D to commercial).
2.Standards should be set for scoring of risks such asseverity, occurrence and detection and where the action points (e.g. no action required, investigate or stopimmediately) are for the levels of risk (e.g. low, mediumor high risk or risk priority number ranges).
3.Procedures can be developed for the use of riskmanagement tools.
4.Organizational responsibilities should explain who”owns” the quality risk management plan, who thestakeholders are, etc.
Producing medicines entails some level of risk. Under-standing and managing the risk is a requirement for providing safe medicines to the public. Ignorance is not an acceptable excuse; neither is “that’s how we did it before.” ISPE, as a catalyst for change, has provided the industry with a practical method to employ ICH Q9 to manage the risk of cross-contamination. Several excerpts from recent FDA warning letters or 483s indicate the FDA expects manufacturers to assess the risk of cross-contamination when using multi-product facilities. For example, this excerpt from a 2010 Warning Letter supports the principles within Risk-MaPP: “FDA encourages sound risk assessment approaches to address hazard identification, exposure consequences, and implement controls designed to prevent and detect cross-contamination. To achieve an acceptable level of risk require sound and risk-based assurance that one drug does not contaminate another drug.”
As Edwin Melendez of the FDA stated during the DC launch, this guide helps make the current practice as referenced by the “c” in the cGMPs available to all manufacturers, large and small. He also stated this approach applies not only to highly hazardous compounds, but equally to all compounds, including aspirin.