Recently, an international regulatory agency challenged Elan Drug Technologies’ manufacturing services business, now part of Alkermes plc, to develop an approach for managing risk at its multiproduct facility in Athlone, Ireland. The plant processes many different active pharmaceutical ingredients (APIs), including high potency APIs (HAPIs).
Working closely with PharmaConsult Ltd.’s Stephanie Wilkins, cochair of ISPE’s Risk-MaPP task team, the facility responded with a Master Matrix based on Risk-MaPP, a risk-based framework derived from principles outlined in ICH Q9. Risk-MaPP is designed to allow companies to identify and focus on critical risk areas to help prevent cross-contamination and ensure that controls applied are appropriate and commensurate to the risk. The Master Matrix, in turn, is a spreadsheet that offers a visually effective way to see where cross-contamination risks, both process-related and product-related, are highest, allowing appropriate actions to be taken. This tool allows Alkermes to assign a numeric value, not only to each potential source of cross-contamination risk, but also to products that are vulnerable to cross contamination.This article will briefly summarize how the Master Matrix was implemented and what results it has shown so far.Alkermes considers the “opportunity to contaminate” as a function of the frequency of the given product’s manufacture. In addition, the company characterizes source batches or dosage forms at risk of cross-contamination by evaluating the following:• toxicity • quantity of active used per batch• process train used in product manufacture • level of containment and the energies employed in processing• proximity to other products and the use of shared equipment • opportunity to contaminate • dosing regime of the product and in particular the number of daily doses contained in a batch• frequency of the ingredient’s or product’s manufacture• any other products manufactured on site that might be contra-indicated for users of the target drug.The goal is to identify and highlight points at which high risk and high vulnerability coexist. The elements of the matrix can be divided into five subsections or “elements.”1. Product DataThe first step in building the Master Matrix was to list products manufactured on site. Internally, to simplify communication, product names were used, while externally (and below) product numbers were employed to ensure confidentiality (See Table 1).Populating the columnsFor each product, the applicable therapeutic area, dosage type, and route of administration are described. While Alkermes’ Ireland Facility is primarily a solid dose producer, liquids and a small number of injectable products are also manufactured. Clearly, information on the route of administration and on the targeted use of the drug product informs those reviewing the matrix as to how compromised the defences of patients using these products might be. Keeping the patient in mind at all times, the matrix also notes the “contra-indication” of drugs. While this has not proved as useful as originally expected, this was included to highlight any areas where a drug product may be manufactured adjacent to or sharing equipment with, another product whose patient information leaflet (PIL) recommends that they not be used by patients in combination.At the Athlone site, Alkermes also handles (largely in development) a small amount of controlled substances or scheduled drugs. While not of any special concern in cross-contamination assessments, a column to highlight such APIs has been included on the matrix.Numeric valuesThe first significant numeric value entered in the matrix is the Acceptable Daily Exposure (ADE)—a measure of an active ingredient’s toxicity defined simply as “the amount of active a person can take every day for the rest of their lives without it having an adverse effect.” For the purposes of Alkermes' Master Matrix, this measurement was interpreted as the maximum allowable daily amount of contaminated active present in one of its manufactured products to which a patient could be exposed without experiencing the therapeutic/adverse effect of the contaminator. Alkermes' view that the ADE should in all cases consider all potential sub-populations negates the need to highlight susceptible (contra-indicated) sub-populations in the matrix. Of particular importance is that the ADE information is provided in a consistent and auditable way. As the ADE is a main pillar in the Alkermes matrix, good scientific assessment and judgment must be applied. Alkermes has based its approach on that described in Section 5.3 of the ISPE Risk-MaPP guidelines. Additional requirements—including the availability of key source data for audit review, qualification of toxicologists performing analysis, as well as checks performed and signed for by the author and reviewer—have also been added. For non-toxicologists, reviewing ADE reports from a variety of sources has proved the greatest challenge, because understanding factors used in derivations reflecting “professional judgments,” “completeness of database,” “similarity to other molecules” and such, are difficult to standardize. In addition differences in judgement and terminology were also encountered. The solution was to request and require “peer review” of the reports involved, to build an independent audit review process on sampled reports (at least initially) and to ensure that providers used the terminology and factors listed in the ISPE guidelines. Furthermore, Risk-MaPP provides guidance on the quantification and measurement of various uncertainty factors, allowing definition of default values. Providers were required to justify when deviations from these default values were chosen. Alkermes used external contracted toxicologists for this body of work.2. Amount of API Needed to Contaminate ProductHaving conservatively established the ADE limits to include all potential sub-populations, it is next important to understand how much unintended active would be needed to contaminate a drug product in order to harm. Simply, it is necessary to relate the maximum potentially prescribed daily dose of all products in manufacture to the actual manufacturing batch size.Consider “x” grams of contaminating active getting into a blend. Assume that contaminant is evenly spread through the blend during processing. If the blend produces 1,000 (maximum) daily doses, then each will contain 0.1% of the contaminating material. If instead the blend produces 1,000,000 daily doses, then the patient will receive 0.0001% of the unwanted contaminating material with the prescribed drug product. Clearly the potential to exceed the ADE is far greater where the blend produces fewer “daily doses.” The toxicity (ADE) of the potentially contaminating material and the amount of it that a patient might unknowingly consume are essential elements in generation of the risk profile (see Table 2).
Alkermes’ initial approach to scoring of processes is also shown in Table 3. Note that some boxes have scores greater than 20. This occurs for two reasons:
- Everything is related to a finished batch size; where multiple components are combined in that final batch, multiplication of each individual component score by the number of components combined in a batch is undertaken. For example, coated beads are manufactured in the CF granulators in component batch sizes of 60-80 kg, but finished (encapsulation) batch sizes are bulked up by combining four of these in a blend. As a result, a 4x “component score” is entered in the matrix.
- A number of Alkermes processes are iterative. Again, taking the example of our CF coated beads, typically multiple layers are used. The first is when active material is coated directly onto a non-pareil core. Such a process is “semi-open” with “medium to high” energy input and is scored a 12. The next coating is of a polymer onto the active core—the potential for active “release” exists but is much reduced as all active has adhered to the bead rather than existing in a powder state and auger feed to an agitated bed. Further, as polymer coating covers more and more of the bead surface, the product design virtually eliminates potential for contaminant generation. The second coat is scored a 10 and all subsequent coats as 5 or 2. All scores from the individual iterations are then combined.
Neither of these products are low ADE products and both have been manufactured for many years, yet the analysis indicates that there should be a focus on where these products are manufactured and where they may come in contact with each other. In short, particular attention should be focused on anywhere a product presenting a relatively high “product risk” is manufactured in close proximity to a product of relatively high “vulnerability.”. This is as described in the flowchart in Figure 3 and for Alkermes has meant that a detailed FMEA analysis is applied to any area where potential cross-over occurs.
Risks have been submitted for each process stage. They are then added together to indicate where targeted improvement of process design might yield greatest impact. Although the Matrix is still a work in progress, Alkermes staff are well informed of considerations required for the safe design and operation of facilities to minimize cross-contamination. In areas of shared activity, review has prompted research and experimental verification. For example, the company has initiated a series of experiments to evaluate the protection afforded by air change rates, pressure differentials and physical barriers where two products are manufactured in processing rooms linked by a shared corridor.ConclusionProcedurally the matrix is formally updated annually or where a change (e.g., new product introduction) is deemed likely to significantly affect the plant’s risk profile. Assessment of the impact of change is ensured through linkage with the site change control process, where now consideration of impact on cross-contamination risk is prompted not just by major product introductions, but also by equipment moves.There remains much to be done on education, on calibration with others in industry, on honing and improving Alkermes' process and on linked themes including setting of cleaning limits, but the Master Matrix has provided Alkermes a very strong foundation and framework on which to build.
About the Authors
Mark O’Reilly joined Alkermes (formerly Elan Drug Technologies) in 1993. He is currently Senior Director of Engineering where his responsibilities include process train and facility design, industrial hygiene and validation. He received his BE from University College Dublin, his MEngSc from the University of New South Wales and his MSc from the University of Manchester.
Aisling Horan joined Alkermes (formerly Elan Drug Technologies) in 2003. She currently works in the validation department with a primary focus on process & cleaning validation and cross contamination. In addition to validation, her experience includes industrial and clinical microbiology. Aisling received her BSc (Hons) in microbiology from the National University of Ireland, Galway (NUIG).