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:
• 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 Data
The 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 columns
For 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.
The 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.