As a toxicologist in the legal department of a pharmaceutical company, he is accustomed to a certain degree of “exoticism”, says Dr. Thomas Pfister of F. Hoffmann La Roche AG. That’s why he feels quite comfortable as a toxicologist in the midst of a group of GMP experts. At the GMP conference held by the PTS Training Service last December, he invited the participants to join him in a “little excursion into the world of threshold values.” He reported on how the ADE concept for controlling cross-contamination had been successfully integrated into the quality assurance system of Roche in Basel, Switzerland.
For reasons of patient safety and product quality, facilities that are used to manufacture different substances must be cleaned in such a manner that cross-contamination is contained to within an acceptable range. Common practice up to now has been to set the maximum value for tolerable residues routinely at 1/1000 of the therapeutic dose of a product. Another widely accepted criterion is that a pharmaceutical product may not contain more than 10 ppm of another product. Some companies, including Roche, now take a different approach and use what is referred to as the ADE value (acceptable daily exposure) as the threshold value. This value is defined as the dosage that in all probability has no adverse effect on health and no undesired physiological effects on someone who is exposed daily to this dosage for a lifetime. The conversion to the ADE concept at Roche in Basel was also made in consideration of several passages of Chapters 3 and 5 of the EU GMP Guide which are presently undergoing revision.
The two passages that deal with threshold values and cross-contamination in these chapters are very similar:
3.6 [...] Quality Risk Management principles should be used to assess and control the risks. Risk assessment should include among other parameters a toxicological evaluation of the products manufactured (see Guideline on setting health based exposure limits for use in risk identifications in the manufacture of different medicinal products in shared facilities.) […]
5.19 A toxicological evaluation should be the basis for the establishment of threshold values in relation to the products manufactured (see Guideline on setting health based exposure limits for use in risk identifications in the manufacture of different medicinal products in shared facilities). Where the toxicological evaluation supports a threshold value, this should be used as an input parameter in risk assessment. […]
“First of all,” according to Thomas Pfister, “there are two basic ways to get protection from potentially hazardous or toxic substances: completely avoid contact or limit the duration and/or frequency of exposure. If neither of these two ways is an option, scientifically well-founded, solid threshold values are needed in order to define a maximum permissible dosage or concentration - permissible because it is harmless.” We encounter such threshold values all around us in our daily lives. For example, you will find them being used for
Toxicological threshold values can be set and incorporated into quality systems for pharmaceuti-cal products and for any substances obtained during the manufacturing process. Depending on the dosage, a typical medicinal product either exhibits no effect, the desired effect, an overdose or toxicity. These properties can be included in safety profiles. For this purpose, first of all, as many sources of information as possible should be evaluated. For example, non-clinical data from experiments on animals and clinical data from studies of phases I and II will yield a safety profile that can be applied to humans. In addition, findings from epidemiological studies or pharmacovigilance can be used to obtain the ADE values. They provide the basis for defining threshold values not only for employees at work (inhalation), but also for patients (oral or par-enteral administration).
Safety profiles can differ greatly for different classes of substances.
Fig. 1: Different Safety Profiles (idealized examples). While the green area (efficacy) is generally not applicable in the case of chemicals, biological medicinal products such as monoclonal antibodies usually have no toxicity (red area).
Approximately three years ago, Roche began to integrate ADE limit values consistently into the quality assurance system. Today they serve as the criterion for the maximum quantity of a sub-stance that may remain as residue in a facility. The earlier definition of the threshold value was generally 1/1000 of the therapeutic dosage. However, visible cleanliness and a concentration of less than 10 ppm of another product are also still valid parameters. A result of this is that the ADE value has found its way into cleaning validation for the purpose of determining the maximum allowable carryover (MAC).
Thomas Pfister describes the principles that apply for setting ADE values: “The values are scientif-ically supported, based on experimental data and, as always, in terms of toxicology they are set with the health of the patients and/or of the employees in mind. The following framework has been defined for implementing the ADE concept:
In addition, the following is called for as part of quality assurance:
“Sometimes there is no way to avoid exposing humans to potentially hazardous materials. In such cases, setting and staying within health-based threshold values are the most important measures for protection from potential harm. Therefore, all active substances and all basic or intermediate products or by-products should have an ADE. This requires a substantial investment of intensive scientific effort,” says Thomas Pfister, “but one that will pay off in the long run.” That is why exchanging data with suppliers and other companies is helpful and desirable. In most cases, the ADE concept yields higher MAC values than the 1/1000 of therapeutic dosage commonly used up to now. However, in some cases far lower threshold values are achieved. In conclusion, the speaker warned against unrealistic expectations: “Limits only offer real protection if they can be measured and monitored.”
Source of information:
GMP Conference, PTS Training Service, 3rd/4th December 2013, Düsseldorf, Germany
Maas & Peither AG – GMP Publishing, Schopfheim, Germany