Guidance on the establishment of acceptable daily exposure limits (ADE) to support Risk-Based Manufacture of Pharmaceutical Products

Health-based limits for active pharmaceutical ingredients (API) referred to as acceptable daily exposures (ADEs) are necessary to the pharmaceutical industry and used to derive acceptance limits for cleaning validation purposes and evaluating cross-carryover. ADEs represent a dose of an API unlikely to cause adverse effects if an individual is exposed, by any route, at or below this dose every day over a lifetime. Derivations of ADEs need to be consistent with ICH Q9 as well as other scientific approaches for the derivation of health-based limits that help to manage risks to both product quality and operator safety during the manufacture of pharmaceutical products. Previous methods for the establishment of acceptance limits in cleaning validation programs are considered arbitrary and have largely ignored the available clinical and toxicological data available for a drug substance. Since the ADE utilizes all available pharmaceutical data and applies scientifically acceptable risk assessment methodology it is more holistic and consistent with other quantitative risk assessments purposes such derivation of occupational exposure limits. Processes for hazard identification, dose response assessment, uncertainty factor analysis and documentation are reviewed.     

The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development

Starting materials and intermediates used to synthesize pharmaceuticals are reactive in nature and may be present as impurities in the active pharmaceutical ingredient (API) used for preclinical safety studies and clinical trials. Furthermore, starting materials and intermediates may be known or suspected mutagens and/or carcinogens. Therefore, during drug development due diligence need be applied from two perspectives (1) to understand potential mutagenic and carcinogenic risks associated with compounds used for synthesis and (2) to understand the capability of synthetic processes to control genotoxic impurities in the API. Recently, a task force comprised of experts from pharmaceutical industry proposed guidance, with recommendations for classification, testing, qualification and assessing risk of genotoxic impurities. In our experience the proposed structure-based classification, has differentiated 75% of starting materials and intermediates as mutagenic and non-mutagenic with high concordance (92%) when compared with Ames results. Structure-based assessment has been used to identify genotoxic hazards, and prompted evaluation of fate of genotoxic impurities in API. These two assessments (safety and chemistry) culminate in identification of genotoxic impurities known or suspected to exceed acceptable levels in API, thereby triggering actions needed to assure appropriate control and measurement methods are in place. Hypothetical case studies are presented demonstrating this multi-disciplinary approach.     

An evaluation of the sensitivity of the Ames assay to discern low-level mutagenic impurities

Low level impurities often reside in active pharmaceutical ingredients (API). Some of these impurities are potentially genotoxic since reactive intermediates are used in the synthetic route for the production of API. Routine mutagenicity testing is conducted in support of clinical trials with the intent to identify genotoxic hazards associated with API. Depending on the amount of impurity present in the API tested, the potency of the impurities and the relative sensitivity of the Ames assay, it is possible that mutagenicity associated with the presence of genotoxic impurities could also be detected while testing API. Therefore, we evaluated published data and generated new information to understand the sensitivity of the Ames assay. Based on a literature survey of approximately 450 mutagens, it was estimated that 85% of mutagens are detected at concentrations of 250 microg/plate or less. Based on this estimate, most mutagens should be detected in an Ames assay testing API concentrations up to 5000 microg/plate if present at a 5% or greater concentration. Data from experiments where several direct and indirect-acting mutagens were spiked into representative API further support the literature-based evaluation. Some limitations of this approach, including toxicity of API and competing metabolism are discussed.     

Comparative evaluation of quality of doxycycline formulations registered in Estonia to those registered in the Russian Federation

The in vitro properties of four Estonian drug market (manufactured in Austria, Germany, and Finland) and four Russian Federation drug market (manufactured in Belarussia and Russian Federation) doxycycline formulations were evaluated using the estimation of the quantitative content and purity of the active pharmaceutical ingredient (API) and the dissolution test. Tolerance limits were set according to the European Pharmacopoeia (for the content and purity of the API) and USP (for the dissolution test) doxycycline monographs. All Estonian drug market doxycycline formulations complied with the tolerance limits in all tests and assays. Most of the Russian Federation drug market doxycycline formulations also passed the tolerance limits, with two minor exceptions: one formulation contained quantitatively API below the USP limit (83.7% instead of the 90%), but all the API was readily released in the dissolution test, the other formulation (capsules) released 80% of API in 39 min instead of 30 min. The general conclusion of the study is that despite some deviations, the Russian Federation drug market doxycycline formulations are comparable with those purchased from the Estonian drug market. Drug Dev Res 69: 58–68, 2008. © 2008 Wiley‐Liss, Inc.     

What to consider for a good quality PDE document?

For the handling of active pharmaceutical ingredients (APIs) and production of medicinal products in shared facilities, the European Medicines Agency (EMA) has introduced the determination of permitted daily exposure (PDE) values to provide limits for cross-contamination. APIs have a desired pharmacological effect in the patient who intendedly uses a certain medicinal product. However, this effect is undesired in a patient that receives this API unintendedly as a cross-contamination of another medicinal product. In particular, for approved APIs for human use, a multitude of data is available on the pharmacological activity as well as adverse effects, which have to be taken into account in PDE setting. Thus, the setting of PDEs for APIs needs a structured scientific evaluation of all properties and identification of the most critical effect, which is the basis for PDE calculation. In this publication, we provide guidance on points for consideration when setting PDEs for APIs, or when evaluating the quality of documents describing the derivation of PDEs received, e.g. by third parties.     

Respiratory cancer risks associated with low-level nickel exposure: an integrated assessment based on animal,epidemiological, and mechanistic data

Increased lung and nasal cancer risks have been reported in several cohorts of nickel refinery workers, but in more than 90% of the nickel-exposed workers that have been studied there is little, if any evidence of excess risk. This investigation utilizes human exposure measurements, animal data from cancer bioassays of three nickel compounds, and a mechanistic theory of nickel carcinogenesis to reconcile the disparities in lung cancer risk among nickel-exposed workers. Animal data and mechanistic theory suggest that the apparent absence of risk in workers with low nickel exposures is due to threshold-like responses in lung tumor incidence (oxidic nickel), tumor promotion (soluble nickel), and genetic damage (sulfidic nickel). When animal-based lung cancer dose-response functions for these compounds are extrapolated to humans, taking into account interspecies differences in deposition and clearance, differences in particle size distributions, and human work activity patterns, the predicted risks at occupational exposures are remarkably similar to those observed in nickel-exposed workers. This provides support for using the animal-based dose-response functions to estimate occupational exposure limits, which are found to be comparable to those in current use.     

Occupational exposure to nanomaterials: Present knowledge and future development

Although unintentional exposure to nanoparticles (NP) is not new in an occupational setting, the global production for specially-engineered nanomaterials (NM) is expected to grow in the next few years, thus requiring an additional recruitment of workers across the world. Among the possible exposure scenarios, the workplaces where NM are produced, processed, used and disposed, may pose specific challenges. Field surveys have shown that workers from nanotechnology industries and R&D facilities have the potential to be exposed by inhalation to aerosols of NM, and skin contamination is not negligible. Owing to the lack of a robust body of scientific evidence on NM hazards, along with the inadequate knowledge on the dose-response relationships as well as long-term consequences to health, only a qualitative risk assessment of a few class of NM is possible. Exposure assessment in new NP processes has begun under the uncertainty about metrology and the lack of internationally recognized occupational standards and exposure limits, but in the near future improvements are expected. Given the limited amount of information about the health risks associated with occupational exposure to engineered NP, the precautionary principle suggests to take measures to minimize worker exposures. Implementing appropriate engineering controls, using personal protective equipment, establishing safe handling procedures, together to monitor worker's health, are all strategic elements of a risk management programme at workplace.     

Background, approaches and recent trends for setting health-based occupational exposure limits: a minireview

The setting of occupational exposure limits (OELs) are founded in occupational medicine and the predictive toxicological testing, resulting in exposure-response relationships. For compounds where a No-Observed-Adverse-Effect-Level (NOAEL) can be established, health-based OELs are set by dividing the NOAEL of the critical effect by an overall uncertainty factor. Possibly, the approach may also be used for carcinogens if the mechanism is epigenetic or the genetic effect is secondary to effect from reactions with proteins such as topoisomerase inhibitors, and mitotic and meiotic spindle poisons. Additionally, the NOAEL approach may also be used for compounds with weak genotoxic effect, playing no or only a minor role in the development of tumours. No health-based OEL can be set for direct-acting genotoxic compounds where the life-time risks may be estimated from the low-dose linear non-threshold extrapolation, allowing a politically based exposure level to be set. OELs are set by several agencies in the US and Europe, but also in-house in major chemical and pharmaceutical companies. The benchmark dose approach may in the future be used where it has advantage over the NOAEL approach. Also, more attention should be devoted to sensitive groups, toxicological mechanisms and interactions as most workplace exposures are mixtures.     

Purity determinations in the bulk drug of the novel indoloquinone antitumor agent EO9

Summary The pharmaceutical development of the investigational cytotoxic drug EO9 included the structural characterization of the bulk drug by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS) and infrared (IR) spectroscopy, and analytical characterization by high-performance liquid chromatography and ultraviolet/visible spectrophotometry. The presence of impurities in the bulk drug was investigated. The intermediates in the synthesis of EO9 were structurally characterized by NMR spectroscopy and MS, and analytically characterized by HPLC analysis with photodiode array (PDA) detection. All of the intermediates were below their limits of detection in EO9 bulk drug. The amounts of residual organic solvents were determined by gas chromatography. Methanol and ethanol were detected, but the amounts present did not exceed the limits as set in the United States Pharmacopeia XXII.     

A quantitative framework to group nanoscale and microscale particles by hazard potency to derive occupational exposure limits: Proof of concept evaluation

The large and rapidly growing number of engineered nanomaterials (ENMs) presents a challenge to assessing the potential occupational health risks. An initial database of 25 rodent studies including 1929 animals across various experimental designs and material types was constructed to identify materials that are similar with respect to their potency in eliciting neutrophilic pulmonary inflammation, a response relevant to workers. Doses were normalized across rodent species, strain, and sex as the estimated deposited particle mass dose per gram of lung. Doses associated with specific measures of pulmonary inflammation were estimated by modeling the continuous dose-response relationships using benchmark dose modeling. Hierarchical clustering was used to identify similar materials. The 18 nanoscale and microscale particles were classified into four potency groups, which varied by factors of approximately two to 100. Benchmark particles microscale TiO₂ and crystalline silica were in the lowest and highest potency groups, respectively. Random forest methods were used to identify the important physicochemical predictors of pulmonary toxicity, and group assignments were correctly predicted for five of six new ENMs. Proof-of-concept was demonstrated for this framework. More comprehensive data are needed for further development and validation for use in deriving categorical occupational exposure limits.     

Drugs hazardous to healthcare workers. Evaluation of methods for monitoring occupational exposure to cytostatic drugs.

We review the literature concerning possible health risks for individuals (e.g. healthcare workers and pharmaceutical plant employees) occupationally exposed to cytostatic drugs. Cytostatic drugs possess toxic properties and may therefore cause mutagenic, carcinogenic and teratogenic effects. Hence, individuals handling these drugs in the course of their employment may face health risks. For this reason, it is important to monitor occupational exposure to these drugs. An overview of exposure monitoring methods is presented and their value is discussed. Most studies involve nonselective methods for biological monitoring and biological effect monitoring, such as the urinary mutagenicity assay and analysis of chromosomal aberrations and sister-chromatid exchanges in peripheral blood lymphocytes. The disadvantages of these biological methods are that their sensitivity is low and it cannot be proved beyond any doubt that the results found were caused by occupational exposure to cytostatic drugs. For occupational health services it is important to have sensitive and specific methods for monitoring exposure to cytostatic drugs. One of the most promising methods seems to be the determination of cyclophosphamide in urine using gas chromatography-tandem mass spectrometry. Several studies have demonstrated exposure to cyclophosphamide and other cytostatic drugs, even when protective measures were taken and safety guidelines were followed. To estimate the magnitude of any health effects arising from this exposure, we calculated the risk of cancer due to occupational exposure to cyclophosphamide on the basis of available human and animal dose-response data and the amounts of cyclophosphamide found in urine. The initial results show an extra cancer risk for pharmacy technicians and nurses.     

Dose-Response Relationships and Threshold Levels in Skin and Respiratory Allergy

A literature study was performed to evaluate dose-response relationships and no-effect levels for sensitization and elicitation in skin- and respiratory allergy. With respect to the skin, dose-response relationships and no-effect levels were found for both intradermal and topical induction, as well as for intradermal and topical elicitation of allergenic responses in epidemiological, clinical, and animal studies. Skin damage or irritation may result in a significant reduction of the no-effect level for a specific compound. With respect to the respiratory tract, dose-response relationships and no-effect levels for induction were found in several human as well as animal studies. Although dose-response relationships for elicitation were found in some epidemiological studies, concentration-response relationships were present only in a limited number of animal studies. Reported results suggest that especially relatively high peak concentrations can induce sensitization, and that prevention of such concentrations will prevent workers from developing respiratory allergy. Moreover, induction of skin sensitization may result in subsequent heightened respiratory responsiveness following inhalation exposure. The threshold concentration for the elicitation of allergic airway reactions in sensitized subjects is generally lower than the threshold to induce sensitization. Therefore, it is important to consider the low threshold levels for elicitation for recommendation of health-based occupational exposure limits, and to avoid high peak concentrations. Notwithstanding the observation of dose-response relationships and no-effect levels, due to a number of uncertainties, no definite conclusions can be drawn about absolute threshold values for allergens with respect to sensitization of and elicitation reactions in the skin and respiratory tract. Most predictive tests are generally meant to detect the potential of a chemical to induce skin and/or respiratory allergy at relatively high doses. Consequently, these tests do not provide information of dose-response relationships at lower doses such as found in, for example, occupational situations. In addition, the observed dose-response relationships and threshold values have been obtained by a wide variety of test methods using different techniques, such as intradermal exposure versus topical or inhalation exposure at the workplace, or using different endpoints, which all appear important for the outcome of the test. Therefore, especially with regard to respiratory allergy, standardized and validated dose-response test methods are urgently required in order to be able to recommend safe exposure levels for allergens at the workplace.     

Dose-response relationships and threshold levels in skin and respiratory allergy

A literature study was performed to evaluate dose-response relationships and no-effect levels for sensitization and elicitation in skin- and respiratory allergy. With respect to the skin, dose-response relationships and no-effect levels were found for both intradermal and topical induction, as well as for intradermal and topical elicitation of allergenic responses in epidemiological, clinical, and animal studies. Skin damage or irritation may result in a significant reduction of the no-effect level for a specific compound. With respect to the respiratory tract, dose-response relationships and no-effect levels for induction were found in several human as well as animal studies. Although dose-response relationships for elicitation were found in some epidemiological studies, concentration-response relationships were present only in a limited number of animal studies. Reported results suggest that especially relatively high peak concentrations can induce sensitization, and that prevention of such concentrations will prevent workers from developing respiratory allergy. Moreover, induction of skin sensitization may result in subsequent heightened respiratory responsiveness following inhalation exposure. The threshold concentration for the elicitation of allergic airway reactions in sensitized subjects is generally lower than the threshold to induce sensitization. Therefore, it is important to consider the low threshold levels for elicitation for recommendation of health-based occupational exposure limits, and to avoid high peak concentrations. Notwithstanding the observation of dose-response relationships and no-effect levels, due to a number of uncertainties, no definite conclusions can be drawn about absolute threshold values for allergens with respect to sensitization of and elicitation reactions in the skin and respiratory tract. Most predictive tests are generally meant to detect the potential of a chemical to induce skin and/or respiratory allergy at relatively high doses. Consequently, these tests do not provide information of dose-response relationships at lower doses such as found in, for example, occupational situations. In addition, the observed dose-response relationships and threshold values have been obtained by a wide variety of test methods using different techniques, such as intradermal exposure versus topical or inhalation exposure at the workplace, or using different endpoints, which all appear important for the outcome of the test. Therefore, especially with regard to respiratory allergy, standardized and validated dose-response test methods are urgently required in order to be able to recommend safe exposure levels for allergens at the workplace.     

Analytical control of genotoxic impurities in the pazopanib hydrochloride manufacturing process

Pharmaceutical regulatory agencies are increasingly concerned with trace-level genotoxic impurities in drug substances, requiring manufacturers to deliver innovative approaches for their analysis and control. The need to control most genotoxic impurities in the low ppm level relative to the active pharmaceutical ingredient (API), combined with the often reactive and labile nature of genotoxic impurities, poses significant analytical challenges. Therefore, sophisticated analytical methodologies are often developed to test and control genotoxic impurities in drug substances. From a quality-by-design perspective, product quality (genotoxic impurity levels in this case) should be built into the manufacturing process. This necessitates a practical analysis and control strategy derived on the premise of in-depth process understanding. General guidance on how to develop strategies for the analysis and control of genotoxic impurities is currently lacking in the pharmaceutical industry. In this work, we demonstrate practical examples for the analytical control of five genotoxic impurities in the manufacturing process of pazopanib hydrochloride, an anticancer drug currently in Phase III clinical development, which may serve as a model for the other products in development. Through detailed process understanding, we implemented an analysis and control strategy that enables the control of the five genotoxic impurities upstream in the manufacturing process at the starting materials or intermediates rather than at the final API. This allows the control limits to be set at percent levels rather than ppm levels, thereby simplifying the analytical testing and the analytical toolkits to be used in quality control laboratories.     

Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin

Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.     

Microbial/enzymatic synthesis of chiral pharmaceutical intermediates

Chirality is a key factor in the efficacy of many drugs; thus, the production of single enantiomers of drug intermediates has become increasingly important in the pharmaceutical industry. Chiral intermediates and fine chemicals are in high demand from the pharmaceutical and agrochemical industries for the preparation of bulk drug substances and agricultural products. There has been an increasing awareness of the enormous potential of microorganisms and enzymes for the transformation of synthetic chemicals with high chemo-, regio- and enantioselectivity. In this article, biocatalytic processes for the synthesis of chiral pharmaceutical intermediates are described.     

Defining occupational and consumer exposure limits for enzyme protein respiratory allergens under REACH

A wide range of substances have been recognized as sensitizing, either to the skin and/or to the respiratory tract. Many of these are useful materials, so to ensure that they can be used safely it is necessary to characterize the hazards and establish appropriate exposure limits. Under new EU legislation (REACH), there is a requirement to define a derived no effect level (DNEL). Where a DNEL cannot be established, e.g. for sensitizing substances, then a derived minimal effect level (DMEL) is recommended. For the bacterial and fungal enzymes which are well recognized respiratory sensitizers and have widespread use industrially as well as in a range of consumer products, a DMEL can be established by thorough retrospective review of occupational and consumer experience. In particular, setting the validated employee medical surveillance data against exposure records generated over an extended period of time is vital in informing the occupational DMEL. This experience shows that a long established limit of 60 ng/m³ for pure enzyme protein has been a successful starting point for the definition of occupational health limits for sensitization in the detergent industry. Application to this of adjustment factors has limited sensitization induction, avoided any meaningful risk of the elicitation of symptoms with known enzymes and provided an appropriate level of security for new enzymes whose potency has not been fully characterized. For example, in the detergent industry, this has led to general use of occupational exposure limits 3–10 times lower than the 60 ng/m³ starting point. In contrast, consumer exposure limits vary because the types of exposure themselves cover a wide range. The highest levels shown to be safe in use, 15 ng/m³, are associated with laundry trigger sprays, but very much lower levels (e.g. 0.01 ng/m³) are commonly associated with other types of safe exposure. Consumer limits typically will lie between these values and depend on the actual exposure associated with product use.     

化学合成原料药上市后生产变更评估思考

目的：为化学合成原料药上市后变更的评估提供思路。方法：通过美国和我国原料药监管要求、 原料药变更影响因素分析原料药变更评估中的关注点。结果：化学合成原料药生产工艺更具有特异性, 所以原料药上市后变更更需要结合品种特点,对变更的风险及研究验证工作进行全面的评估。结论：化学合成原料药变更需从品种特点、人员素质、设施设备、杂质情况、物理性质等五个主要方面进行全面的分析、研究和验证,从而确定变更对原料药和制剂产生的影响。     

Insights into the quantitative relationship between sensitization and challenge for allergic contact dermatitis reactions

The ability of chemical or pharmaceutical agents to induce allergic contact dermatitis (ACD) is of major health and regulatory concern. As such, tests to identify their sensitizing capacity, such as the guinea pig maximization test and the more recently developed local lymph node assay, are broadly used. Ideally, for risk assessment it is useful to translate results from animal data into establishing safe or no-effect levels for occupational or environmental agents. This, of course, would require consideration of the quantitative relationships between sensitizing and challenge doses as well as other exposure conditions. In the present studies, we modeled two sensitizers, 2,4-dinitrochlorobenzene and squaric acid dibutyl ester, over a large range of concentrations using the LLNA and more traditional tests that measure both sensitization and elicitation responses. Both the sensitization and challenge phases provided similar dose-response curves, demonstrating a threshold followed by a shallow linear increase and eventual plateau at increasing doses. Extending earlier studies by P. S. Friedmann (1994, Immunotoxicology and Immunopharmacology, pp. 589-616, Raven Press, New York) in humans, we observed that the minimum dose required to elicit sensitization or challenge was not static, but rather reflected a "sliding-scale." That is, as the sensitization dose was increased, the concentration required to elicit a challenge response was decreased. Correspondingly, as the challenge dose was increased, the dose required for sensitization was lessened. Taken together, these findings indicate that there is a need to consider dose-response relationships for sensitization and challenge in establishing minimum exposure levels for chemicals that cause ACD.     

Implications of hormesis for industrial hygiene

This paper considers hormesis as a valid and potentially valuable alternative hypothesis for low-dose response in the context of occupational health risk assessment. It outlines the current occupational risk assessment paradigm and its use of high-dose toxicological data in setting occupational exposure limits (OELs). This present effort is a call to science to investigate the potential promise of hormesis in providing prima facie experimental evidence for a low-dose threshold of toxic effect to chemical agents. The scientific effort and advancement advised in this piece could also lead to experimentally validated quantitative estimates of the toxic effect extant at occupational exposures in the region of the OEL.