Optimizing OEL and ADE/PDE Compliance in Pharma

Shivangi Yadav*, Patel Dhara, Patel Grishma, Rashmi Rajeghorpade,

Dhananjay Meshram

Department of Pharmaceutical Quality Assurance, Pioneer Pharmacy College-390019,Gujarat India

*Correspondence: yadavshivangi445@gmail.com;

DOI: https://doi.org/10.71431/IJRPAS.2026.5611

INTRODUCTION

In general, the use of pharmaceuticals is advantageous; however, most individuals can be exposed to small doses of them without adverse consequences. The conditions of exposure to drugs in a manufacturing setting are vastly different from the conditions in which drugs are administered under the direction of a physician. In most cases, workers exposed to drugs are not sick and therefore would find any pharmacologic effect encountered to be an adverse effect rather than one that provides therapeutic benefits. Increased risk of unintentional injury could be associated with those workers that are exposed to drug-induced sedation and potentially operating machinery at high speeds. Additionally, there are potential interactions that could occur between drugs being used in the laboratory and drugs that may be administered clinically. There is also the potential for chronic workplace exposure to create increased tolerance or sensitization to the pharmaceuticals that may be needed for treatment of disease. To implement appropriate safety protocols and to reduce the risk of adverse events to workers exposed to pharmaceuticals, the occupational exposure limit (OEL) for pharmaceuticals needs to be established. Most of the generic pharmaceutical items are created in multi-product resources (with the exception of Antineoplastics, Beta-lactam antibiotics, and hormones). Due to the high level of regulation in the pharmaceutical industry, the safety of the patient is the first and foremost aspect of concern; for example, a 1 in 100,000 lifetime risk of cancer from exposure to a product is viewed as an unacceptable level of risk. Moreover, all contaminants present in the pharmaceutical product do no benefit the patient at all. Manufacturers eliminate the presence of cross-contamination within their facility by calculating maximum carryover based on the Acceptable Daily Exposure (ADE) or Permitted Daily Exposure (PDE) values for the API (Active pharmaceutical ingredients), intermediates, cleaning solutions, and solvents used during manufacturing; this ensures that no GMP (Good Manufacturing Practice) violations will occur due to cross-contamination. There were many different terms in the literature prior to the advent of the regulatory terminology "Permitted Daily Exposure", but all established a safety standard for toxic chemicals to be used by various international and national safety agencies or groups. The IPCS (international program for Chemical Safety) uses the term "tolerable daily intake" (TDI) to apply a maximum allowable daily exposure level for persons exposed to any given toxic compound; similarly, the WHO (World Health Organization) and other national and international safety groups and agencies refer to this maximum allowable daily exposure as the "acceptable daily intake" (ADI). The ICH Q3C guidelines provide a new term, Permitted Daily Exposure (PDE), to define the acceptable amount of a residual solvent that may be contained in a pharmaceutical product to prevent confusion over ADI values for identical compounds (ICH Q3C). Health Based Exposure Limits (HBELs) or permitted daily exposures (PDEs) or acceptable daily exposure (ADEs) for active pharmaceutical ingredients (APIs), intermediates, cleaning agents, solvents, etc., are calculated based on a risk assessment for use in avoiding potential contamination of more than one product manufactured in the same location. The European Medicines Agency (EMA) regulatory guidance for establishing HBEL was published on June 1, 2015 (EMA, 2014). The HBEL approach has been implemented to control cross contamination between medicinal products by way of the Pharmaceutical Association.[1],[2]

 Importance of OEL: OELs were established using a historical method based on worker exposure history to determine if a given chemical posed any risk to their health; if a chemical does pose any such risk based on human exposures, then OEL levels would need to be established lower than those found as causing the adverse health effect(1990, 1993). In the latter years of the twentieth century, as laboratory animals were increasingly used in testing for chemical toxicity and as large numbers of epidemiological reports were produced describing the relationship between worker exposures and adverse health effects from chemicals, the historical method was no longer considered adequate for determining OELs. Beginning in the 1970's OELs began to be derived using the "no-observed-effect-level/safety factor" (NOEL/SF) methodology wherein, after reviewing all relevant animal and human studies, a NOEL is identified as the highest level that caused no adverse effect on the most sensitive endpoint (most susceptible human population). Once a NOEL is established, it is then normalized with the application of certain safety/factors (uncertainty factors) to make up for uncertainties or missing data, and to ensure that worker exposure is eliminated or minimized.[3]

Types Of OEL:

8 Hours OEL: The 8-hour OEL is a recommended and established concentration limit of a chemical (present in the worker's breathing zone) over the duration of 8 hours (the length of a typical working day), that protects against negative medium- to long-term effects, while protecting workers who may have had a lifetime of exposure to the chemical.   

15 Min OEL Or Short Term -OEL (STEL) : The Short-term Occupational-exposure Limit (OEL) aims to safeguard workers from adverse health effects (both immediate and short-term toxic effects i.e little irritation) resulting from peak levels of exposure. Typically, the reference period for Short-term OELs is 15 minutes unless noted otherwise.

Celling OEL Or Momentary OEL: The Ceiling OEL represents an atmospheric concentration in the workplace that is permitted not to be exceeded by any substance throughout the entire working day. Ceiling OELs include those substances that are corrosive or irritating in nature and could present serious and irreversible health impacts within a short spaced timeframe (i.e., very early onset). The means by which these analytical measurements of Ceiling OELs shall be conducted have been defined. The following section describes how certain National Approaches apply to establishing a Ceiling OEL for various regions and countries.   [3]

Factor Affecting OEL:

Route to route extrapolation: Worker DNEL must consider human inhalation exposure. If POD is based on exposure via a different route (example: oral, dermal), route to route extrapolation is necessary. When performing the route to route extrapolation process, a default factor of two is used to allow for the possibility of differences between the two routes of absorption; that is, we approximate 50% absorption on tested route versus 100% absorption via inhalation. As with any of the other defaults, if empirical data suggest otherwise, the factor can be changed. In addition, the default assumption for route to route extrapolation for workers include 70 kg body weight and 10 m3 breathing volume for 8 hours.[4]

Allometric Scalling:

To make up for metabolic rate differences amongst species, allometric scaling has been introduced. If inhalation data used to derive the POD come from a human inhalation study or from another animal inhalation study in which bioavailability is assumed equal for both humans and the test animal, then no allometric scaling is required. Conversely, if POD data are derived from an oral or dermal exposure study, then adjustments will be different based upon species (e.g., dogs 1.4; rabbits 2.4; rats 4) based upon Table R.8-3 (ECHA, 2008). Thus, exposure conditions need correction.For cases where exposure does not conform to an 8-hour workday, one can adjust the dose using Haber’s Law: Cn × t=k), where C = concentration of the chemical, t = time of exposure and k = constant. The 'n' value to use will depend how one wants to correct or convert (converting from a shorter exposure to a longer, will require 'n = 1', whereas converting from a continuous exposure rate to an eight hour exposure rate, the 'n' value will = '3'). Lung ventilation has been generally estimated as 10m3/hour for workers during an 8-hour shift with light physical exertion and as 6.7m3/hour for people who are not working.  REACH document (ECHA, 2008).[4],[5]

 Intraspecies differences:

Worker-DNELs are derived for a subpopulation where a smaller amount of intraspecies variability can be anticipated because the study sampled a group of healthy individuals who were not infants and not elderly. For this reason, intraspecies extrapolation for workers would have a factor of 5, whereas the extrapolation factor for the general population would be 10.[6]

 Determination of OEL For HPAPI Process: : In order to manufacture highly potent compounds, it's necessary to have thorough procedures and policies in place regarding the appropriate classification and handling of HPAPIs. Evonik has established a policy on handling potent compounds, which focuses on the following critical areas: • Toxicological evaluations (of compounds that have pharmacological and/or toxicological activity) and establishing both approved occupational exposure limits (OELs) and permitted daily exposure (PDEs) values are based on a "good manufacturing practices" search of published peer-reviewed literature. If sufficient literature/data is not available to develop both an OEL and/or PDE, then either an OEB (occupational exposure band) will be assigned based on an initial safety design review of the toxicological data, or mutagenicity predictions using FDA compliant software will be used to develop tentative OEBs. • A combination of industrial hygiene risk assessing prior to the handling of potent compounds and continuous monitoring and evaluation of the actual industrial hygienic performance based on data collected. • Policies and procedures regarding the proper design of the facility housing the pharmaceutical dosage forms and the associated methods of exposure control that will result in a safe handling environment for both the potent compounds and their pharmaceutical dosage forms at all levels of the organization. Justification shall be provided for all design and exposure control decisions. If no sufficient data is found to justify the safe handling of a given compound, then it is required that the organization shall not use that compound until all necessary conditions for use are established. • The use of training aids and communications methods that will inform/educate the employee about the hazard of a given potent compound while at work and that will educate/inform the employee that has a competent understanding of the control methods employed for the given compound that are designed to prevent exposure. • An effective PM system shall be used to ensure that individual responsibilities for performance have been defined and that all common goals are achieved.[6]

Calculating An OEL For Genotoxic Substance With clear Threshold Dose:

Colchicine does not have a genotoxic effect in a straightforward manner, but it does produce chromosome loss by poisoning the mitotic spindle, which causes the cells to become aneuploid (numerically aberrant for chromosome number). The use of this agent will have produced negative results in both the Ames test regardless of whether the organism was metabolically activated because the molecule does not directly interact with DNA. The chromosome aberration assay conducted using human white blood cells (lymphocytes) showed no evidence of aneuploidy through 0.49 mg/kg (maximum dose tested) level of exposure to colchicine, although at this level it would also have been impossible to produce aneuploidy because there were no disrupted cells due to mitotic nondisjunction or chromosomal aberration. The maximum amount of exposure to colchicine that has been correlated with an increase in the percentage of cells that were tetraploid (in mitotic arrest) and had dissociated chromatids (centromeric chromosome aberrations) occurred at 0.63 mg/kg (Wang et al., 2006). Threshold levels, for the production of chromosome loss by colchicine in vivo, are approximately 0.49 mg/kg within an organism. Based upon data identified in tests for derivative of DNA damage (Kirsch-Volders et al., 2003) as compared to previous studies of other compounds for the same or similar effects (Elhajouji et al., 1997), the difference in the two sets of testing numbers would be expected to be at least a 50% underestimation of chromosome loss for colchicine as well. Therefore the Occupational Exposure Limit (OEL) value can be calculated based upon the 0.49 mg/kg NOAEL for in vivo testing as will as on the 0.63 mg/kg therapeutic dose of colchicine being used to treat gout (Cammerer et al., 2010; Guerard et al., 2014); in this case the NOAEL value can be identified as the Lowest Observed Effect Level (LOAEL) and an appropriate correction factor applied to extrapolate down to NOAEL.[7]

 Calculating An OEL For Genotoxic Substance Without Threshold Dose:

A large part of the overall CAF in the previous but earlier discussed examples was due to the uncertainty present in the original data sets and the range of variability when converting the data sets to the desired target population. According to the U.S. EPA, there are several recommendations regarding the maximum acceptable AF for chronic reference value of any substance but not including bioavailability and accumulation potential AFs that apply to that specific substance (U.S. EPA, 2002). The example of paclitaxel provides an example where a factor of 10 was used to extrapolate from the original animal studies that were performed over relatively short duration to chronic exposure to paclitaxel. Consequently, the CAF used in this particular example is reasonable, based upon the data sets that are available. Further investigations are needed to justify a reduction of uncertainty that would provide support for fewer AFs.[8]

MATERIAL AND METHOD:

Identification and Compliance of FDA Approved SMKIs:

We have compiled a list of FDA-approved small molecule kinase inhibitors (SMKIs) using Rosko ski (2025) and the FDA Approved Drug Database. Any SMKI had to be FDA approved by 31 March 2025. Non-small molecules and products that were not classified as kinase inhibitors were excluded from this list, resulting in a total of 86 SMKIs for analysis. The primary therapeutic targets, as well as non-clinical and clinical data associated with each marketed SMKI, were taken from Rosko ski (2025) and each drug’s respective approved product labeling. A complete list of approved drug labels was obtained from the FDA website (Drugs FDA). All drug label information was reviewed and extracted by at least two independent authors; if there were disagreements regarding extraction, they were resolved by consensus.[9]

Evaluation of Non-Clinical data for approved SMKIs:

We collected and reviewed all available genotoxicity (mutagenicity/clastogenicity/aneugenicity), carcinogenicity, development/reproductive toxicity (DART) data on all SMKI drugs from their labels. We used the UN GHS Definitions and Criteria to classify whether an SMKI was "positive" for carcinogenicity, developmental toxicity, and/or reproductive toxicity (United Nations Economic Commission for Europe, 2023). We classified a compound as developmental or reproductive toxicant if study data supported DART-related positive results.If a study's results did not support being classified as a DART active, but showed potentially active results close to a THR, we conservatively classified the compound as positive for DART activity. We review and reach team consensus on cases that are ambiguous (e.g., identification of embryofetal effects due only to DART activity caused by maternal toxicity) with two or more reviewers. [9]

 Evaluation of Clinical Data For FDA Approved SMKIs:The clinical data that was collected included intended route(s) of administration, minimum therapeutic dose per day and sensitive subpopulation information. We recorded the lowest recommended therapeutic dose (mg/kg) in situations where there were multiple therapeutic dosing restrictions. When determining if sensitive subpopulation data should be included, we considered whether renal or hepatic impairment required a reduced dose and whether the drug had known potential to interact with CYP inducers or inhibitors.[9]

Estimation of OELS and Mapping of OEBs For FDA- Approved SMKIs:

approved SMKIs intended to be administered via the oral route (n = 83). We excluded SMKIs administered via other routes from the OEB analysis including netarsudil (RHOPRESSA®) (ocular), temsirolimus (TORISEL®) (IV), and trilaciclib (COSELA®) (IV). The OELs (and subsequent OEBs) estimated from this broad approach are not intended to substitute for the respective company- established limits which are generally based on proprietary toxicology data as well as a more detailed review of available information. The estimated OELs and mapped OEBs herein utilize a generalized approach (as detailed below) with the intention of providing guidance in the establishment of speculative HBELs for data-poor SMKIs.[10]

 Occupational hazard and exposure Consideration:

Each biologic product will need to be assessed independently as they tend to be very specific to their target(s) and usually have a high degree of potency. The potential for accumulation due to long half-life, pharmacodynamics and developmental toxicity must also be part of the hazard assessment for biologics. Regarding exposure risk, the risks of being exposed via dermal, oral and inhalation will generally be low. Compounds greater than 500 Da are not likely to be bioavailable by means of dermal exposure (Bos and Meinardi 2000). When exposed in the occupational setting, biologics with a MW greater than 10 kDa are also likely to have low systemic exposure potential by inhalation (e.g. BA<1%) (Gould et al. 2018; Pfister et al. 2014b). Few studies have evaluated inhalation BA of Fc-fusion proteins, with inhalation BAs ranging from 20-50% which is much higher than the BA we observe for mAbs; this illustrates the need to consider the binding component when estimating the inhalation BA of fusion proteins (Gould et al. 2018; Dumontet al. 2005; Pfister et al. 2014b). It is not safe to assume that low BA will apply if there are drug targets within the lung or skin. At this time, there are no validated in vitro or in vivo models to evaluate the potential for respiratory sensitization.[11]

Health hazard Assessment:

Biologic materials may lead to concerns about immunogenicity when administered. The immune system may react to biologics due to their potential to produce a hypersensitivity reaction caused by foreign proteins and/or other substances in the biologic. Humanized monoclonal antibodies (mAbs) are less likely to cause immunogenicity than murine mAbs because they have a lower proportion of foreign protein (Halsen and Kramer, 2011). Despite being relatively safe, fusion protein therapies have been reported to cause a variety of adverse events associated with hypersensitivity reactions of varying degrees (e.g., anaphylaxis, skin rashes), infusion and injection site reactions (20-50% of patients), and cytokine release syndrome (also sometimes referred to as "cytokine storm") (Baldo, 2015). The way a particular fusion protein interacts with the recipient's immune system should also be considered when assessing potential health risks associated with the evaluated fusion protein product. Since many fusion proteins interact with the immune system, they can increase the risk of developing infections, decrease the function of the immune system, and create chances of autoimmune reactions occurring. For example, while the adverse effects associated with etanercept (fusion protein) are generally limited (such as fever, headache, local injection site reactions, mild allergy and itching) (Baldo 2015), some of the skin reactions due to fusion proteins are the result of possible direct targeting events rather than typical hypersensitivity reactions (e.g., response to agents that target epidermal growth factor receptor or EGFR, which often lead to non-immune-mediated adverse skin events) (Baldo, 2015). Additionally, when fusion proteins have been conjugated to polyethylene glycol (PEG), there is concern surrounding the lack of biodegradability associated with this form of conjugation, which is an additional potential patient safety issue.[12]

 Risk Assessment in OEL Setting:

 Qualitative Assessment of Health effects: Identifying therapeutic substances' possible impact on work safety needs to precede evaluating and using that knowledge to create limits for controlling the adverse health effects of those substances arising from work-related exposure. Evaluating the possible effects of therapeutically used substances on work safety should also prioritize effects that relate closely to either short-term or long-term work-related exposure. If this is not done sufficiently initially, a great deal of unnecessary effort could be made to establish a limit to prevent an adverse health effect associated with a therapeutically used substance not likely to be found in a work-related setting and, at the same time, leave significant work-related adverse health effects resulting from using that therapeutic product unattended. Adverse health effects may also direct choice of methods for health surveillance and environmental monitoring. Paragraph 3 of the COSHH ACOP suggests that health-safety professionals use those methods to help identify hazardous properties of substances at work, and such methods can also be applied to therapeutic products.[13]

Therapeutic desired health effects: These medicines have been studied for their primary use by researchers working in the field to learn about their effects on humans and animals. Researchers will be able to provide scientific evidence related to the manner in which these medicines affect the human body when reporting to the workplace based on the information they gathered from previous studies of these substances. Any immediate or rapid effects on the body, such as decreased heart rate, decreased blood pressure, and altered mental status, will be relevant for the workplace. The potential chronic or long-term occupational effects of these medicines will also be assessed, as their effects on normal hormones and hormone production would cause chronic occupational effects. However, analgesics (medicines used for relief from pain) and medicines that kill or incapacitate infectious agents (pathogens) may not cause relevant occupational effects in the workplace when evaluated independently.[13]

 Evidence by analogy: As there are no studies of the occupation related degradation effects of pre-marketing therapeutic usage for the organs that will first come into contact with the agent (skin, eye, nose and lung) when those changes are clearly specific to people and not available from studies on animals, pre-marketing therapeutic experience does not provide a reliable basis to anticipate adverse occupational experiences at the site of first contact. However, there are other human experiences that can assist to provide guidance. For example, when an agent was marketed as an oral laxative, there was no anticipation of developing respiratory hypersensitivity from exposure to the active ingredient (Ispaghula). However, the active ingredient originates from a plant family that is known to produce respiratory sensitivities (asthma) — plantain. The pharmaceutical industry often uses structure/ activity relationships to assist in attempting to predict the desired effects of an agent, and similarly, these relationships can be used to assist in predicting the potential for the development of adverse occupational experiences. While in practice, these techniques have not been routinely examined for use in predicting adverse occupational effects from exposure to therapeutic agents, there are undoubtedly lessons that can be learned from those organizations involved in the pharmaceutical industry that will be beneficial for those organizations that do not have formal computerized applications of these types of techniques to evaluate adverse occupational effects.[14]

 Health Surveillance: Health monitoring will, by whatever means, be able to identify occupation-related negative effects on health; some of which would have been highly unpredictable for different reasons. In monitoring the health of a working population exposed to therapy, one can clinically suspect that any symptom that is present affecting the first point of contact (eye, skin, nose and lung) may be occupation related, even if this is contrary to what would be clinically expected based on the therapy received. However, the validity or invalidity of such assumptions about an occupational origin for these symptoms should be confirmed or disproved through an appropriate investigation. Assumptions that adverse health effects are "idiosyncratic," infrequent and only affect "susceptible individuals" needs to be avoided uncritically.[14],[15]

Qualitative Assessment of health effect and their relationship exposure:

Pharmacology data:

SARGENT and KIRK (1988) have indicated that data derived from laboratory animal studies and clinical trials may be used as a basis to derive OELs. However, the limitations of these types of approaches need to be recognised (ECETOC, 1984). There are major differences in the pharmacokinetic profile between the two types of exposure - occupational and therapeutic. When considering a therapeutic product (e.g., codeine) that is inhaled as a respirable, soluble dust, the codeine will quickly and completely be absorbed into the systemic circulation compared to a therapeutic product administered via the oral route, where absorption may be slow, partial and will be further metabolized by the liver (DOLLERY et al., 1971; PEPELKO and WITHEY, 1985). Therefore, in terms of bioavailability, the codeine administered by an occupational route has much more in common with intravenous administration than an oral route of administration.[15]

 Environmental Monitoring Strategy:                      

If a health-related assessment has determined that monitoring of exposure is needed, then the monitoring of the exposure to the therapeutic substance can be done in the same way that other toxic substances are monitored (HEALTH AND SAFETY EXECUTIVE, 1989b). The objectives of the environmental monitoring strategy for the substance and the determination of the time weighting for the OEL (exposure limits) must be relevant to the health effect and to the work practice associated with the exposure. For example, if an acute adverse health effect may occur as a result of a vessel charging or discharging procedure, then the monitoring strategy should include short-term monitoring and an OEL based on a 10-minute duration. For example, an acute adverse effect in the central nervous system that may occur after exposure to benzodiazepines, opiates and/or tropic alkaloids may include a change in behavior, sedation and/or loss of consciousness. Acute adverse health effects on the heart, for example, as a result of beta-adrenergic agonists, and/or on the lungs, for example, as a result of beta adrenergic antagonists may occur. Conversely, if a chronic adverse health effect, such as hormonal stimulation and/or suppression could occur as a result of a continuous operation, such as packing, then the monitoring strategy should consist of monitoring based on a full-shift OEL. The sampling method used must take into account both the physical nature of the substance and the adverse health effect that it produces. Therefore, for a highly soluble therapeutic substance that exerts adverse health effects, the choice of sampling method must take into account the duration and the frequency with which these effects occur.[16]

Biological Monitoring: When it comes to determining an OEL, using either biological monitoring or biological effect monitoring alone will not provide adequate data for development. Under certain conditions, however, if there is enough pharmacological data for a therapeutic substance and that pharmacological data can be used to relate the levels of that substance in human blood with the risk for adverse health effects, then you may be able to conduct both biological and occupational exposure and use biological monitoring as a means to bridge those two data sets (HARRINGTON et al., 1978a, b; BAXTER et al., 1986). If the measurements are sensitive enough, extrapolating to an OEL that would correspond with no health effect as determined by biological monitoring may be possible. [17]

Acceptable Daily Exposure (ADE)

Hazard Identification:

Each hazard submission begins with obtaining and analyzing all of the relevant available physicochemical data, as well as any available animal or human data that can assist in providing an understanding of how to characterize a hazard. As the API is developed for human use, the knowledge of what data exists and the quality of what exists will continue to improve. In many cases, when the ADE has been established by the innovator of an API, the regulatory filing will include the most comprehensive source of data available as part of the application. In many cases where the innovator has not established an ADE for an API, the only means to supplement the existing database is to perform a search of the medical literature. Many of these searches should include publicly available databases, including the FDA’s Summary Basis of Approval database (drugs@fda.com), the National Library of Medicine’s PubMed, Toxline, DART and CCRIS; however, _many searches will also use subscription databases and many commonly used Pharm and Tox reference texts_. For currently marketed drugs, prospective drug information can be obtained from the Prescribing Information available free of charge at many public websites and which is the same as what pharmacists receive with Package Inserts accompanying their drug supplies. A Clinical Investigator’s Brochure for a drug that is in development can provide substantial drug information but will often only be available from the innovator. Each of the mentioned sources should be searched in order to complete the hazard identification component of the risk characterization process of an API, and thus start the risk assessment process.[18]

Types of available Data for hazard characterization:

To begin developing an ADE, one must first conduct a comprehensive collection of information for the chemical being studied. The collection of a large, precise amount of information about a chemical is referred to as a literature review and is the most significant factor in performing hazard characterization (or a priori risk assessment). Searching high-quality literature is essential and systematic search methods can increase the amount of high-quality information found by searching multiple databases and other sources of information about the chemical being evaluated (Sandhu et al., 2014). A systematic review is also documented so that other people can conduct/repeat the systematic review. Currently, no guidelines or regulations exist from any regulatory body regarding how to conduct an effective systematic review; however, some general guidance documents exist (EFSA, 2009; Rhomberg et al., 2013). A toxicologist or qualified expert in our area should be the individual who does all of the literature searching or reviewing. While developing a systematic review strategy is helpful in guiding the literature search, literature searching can also be an "art" that is done efficiently by an expert who can quickly and accurately identify alternative data streams or sources based on the results of their initial search. In reality there are many compounds with much data and many compounds with not much data; there is no search that is the same as any other.[19]

ADE As a Metric for Assessing Risk:

The 2010 Risk-Mapp Guide set forth the acceptable daily exposure (ADE) for assessing the risk of pharmaceutical manufacturing worker exposure and patient safety (for example, regarding cleaning validation) based on data available prior to clinical trials and during clinical trials for each compound. Based on ICH Q9 principles, the level of controls needed and the level of effort, formality, and documentation (including validation) associated with implementing those controls will occur according to the level of risk. Thus, it is important to have a way to measure risk. This article will clarify how the current practice of categorizing compounds as belonging either to one of two categories (highly hazardous or non-hazardous) is incorrect, and that the hazards presented to patients by drugs should be seen on a continuum, as indicated in the Risk-Mapp document. The article describes a new way of rating the hazard presented by drugs based upon the ADE that can be used as a visual aid to easily assess and rank the relative hazards of drugs manufactured on shared facilities or equipment.[20]

Skin Sensitization:

Several studies have been performed in reaction to a particular area of research being established for the characterization of adverse outcomes related to skin sensitization. There remains a great deal of uncertainty regarding this end effect, but it appears that the ability of a substance to interact with proteins present in the human body is closely associated with both the likelihood of that chemical becoming a skin sensitizer as well as its potency at doing so (Roberts & Aptula, 2008; Roberts et al. 2007a & b).Empirical in-vivo and in-vitro testing have provided support for the development of quantitative structure-activity relationship predictive models on many types of possible structural characteristics (e.g., Michael acceptor & etc., SNAr electrophiles) (Enoch & Roberts, 2013; Roberts & Aptula, 2014).Safford et al. (2011) have used anLLNA data analysisto estimate dermal sensitization thresholds (DST) for compounds that were considered to be non-reactive with skin proteins and more recently for those that reacted with them (Safford et al. 2015).  The DST values for these two groups of substances were calculated to be 900 & 64 mg/cm2, respectively, and these values will become added to our collection of other threshold values for pharmaceuticals.[21],[22]

PDE (Permitted Daily Exposure)

In the pharmaceutical manufacturing industry, when more than one drug product is produced at a shared facility or using shared equipment, there may be some residual drug product left over from the previous batch (drugs) prior to producing the new batch of drug product. This residual product can be transferred from the previous drug product to the new one, creating an opportunity for cross-contamination. The permitted daily exposure (PDE) and acceptable/allowable daily exposure (ADE) refer to the amount of drug product that can be considered safe to expose humans to via any route without the drug producing an adverse effect.[23]

Material and Method:

This research paper covers all of the scientific data that can be gathered from the derivation of high biopharmaceutical exposure limits (HBELs). It reviews the peer-reviewed literature on the databases of PubMed and ScienceDirect using the keywords "pharmaceuticals" and "PDE" and uses all relevant references published until March 2021. In this case, we present an example of how to calculate the PDEs of Tobramycin (CAS No. 32986-56-4) for ocular administration and Asa (CAS No. 50-78-2) for oral administration. The calculation of the Acetyl Salicylic Acid PDE has been detailed to illustrate that all of the preclinical/clinical/pharmacovigilance data must be considered in order to derive the appropriate PDE. This exercise serves to give individuals working in the area of pharmaceutical exposure the understanding that a comprehensive assessment of all available data is required for the derivation of a PDE or HBEL.[24],[25]

RESULT AND DISCUSSION:

A Point of Departure is a dose of exposure (nonclinical or human) which produces a specified amount of response for the identified critical effect being evaluated. For nonclinical RA data, the PoD is based upon a NOAEL or LOAEL (non-adverse and adverse effects observed, respectively) from humans or animals, or from clinical or epidemiologic studies. When considering the reliability of nonclinical RA studies, studies from labs subject to Good Laboratory Practices have more credibility and reliability than those done in a non-regulated environment like a University research lab. Reliability can also be verified using Klimish Scores when reviewing the literature. In those cases where a NOAEL is not available or a LOAEL cannot be clearly characterized, the lowest therapeutic dose or the highest daily dose found to have benefits as a therapeutic agent can be considered as the PoD. The various PoDs that can be used for PDE calculations are depicted in the figure below . The expectation at the lowest therapeutic dose is that the potential benefits from the therapeutic use outweigh any potential adverse effect.[26]

Reproductive Toxicology Consideration:

Thalidomide was a widely used sedative that had been marketed around the globe until an actual teratogen was discovered back in the 1960's. Even though the product was no longer being marketed in the United States during this time frame, thalidomide has now become available for investigational purposes to treat several different diseases. The product is available as an oral capsule formulation (50, 100, 150, and 200 mg) and carries with it a "black box" warning on its label which states that one capsule (the strength does not matter) taken by a pregnant woman has the ability to result in serious birth defects. Data from repeat-dose oral toxicity studies have been published characterizing the systemic adverse effects of thalidomide when tested in dogs and rodents. In a 53-week oral toxicity study of dogs (0, 43, 200, or 1,000 mg/kg/d), thalidomide did not produce any significant concerns for the development of systemic toxicity. The results of the study indicated that mammary duct dilation and/or glandular hyperplasia developed in some of the female dogs and bile pigment was present in the livers of dogs at the high dose(s). The authors of the study listed 200 mg/kg/d as the no-observed-adverse-event-level (NOAEL) for thalidomide in dogs.[27]

Methodology:

Calculation Of PDE:

The PDE report for the Active Pharma Ingredient was requested by 150 worldwide pharmaceutical companies with a total of 1200 active substances. This evaluation was undertaken by Experts at AETOX/EUROTOX; The PDE value was calculated using guidance from both ICH Q3C (R4): Residual Solvent Impurities, ICH Q3D (Sept 2015): Elemental Impurities and by VICH GL18(R) (Veterinary Residual Solvent Impurities). Each active pharmaceutical ingredient was evaluated based upon a toxicological review of literature on the hazardous properties and the critical effects related to each active pharmaceutical ingredient. The POD (point of departure) was established from this toxicity literature and used to calculate the PDE for each active pharmaceutical ingredient.

The literature was reviewed to perform the toxicological evaluations to identify both potential hazards and relevant effects of the substance. The following data structures were used to determine the point of departure (POD) for each case. PODs were determined individually for each case, using the available data to determine which is the most accurate value to begin with for that particular case. Due to the different types of POD used, they are as follows: no observed adverse effect limit (NOAEL), no observable effect limit (NOEL), lowest observed adverse effect limit (LOAEL), lowest observable effect limit (LOEL), and threshold of toxicological concern (TTC).[28];[29]

Overview of the essential factors in ocular pharmacokinetics:

Most of the topical ocular medications used in clinical practice today consist of small molecules with moderate lipophilicity. The highest molecular weight that has been documented so far to allow conjunctival penetration of drug molecules is around 20 to 40 kDa. Clinical studies have demonstrated that these drugs are rapidly absorbed (within minutes) into the systemic circulation (Boddu et al. 2014; J€ arvinen et al. 1995; Urtti 2006) after topical administration to the eye, either directly from the conjunctival sac through local capillary blood vessels, or through the adjacent and very vascularized nasal cavity. Although there have only been limited number of published studies in the scientific literature assessing the systemic absorption of topical ocular medications in humans (Urtti and Samilinen 1993), such absorption rates for the topical ocular compounds timolol (100% absorbed through the eye) and pilocarpine (up to 80% absorbed through the eye) do exist. In most cases, it has been estimated that approximately 90% of the total amount of drug administered topically to the eye will be available in the systemic circulation (Kim et al. 2014; Zafar et al. 2016). Systemic effects resulting from drugs administered topically to the eye must be identified and documented as part of the full health risk assessment of individual topical Ocular products. In general, the amount of drug applied topically to the eye is so low that systemic concentrations would likely be undetectable or that supporting clinical data do not exist (Kompella et al. 2010); however, in some circumstances, exceptions have been noted for molecules which exert their actions on receptors that are not solely found in the eye. [30]

Operation and Process Management: Operations and process management deals with ensuring that people responsible for developing ADEs/PDEs as well as product quality acceptance limits (e.g., swab/rinse limits) are qualified to perform these tasks, and also how to communicate and implement these types of limits internally and externally.

More communication (internally, externally, between companies and governments) is needed. It is important to share data when contamination arises from using shared facilities between multiple companies. Even though some companies have compound-specific methods for performing operational procedures on specific compounds (e.g., intermediates, degradants, impurities, large molecules and small molecules)), there is still a need for additional guidance and harmonization.

A decision framework on developing ADEs/PDEs for specific compounds would be helpful for addressing the question of whether or not derivation is necessary to establish the limits. The framework should provide enough flexibility so it can match the respective management practices for each individual company, be well documented on the reasoning behind decisions, meet regulatory expectations, and allow for the evolution of science. [31]

Stakeholder Communication:

In Using the Advance Design Engineering/Process Design Engineering (ADE/PDE) Methodology, Safe and Effective Dose is Calculated and Established In Order to Provide Uniformity of Technologies and Practices Among Crossover Functional Roles (e.g., Manufacturing), Which Will Include All Department Users of the Same Technology/Practice In a Complex Organization.

• The ADE/PDE Must Be Scientifically Plausible, Therefore, The Data Required To Conduct The Evaluation Must Have Been Collected, Analyzed and Assessed Accordingly, Utilized in The Most Acceptable Methodologies, Be Scientifically Validated, And Utilized Using Current Data Sources.The Treatment Of Any Data Gaps Or Associated Uncertainties Should Be Addressed Through Alternative Means (e.g., Using Adjustment Factors).[32]

Specific Consideration:

Active Substance with a genotoxic Potential:

There is a perceived threat of any level of exposure to genotoxic (active) substances that do not have a measurable threshold and so every level has some risk. To this end, the "European Medicines Agency" (EMA) has defined the Threshold of Toxicological Concern((TTC)) for non-threshold related genotoxicants as a TTC of 1.5 µg/person/day. The TTC is the amount of genotoxic impurity that would lead to a lifetime risk of one additional case of cancer (i.e., an excess risk) in a population of one hundred thousand exposed individuals. When, in fact, exposure periods for residual active substances will generally be much shorter than a lifetime, exposure to 1.5 µg/person/day will result in an excess risk of no greater than 1x10^-6.

When the product that could be contaminated with residue from the Use of Active Ingredients is a veterinary product, it should be determined using a similar TTC, but it should be converted from the TTC per person basis to the TTC per kilogram of body weight as described above.[33]

Immunotoxicity:

According to White (10) and others, the IgM antibody-forming cell (AFC) response to the T-dependent antigen sheep red blood cells (sRBC)—the plaque assay—was used for the study of immunotoxicity in female Sprague Dawley rats (5/group). Animals were given 4 weeks of exposure followed by an intravenous injection of sRBC for immunization 4 days before the end of the study. The rats' spleens were taken, weighed, and the IgM antibody-forming cell response was tested using a modified version of Jerne's haemolytic plaque assay. The following outcomes were determined for the spleen per rat: amount of cells per spleen, number of AFCs per ten cells in the spleen, and number of AFCs per spleen. A statistically significant increase in spleen relative weight was observed in the 2,000 mg/m3 dose group (21%) but this effect could not be established to be biologically significant as there was no evidence of dose response. There was no effect on thymus relative weights, and there was no effect of G/DIPE on the number of spleen cells. G/DIPE resulted in no effect on the total number of spleen cells but a statistically significant depression of the IgM antibody-forming cell response to the T-dependent antigen (sRBC) in the high dose (20,000 mg/m3) animals (63% lower than the control group). The NOEL was determined to be 10,000 mg/m3 for G/DIPE. The same study reports a similar finding of decreased humoral immune responses in the animals.[34]

Discussion: There has been a significant transformation in how OELs are derived over the years. Historically, the derivation was mainly based on occupational exposure data. P Uncertainty factors and adjustment factors typically will be used for interspecies variability, intraspecies variability, exposure duration, and limitations in available data; these can provide a scientifically valid approach to potentially decreasing the risk of adverse health effects due to occupational exposure.

ADE and PDE calculations have proven to be very useful for preventing cross-contamination between products manufactured in the same facility using common equipment. If more than one product is manufactured in a single facility using the same equipment, residual materials from one product can contaminate another product. The purpose of ADE and PDE calculations is to establish acceptable levels of exposure through which adverse health effects are not expected to occur. Furthermore, the results of ADE and PDE calculations provide the basis for cleaning validations, contamination control programs, and compliance with regulations. The implementation of health-based exposure limits have also improved product quality assurance and have improved patient safety during the manufacturing of pharmaceuticals.

In the process to derive ADE and PDE values, toxicological evaluations must all be conducted and documented. HPAPIs = Highly Potent Active Pharmaceutical Ingredients. These substances may be extremely potent either pharmacologically or toxicologically at very low levels of exposure. Some HPAPIs pose substantial risks at low exposure levels therefore require Manufacturers to develop special containment systems, etc., for handling them safely. Manufacturers should employ scientifically based OELs and PDEs to implement effective engineering control strategies, provide PPE, perform monitoring, and train their employees on HPAPI exposure issues.

There are many sources of guidance provided by regulatory authority organizations such as the EMA & ICH to help determine how to handle HPAPI containment. The EMA and ICH typically develop documents that provide guidelines for implementing HBELs (Health-Based Exposure Limits) throughout pharmaceutical manufacturing. In general, these documents focus on a risk-based approach to controlling contamination and require manufacturers to apply scientifically valid toxicological principles when establishing HBELs. The pharmaceutical industry appears to be continuously embracing scientific methodologies in determining Risks associated with HPAPI-related exposure to promote superior levels of evidence-based and uniform Risk Management Practices throughout the industry.[34],35]

CONCLUSION:

Occupational Exposure Limits (OELs), Acceptable Daily Exposure (ADE), Permitted Daily Exposure (PDE), and Health Based Exposure Limits (HBELs) are now regarded as essential to risk assessment and contamination control in pharmaceutical companies. The rise in shared manufacturing facilities and the use of highly potent active pharmaceutical ingredients creates the need to establish scientifically validated exposure limits that will be used to protect the health of both patients and workers. These exposure limits are considered critical tools in minimizing occupational health-related workplace incidents and minimizing the probability of product cross-contamination while supporting continued compliance with regulatory requirements.The establishment of OEL, ADE, and PDE limits requires an in-depth evaluation of the available scientific literature to determine the adequacy of toxicology, pharmacology, clinical, and occupational exposure data. In order to derive adequate exposure limits, an appropriate Point of Departure (POD) must also be established. The POD can use several types of data such as NOAEL (No-Observed-Adverse-Effect-Level), LOAEL (Lowest-Observed Adverse-Effect-Level), NOEL (No Effect Level), or Therapeutic Dose to create reliable exposure limits. To further improve the accuracy of risk assessments, uncertainty factors or adjustment factors may also be applied. Using uncertainty or adjustment factors allows an accurate assessment of interspecies variability, individual human sensitivity, and data limitations. The systematic application of these approaches in part ensures that the established exposure limits are scientifically based and protective. ADE (acceptable daily exposure) values, as well as PDE (permitted daily exposure) values, are extremely important aspects of pharmaceutical manufacturing and are utilized to both support cleaning validation programs and establish criteria for acceptable levels of residual contamination. The application of established ADE/PDE limits will further aid manufacturers in maintaining the quality of their products, lessen the risk of cross-contamination, and protect patient safety when utilizing multi-product facilities. Also, implementation of HBELs (Health-Based Exposure Limits) has increased the use of scientifically supported contamination control approaches in the pharmaceutical industry. Within the field of exposure limits derivation, despite numerous advances; challenges still exist such as the lack of toxicology information for many newly developed chemicals, inconsistencies between the various studies available to help assess the safety of a product, and increased complexity associated with currently manufactured pharmaceutical products. Upcoming efforts should be aimed at improving data quality; increasing cooperation among government regulatory agencies and their respective industries; developing internationally accepted guidelines for determining exposure limits; and refining current risk assessment methods through further research that would enhance employee protection and ensure product safety.

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