What is SMEPAC testing in the pharmaceutical industry?

SMEPAC is an acronym for the International Society of Pharmaceutical Engineers (ISPE) “Standardized Measurement of Equipment Particulate Airborne Concentration” Guideline (First Edition 2005). In 2012, ISPE published its Second Edition and changed the title to “Assessing the Particulate Containment Performance of Pharmaceutical Equipment” (hereafter known as the “Guideline”) and incorporated the document into ISPE’s Good Practice Guide collection. It should be noted that a revised Guideline is expected to be published in 2023-24.

Seven tips to help prevent regulatory audit findings related to HBEL documentation

Every manufacturer of medicinal or veterinary products needs to obtain and keep current health-based exposure limits (HBELs), also known as acceptable daily exposure (ADE) limits or permitted daily exposure (PDE) limits, for all their products. With increased globalization of pharmaceutical manufacturing and the rising number of regulatory audits, facilities need the right toxicology partner to ensure compliance with complex international pharmaceutical standards and guidance. Let’s explore preventative actions to consider.

What is OEL Testing?

Believe it or not, but here at Affygility Solutions, a leading provider in potent compound safety services, we often get asked "What is OEL testing?” Well, it depends upon what exactly a person is asking. However, OEL testing can be defined as the physical collection of airborne (or surface level) occupational hygiene samples and comparing those results to an established occupational exposure limit (OEL) for an active pharmaceutical ingredient. These are typically performed using industrial hygiene sampling pumps or swipe samples. OEL testing cannot be performed remotely or by mathematical calculation, but needs to be performed onsite by a certified industrial hygienist. For remote regions of the world, this often makes the cost for performing OEL testing cost prohibitive. However, Affygility Solutions has the experience to help.

2022 data: What percentage of drug compounds are highly potent?

Based on 2022 data, the percentage of drug compounds that are considered highly potent (HPAPIs) is approximately 41%. This percentage is based on a review of over 2,000 OEL Fastrac monographs in Affygility Solutions’ online catalog that have occupational exposure limits (OEL) less than 10 µg/m³. This represents over a 15% increase in the previously reported number that was based on outdated 2013 data. This percentage is further supported by an analysis of all the new chemical entities (NCE)s that have been approved by either the FDA or EMA between 2018 through 2021 YTD. This analysis indicates that 45.5% of all small molecule NCEs are highly potent. It should be noted that these are marketed HPAPI products, not products in development.

OEL / PDE Monographs: Criteria for Toxicology Partner Selection

When purchasing occupational exposure limits (OEL) and permitted daily exposure (PDE) monographs for active pharmaceutical ingredients, it’s important to select a toxicology partner with a quality-focused process. In this article we will explore the top criteria to consider when evaluating a toxicology service partner.

Brazil/ANVISA joins the Pharmaceutical Inspection Co-operation Scheme (PIC/S)

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) organization announced today that Brazil/ANVISA (“Agencia Nacional de Vigilancia Sanitaria”) has been formally accepted into the PICs organization starting January 1st, 2021. According to the PIC/S website, “A paper assessment was carried out followed by an on-site assessment visit which took place in October 2019, after a reorganisation at ANVISA. The assessment report was finalised in the course of 2020.” The PIC/s organization also noted that “This is the first time in PIC/S’ history that an assessment process is completed by written procedure rather than at a Committee meeting. This was due to the situation with Covid-19 which prevented a Committee meeting taking place in 2020.”

What is a DABT?

A DABT is an acronym for the professional designation Diplomate American Board of Toxicology, which is awarded to a person that has met certain educational, experience, and certification examination requirements in the scientific field of toxicology.

The qualification criteria, process, and certification examination is administered by the non-profit organization American Board of Toxicology (ABT). According to the ABT, the first DABT certification examination was given on August 4th, 1980. As of February, 2020 there are 2552 total active DABTs located in 29 countries.

Post Covid-19 Environmental Health and Safety in the Pharmaceutical Industry

At the time of this writing, according to the John Hopkins Covid-19 dashboard, over 3.1 million people in the world have been confirmed to have the disease Covid-19, and more than 227,000 people have died. Hospitals and other healthcare facilities are overwhelmed with Covid-19 patients and many sectors of the economy have been shut down, resulting in 26 million layoffed workers.

Despite all the bad news, environmental health and safety (EH&S) professionals need to see the current Covid-19 crisis as an opportunity. An opportunity for greater involvement rather than a crisis. An opportunity that is not about making predictions - since we don’t know what is going to happen in 6 months, 12 months, or 3 years - no one can do that. This opportunity should be about the contributions that EH&S departments can make in building a more resilient and agile organization, so when the next crisis occurs we will be better prepared

Occupational Health Categorization: Structurally Related Compounds and Toxicity

Can a Structurally Similar Compound help Determine the Occupational Health Categorization?

Often, in early pharmaceutical compound development, the available toxicology information for a discovery compound is very limited. Here at Affygility Solutions’ one of the questions that we get asked in order to help determine appropriate occupational health categorization is “Are there similar, chemically-related active pharmaceutical ingredients to the current compound of interest?”. The thought behind this is that while there may be limited toxicology information for the current compound, developed pharmaceuticals that are similar in structure may provide clues to toxicological behavior.

Occupational Health Categorization vs. GHS Health Hazard Categories: The categories have different meanings!

Introduction to Occupational Health Categorization Systems for Active Pharmaceutical Ingredients

Since the late 1980s, pharmaceutical manufacturers and contract manufacturing organizations (CMOs) have been familiar with occupational health categorization (OHC) systems. As a review, the OHC category assignment for an active pharmaceutical ingredient is determined by its inherent toxicity and potency, and the OHC category assignment is linked to the control band assignment that determines the engineering, administrative, and personal protective equipment needed to ensure safe handling.

Seven essential questions for vetting toxicology providers of HBEL monographs

The Regulatory Requirement to Vet Your Toxicology Provider

On June 1, 2020, the Pharmaceutical Inspection Co-Operation Scheme (PIC/S) released its guidance on the establishment of Health-Based Exposure Limits (HBEL) when different medicinal products are produced in shared facilities. Findings are detailed in the PIC/S PI 046 HBEL Guide.

Furthermore, on June 1, 2015, the European Medicines Agency (EMA) adopted guidance titled: “Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities.” This guideline was later followed by an accompanying: “Questions and answers on implementation of risk-based prevention of cross-contamination in production (EMA/CHMP/CVMP/SWP/169430/2012)”, which was published on April 19, 2018.

The definition of Permitted Daily Exposure revisited

Introduction of the term PDE

In the context of setting health-based exposure limits for the prevention of cross-contamination of different medicinal products, the term permitted daily exposure (PDE) was first defined in the European Medicines Agency (EMA) Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (hereafter referred to as the “HBEL guideline”) in December 2012 (draft version). And, that guideline went into effect on 01 June 2015. In the EMA’s HBEL guideline, the term permitted daily exposure was defined as follows:

“The PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime.”

What determines if a compound has hormonal activity and are all hormonal compounds highly potent?

What determines whether or not a compound demonstrates hormonal activity?

The question of whether or not a compound demonstrates hormonal activity is complex and cannot be addressed by any simple assay or set of assays. To fully test the potential of a compound to demonstrate hormonal activity, it must undergo extensive studies that can take long periods of time (up to years) to complete. The United States Environmental Protection Agency (USEPA) has an extensive endocrine disruptor screening program. This program is an example of the batteries of tests, in vitro and in vivo, that a compound would go through in order to establish whether or not it demonstrates hormonal activity. Even then, the results are sometimes debated and there is often not a clear yes or no answer. For some compounds, whether or not hormonal activity is demonstrated, has been hotly debated for years.

Chemical Abstracts Service Registry Number (CASRN or CAS): What's That All About?

When you request an occupational exposure limit (OEL), an acceptable daily exposure (ADE) value, a permitted daily exposure (PDE) value, or occupational health categorization (OHC) determination for an active pharmaceutical ingredient from Affygility Solutions, we will always ask you for the chemical’s CAS registry number (CASRN or just CAS for short), but did you ever wonder, “Why do I need to provide this information with my request?” Or, perhaps, “What is the CAS number and where does it come from?” Or maybe even, “How is it used when there are different forms of the API, like salts?” In this issue of the Potent Compound Corner, our toxicology team will dive in to answer these questions for you.

Insider on Affygility Solutions’ new Senior Director of Occupational Toxicology and his role in establishing OEL/PDE monographs

Back in December of 2018 our newest DABT-certified, PhD toxicology member Dr. James Damewood (Jim) joined the Affygility Solutions’ team. In this Potent Compound Corner article, Ashley Calhoun, Social Media Marketing Associate/Event Planner for Affygility Solutions, has a discussion with Jim so you can get to know Affygility Solutions’ toxicology team a little bit better!

Top trends in potent compound safety to watch out for in 2019

Often I get asked by other environmental health and safety (EHS) professionals and conference organizers, “What are the top trends in potent compound safety that I need to watch out for in the coming year?” While predicting trends is often a futile effort and because of the “Gradually, then suddenly” effect, things can change overnight, I will give it a shot.

When do you need an occupational exposure band vs. an occupational exposure limit?

Here at Affygility Solutions we often get asked, “When do I need an occupational exposure band (OEB) or occupational hazard categorization (OHC) report vs. an occupational exposure limit (OEL) monograph?” Well, let me explain.

Occupational exposure band reports are intended for early stage compounds with limited or no human data. The objective of an OEB report is to assign an early stage compound to a control band, without providing a specific numerical occupational exposure limit (OEL) or numerical acceptable daily exposure (ADE) (aka permitted daily exposure (PDE) value). And while the expert occupational toxicologist may perform some “back of the envelope” calculations to determine the appropriate control band assignment, it is unwise to present these calculations in the OEB report since the numbers will significantly change as the compound moves through development. In addition, the expert occupational toxicologist authoring the OEB report may also employ a “read-across” or professional judgement approach to similar compounds based on the compound of interest’s specific molecular structure.

Cross-contamination in Shared Facilities Guidance by PIC/S goes into force July 1st, 2018

On July 1st, 2018, the Pharmaceutical Inspection Convention Scheme (PIC/S) on Cross-contamination in Shared Facilities Guidance goes into force. This includes the additional guidance on establishing health-based exposure limits (HBELs) for shared facilities. These Chapters of the PIC/S GMP Guide have now been aligned with principles of Quality Risk Management. Chapter 3 and 5 of the PIC/S GMP Guide have been revised to include requirements to prevent cross-contamination, and the HBEL guidance discuss the requirement for PDEs (aka ADEs) in shared facilities. At first review, these guidance documents appear to almost mirror the EMA’s guidance on similar topics.

What is an OEB 5 compound?

OEB 5 compounds are active pharmaceutical ingredients that have been assigned to an occupational exposure band (OEB) rating of 5, or the most severe rating in a 5-band occupational exposure banding system. A rating of OEB 5 represents those APIs that may have any of the following properties:

• Are highly potent (therapeutic doses less than 0.5 mg/day); or
• Have significant adverse effects at low doses (life-threatening, irreversible, or severe sensitizers); or
• May be genotoxic, carcinogenic, or have reproductive effects at relevant doses.

Depending on the company’s specific banding system, OEB 5 compounds typically would have numerical occupational exposure limits (OEL) less than 1 μg/m³ or an ADE or permitted daily exposure (PDE) of less than 5 ug/day. This information will be listed on the PDE report for the specific active pharmaceutical ingredient.

Who's got the monkey?

Back in the spring of 1986, I was in Kellyville, OK attending the Dowell-Schlumberger (DS) field engineers training school. I remember it quite well because I was there when the Space Shuttle Challenger exploded and we also got to spin doughnuts with 18-wheel tractor units.

However, besides rooming with a bunch of Texans and picking up a Texan accent in a matter of weeks, one of the important things that I experienced in training school was how to manage roughnecks and how to delegate (BTW - roughnecks could come up with swear words that I couldn't even imagine).

One of our readings and discussions on delegating was about "Who's Got the Monkey?" This was based an article written in 1974 in the Harvard Business Review (HBR), but then republished in 1999. The gist of the article is how employees attempt to put the next move on the back of their managers, so when something gets held up or doesn't turn out right it's the manager’s fault and not theirs.

Should you panic when the occupational exposure limits changes?

In the field of occupational toxicology for the pharmaceutical industry, it is quite common to see the numerical value for an occupational exposure limit (OEL) or OHC assignment change over the course of product development. New data, longer studies, and more human experience with the compound all have the potential to cause the OEL or OHC to change. In addition, once the product is on the market, there may be adverse events reported that were not observed in the clinical development of the product.

In most cases, as the data gets more comprehensive, the numerical OEL value goes higher in value and the exposure control band assignment goes down (i.e. from an exposure control band 3 to an exposure control band 2); however, while rare, occasionally the numerical OEL will decrease in value such that the OHC goes up (i.e. OHC from 2 to 3). In these cases it is often a challenging risk communication issue for the EHS professional because employees will be asking questions such as “Was I over-exposed?” or “Will I be harmed?” This is where it is important that an environmental, health and safety professional in the pharmaceutical industry have a strong understanding of the underlying concepts and assumptions behind occupational exposure limits. These concepts include the following:

Ten ways to run a better conference call

If you’re an EHS professional for a multi-facility company, conference calls can be an unfortunate way of life. These calls are often frustrating and seem like a complete waste of precious time; however, there are certain things you can personally do to make them more productive. Here’s ten suggestions…

Do I need a dedicated facility for my highly potent active pharmaceutical ingredient?

One of the most frequently asked questions that we receive at Affygility Solutions is “Do I need a dedicated facility or equipment for my highly potent active pharmaceutical ingredient?” While this seems like a fairly simply question, the answer is actually quite complex; and, in order to answer this question, someone would need to know a lot more about your specific operation. So, let’s walk through the basic thought process on how we would answer this question.

Risk Assessment

One of the key concepts when making the determination for a dedicated facility, is the concept of risk assessment, and, the first question we would ask you is “What does your risk assessment process say?” As indicated in the EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use - Part 1 Chapter 3: Premises and Equipment and shown in Image 1 below, Quality Risk Management principles must be used in making the determination whether a dedicated facility is required.

Five Uncomfortable Things that will Make You a Better EHS Manager

As we near the end of 2017, it becomes that time of year where we start to think about how we can do better in 2018. From a professional standpoint, often these plans take the form of establishing goals and objectives for the year.

However, just as important as the goals and objectives are for the company, it is equally important that you establish a few personal (and private) goals that will make you a better (and happier) EHS Manager.

Based on over 31 years of professional experience, here are five things, that while they might make you feel uncomfortable, it will go a long way to making you a better, happier, and more effective manager.

Your next potent compound safety gig might be at Amazon

Historically, the pharmaceutical space has been widely considered to be “Amazon-proof”—complex healthcare systems, high regulatory hurdles, stringent warehousing requirements, and a complicated billing system are all solid reasons for Amazon (AMZN) to not make the move into such a challenging industry vertical. However, a recent search for the query "Life Sciences" on the amazon.jobs site revealed over 1500 job openings. So clearly, Amazon does have interest in the healthcare and life sciences space.

Where Amazon could find leverage

Amazon is not a stranger to selling pharmaceuticals online. For instance, according to the Japan Times, in April of this year, Amazon announced same-day delivery service for both food and medicine. In addition, Amazon already sells beauty care, personal care products, vitamins, diet supplements, over-the-counter pharmaceuticals, and some medical supplies online. Amazon could easily leverage the above experiences to ease the transition into the prescription pharmaceutical industry.

From a technology standpoint, Prime Now, Alexa Echo and Dot, Dash buttons, and their AI-driven recommendation system are additional leverage points where Amazon could reduce customer friction, lower costs, and increase revenue for the company. You can also expect, due to the large scale that they would be operating, that Amazon would use its innovation expertise to automate as much of the fulfillment process as possible.

The Proper Use of Assigned Protection Factors and Maximum Use Concentrations

Under the Occupational Safety and Health Administration’s (OSHA) Respiratory Protection Standard (29 CFR 1910.134), APFs and MUCs are used in the proper selection of respiratory protection equipment for non-IDLH (immediately dangerous to life and health) atmospheres.

Employers must select respirators using Table 1.0: Assigned Protection Factors. They also must consider MUC’s before respirator selection. Selection of respirators should be based on the actual airborne contaminant level found in the workplace. Determining the actual airborne contaminant level typically requires industrial hygiene monitoring.

In addition, for the APFs and MUCs to be properly applied, all respirators must be fit-tested and used in accordance with all local and federal regulations. The APF/MUC will not be accurate for employees that are not clean shaven, have hair that interferes with the fit of a tight-fitting respirator, have a poor fitting respirator, or an improperly selected cartridge. Employees wearing tight-fitting respirators with facial hair that interferes with the fit is a common deficiency found during potent compound safety gap assessments.

What is an occupational exposure limit and why are they important?

Here at Affygility Solutions, we often get asked the question, “I’m being told that I need to find out the OELs for all my active pharmaceutical ingredients, but I don’t even know why I need them. Can you help?”

What is an Occupational Exposure Limit (OEL)?

So let me explain: Occupational exposure limits (OELs) are defined as the time-weighted average concentration of a contaminant, measured in the employee’s breathing zone, that is considered to be safe for the majority of healthy workers, for an eight-hour work shift and a forty-hour work week, and entire working lifetime.

OELs are health-based values that are established by expert toxicologists reviewing existing published, peer-reviewed literature, and scientific databases. In addition, for new chemical entities (NCEs), it may be necessary to review pre-clinical and clinical data to determine the OEL. Based on the currently available information, the expert toxicologists formulate a conclusion on the level of exposure that the average worker can experience without adverse health effects.

Welcome to Potent Compound Corner

We're excited to announce and welcome you, readers, to the newest Affygility (virtual) publication: Potent Comound Corner.

We'll invigorate your mind, help keep you clued in to the latest EHS topics and ideas, and hopefully amuse you once in awhile.

Stay tuned to this space and you can expect to find…