Potent Compound Corner

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.

Question 4 (Q4) of this Q&A document was listed as “What competencies are required for the person developing the Health-Based Exposure Limits (HBEL)?” The EMA went on to state the following:

“Where experts are contracted to provide the HBEL, contractual agreements in compliance with Chapter 7 requirements should be in place prior to work being conducted. It is not considered acceptable for manufacturers to ‘purchase’ HBEL assessments without recording an assessment of the suitability of the provider (including the specific technical expert) as a qualified contractor.”

While the vendor assessment procedures vary from company to company, they are at least seven questions that should be asked of any toxicology provider before selecting them as a qualified contractor for preparing your health based exposure limit monographs. These questions are as follows:

1. What are the educational and experience qualifications of all members of the team that will be preparing your health-based exposure limit monographs?

As a bare-minimum requirement you should obtain the following documents:

  • Current CVs of all members of the toxicology group that will be preparing and reviewing your health-based exposure limit (HBEL) monographs. While not an absolute requirement of the EMA HBEL guideline, it is recommended that at least one member of the toxicology team be DABT or ERT certified. This makes it easy for regulatory inspectors to determine if a person is “qualified” and able to oversee the more junior staff.
  • Current version of the company’s organizational chart (organogram) depicting the reporting structure of the toxicology group and any members of the quality team.

2. Do they have the technical and support staff needed to handle large orders of ADE/PDE monographs in a timely manner?

When a large order of ADE/PDE monographs is placed, it generally takes many internal team members to ensure that the order is processed smoothly, producing quality monographs that are delivered on-time. These team members can include:

  • Sales professionals to make sure that the order is properly quoted and that all client-required documentation (technical agreements, confidentiality agreements, purchase orders, tax-related forms) have been completed and returned to the client.
  • Project managers to ensure that the work is properly scheduled. that requisite timelines are followed, and that all CAS registry numbers for each HBEL monograph have been verified.
  • Qualified and experienced toxicologists to perform the process of preparing the HBEL monographs.
  • Quality personnel to ensure that all HBEL monographs receive a peer-review and quality review prior to being transmitted to the client.
  • And finally, administrative and accounting personnel to enter all HBEL monograph orders into a records management system so that it can be recovered for many years later.

Another quick way to vet the current staff members of a potential HBEL monograph contractor is to use LinkedIn and search for the company name, select the company name from the list, and then select “People” from the company profile menu. You will now have a complete listing of all current employees with the specific consulting company. For example, here is the team at Affygility Solutions’ LinkedIn company profile. Beware of toxicology contractors that throw around the word “team” but have no listing of specific employees on the About Us or Staff section of their website, you may just find yourself working with a team of one.

3. What is the policy on updates for previously purchased monographs?

The answer to question 1 (Q1) in the EMA HBEL Q&A states that “The toxicological or pharmacological data, on which the HBEL calculation relies, requires periodical re-assessment throughout a product’s lifecycle.”

What this means is that a HBEL monograph is not a static document, never to be changed. Just like any other document in a quality program, HBEL monographs require a periodic review and update. Prior to purchasing HBEL monographs from a toxicology contractor, you should get an understanding of what is the process for receiving these needed updates. How will you be notified of an update? What is the frequency of updates? Will you incur an additional charge for the updates?

These are all questions that should be considered in the total cost of obtaining and maintaining compliant monographs. At Affygility, customers are notified when a previously purchased HBEL is updated and they are provided with this update free of additional charges.

4. What is their policy on post-purchase technical support?

Prior to selecting a toxicology contractor, the client should make a determination of what is the toxicology contractor’s policy of post-purchase support should technical questions arise during regulatory inspections or other audits. Will it be provided separately? At what rate? Or, will simple questions be answered without charge?

5. Do they have the basic elements of a Quality System in place and what proof can they provide to demonstrate this system?

As you know, at a minimum, a Quality System should have a quality policy statement, an organizational chart with assignment of responsibilities, initial and on-going training requirements, and a corrective/preventative action program. Find out in advance what Quality System your toxicology provider has in place.

6. Do they have general and professional liability insurance with worldwide coverage?

While it is difficult to believe that any company would operate without basic general liability and professional liability insurance, there are many companies who do not have such coverage. As you know, most pharmaceutical companies have minimum insurance requirements for their contractors and require them to provide certificates of insurance prior to beginning work. Ask before getting started with any toxicology provider.

7. Do they have adequate administrative support?

Post-sale administrative support is an important, but often overlooked, need for many clients. Here at Affygility Solutions we spend a significant amount of time doing the following for clients:

  • Running reports for clients to determine their previously purchased HBEL monographs.
  • Updating document delivery systems with current emails to ensure that updates are delivered to the right individuals in your company.
  • Producing financial client account statements that are necessary for client financial audits.
  • Providing certificates of tax residency forms and 10F forms to foreign countries.
  • Retrieving, producing, and processing marked “paid” invoices.


While at first it may appear that selecting a toxicology provider is a simple task and that all providers are the same, there are many details that should be considered upfront in order to prevent wasted time and money.

Here at Affygility Solutions we have worked hard to assemble a complete team of professionals to ensure that client has a positive experience throughout the lifecycle of our partnership. If you have any questions or need additional information, please contact us.

Published November 24, 2019 / Updated November 8, 2021

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Get in touch with the Corner crew at pcc@affygility.com.