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 as follows.

"I see that my compound is rated as a Category 4 or 5, does that mean I need a dedicated facility or equipment for my highly potent active pharmaceutical ingredient?”

The reason that people still believe they need a dedicated facility for highly potent compounds is that they are relying on specific language that was in the now outdated EMA regulations. Once the concept of health based exposure limits was introduced, this all changed. It is important to critically review the following paragraph in the HBEL Guidance. The key terms in this paragraph are "certain classes of medicinal product have previously been required to be manufactured in dedicated.." and "Until now no official guidance is available.."

What the above paragraph means in that in order to determine if you can handle a product in a multi-product facility, you have to perform a science and risk-based assessment.

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 site-specific operation. So, let’s walk through the basic thought process on how we would answer this question.

First, understand that they are many different control banding systems. Just because something is categorized as a control band 4 or 5 does not immediately mean that you need a dedicated facility. Make sure you know the differences in the banding systems and know that once you have a numerical OEL and ADE, the control band becomes less important.

Here at Affygility Solutions we use a 5-band system, but we deal with at least 14 different banding systems on a weekly basis. Below is a chart comparing the Affygility Solutions control band to many of the other ones in common use.

Second, "What does your risk-assessment say?

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.

As you may know, one of the key concepts to understanding risk is expressed by the following equation:

Risk = Hazard X Probability of Occurrence

Where;

Hazard is equal to the hazard or severity of the compound itself, and that hazard is based solely on the toxicology of the specific molecule. The hazard does not change with increase in scale, its physical form, or the energy in the process. Assessing the hazard of a specific compound requires a toxicological evaluation by an expert toxicologist in order to determine the acceptable daily exposure (a.k.a permitted daily exposure) of the specific compound. Additionally, terms such as highly potent, cytotoxic, or similar terms lack regulatory definition and should be avoided when expressing the degree of hazard.

And,

Probability of occurrence is based on the likelihood of either occupational exposure or cross-product contamination occurring. The factors involved in the probability of occurrence include the scale of the process, the physical form of the product or formulation, the percentage of the API in the formulation, the existing controls and procedures that are in place, and many others.

So, the key part in making the the determination whether a dedicated facility or equipment is required is answering the question whether your risks are being managed to an acceptable level or not. A good framework for developing and implementing a quality risk management program can be found in the International Society of Pharmaceutical Engineers’ Risk Based Manufacture of Pharmaceutical Products Baseline Guide.

Key Questions that Your Risk Assessment Should Answer

The key questions that your risk assessment should answer will include:

1. Can the risk be adequately controlled by operational and/or technical measures? These operational and technical measures may include adequate segregation of products, separation of HVAC systems, the use of engineering controls, effective standard operating procedures, and many other measures.
2. Does the scientific data from the toxicological evaluation by an expert toxicologist indicate that the risk can be controlled? Note: There are some compounds where the risk cannot be adequately predicted because of unclear dose-response relationship (beta lactams or sensitizers).
3. Can the relevant residue limits that are derived from the toxicological evaluation, and used in cleaning validation processes, be adequately detected by a validated analytical method? Note: This is where many companies find difficulties when proposing to handle compounds with low ADEs. In these cases, the swab limits have very low limits that may require product specific analytical methods with low limits of detection.

As you can see from the above discussion, making the determination whether a dedicated facility is required or not involves much more than just having an occupational exposure limit or an acceptable daily exposure value. It involves having a thorough understanding of your risks and how you manage them.