In July, our oral solids experts presented a Highly Potent Oral Solids webinar. For more insights, take a look at this Q&A on the challenges and considerations for a highly potent oral solids project.

Does anything change with containment when evaluating a small batch size?

Containment requirements are independent of batch size for both commercial and pilot scale. Depending on the minimum equipment working capacity, it is possible to decrease the batch size to fit project requirements and expectations and manufacturers can select the right batch size in accordance with equipment working capacity.

How can I evaluate if a CDMO has appropriate HPAPI handling capabilities?

HPAPI manufacturing is complex and requires the right controls and experience. Look for a partner who not only offers the capacity and technical capabilities but also the experience.

It is important to evaluate:

• Engineering controls and procedures to ensure they are in place to safely handle the compounds
• The cleaning and verification procedures that prevent cross-contamination
• Whether the CDMO previously handled the scale up of potent compounds successfully

A CDMO that is capable of handling HPAPI compounds would be able to address these important factors.

How do you decide if a manufacturing line or the operation suite can handle multiple products including hormones?

Segregation and dedicated facilities are required when physical and procedural controls cannot limit the risk of cross contamination to an acceptable level.

The risk of cross contamination is determined though ARL (acceptable residue level) criteria and the calculation of ARL and cleanliness limits are based on the product’s toxicological information.

The information on cleaning together with the corresponding risk analysis are the two criteria for introducing new products in the multiple products areas or keeping the areas segregated.

What are the cost implications of a high containment suite compared to a non-potent production line?

The additional high containment equipment and HVAC requirements in a high containment suite will typically add around 30-40 percent more to the capital cost compared to a standard suite.

Operational costs will be affected by three primary considerations: HVAC use, cleaning requirements, and batch size.

A high potency area will be designed for 12 air changes per hour (acph) and typically operate at 10 acph compared to 5/6 acph for a low potency area (subject to occupational hygiene monitoring). This could result in a high potency area using 40 percent more HVAC energy that a low potency area.

If a high potency area is running smaller batch sizes or more frequent cleans the increased cleaning requirements would impact the water usage. The water for cleaning is generally heated and the purified water for washing has to be generated, which will both lead to higher energy costs.

The use of dedicated suites for low volume, high potency products with the suite sitting idle or the equipment train not operating at full capacity would result in a significant additional cost of goods. All of the base load energy requirements will continue regardless of the volumes produced.

Should the primary packaging always take place at the same site as the bulk production?

It is not mandatory for primary packaging to take place at the same site as bulk production. An assessment needs to be made of drug product Occupational Exposure Limits (OEL) and containment for primary pack lines designed to handle the drug product with segregated feed room.

It’s important to ensure that the design specifications of the technology or device used in this process meet the required accessibility, batch size, and containment performance. Regardless of the process, containment integrity remains the key challenge, requiring effective performance testing and maintenance programs.

In what way does the Quality Control (QC) process differ for highly potent oral solids?

The QC process shares similarities, however, if sampling is required of the HPAPI, dedicated rooms are needed in the highly potent facility or pre dispensed samples should be supplied with the API. Dedicated labs are also required for some API and drug product to protect analysts conducting the QC.

The Personal Protective Equipment and high containment systems (i.e., glove box) are also more robust. Training of chemical analysts is necessary for the handling and storage of highly potent samples in line with the safety data sheet.

What are the cleaning and validation procedures that prevent cross-contamination?

The cleaning requirements for manufacturing areas and equipment must be described in written procedures which indicate:

• The choice of the cleaning agent
• The cleaning method and records
• The method control
• Acceptance criteria

Where equipment is multipurpose and used for the manufacture of different products, a matrix approach is designed to allow validating the cleaning processes based on the assessment of the worst-case scenarios. This validation is assessed and reviewed when a new product is manufactured on site to prevent of cross-contamination. The facility will also need to be qualified for the appropriate air lock and HVAC system requirements to prevent cross contamination.

How do you verify the degree of containment and control of your operations? How do you address surrogate testing and API occupational hygiene evaluations?

During the design phase, the rooms where the API will be exposed are identified and the areas that will have high and low contamination are defined. Based on this information, the HVAC system is built providing a negative pressure cascade and an airlock system to ensure the containment of the assets and prevent cross-contamination.

Tests and acceptance criteria are defined to demonstrate that the HVAC system has been installed in accordance with the project specifications. Systems are installed for each room / area to constantly monitor the pressure values and provide visual and acoustic alarms if the conditions are not within the predetermined ranges. The staff are trained to be aware that, in the event of an alarm, no activities can be carried out until the standard conditions are restored.

The control systems are checked periodically according to a schedule managed by specific management systems.

Surrogate testing

• Verification of containment performance is carried out on new equipment before the design is delivered to the final user.
• Containment equipment is engineered tools to prevent/reduce operator exposure to chemical agents and limit the need to rely on respiratory protective equipment as the primary control.
• Verification/containment testing is the system used to demonstrate that the equipment meets the design specifications.
• The surrogate test material is a powder, usually a non-API powder, that is used to simulate operations in the containment device.

API occupational hygiene evaluations

• Health monitoring should be established, which includes health protocol, fitness for work and health records of all personnel.
• Preventive and protective measures for individual workers should be reviewed based on the results of clinical and biological examinations carried out on an annual basis.
• The company doctor should provide employees with adequate information on their health surveillance.

Who should perform the assignment of occupational exposure bands (OEBs) to APIs?

The assignment of bands should be performed by individuals trained in occupational toxicology who understand the pharmacology of the drug substances.

To start the conversation on how we can support your highly potent oral solids, contact us today.