The Role of Dry (Water-free) Process Equipment Cleaning in Continuous Pharmaceutical Manufacturing

Unlike batch manufacturing, where drug substances or finished products are made with separate unit manufacturing steps with intermediate storage and testing between steps that sometimes take place in different global manufacturing locations, continuous pharmaceutical manufacturing allows each element of manufacturing to take place in a continuous process in a single facility. This compresses the manufacturing time, improves quality, reduces costs, and increases overall efficiency.

As highlighted in FDA’s March 2023 continuous manufacturing guidance (1), the concept of continuous manufacturing is particularly well suited for downstream processing for biopharmaceutical production and the manufacture of solid oral dosage forms. As the order of 60% of the sales volume of drug products continues to be solid oral dosage forms, this technology review will concentrate on the manufacture of compressed tablets and powder-filled capsules, where the batching, milling, mixing, tablet compression, or filling of dry powders in capsules applies more to dry (water-free) process equipment cleaning over the more common wet cleaning.

Industry and regulatory obstacles to dry cleaning implementation and risk mitigation

Although regulatory agencies such as FDA support the transition from batch to continuous manufacturing, the pharmaceutical industry has been slow to embrace this change. A self-audit of the sparse history of continuous manufacturing submission, review, and approval point to FDA not being the major obstacle to the transition (2). FDA’s Center for Drug Evaluation and Research (CDER) published a draft guidance in 2019 outlining quality considerations for continuous manufacturing (3). Earlier in 2014, CDER stablished the Emerging Technology Program (ETP), a collaborative program where industry representatives can meet with Emerging Technology Team (ETT) members to resolve potential technical and regulatory issues around the development and implementation of a novel technology prior to filing a regulatory submission. Examples of ETP-accepted emerging technologies in 2022 are continuous manufacturing of small-molecule drug substances and drug products and continuous manufacturing for biological molecule downstream processing.

Among the regulations pertinent to cleaning during continuous manufacturing is Code of Federal Regulations (CFR) Title 21, Part 211.67 (21 CFR 211.67), “Equipment Cleaning and Maintenance” (4), which states that documentation should include:

• responsibility for equipment cleaning and maintenance

• cleaning and sanitization schedules
• a detailed description of the cleaning procedure
• removal of previous batch identification
• protection of clean equipment
• inspection of equipment prior to use.

In addition, the 2016 FDA Guidance for Industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (5) states the following:

“Equipment maintenance and cleaning (Section 5.2). Written procedures should be established for cleaning equipment and their subsequent release for use in the manufacture of intermediates and APIs. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. These procedures should include the following (Section 5.21):

• assignment of responsibility for cleaning of equipment
• cleaning schedules, including, where appropriate, sanitizing schedules
• a complete description of the methods and materials, including dilution of cleaning agents used to clean equipment
• when appropriate, instructions for disassembling and reassembling each article of equipment to ensure proper cleaning
• instructions for the removal or obliteration of previous batch identification
• instructions for the protection of clean equipment from contamination prior to use
• inspection of equipment for cleanliness immediately before use, if practical
• establishing the maximum time that may elapse between the completion of processing and equipment cleaning, when appropriate” (5).

Peer-reviewed

Submitted: Oct. 9, 2023
Accepted: April 2, 2024

References

1. FDA. Guidance for Industry, Q13 Continuous Manufacturing of Drug Substances and Drug Products (CDER, March 2023).
2. Fisher, A. C.; Liu, W.; Schick, A.; et al. An Audit of Pharmaceutical Continuous Manufacturing Regulatory Submissions and Outcomes in the US. Int. J. Pharm. 2022, 622, 121778. DOI: 10.1016/j.ijpharm.2022.121778
3. FDA. Draft Guidance for Industry, Quality Considerations for Continuous Manufacturing (CDER, February 2019).
4. CFR Title 21, Part 211.67 (Government Printing Office, Washington, DC) 162.
5. FDA. Guidance for Industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (CDER, CBER, April 2016).

About the authors

Donald Singer is principle microbiology global consultant at Ecolab Life Sciences, and Tony Cundell is principal consultant at Microbiological Consulting.

Article details

Pharmaceutical Technology®
Vol. 48, No. 8
August 2024
Pages: 22–28

Citation

When referring to this article, please cite it has Singer, D.; Cundell, T. The Role of Dry (Water-free) Process Equipment Cleaning in Continuous Pharmaceutical Manufacturing. Pharmaceutical Technology 2024, 48 (8), 22–28.