The importance of the Certificate of Analysis and updating the Master Formulation Record

By Lori A. DeVito, RPh., HDDP, PCAB Compounding Pharmacy Specialist

When compounding with APIs for non-sterile and sterile preparations in USP <795> and USP <797>, a quality assurance program must be in place per USP <1163> Quality Assurance in Pharmaceutical Compounding. USP <797> contains an entire section titled “Quality Assurance (QA) Program.” Quality Assurance is also mentioned throughout the Appendices. USP<1163> is specifically referenced in USP<795> under “Responsibilities of the Compounder“ and “Compounding Process.”

In this issue, we will continue our journey, maneuvering through USP chapters and delving into the importance of USP <731> Loss of Drying (enforceable) and USP <1160> Pharmaceutical Calculations in Pharmacy Practice, which are referenced within USP <1163> Quality Assurance in Pharmaceutical Compounding.

When an Active Pharmaceutical Ingredient (API) is received, the Certificate of Analysis (CofA) should be reviewed and the Master Formulation Record updated. Since the CofA for each API is specific to each lot number, the same API can yield different results even though it meets the USP requirements. One of the most significant reasons a compounded preparation can be out of specification (OOS) is that the Master Formulation Record (MFR) was not updated to reflect the most recent Certificate of Analysis (CofA) of the API’s specific manufacturer and lot number. Compounding software will make adjustments, but will only be accurate if the correct information is entered from the CofA upon receipt of the inventory!

Certificates of analysis provide an overview of test results obtained from the API. Review the water correction, assay correction and salt-to-base correction to see if any or all need to be adjusted for the final compounded preparation. With regards to Loss of Drying, the Assay section and the Water section of the  CofA are necessary for calculating and are referenced in USP <1160> Pharmaceutical Calculations in Pharmacy Practice, which also touches on how to calculate salt forms, esters and hydrates. Depending on the salt form, you may also need to make salt-to-base corrections.

The term Loss of Drying (LOD) indicates the amount of moisture that the API has absorbed in the manufacturing and storage process. If this is not adjusted, it can greatly change the final product when compounding. The higher the LOD, the more the API can absorb water. This could result in a reduction in potency, especially if the API was stored incorrectly or in an area with high humidity. For example: An LOD of 7% means that 100mg of an API (weighed) will contain 7mg of water. The water correction factor is: 100/(100-7.0) = 1.075. The water correction factor is more accurate than using the Molecular Weight. (USP <1160> shows a good example of the difference in MW versus using LOD.)

The Water section of the CofA represents the water that is a part of the chemical formula versus the water that has been absorbed and/or loss on drying, which indicates the amount of moisture the API has absorbed in the manufacturing and storage process. USP does allow for a percentage of water, but the CofA would be more accurate.

When you receive an API, have clear documentation, including date of receipt, open date, and transfer date. Since some drugs retain full chemical stability, but can gain or lose moisture during storage and use, be sure storage precautions are followed, such as maintaining storage area humidity and “keeping the lid on” when not in use! (Remember, if you receive an API without an expiration date, the maximum expiration date is three years.)

Include Loss of Drying (LOD) as part of staff training and include calculations in didactic testing to be sure your staff fully understands the concept. For potency testing during competencies, have the staff compound using an API with a high LOD, which will reveal any LOD/calculation issues.

Monitoring moisture content per USP <731> Loss on Drying for quality assurance is useful in identifying problematic batches, which can save time/money, but more importantly, ensure the product’s potency is accurate and consistent.

The Bottom Line: Anytime an API is received, look at the CofA and pull your current Master Formulation Record. Be sure the MFR reflects the Manufacturer and Lot numbers of the received API. Double-check the Assay, Water and Salt-to-Base sections. Follow USP <731> Loss of Drying and USP <1160> Pharmaceutical Calculations in Pharmacy Practice to avoid any potency issues.

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