The learning objectives for this week's 483:

1. Explain the typical out of specification range of potency for many compounded formulations
2. Discuss a type of testing that is both economical and scientifically sound
3. Discuss the 5 elements of an SOP on potency testing should include

This week we'll be looking at one observation the FDA made at a facility concerning the potency testing of their drug products. While there's not much direction given to pharmacies through USP Chapter <797>, there's still a need for testing this critical attribute of our preparations. In fact, <797> doesn't give us any requirements for testing for potency or the interval at which we should test our preparations.

USP Chapter <1191>, Stability considerations in dispensing practice, only helps us look for signs of chemical instability (i.e. potency) but still gives us no interval to guide the frequency of potency testing that should be performed.

USP Chapter <1191> says:

Pharmacists should avoid ingredients and conditions that could result in excessive physical deterioration or chemical decomposition of drug preparations, especially when compounding...Pharmacists should establish and maintain compounding conditions that include the ensuring of drug stability to help prevent therapeutic failure and adverse responses.

USP Chapter <1191>, Stability Considerations in Dispensing Practice

Throughout the rest of USP <1191>, it talks about what can cause chemical instability and the signs you should look for in particular dosage forms. However, even <1191> gives no direction on how frequently potency should be tested on sterile preparations

Observation 8

Going by this 483 observation, the FDA would like to see:

• A plan in place for how frequently you're testing your preparations for potency
• The acceptable criteria for potency (less or greater than 10% loss/gain of potency)
• Written SOPs for the frequency and criteria of your potency testing program
• Written SOPs for what to do when a preparation falls out of specification for potency

So how do compounders come up with a frequency for testing their batches for potency? In manufacturing there's a concept known as "skip lot" testing for critical attributes of products for processes that are under a state of control. However, the manufacturer must justify this decision to perform skip lot testing.

In an FDA Guidance, "Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances" the FDA gives details on what attributes could be chosen for skip lot or periodic testing:

Data generated during product development may be sufficient to justify skip lot testing or elimination of some or all attributes from the specification.

Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

There's no debate on whether potency testing will give extra assurance that your product/preparation is of the purported and expected potency which in turn ensures the safety of the preparation for the patient. However, cost does become a factor as extra testing increases the cost of a batch and will be passed on to the patient.

I'd like to suggest a scientifically and statistically sound procedure for determining how often compounders test for potency. Let's talk about what you would want to have in an SOP that dictates potency testing for your compounded preparations (sterile or non-sterile).

The SOP should consist of:³

• Verifying that the compounded preparation is correct at the start of the program by appropriate potency testing in an independent quality control lab.
• Choosing a sampling interval, which will define the maximum out of specification (OOS) limits that will be detected (Surprisingly, these intervals can be relatively long. For example a failure rate greater than 5.5% should be detected if every 25th lot (or batch) of a preparation is tested, which is a 4% sampling plan)
• Setting up a scheduled or random sampling plan for the preparation to be sent out for potency testing
• Collecting and recording the testing data
• Reverifying the preparation if it fails a test or if changes are made to the formula, procedures or people making the preparation

The key to a skip lot testing program is the initial testing and results. The initial verification test(s) should illustrate that the product's potency attribute is under a state of control through the processes and procedures used for compounding that particular preparation.

At first, perhaps sending 3 consecutive verification batches off for potency testing to verify all are within the specified potency range (e.g. +/- 10% the preparation's potency is greater than 90% and less than 110% of the labeled concentration) would suffice for maintaining that your process and preparation are under a state of control.

That being said, if all verification batches are within specification you can now justify an interval based on statistical data. The table below provides guidance on the frequency for potency testing batches and the percentage of the time it should detect an out of specification result.

Zolner W, IJPC, Quality-Control Analytical Methods: A Guide to Quality Control Testing for the Compounding Pharmacist, Volume 10 No. 4 July August 2006

Just to explain the table a little further:,

• 2% sampling rate means you'll be sampling 1 lot out of every 50 and this will detect an OOS failure greater than 10% of the time.
• 3% sampling rate is testing 3 lots out of 100 or 1 out of every 33 batches
• 4% would be testing 1 out of every 25 lots
• 5% would be testing 1 out of every 20 lots
• 50% would be testing every other lot

For regulators you should be able to show that your process is under a state of control for your compounds, you've established a procedure for potency testing and that you have a procedure in the case of a potency failure.

When you have a potency failure you'll need to figure out the root cause, correct the problem and re-validate the compound for potency. If you'd like a guide on how to go about finding the root cause check out this post on investigations and CAPAs.

References

1. USP Chapter <1191>, Stability Considerations in Dispensing Practice
2. Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
3. Zolner, W; International Journal of Pharm Compounding, Quality-Control Ana