why do i test, what do i test & when do i test it? · why do i test, what do i test & when...

Why Do I Test,What Do I Test

& When Do I Test It?

Ross Caputo, PhD Chief Technical OfficerEagle Analytical Services

Disclosures

“I, Ross Caputo, declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.”

Learning ObjectivesAt the conclusion of this program, the participating pharmacist or pharmacy technician will be able to:

• Discuss why science-based testing must be performed and determine when preparations require testing

• Name available testing methods for chemical and biological attributes of sterile and non-sterile compounds

• Identify how to develop a science-based testing program as part of a pharmacy's Quality System

WHY TEST?

Why is testing compounds so

important?

Why Test?

• USP and FDA guidelines mandate specific testing requirements for compounded preparations.

• These science-based guidelines have been established to ensure medication quality and patient safety.

These guidelines are not just suggestions, they are considered enforceable by the FDA!!!

Why Test?• Testing must be performed:

– To validate compounding processes

– To validate compounding personnel

– To establish extended beyond-use-dating

– To verify that a compound falls within labeled specifications

– To identify microorganisms captured during environmental monitoring

– As part of the Quality Program required in USP <795> and <797>

Where to Test?

Compounders are responsible for vetting the laboratories they use for testing.

• FDA registered

• DEA registered

• ISO 17025 Accredited

Choose a laboratory that

is:

WHEN TO TEST

When should compounds be tested?

When to Test

Testing for Release

• Validate safety & quality of a compound

• Comply with USP, ISO, & FDA regulations

Stability Studies

• Scientifically justify extended BUD

• Observe stability of preparation over time

• Determine storage conditions

Environmental Sampling

• Identify microbes

• Determine corrective actions

When: Testing for Release

• To comply with guidelines set by regulatory agencies, compounders must ensure the quality, safety, and stability of compounded preparations.

• To accomplish this, preparations can be tested prior to release for:

• Sterility

• Bacterial endotoxins

• Potency

• Microbial enumeration

WHAT TO TEST

Testing for Release

WHAT: Testing for Release

Release tests for sterile products

• <71> Sterility Testing

• <85> Bacterial Endotoxin Testing

• <621> & <851> Potency Testing

Release tests for non-sterile

products

• <61> Microbial Enumeration Testing

• <62> Microbial Examination for Specified Microorganisms

• <621> & 851> Potency Testing

WHAT TO TEST

Release Tests for Sterile Products

• 503A facilities are required to sterility test CSPs that:

– Are produced in batches of 25+ units

– Exceed USP <797> beyond-use-dating guidelines

• 503B facilities are required to test every batch of sterile drug product prepared.

• Testing must follow a compendial (or better) methodology to support the claim that a product is sterile.

WHY: Sterility Test

WHY: Sterility Test

USP <71> sterility test

• <71> defines the compendial requirements for conducting sterility tests

• 14 day incubation period

Rapid ScanRDI

sterility test

• Utilizes fluorescent labeling and laser scanning to detect bacteria, mold, yeast & fungus

• 2 day turnaround time

• Sensitive enough to detect presence of a single cell

• Method Suitability Testing (MST) must be performed before sterility test results can be used to claim that a product is sterile.

• MST only needs to be completed once for any given formulation based on the largest batch size and highest concentration that will be produced.

• The MST should be performed by the same laboratory that will conduct the sterility tests.

WHY: Method Suitability Testing

WHY: USP <71> MST

• Suitability test to confirm that the growth media supports the growth of certain microorganisms

• Validation test to demonstrate that no components of the preparation inhibit microbial growth

USP <71> MST consists of two components:

WHY: Rapid ScanRDI MST

• Confirms that formula & excipients do not cause interference with auto fluorescence of preparation

• Validates that components of formula do not inhibit uptake of fluorescent dye by viable organisms

Rapid ScanRDIMST consists

of two components:

WHY: USP <85> Endotoxin Test

As bacterial endotoxins can pose health and safety hazards to patients, quantities of bacterial endotoxins cannot exceed threshold limits defined in USP <85>.

USP <85> outlines testing requirements used to quantify the presence of bacterial endotoxins in CSPs.

• Potency tests are designed to determine the concentration of an active drug in a sample.

• 21 CFR 211 requires laboratory determination of the identity and strength of each active ingredient prior to a preparation’s release.

• USP <621> & <851> outline compendial methods for potency testing, such as using HPLC / UHPLC & Spectrographic instrumentation.

WHY: Potency Testing

WHAT TO TEST

Release Tests for Non-sterile Products

• The presence of microorganisms in nonsterile preparations has the potential to:

– Reduce and / or inactivate therapeutic activity

– Adversely affect the health of patients

• Producers of compounded products are therefore required to ensure that nonsterile preparations have a low bioburden.

WHY: Microbial Enumeration Testing

WHY: <61> Microbial Enumeration Testing

Nonsterile products are required to comply with established specifications for

microbiological quality as outlined in USP <61>.

USP <61> microbial enumeration tests provide a quantitative evaluation of a product’s microbial

content to demonstrate compliance with established specifications.

• Table 1 in USP <1111< sets acceptance criteria for the presence of microorganisms in a nonsterile preparation based on its route of administration.

• The presence of these objectionable pathogens & microorganisms cannot exceed the acceptance criteria.

• USP <62> testing is designed to demonstrate compliance with these requirements by quantifying the presence of specified microorganisms.

WHY: <62> Tests for Specific Microorganisms

WHEN: Final Release Testing

503A 503B

Test Non-Sterile Sterile Non-Sterile Sterile

Closure integrity Initially in stability Initially in stability Initially in stability Initially in stability

USP 71* sterility Every batch Every batch

USP 85 endotoxin Every batch*** Every batch

Potency ** Every dosage form every 6 months every technician, plus weight measure

Initially every formula then annually

Every batch Every batch

Visual Every batch Every batch Every batch Every batch

Particulate/pH Initially in stability Initially in stability Initially in stability Initially in stability

WHEN TO TEST

Stability Studies

WHY: Stability Study

Purposes of Stability Testing:

• Determine the beyond-use-date of a preparation

• Provide evidence on how environmental factors such as temperature, humidity, and light affect the quality of a preparation over time

• Establish appropriate storage requirements


Stability studies test:

• The physical, chemical, biological & microbiological attributes of a preparation

• Preservative content & antimicrobial effectiveness

• Functionality (closure-container integrity testing, dose delivery system testing)

• 503A facilities

– Required to justify the beyond-use-date of compounded preparations whenever they exceed the BUD guidelines outlined in USP chapters 795 & 797

– Required to test one lot

• 503B facilities

– Required to perform a stability over time study using a stability indicating method for all compounded formulations

– Required to test at least three lots


• USP <797> discourages compounders from using only publications to justify an extended BUD as this can only provide a “theoretical BUD”:

– “Theoretically predicted beyond-use dating introduces varying degrees of assumptions and hence, a likelihood of error or at least inaccuracy” (USP <797>)

– “It should be recognized that the truly valid evidence of stability for predicting beyond-use dating can be obtained only through product-specific experimental studies” (USP <797>)


WHAT TO TEST

Stability Study Protocols

• Sterile & non-sterile

– Method Verification

– Stability Indicating Assay

– <1207> Container Closure Integrity

– <51> Antimicrobial Effectiveness

– <1163> Quality Assurance Tests

WHAT: Stability Study Tests

• Sterile

– <71> Sterility

– <85> Endotoxin

– <788> Particulate Count

• Non-sterile

– <61> Microbial Enumeration

– <62> Microbial Identification

WHAT: Stability Study Tests

• A stability indicating assay:

– Determines the strength of active ingredients in a preparation

– Distinguishes active ingredients from their degradation products

– Allows a reliable estimation of the quantity of degradates in a preparation

WHY: Stability Indicating Assay

All stability studies require the use of a stability indicating assay.

• Method development is the process of developing stability indicating assays for any particular formulation.

• Method verification is required to demonstrate that the testing used in a study is accurate, appropriate, and will result in meaningful data.

• Method verification only needs to be completed once for any given formulation.

WHY: Method Verification

WHY: Method Verification

Chapter 211 of the Code of Federal Regulations requires:

• Testing methods to be reliable, meaningful, and specific

• Verified under the actual conditions of use

• Documentation of “the accuracy, sensibility, specificity, and reproducibility of test methods”.

• As sterile products must remain free of microbial contamination throughout their entire shelf-life, sterility is considered to be a stability characteristic.

• Therefore, stability protocol should include confirmation of continuing sterility throughout the shelf-life.

• Minimally, sterility testing is performed at the start and the end points of a stability study.

WHY: Sterility Testing

• Sterility testing alone does not provide enough evidence of a product’s continuing sterility due to practical & scientific limitations:

– Only detects microorganisms present at the time of the test

– Only detects microorganisms capable of growth in growth media used

– Destructive of samples tested

• As a result, container-closure integrity (CCI) testing is recommended to demonstrate the sterility of a preparation throughout its shelf-life.

WHY: <1207> Container-Closure Integrity Testing

WHY: <85> Endotoxin Test

Sterile preparations must remain within bacterial endotoxin limits throughout a product’s shelf-life.

Bacterial endotoxin testing is performed at the initial time point and the end time point of a stability study.

WHY: Particulate Count Test

As per USP <1>, parenteral injections and infusions must

be essentially free of particulate matter.

A USP <788> Particulate Count test is required to demonstrate compliance

with subvisible particulate matter limits.

• As per USP <788>, ophthalmic solutions must be essentially free of particulate matter.

• <788> requires a particulate count test for all ophthalmic solutions for which the monograph includes a test for particulate matter.

• Ophthalmic gels, emulsions, and suspensions are exempt from these requirements.

WHY: Particulate Count Test

• USP <1163> recommends different quality assurance tests for stability protocols based on the preparation form.

• USP <1163> recommends pH measurements as per <791> as part of a stability study.

– pH measurements are indications of degradation and other product changes throughout the shelf-life.

• <1163> also recommends a visual inspection of the appearance of the product at each time point to inspect for any physical abnormalities, leaking, color changes, turbidity, viscosity, etc.

WHY: pH & Appearance

WHY: Microbial Enumeration Tests

Compounders are required to ensure that nonsterile preparations have a low

bioburden.

USP <61> & <62> quantify the presence of microorganisms in nonsterile preparations.

WHAT TO TEST


• Environmental Sampling (ES) should be one aspect of any well-developed quality management program.

• A robust ES program demonstrates that the sterile environment maintains acceptable viable and nonviable particle limits during its ongoing operations.

• An ES program seeks to detect microorganisms, potential hazards, and other adverse trends, allowing compounders to take corrective actions before a CSP becomes contaminated or another problem occurs.

WHY: Environmental Sampling

• An in-house ES program can consist of using media plates to take air and surface samples and monitoring the plates for the growth of colony forming units (cfus) as they incubate.

• Table 2 in USP <797> defines Action Levels based on the number and location of cfus identified.

• When Action Levels are exceeded, the pharmacy must initiate an investigation and develop a corrective action plan.

WHY: Environmental Sampling

WHEN TO TEST


• USP <797> provides Action Levels & Alert Levels based on the numbers of cfus identified during environmental sampling.

• Even if Action Levels are not exceeded, <797> requires the microorganisms to be identified to ensure that there are no highly pathogenic (and potentially fatal) microorganisms in the sterile environment1.

• Any cfus recovered must be identified and a corrective action plan developed based on the type(s) of microorganism(s) recovered.

WHEN: Environmental Sampling

WHEN: Environmental Sampling503A 503B

Test Microbiological Physical Microbiological Physical

HVAC non-viable all

controlled area

6 month certification

Monitor pressure, temp

24/7

6 month certification

Monitor record

temp/RH/Pressure 24/7

Surface

ISO 5 weekly

Other ISO areas monthly

ISO 5 every batch,

Others daily

Air

Monthly

2 growth media

ISO 5 every batch,

Others daily

Fingertip ISO 5 Every compounding day Every batch

Media fills Each semi annually Each semi annually

Questions?

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