Module 2: Regulations

© Institute for International Research, Inc. 2006. All rights reserved.

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Module 2 Purpose and Objectives

 Module Purpose:  Content will presuppose a sterile lyophile in glass vials and will review general regulatory requirements.

 Module Objectives:  After this module, you will be able to  Identify essential testing requirements  Understand what makes a machine comply with cGMP sterility and cleaning  Participate in a discussion of event recovery international

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End Testing Requirements

        USP <1>Injections <905> Uniformity of Dosage Units <85> Bacterial Endotoxin <921> Water Determination Reconstitution time Identification & Assay Elegance?

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USP <1>

 Injectable Finished Product Requirements  Product must pass USP sterility test  There will probably be an endotoxin specification  Reconstituted product must pass a visible particle inspection  Reconstituted product must pass a Small Volume parenteral particulate test.

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Uniformity of Dosage Units

 Tier Testing 1:  No more than 1 of the 10 dosage units lies outside the range of 75% to 125% of the label claim and none of the 10 doses is outside the range of 65% to 135% of the label claim. If 2-3 units are outside 75% to 125% of the label claim, but no unit outside 65% to 135% of the label claim, test 20 additional units.

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Uniformity of Dosage Units

 Tier Testing 2 (on 20 additional units)  No more than 3 of 30 dosage units are outside the range of 75% to 125% of the label claim and none of the 30 dosage units is outside the range of 65% to 135% of the label claim.

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Bacterial Endotoxin

   The general requirement for injectables is less than or equal to 0.25 EU/mL of reconstituted product. This becomes a problem if the reconstitution volume is less than the fill volume for lyophilization.

Some drugs may have a specific limit Note: ophthalmics and intrathecals will have a lower limit.

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Moisture Determination

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 Sulfur Dioxide Titration I 2 + SO 2 +2H 2 O 2HI + H 2 SO 4 In Aqueous Solution, this reaction works very well to titrate sulfur dioxide and it is overwhelmingly shifted to the right by the enormous concentration of water.

Karl Fischer figured out that he could titrate water in a non-aqueous solvent and pull the equilibrium to the right by using a neutralizing base to remove the H 2 SO 4 .

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Karl Fischer Reaction

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CH 3 OH + SO 2 + RN ==> [RNH]SO 3 CH 3 I 2 RN pH = 5 to 7 H 2 O [RNH]SO 4 CH 3 + 2[RNH]I RN = Pyridine international

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Karl Fischer Reactions

  Volumetric KF – Measures the volume or weight of added titrant.

Coulometric KF – measures the current generated during the titration.

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Reconstitution Time

 Must be measured by a standard procedure  Solution should be determined versus a standard.

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Other Tests

   Assay Elegance Stability – Moisture instability due to stopper adsorption of water international

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Sterility – Filtered Gasses

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Dead Legs

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Chamber penetrations

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         Door including Window(s) & Door Ports Isolation valve (path to condenser) Capacitance Manometer 0 – 2 torr Pressure (full vacuum to 15+ psi) CIP/Steam/Gas inlet Thermocouple inlet Stoppering Ram inlet Validation Port(s) Shelf coolant Inlet & Exit Drain international

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Leak Testing

    PDA specification is 0.02 mbar ∙liter/sec 0.02mbar = 15 mtorr Example: If a system (chamber + condenser) has an internal volume of 2267 liter, then it should have a pressure rise of less than international

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Volume Determination

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Volume and Leak Test Data

Note the potential for large error in the calculation if the known volume and pressure aren’t accurate.

Atmospheric pressure varies from day to day.

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Leak Rate Calculation

 Once the volume is known, the leak rate can be calculated.

Each lyophilizer will have a different Leak Specification (in mtorr/min or mtorr/hr) depending on its volume.

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Normal Cycle Variance

  Freezing – everything must be solid.

 Target is usually -50  C. Range is -40 to -50.

Vacuum – Variation in a dry chamber should be slight. E.g. 100mtorr +1mtorr  Variation during a run will depend on how well the PID loop is tuned and what software control scheme is used.

 100mtorr + 25 mtorr may be seen. If so, it should be quick – full cycle every 5 min.

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Normal Cycle Variance

 Condensers: Within a small time frame (10 minutes) variance may be + 2  C.

 Drift during a run is common. Often, there is no set point. The condensers are run as cold as possible using the available compressor power. Drift is caused by shunting coolant to the shelf package.

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Normal Cycle Variance

 Shelves: A dry shelf specification is often + 1  C. When product is on the shelves, the ability to hold a temperature will depend on the available coolant. Most users will continue to demand + 1  C from setpoint. international

Shelf Temperature Under Load

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Red = SetPoint Blue = Shelf In Green = Shelf Out international

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Cleaning

      Use CIP if available. Otherwise, do a thorough manual cleaning.

Check for broken glass.

Validate with Riboflavin and a black light.

Test with Swabs followed by TOC.

Clean to background

cleaning.

– about 500 ppb

Sterilization is not substitute for

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Issues

 An unending list.

 Power Outage  Chamber overload  Equipment failure (long sublist)  Data recording failure  Software error  Operator error  Sensor failure   Investigate to assure non-recurrence.

Use good science.

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Exercise 2.1:

Heating of the Filter Housing Steam Sterilization of Filter Interim Drying of Filter Media Fill Housing with Water for Testing Perform Water Intrusion Integrity Test Drain Filter Housing Dry Filter Media Valve for Nitrogen Pressure Control international

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Module 2 Quiz

 Participant Directions:  Divide into pairs  Take 5 minutes to complete quiz  Correct answers will be reviewed as a large group during debrief international

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Question 1 of 3

 1.

Quiz Question: A ‘dead leg’ is a closed end pipe that is how many pipe diameters away from the vessel?

a.

b. c.

3 pipe diameters 6 pipe diameters 9 pipe diameters international

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Question 2 of 3

 Quiz Question: 2. When does USP <788> Particulate Matter in Injections apply?

a. Always on a sample after reconstitution.

b. Whenever a sample >100 mL is reconstituted with sterile liquid.

c.

f.

Always, if reconstituted with sterile liquid.

d. Whenever a specific monograph requires the test.

e.

Answers ‘b’ and ‘d’ None of the above international

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Question 3 of 3

 Quiz Question: 3. Suppose a product has failed to advance out of freezing. i.e. The product froze correctly, but the condensers never reached set-point and thus vacuum was not initiated and primary did not start.

What to do?

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Module 2 Summary

   Required Testing for a Pharmaceutical Lyophilization Product.

Basic Pharmaceutical Equipment Requirements Begin thinking about event recovery.

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