GMP and Quality Control: An Industry Perspective. Steven S. Zigler, Ph.D. PETNET Pharmaceuticals, Inc. Knoxville, Tennessee

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1 GMP and Quality Control: An Industry Perspective Steven S. Zigler, Ph.D. PETNET Pharmaceuticals, Inc. Knoxville, Tennessee

2 GMP in Preparation of Precursors Not necessary However, we need stability data

3 Topics Quality Assurance (QA) QC testing and it s role within QA Good manufacturing practice and QA PET GMP s and QC QA/QC challenges associated with a commercial PET distribution network

4 Why is PET Different?? Time-critical production environment Time required for QC Out-of of-specification investigations Highly distributed production model Many production facilities required for nationwide supply Relatively small number of people at each facility Staffing levels impact the separation of QC from production and second person checks One vial = One batch QC sample and patient doses removed from same vial Many batches required for nationwide supply

5 Seattle Portland Sacramento Palo Alto LA Irvine Phoenix Denver Omaha Dallas Minneapolis Peoria St. Louis Chicago Louisville Kansas City Nashville Tulsa Little Rock Knoxville New Orleans Detroit Cleveland Indianapolis Cincinnati B ham Atlanta Albany Raleigh Columbia Jacksonville Boston New York Philadelphia Winston-Salem San Antonio Houston Tampa Fort Lauderdale

6 Quality Assurance (QA) A wide-ranging concept covering all matters that influence a product s quality All organized efforts to ensure that a product possesses the quality required for its intended use The quality of a product cannot be established by end-product testing alone A QA program builds quality into a product

7 QC Testing and it s Role within QA Quality Control (QC) testing is a narrow- ranging concept that deals with sampling, testing and release Applies to materials, components and finished products Ensures that the item of interest meets intended specifications QC testing is one of several elements of a QA program

8 Good Manufacturing Practice (GMP) A Quality Assurance program encoded in FDA regulations Goal is to prevent contamination, mix-ups and errors Covers all matters that influence the quality of a drug Personnel, equipment, facilities, materials, procedures, quality control, etc. Requires a Quality Control Unit that is separate from production Addresses the inherent conflict of interest that arises when the producer does the testing

9 Good Manufacturing Practice for PET Draft proposed rule published by FDA in March 2002 Proposed separate PET GMP requirements 21 CFR Part 212 Public hearing in May 2002 Among other things, described a QC unit for PET facilities

10 Responsibilities of QC Unit Oversee production operations Examine incoming raw materials and components Examine finished products Review and approve procedures and specifications Review documentation for accuracy and completeness Investigate errors and develop corrective actions

11 QA/QC Challenges Associated with a Commercial Distribution Network Time required to complete QC testing Equipment qualification and routine verification Out-of of-specification (OOS) investigations Second person checks Separation of QC and production Traditional GMP approach will not work Round peg/square hole

12 Go Ahead and Try but it just doesn t fit!

13 Time Required to Complete QC Testing Test Specification Schedule Physical Characteristics Color Clarity Visible particulate matter Colorless Clear Free of particulates Each batch; prior to release. Radiochemical ID/purity Not < 90% [ 18 F]FDG Each batch; prior to release. Radionuclidic identity T 1/2 = min Each batch; prior to release. Radioactive concentration mci/ml Each batch; prior to release. Chemical Purity K222 < 50 µg/ml Each batch; prior to release. Cl-DG < 1 mg/batch Annually; performed on decayed sample; send to Corporate for testing. Residual Solvents EtOH: % w/w Each batch; prior to release. CH3CN: 0.4% w/w ph Each batch; prior to release. Membrane filter integrity Passes test Each batch; prior to release. Bacterial endotoxin (LAL) Less than 175/V Each batch; start incubation EU/ml (where V is prior to release. max dose volume) Sterility Absence of bacterial Each batch; may inoculate Radionuclidic purity growth after 14 days Not < 99.5% of gamma emissions correspond to 511 kev day following production. Monthly; performed on a 48-hr decayed sample; send to Corporate for testing.

14 Equipment Qualification Equipment must be qualified prior to use Installation and after major repair Qualification requirements must be commensurate with time and staffing limitations Routine calibration of instruments Number of calibration standards Number of analyses at each concentration

15 Routine Verification Must establish proper function of equipment before routine operation Verification requirements must be commensurate with time and staffing limitations Analysis of standards prior to product analysis Equipment failures Must provide a conditional release for certain major analytical equipment failures

16 Out-of of-specification (OOS) Investigations Based on Barr vs. FDA case in late 1990 s When a QC test yields a result that is OOS, we must determine if the result is due to an analytical error or a true product failure OOS does not automatically mean failure Cannot test until you get the desired resulted OOS investigations must be suitable for PET Balance half-life life with added test requirements Has not been specifically addressed by FDA for PET

17 Second Person Checks Even the busiest distribution facility has times when only one person is present However, there are times when we must check our work to minimize the risk of contamination, mix-ups and errors. Checks must be commensurate with time and staffing limitations It must be possible for one person to check their own work

18 Separation of QC and Production Finally, we must address the separation of the QC organization from the production organization The target is the inherent conflict of interest when the producer does the testing Quality-based decisions (e.g., batch rejection) cannot be overridden by production-based criteria As always, the approach must be suitable for PET What s the solution?

19 Separation of QC and Production One element of a solution We need to differentiate the execution of the QC function from the oversight of QC function Execution of QC occurs at a local level Oversight can occur remotely (i.e., a corporate QA/QC department) This allows a separate organizational element to oversee the activities of the facility

20 Separation of QC and Production A second element of a solution At the local level, create organizational accountability without a separate organizational element How? Assign responsibility for quality-related matters to an individual at each facility Quality System Officer or QSO Similar concept to the familiar RSO Requires training, understanding and buy-in at all levels of the organization, including Senior Management

21 Proposed QSO-Based Organization Senior Management Production Department Quality Affairs Department Facility Management Mid-Level Management Quality System Officer (QSO)

USP Chapter 823 USP 32 (old) vs. USP 35 (new)

USP Chapter 823 USP 32 (old) vs. USP 35 (new) Sally W. Schwarz, MS, BCNP Research Associate Professor of Radiology Washington University School of Medicine St. Louis, MO Why USP Chapter ? FDA has