- Email: [email protected]
A quality system for PET: An industry perspective
Nuclear Instruments and Methods in Physics Research B 241 (2005) 645–648 www.elsevier.com/locate/nimb
A quality system for PET: An industry perspective Steven S. Zigler a
a,*
, Kenneth Breslow b, Michael Nazerias
b
PETNETÒ Solutions, 810 Innovation Drive, Knoxville, TN 37932, USA b CTI Molecular Imaging, Knoxville, TN 37932, USA Available online 14 November 2005
Abstract Quality systems have been employed in a variety of industries to develop and supply products that meet customer expectations and regulatory requirements. Most quality systems address organizational structure, design controls, production, complaints, audits, corrective actions and preventive actions. This paper describes PETNETÕs efforts to develop a quality system for use in the production of PET tracers. Our goal is to ensure quality products and to facilitate compliance with impending PET good manufacturing practice (GMP) regulations. Ó 2005 Elsevier B.V. All rights reserved. PACS: 87.58.Fg; 87.58.Ji Keywords: FDG; PET; Quality system
1. Introduction The first commercial facility in the United States for the production of PET tracers opened in 1990. This facility initially prepared and distributed about 10 doses/week. Today, at least ten different suppliers commercially distribute 2-deoxy2-[18F]fluoro-b-D-glucose ([18F]FDG). We estimate
* Corresponding author. Tel.: +1 865 218 2450; fax: +1 865 218 3809. E-mail address: [email protected] (S.S. Zigler).
that the total market for [18F]FDG now exceeds 10 000 doses/week. With over forty US production facilities, PETNET is the worldÕs largest supplier of [18F]FDG. Of course, the short half-life of positron-emitting radionuclides dictates a highly distributed network of production facilities. Depending on the level of production, each PETNET facility has a small staff, typically between 2 and 6 employees. Compared to a production model consisting of a single production facility, PETNETÕs distributed model presents several management challenges, including the management of quality-related functions. In order to meet this challenge, PETNET has taken
0168-583X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nimb.2005.07.112
646
S.S. Zigler et al. / Nucl. Instr. and Meth. in Phys. Res. B 241 (2005) 645–648
a quality system approach to the management of quality-related functions. Our approach simultaneously combines traditional approaches to quality systems and recognizes the unique PET distribution model.
tion of a quality system by the FDA in their approach to medical device regulation [5], and their recent publication of a draft guidance document related to quality systems and GMP for pharmaceuticals [6].
2. Key elements of a quality system
3. PETNETÕs quality system
A quality system is the part of a companyÕs management strategy related to the establishment and fulfillment of quality policies and objectives [1]. Quality systems should be documented and their effectiveness monitored through management reviews. A typical quality system contains two major elements: quality planning and quality assurance. Quality planning focuses on the establishment of quality-related policies and objectives. These policies and objectives are described in a quality manual, which applies to the entire company and is approved by senior level management. Quality assurance (QA) focuses on the fulfillment of quality-related policies and objectives. A common viewpoint of QA is ‘‘building quality into the product’’ through, among other things, documentation, specifications, training and quality control (QC).1 Regulatory requirements in the pharmaceutical industry are described in good manufacturing practice (GMP) regulations [2]. As one of its mandates in the FDA Modernization Act of 1997, the Food and Drug Administration (FDA) is developing GMP regulations for PET [3,4]. GMP regulations are designed to ensure the safety, purity and efficacy of pharmaceuticals through the establishment of a QA program. Thus, a quality system has a broader scope than GMP, but the execution of an effective quality system assures compliance with GMP. Because the pharmaceutical industry has traditionally focused on the application of GMP, it has been slow to consider the potential benefits a quality system [1]. This is changing, however, as evidenced by the applica-
Our quality system is a three-tiered hierarchy. Level 1 consists of policies described in the quality manual. These policies address personnel, facilities, equipment, materials, production, QC, labeling, documentation, validation, complaints, audits and corrective/preventive actions (CAPA). PETNETÕs policies are guiding principles that describe ‘‘what’’ must be done. Level 2 of PETNETÕs quality system consists of procedures. These procedures are more detailed than policies and describe ‘‘how’’ something must be done. Procedures include step-by-step instructions, raw materials specifications, equipment and personnel qualifications, master formularies, batch records, audit checklists and forms. Level 3 consists of records, including completed batch records, training records, validation records, qualification records, complaints, calibration records, etc. The hierarchy of PETNETÕs quality system is illustrated in Fig. 1. PETNET relies on several organizational elements to implement its quality system: a Quality System Committee, the Quality and Regulatory department, the Operations department, and Quality System Officers. The quality manual
1
Quality control (QC) testing is frequently confused with ‘‘QA testing’’. QC testing is the part of QA concerned with sampling, testing and release of materials and finished products. QC testing is a sub-set of QA.
Level 1 Policies (Quality Manual)
Level 2 Procedures
Level 3 Records
• Personnel • Facilities • Equipment • Materials • Production/QC
• Labeling • Documentation • Validation • Complaints • Audits
• Instructions • Audit checklists • Material specs • Forms • Qualification • Master formularies • Batch records • Completed batch records • Completed test records • Qualification records • Training files • Calibration records • Audit reports, etc.
Fig. 1. Hierarchy of PETNETÕs quality system.
S.S. Zigler et al. / Nucl. Instr. and Meth. in Phys. Res. B 241 (2005) 645–648
defines the interfaces between these organizational elements. 3.1. Quality system committee (QSC) The QSC has members from the Quality and Regulatory (Q&R) department, the Operations department and senior management. The mission of the QSC is to establish policies for the quality system, provide management review of the quality system, approve changes to the quality system and assure implementation of the quality system through the Q&R department. 3.2. Q&R department The corporate Q&R department oversees production operations to ensure that finished products have adequately defined identity, strength, quality and purity. In addition, the Q&R department facilitates all aspects of the quality system, including the approval of policies and procedures. 3.3. Operations department The Operations department provides organization and control of all production facilities, equipment and production personnel. The Operations department also contains technical expertise for the development of new processes and procedures. 3.4. Quality system officers (QSO’s) Each PETNET production facility is staffed with a QSO. Organizationally, QSOÕs are part of the Operations department, but are responsible for quality-related activities. QSOÕs are the Q&R liaison to each facility on quality-related matters.
4. Unique features of PETNETÕs quality system PETNETÕs quality system recognizes the unique distribution model dictated by short-lived positron-emitting radionuclides. Specifically, our quality system addresses the separation of production and QC that is typically part of GMP requirements [3]. Due to the small staff at each production
647
facility, it is not tenable to employ a dedicated QC unit. Our quality system addresses this in two ways. First, we differentiate between oversight of QC functions and execution of QC functions. The oversight role includes: (a) approval of specifications, methods and procedures, (b) assurance of compliance with approved procedures and (c) assurance of investigations for errors, failures and complaints. We provide remote oversight of the QC function through our corporate Q&R department via batch record reviews and annual compliance assessments. Execution of the QC function is the responsibility of personnel located at each production facility. Examples of these functions include: acceptance/rejection of components, labeling and final products. Second, we hold the QSO at each facility accountable for assuring proper execution of QC responsibilities. A decision to reject a batch due to a QC failure is not subject to further review or revocation by another organizational unit or person. We have conducted training to ensure that all members of the organization understand and support the responsibilities of the QSO. Our quality system also addresses the documentation requirements of GMP. Typically, a batch record is a completed version of the master formula. Since the master formula contains detailed batch instructions, this would result in excessive paperwork for the numerous daily batches prepared within PETNET. Instead, our batch record is a sub-set of the master formula, containing only pertinent data with references to the master formula and other procedures.
5. Conclusions PETNETÕs quality system is an evolutionary effort. With the adoption of an effective system that simultaneously recognizes the fundamental requirements of quality management and the unique aspects of PET tracer production, we can cost-effectively and consistently supply high quality products that meet customer expectations and regulatory requirements. Furthermore, these concepts provide the basis for a broad platform that could assure industry-wide uniformity.
648
S.S. Zigler et al. / Nucl. Instr. and Meth. in Phys. Res. B 241 (2005) 645–648
References [1] Oliver Schmidt (Ed.), Pharmaceutical Quality Systems, CRC Press, 2000. [2] US Code of Federal Regulations, Title 21, Parts 210 and 211.
[3] Federal Register, Vol. 62, no. 244, December 19, 1997, p. 66522. [4] Federal Register, Vol. 67, no. 62, April 1, 2002, p. 15344-5. [5] US Code of Federal Regulations, Title 21, Part 820. [6] Federal Register, Vol. 69, no. 191, October 4, 2004, p. 59256.
A quality system for PET: An industry perspective Steven S. Zigler a
a,*
, Kenneth Breslow b, Michael Nazerias
b
PETNETÒ Solutions, 810 Innovation Drive, Knoxville, TN 37932, USA b CTI Molecular Imaging, Knoxville, TN 37932, USA Available online 14 November 2005
Abstract Quality systems have been employed in a variety of industries to develop and supply products that meet customer expectations and regulatory requirements. Most quality systems address organizational structure, design controls, production, complaints, audits, corrective actions and preventive actions. This paper describes PETNETÕs efforts to develop a quality system for use in the production of PET tracers. Our goal is to ensure quality products and to facilitate compliance with impending PET good manufacturing practice (GMP) regulations. Ó 2005 Elsevier B.V. All rights reserved. PACS: 87.58.Fg; 87.58.Ji Keywords: FDG; PET; Quality system
1. Introduction The first commercial facility in the United States for the production of PET tracers opened in 1990. This facility initially prepared and distributed about 10 doses/week. Today, at least ten different suppliers commercially distribute 2-deoxy2-[18F]fluoro-b-D-glucose ([18F]FDG). We estimate
* Corresponding author. Tel.: +1 865 218 2450; fax: +1 865 218 3809. E-mail address: [email protected] (S.S. Zigler).
that the total market for [18F]FDG now exceeds 10 000 doses/week. With over forty US production facilities, PETNET is the worldÕs largest supplier of [18F]FDG. Of course, the short half-life of positron-emitting radionuclides dictates a highly distributed network of production facilities. Depending on the level of production, each PETNET facility has a small staff, typically between 2 and 6 employees. Compared to a production model consisting of a single production facility, PETNETÕs distributed model presents several management challenges, including the management of quality-related functions. In order to meet this challenge, PETNET has taken
0168-583X/$ - see front matter Ó 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.nimb.2005.07.112
646
S.S. Zigler et al. / Nucl. Instr. and Meth. in Phys. Res. B 241 (2005) 645–648
a quality system approach to the management of quality-related functions. Our approach simultaneously combines traditional approaches to quality systems and recognizes the unique PET distribution model.
tion of a quality system by the FDA in their approach to medical device regulation [5], and their recent publication of a draft guidance document related to quality systems and GMP for pharmaceuticals [6].
2. Key elements of a quality system
3. PETNETÕs quality system
A quality system is the part of a companyÕs management strategy related to the establishment and fulfillment of quality policies and objectives [1]. Quality systems should be documented and their effectiveness monitored through management reviews. A typical quality system contains two major elements: quality planning and quality assurance. Quality planning focuses on the establishment of quality-related policies and objectives. These policies and objectives are described in a quality manual, which applies to the entire company and is approved by senior level management. Quality assurance (QA) focuses on the fulfillment of quality-related policies and objectives. A common viewpoint of QA is ‘‘building quality into the product’’ through, among other things, documentation, specifications, training and quality control (QC).1 Regulatory requirements in the pharmaceutical industry are described in good manufacturing practice (GMP) regulations [2]. As one of its mandates in the FDA Modernization Act of 1997, the Food and Drug Administration (FDA) is developing GMP regulations for PET [3,4]. GMP regulations are designed to ensure the safety, purity and efficacy of pharmaceuticals through the establishment of a QA program. Thus, a quality system has a broader scope than GMP, but the execution of an effective quality system assures compliance with GMP. Because the pharmaceutical industry has traditionally focused on the application of GMP, it has been slow to consider the potential benefits a quality system [1]. This is changing, however, as evidenced by the applica-
Our quality system is a three-tiered hierarchy. Level 1 consists of policies described in the quality manual. These policies address personnel, facilities, equipment, materials, production, QC, labeling, documentation, validation, complaints, audits and corrective/preventive actions (CAPA). PETNETÕs policies are guiding principles that describe ‘‘what’’ must be done. Level 2 of PETNETÕs quality system consists of procedures. These procedures are more detailed than policies and describe ‘‘how’’ something must be done. Procedures include step-by-step instructions, raw materials specifications, equipment and personnel qualifications, master formularies, batch records, audit checklists and forms. Level 3 consists of records, including completed batch records, training records, validation records, qualification records, complaints, calibration records, etc. The hierarchy of PETNETÕs quality system is illustrated in Fig. 1. PETNET relies on several organizational elements to implement its quality system: a Quality System Committee, the Quality and Regulatory department, the Operations department, and Quality System Officers. The quality manual
1
Quality control (QC) testing is frequently confused with ‘‘QA testing’’. QC testing is the part of QA concerned with sampling, testing and release of materials and finished products. QC testing is a sub-set of QA.
Level 1 Policies (Quality Manual)
Level 2 Procedures
Level 3 Records
• Personnel • Facilities • Equipment • Materials • Production/QC
• Labeling • Documentation • Validation • Complaints • Audits
• Instructions • Audit checklists • Material specs • Forms • Qualification • Master formularies • Batch records • Completed batch records • Completed test records • Qualification records • Training files • Calibration records • Audit reports, etc.
Fig. 1. Hierarchy of PETNETÕs quality system.
S.S. Zigler et al. / Nucl. Instr. and Meth. in Phys. Res. B 241 (2005) 645–648
defines the interfaces between these organizational elements. 3.1. Quality system committee (QSC) The QSC has members from the Quality and Regulatory (Q&R) department, the Operations department and senior management. The mission of the QSC is to establish policies for the quality system, provide management review of the quality system, approve changes to the quality system and assure implementation of the quality system through the Q&R department. 3.2. Q&R department The corporate Q&R department oversees production operations to ensure that finished products have adequately defined identity, strength, quality and purity. In addition, the Q&R department facilitates all aspects of the quality system, including the approval of policies and procedures. 3.3. Operations department The Operations department provides organization and control of all production facilities, equipment and production personnel. The Operations department also contains technical expertise for the development of new processes and procedures. 3.4. Quality system officers (QSO’s) Each PETNET production facility is staffed with a QSO. Organizationally, QSOÕs are part of the Operations department, but are responsible for quality-related activities. QSOÕs are the Q&R liaison to each facility on quality-related matters.
4. Unique features of PETNETÕs quality system PETNETÕs quality system recognizes the unique distribution model dictated by short-lived positron-emitting radionuclides. Specifically, our quality system addresses the separation of production and QC that is typically part of GMP requirements [3]. Due to the small staff at each production
647
facility, it is not tenable to employ a dedicated QC unit. Our quality system addresses this in two ways. First, we differentiate between oversight of QC functions and execution of QC functions. The oversight role includes: (a) approval of specifications, methods and procedures, (b) assurance of compliance with approved procedures and (c) assurance of investigations for errors, failures and complaints. We provide remote oversight of the QC function through our corporate Q&R department via batch record reviews and annual compliance assessments. Execution of the QC function is the responsibility of personnel located at each production facility. Examples of these functions include: acceptance/rejection of components, labeling and final products. Second, we hold the QSO at each facility accountable for assuring proper execution of QC responsibilities. A decision to reject a batch due to a QC failure is not subject to further review or revocation by another organizational unit or person. We have conducted training to ensure that all members of the organization understand and support the responsibilities of the QSO. Our quality system also addresses the documentation requirements of GMP. Typically, a batch record is a completed version of the master formula. Since the master formula contains detailed batch instructions, this would result in excessive paperwork for the numerous daily batches prepared within PETNET. Instead, our batch record is a sub-set of the master formula, containing only pertinent data with references to the master formula and other procedures.
5. Conclusions PETNETÕs quality system is an evolutionary effort. With the adoption of an effective system that simultaneously recognizes the fundamental requirements of quality management and the unique aspects of PET tracer production, we can cost-effectively and consistently supply high quality products that meet customer expectations and regulatory requirements. Furthermore, these concepts provide the basis for a broad platform that could assure industry-wide uniformity.
648
S.S. Zigler et al. / Nucl. Instr. and Meth. in Phys. Res. B 241 (2005) 645–648
References [1] Oliver Schmidt (Ed.), Pharmaceutical Quality Systems, CRC Press, 2000. [2] US Code of Federal Regulations, Title 21, Parts 210 and 211.
[3] Federal Register, Vol. 62, no. 244, December 19, 1997, p. 66522. [4] Federal Register, Vol. 67, no. 62, April 1, 2002, p. 15344-5. [5] US Code of Federal Regulations, Title 21, Part 820. [6] Federal Register, Vol. 69, no. 191, October 4, 2004, p. 59256.