The Food and Drug Administration (FDA) Modernization Act (the Modernization Act) of 1997 directed FDA to establish current good manufacturing practice (CGMP) requirements for positron emission tomography (PET) drugs. As directed by the US Congress in the Modernization Act, the costly CGMP regulations which the FDA applies to large pharmaceutical manufacturers are not appropriate for the PET drugs due to the unique properties of these drugs mainly the short half-lives. In consideration of the unique nature of PET drugs and PET drug production, FDA instituted specific CGMP requirements in 21 Code of Federal Regulations (CFR) part 212. Sections 1 and 2 of this book chapter illustrate the significant different aspects and the rationales for such differences between part 212 and parts 210/211 which are the CGMP requirements for non-PET drugs. The PET drug CGMP regulation found in part 212 also provides a more flexible regulatory framework for investigational PET drugs for human use produced under an investigational new drug application (IND) in accordance with part 312 and PET drugs produced with the approval of a Radioactive Drug Research Committee (RDRC) in accordance with part 361. The PET CGMP requirements for these PET drugs can be met either by compliance with part 212 or by producing such drugs in accordance with the 32nd edition of the United States Pharmacopeia (USP) General Chapter <823>, “Radiopharmaceuticals for Positron Emission Tomography – Compounding,” which was published in 2009. In 2012, USP revised and renamed this General Chapter <823>, “Positron Emission Tomography Drugs for Compounding, Investigational, and Research Uses.” FDA is currently considering whether to amend the PET CGMP regulations to incorporate this revised chapter into part 212. Section 4 describes format/content of the revised USP General Chapter <823> which is very much in line with part 212 and offers more flexible requirements than the <823> in 32nd USP.

FDA expects to perform a CGMP surveillance inspection of each PET facility once every 2 years on average, but may visit some sites more than once every 2 years when warranted, such as when the site is named in an application for a new type of PET drug product or has undergone substantial change. As part of the drug approval process, a preapproval inspection (PAI) will be performed by the FDA inspector(s) to provide assurance that a PET drug production facility that is named in a drug application is capable of producing the PET drug in accordance with CGMPs and that the submitted application data are reliable, accurate, and complete. Section 5 summarizes the major deficiencies identified by the FDA inspectors during their 2013 and 2014 inspection programs at various PET drug production facilities in the United States.

Keywords

PET drugPET drug productFDACurrent good manufacturing practice (CGMP)USPUSP <823>Quality assuranceQuality controlActive pharmaceutical ingredientSpecificationsMaster production and control recordBatch production and control recordSub-batchSystem suitabilityProcess verificationStability testingFinished-product testingConditional final releaseOut of specification

7.1 Introduction

Positron emission tomography (PET) radiopharmaceuticals are unique among radiopharmaceuticals because of their short half-lives. There are four positron-emitting radioisotopes that are considered the biologic tracers, carbon-11, nitrogen-13, oxygen-15, and fluorine-18. ¹¹C (t _½ = 20.4 min), ¹⁵O (t _½ = 2.1 min), and ¹³N (t _½ = 10 min) are referred to as the essentials of life. They can be easily substituted directly into biomolecules without changing the properties of the molecule. ¹⁸F (t _½ = 110 min) is not a normal constituent of biological molecules but can often be substituted for a hydroxyl group as in the case of deoxyglucose or can be substituted for a hydrogen atom in a molecule or placed in a position where its presence does not significantly alter the biological behavior of the molecule. Fluorodeoxyglucose (¹⁸FDG) is currently the most widely used PET radiopharmaceutical in clinical oncology in addition to its clinical applications in cardiology and neurology. ¹⁸FDG is one of the important factors for the wide acceptance of PET imaging in clinical practice. The application of PET in clinical oncology is increasing since many molecular targets relevant to cancer can be labeled with positron emitter radionuclides.

The concept of PET and the design and construction of PET scanners were initiated in the United States back in the late 1950 [1–3]. However, the benefits of PET imaging were not widely available to American patients for many years due to “lack of reimbursement and inappropriate and costly regulations promulgated by FDA” [4]. The same current good manufacturing practice (CGMP) requirements that FDA typically applies to large drug manufacturers were also placed on the production of PET radiopharmaceuticals without taking into consideration the special properties of these drugs (e.g., short half-lives). In order to make PET imaging technology more accessible to the US patients at reasonable cost, the US Congress establishes a new regulatory framework for PET drugs within the Food and Drug Administration Modernization Act of 1997 (FDAMA) which was signed by President Bill Clinton on November 21, 1997 [5].

Specifically, section 121(c)(1)(A) of 1997 FDAMA directed FDA to establish CGMP requirements for PET drugs [5]. In the Federal Register (FR) of September 20, 2005 (i.e., 70 FR 55038), FDA published a proposed rule to establish CGMP requirement for PET drugs [6]. On December 10, 2009, FDA issued a final rule in 74 FR 65409 [7] and an accompanying guidance document to establish specifically “tailored” CGMP requirements for PET drugs [8].

These requirements are codified in the Title 21 of the Code of Federal Registrations (CFR) part 212 (part 212) [7]. The deadline for this regulation to become effective was originally set on December 12, 2011 [7]. Two years later, with the deadline looming, FDA received numerous requests for extending the submission deadline. FDA was concerned about preventing access to the PET drugs, and therefore this deadline was extended by the FDA to June 12, 2012 [9].

7.2 PET Drug

7.2.1 Is PET Drug for Imaging or Therapy or Both?

“PET drug” as defined in part 212 is “a radioactive drug that exhibits spontaneous disintegration of unstable nuclei by the emission of positrons and is used for providing dual photon positron emission tomographic diagnostic images” (emphasis added) [10]. Under section 121(a) of the FDAMA (codified as section 201(ii)(1)(A) of the Food, Drug, and Cosmetic Act [FD&C]) [5, 11], a compounded PET drug is defined as a drug that “exhibits spontaneous disintegration of unstable nuclei by the emission of positrons and is used for the purpose of providing dual photon emission tomographic diagnostic image” (emphasis added). The word “diagnostic” in each of these two definitions appears to indicate that part 212 [10] and the provisions of the FDAMA concerning PET drugs [5] do not apply to PET drugs used for therapeutic purposes.

7.2.2 Definition of PET Drug

The definition of PET drug as stated in part 212 specifically includes any nonradioactive reagent, reagent kit, ingredient, nuclide generator, accelerator, target material, electronic synthesizer, or other apparatus or computer program to be used in the preparation of a PET drug [10]. Once again, this definition closely parallels the definition of PET drug in section 121(a) of the FDAMA [5].

It seems that the inclusion of these “ancillary” components and equipment (e.g., nuclide generator, accelerator, electronic synthesizer, etc.) is overly broad and not appropriate within the practical and technical definition of a drug. However, since these items were included in definition of “compounded PET drug” as stated in the section 121 (a) of the FDAMA [5], FDA felt that the definition of “PET drug” in the final rule should include these items as well [7]. Thus, these “ancillary” items are also subject to the same CGMP requirements for PET drugs as stipulated in part 212 [10].

7.2.3 PET Drug Versus PET Drug Product

Part 212 defines “PET drug product” as a finished dosage form of a PET drug, and it is included in the FDA definition for “PET drug” [10]. As such, the CGMP requirements for PET drugs do apply to PET drugs, as well as PET drug products.

7.2.4 Compounded and Noncompounded PET Drugs

The FDAMA does not have separate regulations for compounded PET drugs and noncompounded PET drugs [5]. In fact, section 121(b) of the FDAMA states that 4 years after the date of enactment of the FDAMA or 2 years after the FDA establishes approval procedures and CGMP requirements for PET drugs, whichever is longer, the CGMP requirements established by the FDA for PET drugs will apply to compounded or noncompounded PET drugs [5]. In other words, once the aforementioned condition is met, all PET drugs (including compounded PET drugs) would be subject to PET drug CGMP requirements.

During either of these two time frames, section 121(b) of the FDAMA indicated that a compounded PET drug was not adulterated if it was compounded, processed, packed, or held in conformity with the PET compounding standards and official monographs of the United States Pharmacopeia (USP) [5].

7.2.5 PET Drug Production Versus Practice of Pharmacy

Although part 212 defines “production” of a PET drug as the manufacturing, compounding, processing, packaging, labeling, reprocessing, repacking, relabeling, and testing of a PET drug [10], FDA has traditionally deferred the dispensing of a patient-specific dose and the use of the drug product to state and local authorities. As such, these postproduction activities are regarded by the FDA as the practice of medicine and pharmacy. Consequently, a guidance – a version marked on the front cover with Small Entity Compliance Guide – issued by the FDA in 2011(Guidance) stated that production includes all operations only to the point of final release of a finished dosage form [12]. In general, a routine FDA inspection to ensure compliance with CGMP would focus on activities up to and including the point of final release of a PET drug product [12].

7.3 CGMP for PET Drugs

CGMP is a minimum standard that ensures that a drug meets the requirements of safety, as well as it has the identity, strength (or potency), quality, and purity characteristics as it is represented to possess. CGMP is demonstrated through written documentation of procedures and practices.

After visiting several PET drug production sites, FDA concluded that a PET drug producer’s status as either a not-for-profit or for-profit entity does not and should not have any significant bearing on the safety, identity, strength, quality, and purity of PET drugs that it produces and distributes for administration to patients. The same conclusion goes to the methods, facilities, and controls that a PET drug production facility needs to ensure product’s safety, identity, strength, quality, and purity. Instead, FDA believes production, and CGMP differences among PET drug producers are primarily a function of the size, scope, and complexity of their production operations.

Consequently, FDA approach to the CGMP regulation for PET drugs has been shaped largely by the statutory and the imperatives of product’s safety, identity, strength, quality, and purity, rather than commercialization or reimbursement concerns. In fact, FDA found that implementing certain production standards and controls could further ensure the production of suitable PET drugs, regardless of differences among the various PET drug production facilities. FDA believes that the welfare of a patient undergoing a PET scan should not depend on where a particular PET drug was produced.

7.3.1 Unique Aspects of PET Drug Production

PET drug manufacturing procedures differ in a number of important ways from those associated with the manufacture of conventional drug products, mainly due to the short half-lives of PET radioisotopes. These unique aspects are as follows:

Because of the short physical half-lives of PET radioisotopes, prolonged manufacturing time significantly would erode the useful clinical life of PET drugs. Likewise, the produced PET drug product is administered to the patient usually within a matter of hours. Due to a relatively small number of patients per day, PET drug production facilities generally manufacture the products in response to daily demand. Thus, a maximum of only a few lots are manufactured per day, with one lot equaling one multiple-dose vial.
Because one lot equals one multiple-dose vial containing a homogeneous solution of a PET drug product, results from end product testing of samples drawn from the single vial have the maximum possible probability of being representative of all the doses administered to patients from that vial. This special characteristic of the produced PET drug prevents sampling or testing error.
An entire lot may be administered to one or several patients, depending upon the radioactivity remaining in the container at the time of administration. Consequently, the administration of the entire quantity of a lot to a single patient should be anticipated for every lot manufactured. This is an important consideration when establishing the testing limits for certain attributes such as endotoxins and impurities.
PET drugs usually do not enter a general drug distribution chain. Rather, the entire lot (one vial) is usually distributed directly from the PET drug production facility either to a single medical department or physician for administration to patients or to a nuclear pharmacy for dispensing. Distribution may occur to other PET centers when the geographic proximity will allow for distribution and use within the PET drug product’s half-life parameters.
The quantities of radioactive active ingredients contained in each lot of a PET drug generally vary from nanogram to milligram amounts, depending upon various product parameters.

7.3.2 Part 212 Versus Parts 210 and 211

In consideration of these unique natures of PET drugs and PET drug production, FDA recognized that application of certain provisions of the CGMP regulations in parts 210 and 211 [13, 14] to the manufacture of PET drugs might result in unsafe handling or be otherwise inappropriate [7]. Thus, part 212 differs in many significant ways from the CGMP requirements for non-PET drugs found in the regulations of parts 210 and 211[12–14].

Included among these differences are the following (to be described in more details later):

Fewer required personnel with fewer organizational restrictions consistent with the scope and complexity of operations
Allowance for multiple operations (or storages) in the same area as long as organization and other controls are adequate
Streamlined requirements for aseptic processing consistent with the nature of the production process
Streamlined quality assurance (QA) requirements for components
Self-verification of significant steps in PET drug production consistent with the scope and complexity of operations
Same-person oversight of production, review of batch production and control records (please refer to the section titled “Production and Process Controls” for the distinction between master production and control record and batch production and control record), and authorization of product release consistent with the scope and complexity of operations
Greater flexibility in approaches to determining whether PET drug products conform to their specifications
Specialized QA requirements for PET drugs produced in multiple sub-batches (sub-batch means a quantity of PET drug having uniform character and quality, within specified limits, that is produced during one succession of multiple irradiations, using a given synthesis and/or purification operation) [10]
Simplified labeling requirements consistent with the scope and complexity of operations

7.3.3 Application of Part 212

The regulations in part 212 apply only to the production, quality control (QC), holding, and distribution of PET drugs [10]; human drugs that do not meet the definition of a PET drug must be manufactured in accordance with the CGMP requirements in parts 210 and 211 [13, 14]. Part 212 regulations are designated to be sufficiently flexible to accommodate the unique aspects of PET drugs [10].

However, section 212.5(b) also gives producers of PET drugs under the review of an investigational new drug application (IND) or under a Radioactive Drug Research Committee (RDRC) the option of following the CGMP regulations in part 212 or producing PET drugs in accordance with General Chapter <823> (USP <823>) of the 32nd edition of the USP Radiopharmaceuticals for Positron Emission Tomography – Compounding [10, 15].

Originally developed in 1990, USP <823> sets forth requirements for PET drug production, including control of components, materials, and supplies, verification of procedures, stability testing and expiration dating, QC, and sterilization and sterility assurance [15]. The 1997 FDAMA stipulates that a compounded PET drug is adulterated unless it is produced in conformity with the USP compounding standards (including USP <823>) and official monographs for PET drugs [5].

The main reason that the FDA allows USP <823> to constitute CGMP standards for IND and RDRC PET drugs is to “allow more flexibility during the development of these drugs” [12]. Although the provisions in USP <823> [15] are generally less specific and explicit than the requirements in part 212 [10], FDA believes that provisions in USP <823> are “adequate to ensure that investigational and research PET drugs are produced safely under appropriate conditions” and are “appropriate CGMP requirements for the investigational and research stage of development” [12]. FDA also recognizes that the majority of these investigational and research PET drugs do not have commercial potential [12], and, therefore, it is not necessary to subject these drugs under the stipulations of part 212, which is more geared to approved or to-be-approved PET drugs [10].

Better compliance outcome is another reason that FDA permits producers of IND and RDRC PET drugs to choose USP <823> as an alternative standard for meeting CGMP requirements [12]. FDA stated that because “most PET drug producers are very familiar with the requirements in Chapter <823>, allowing producers to meet the CGMP requirements for investigational and research PET drugs by following Chapter <823> should greatly facilitate producers’ compliance with the CGMP requirements” [12].

Nevertheless, once a PET drug producer intends to seek marketing approval for a PET drug or a new indication, the production of the PET drug to be used in phase 3 study should be conducted in accordance with the CGMP requirements for PET drugs as stipulated in part 212 which is mainly designated as CGMP requirements for approved PET drugs [8].

7.3.4 QA and QC

On the initiative taken by the FDA, the term “quality control” was replaced with “quality assurance” [8]. Nevertheless, the term “quality control” still appears in the definition of the term “batch production and control record” [10]. The Guidance lists the term “quality control” in the document seven times [12]. Please refer to the section titled “Revised USP <823>” for the definitions of “quality control” and “quality assurance.”

7.3.5 Personnel and Resources

Section 212.10 requires a PET drug production facility to have a sufficient number of personnel with the necessary education, background, training, and experience to enable them to perform their assigned functions correctly [10]. Each site also must provide adequate resources, including equipment and facilities, to enable their personnel to perform their functions. This section only addresses personnel issues whereas the resources aspects (facilities and equipment) are discussed in section titled “Facilities and Equipment.”

A small PET drug production operation is not properly characterized in part 212 [10]; however, it is stated in the Guidance as one that produces only one or two batches each day (or week) of a single PET drug [12]. As such, it may be adequate to employ only a few employees (typically at least two persons) to accomplish all production and QA functions. The Guidance further elaborates that one individual can be designated to perform the production as well as QA functions, provided this person is highly qualified in the performance of all such functions [12]. Self-checks in such a PET drug production facility are also permissible as indicated in the Guidance [12]. This is not allowed under current part 211 in which second-person checks are required at various stages of productions as well as test verification [15].

7.3.6 QA

Section 212.20 requires PET drug production facilities to establish and follow written QA procedures for production operations, materials, specifications and processes, and production records to ensure drug.

The Guidance recommends each PET drug production facility to establish a QA function which consists of execution and oversight activities related to QA requirements [12]. It further suggests the following activities to be handled by the execution and oversight of QA function, respectively [12]:

Execution activities of QA function include the following:

Examine and evaluate each lot of incoming material before use to ensure that the material meets its established specifications.
Review the production batch records and laboratory control records for accuracy, completeness, and conformance to established specifications before authorizing the final release or rejection of a batch or lot of a PET drug.
Ensure that deviations from normal procedures are documented and justified.

Oversight activities of QA functions include the following:

Approve procedures, specifications, process, and methods.
Ensure that personnel are properly trained and qualified, as appropriate.
Ensure that PET drugs have adequately defined identity, strength, quality, and purity.
Ensure that all errors are reviewed. When it is determined that an investigation is appropriate, document the investigation and take corrective action(s) to prevent the recurrence of the errors.
Conduct periodic audits to monitor compliance with established procedures and practices.

For PET drug production facilities currently producing one or two PET drugs, the Guidance indicates that employees located at the facility can perform both the daily execution and oversight functions [12]. On the other hand, a PET drug production organization managing multiple production facilities may designate the oversight duties to an internal QA department or an outside consultant to achieve a more objective and efficient management [12].

7.3.7 Facilities and Equipment

7.3.7.1 Facilities

Section 212.30(a) requires a PET drug production facility to have adequate facilities to ensure the orderly handling of materials and equipment, the prevention of mix-ups, and the prevention of contamination of equipment or product by substances, personnel, or environmental conditions that could reasonably be expected to have an adverse effect on product quality [10].

For the potential sources of contamination, the Guidance points out that they include particulate matter, chemical, and microbiological materials [12]. The general principles for preventing mix-ups as suggested by the Guidance are equipment to be appropriately located, work areas to be organized and proximally located, components to be properly labeled and kept separate according to the classifications (i.e., quarantined, approved, or rejected), and access these aforementioned items to be restricted to authorized personnel [12].

Section titled “Facility Design and Environmental Control” in USP General Chapter <797> Pharmaceutical Compounding – Sterile Preparations is a good reference for a proper setup of an aseptic processing area [16]. Some precautions suggested by the Guidance should be followed to help maintain the appropriate air quality of the aseptic workstation [12]:

Sanitize the aseptic workstation before each operation.
Keep items within a laminar airflow aseptic workstation to a minimum and do not interrupt the airflow.
Have operators wear clean lab coats and sanitized gloves when conducting an aseptic manipulation within the aseptic workstation.
Frequently sanitize gloved hands or frequently change gloves when working in the aseptic workstation. Examine gloves for damage (tears or holes) and replace them if they are damaged.
Sanitize the surface of non-sterile items (e.g., test tube rack, the overwrap for sterile syringes, filters) and wipe with an appropriate disinfectant (e.g., sterile 70 % isopropyl alcohol) before placing them in the aseptic workstation.

7.3.7.2 Equipment

Section 212.30(b) requires the implementation of procedures to ensure that all equipment that would reasonably be expected to adversely affect the identity, strength, quality, or purity of a PET drug, or give erroneous or invalid test results when improperly used or maintained, is clean, suitable for its intended purposes, properly installed, maintained, and capable of repeatedly producing valid results [12]. Activities in accordance with these procedures must be documented [12]. Section 212.30(c) stipulates the equipment to be constructed and maintained so that surfaces that contact components, in-process materials, or drug products are not reactive, additive, or absorptive so as to alter the quality of the PET drug [10].

For any newly installed equipment, the Guidance recommends a three-step process – installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) – to qualify the new equipment before its first use in order to ensure it was installed correctly, was operated adequately, and is capable of producing the anticipated results [12].

Normally, the equipment vendor verifies that the equipment is installed correctly (IQ) and operates according to specifications, OQ. Before the equipment is used for production, personnel in the PET drug production facility should verify that the equipment, when operated under actual production parameters or selected method, produces consistent results within established specifications – PQ [12].

Representative equipment is discussed in the Guidance to illustrate how it should be controlled [12]. Some examples are listed below:

The provisions contained in the USP General Chapter <1015> Automated Radiochemical Synthesis Apparatus can help ensure proper functioning of a synthesis apparatus [17].
Microbiological monitoring (e.g., using settle plate) in the aseptic workstation should be conducted during sterility testing and critical aseptic manipulation.
In order to make sure that a gas chromatograph (GC) or a high-performance liquid chromatograph (HPLC) system is functioning correctly, a suitability testing should be conducted. At least one injection of the standard preparation (reference standard or internal standard) should be done before the injection of test samples into a GC or HPLC system.

7.3.8 Control of Components, Containers, and Closures

Section 212.40(a) and (b) requires PET drug production facilities to establish, maintain, and follow written procedures for the control (i.e., receipt, log-in, identification, storage, handling, testing, and acceptance and/or rejection) of components, containers, and closures. Appropriate written specifications for the components, containers, and closures must be established [10]. Section 212.40(c) establishes the minimum standards for controlling components, containers, and closures from receipt to consumption [10]. Any incoming lot must be appropriately designated as quarantined, accepted, or rejected. One must use a reliable supplier for each component, container, and closure [10]. Section 212.40(d) requires that components, containers, and closures be handled and stored in a manner that prevents contamination, mix-ups, and deterioration [10]. Section 212.40(e) requires that PET drug production facilities keep a record of each shipment of each lot of components, containers, and closures that they receive [10].

The Guidance defines “reliable vendor” as “qualified vendors,” and a vendor is qualified when there is evidence to support its ability to supply a material that consistently meets all quality specifications [12]. It is preferable as suggested by the Guidance to have more than one qualified vendor for a component [12].

For acceptance testing, the specific identity test is only required if the finished-product testing does not ensure that the correct components have been used or if an inactive ingredient (e.g., 0.9 % sodium chloride solution) was prepared on site from a component that is not subject to finished-product testing [10, 12]. Otherwise, examination of a certificate of analysis (COA) provided by the supplier should be sufficient [10].

7.3.9 Production and Process Controls

Section 212.50 requires adequate production and process controls to ensure consistent production of a PET drug that meets the applicable standards for identity, strength, quality, and purity [10].

7.3.9.1 Master Production and Control Record and Batch Production and Control Record

Section 212.50(b) requires PET drug production facilities to have master production and control records that document all steps in the PET drug production process [10]. Master production and control record (or master record) is a principal document that describes how a drug product is made. It is used to derive an individual batch record (i.e., batch production and control record) and specifies how each batch is to be produced. Since the master record is a compilation of detailed step-by-step instructions, it has been suggested, during the comment period for the final rule, to change the term “control record” to “control procedure” [7]. However, FDA did not accept it because “control record” is a standard term used in the production of drugs [7].

Section 212.50(c) requires that a batch production and control record (i.e., batch record) be created for each new batch of a PET drug [10]. The batch record provides complete traceability and accountability for production and control of each batch of drug product.

7.3.9.2 Radiochemical Yield Limit

Section 212.50(b)(1) through (b)(6) listed certain items of information that would be required in a master record [10]. One of these required information, as described in section 212.50(b)(6), is a statement of acceptance criteria on radiochemical yield [10]. In the 2005 proposed rule, section 212.50(b)(6) described this statement as acceptance criteria on radiochemical yield (i.e., the minimum percentage of yield beyond which investigation and corrective action are required) (emphasis added) [7].

During the comment period of the 2005 proposed rule, one comment suggested the deletion of this requirement [7]. The comment indicated that radiochemical yields could have significant variations even in a well-controlled PET manufacturing operation and that many factors could affect the yield [7]. The comment maintained that radiochemical yield is not a significant predictor of product quality [7]. According to the comment, discarding useful quality product and having to produce another lot based on arbitrary radiochemical yield increase radiation exposure [7].

FDA’s response to this comment was that although a low radiochemical yield would not necessarily require the rejection of a batch, low radiochemical yield can be a useful predictor of control of the production process for a PET drug [7]. FDA further articulated that a low radiochemical yield might result from a leak in the production system that introduces an extraneous substance, resulting in a contaminated product that might not be easily purified [7].

As such, FDA concluded that repeated occurrences of low radiochemical yield or a downward trend in radiochemical yield should prompt an investigation and, if necessary, corrective action [7]. Nevertheless, FDA did revise section 212.50(b)(6) to require a statement of action limits, rather than acceptance criteria, on radiochemical yield, because not meeting the radiochemical yield limits would require investigation and corrective action but not necessarily rejection of the batch [10]. This is one good example to illustrate the openness and willingness of FDA to work with the PET community during the establishment of PET drug CGMP regulations.

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Tags: Basic Science of PET Imaging

Oct 13, 2017 | Posted by admin in GENERAL RADIOLOGY | Comments Off

Radiology Key

Fastest Radiology Insight Engine

Regulatory Aspects of PET Radiopharmaceutical Production in the United States

7. Regulatory Aspects of PET Radiopharmaceutical Production in the United States

7.1 Introduction

7.2 PET Drug