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Guidance
PET Drug Products – Current Good
Manufacturing Practice (CGMP)
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be
identified with the docket number listed in the notice of availability that publishes in the Federal
Register.
For questions regarding this draft document contact Brenda Uratani, 301-827-8941.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2005
Compliance
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Guidance
PET Drug Products – Current Good
Manufacturing Practice (CGMP)
Additional copies are available from:
Office of Training and Communications
Division of Communications Management
Drug Information Branch, HFD-210
5600 Fishers Lane
Rockville, MD 20857
(Tel) 301-827-4573
(Internet) http://www.fda.gov/cder/guidance/index.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
September 2005
Compliance
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TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 2
III. PET DRUGS AND CGMP REQUIREMENTS ............................................................. 4
A. What is a PET Drug?..................................................................................................................... 4
B. What is CGMP? ............................................................................................................................. 5
C. Distinguishing Between PET Drug Production and the Practice of Pharmacy ....................... 5
IV. PERSONNEL RESOURCES ........................................................................................... 5
A. Regulatory Requirements ............................................................................................................. 5
B. Organization and Staffing ............................................................................................................. 6
C. Personnel Qualifications................................................................................................................ 6
V. QUALITY ASSURANCE ................................................................................................ 7
A. Regulatory Requirements ............................................................................................................. 7
B. The Activity and Responsibility of the Quality Assurance Function ........................................ 7
VI. FACILITIES AND EQUIPMENT .................................................................................. 8
A. Regulatory Requirements ............................................................................................................. 8
B. Facilities .......................................................................................................................................... 8
1. General ............................................................................................................................................ 8
2. Aseptic Processing Area .................................................................................................................. 9
C. Equipment .................................................................................................................................... 10
1. Production Equipment ................................................................................................................... 10
2. Quality Control Equipment ............................................................................................................ 13
VII. CONTROL OF COMPONENTS, CONTAINERS, AND CLOSURES .................... 15
A. Regulatory Requirements ........................................................................................................... 15
B. Control of Components, Containers, and Closures .................................................................. 15
1. Vendor Selection ............................................................................................................................ 15
2. Receipt of materials ....................................................................................................................... 15
3. Acceptance, release, and storage of materials .............................................................................. 16
4. Acceptance Testing ........................................................................................................................ 16
5. Handling of components, containers, and closures ....................................................................... 17
6. Records .......................................................................................................................................... 18
VIII. PRODUCTION AND PROCESS CONTROLS........................................................... 18
A. Regulatory Requirements ........................................................................................................... 18
B. Master Production and Control Records/Batch Production and Control Records ............... 18
C. Microbiological Control on Aseptic Processing and Sterilizing Filtration ............................. 21
1. Water .............................................................................................................................................. 21
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2. Glassware ...................................................................................................................................... 22
3. Transfer Lines ................................................................................................................................ 22
4. Resin columns ................................................................................................................................ 22
5. Components ................................................................................................................................... 22
6. Qualification for aseptic processing .............................................................................................. 22
7. Sterilizing filtration ........................................................................................................................ 23
8. Environmental and personnel monitoring ..................................................................................... 23
D. Process Verification and Computer Control ............................................................................. 23
1. Process verification under 212.50(f) (2) ........................................................................................ 23
2. Computer control ........................................................................................................................... 24
IX. LABORATORY CONTROLS ...................................................................................... 24
A. Regulatory Requirements ........................................................................................................... 24
B. Laboratory Controls .................................................................................................................... 25
X. STABILITY TESTING .................................................................................................. 26
A. Regulatory Requirements ........................................................................................................... 26
B. Guidance on Stability .................................................................................................................. 26
XI. FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA ... 27
A. Regulatory Requirements ........................................................................................................... 27
B. Finished Product Testing ............................................................................................................ 27
C. Microbiological Tests for Sterile PET Drugs ............................................................................ 27
D. Accepting and Releasing a Batch (Lot) ...................................................................................... 28
E. Conditional Final Release............................................................................................................ 29
F. Rejection and Reprocessing ........................................................................................................ 29
XII. LABELING AND PACKAGING .................................................................................. 29
A. Regulatory Requirements ........................................................................................................... 29
B. Recommendations on Labeling and Packaging......................................................................... 30
XIII. DISTRIBUTION ............................................................................................................. 30
A. Regulatory Requirements ........................................................................................................... 30
B. Recommendations ........................................................................................................................ 30
XIV. COMPLAINT HANDLING ........................................................................................... 31
A. Regulatory Requirements ........................................................................................................... 31
B. Recommendations ........................................................................................................................ 31
XV. RECORDS ....................................................................................................................... 31
A. Regulatory Requirements ........................................................................................................... 31
B. Recommendations ........................................................................................................................ 31
REFERENCES ............................................................................................................................ 33
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1
2 Guidance1
3
4 PET Drug Products –
5 Current Good Manufacturing Practice (CGMP)
6
7
8
9
10 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current
11 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to
12 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of
13 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA
14 staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call
15 the appropriate number listed on the title page of this guidance.
16
17
18
19 If you plan to submit comments on this draft guidance, to expedite FDA review of your comments, please:
20
21 Clearly explain each issue/concern and, when appropriate, include a proposed revision and the
22 rationale/justification for the proposed change.
23 Identify specific comments by line number(s); use the PDF version of the document, whenever possible.
24
25
26 I. INTRODUCTION
27
28 This draft guidance is intended to help PET drug producers better understand FDA’s thinking
29 concerning compliance with the proposed CGMP regulations. The guidance addresses
30 resources, procedures, and documentation for all PET drug production facilities, academic and
31 commercial. In some cases, the guidance provides practical examples of methods or procedures
32 that PET production facilities could use to comply with the proposed CGMP requirements. In
33 developing this draft guidance, FDA has taken into consideration relevant issues, concerns, and
34 questions raised at the public meetings held with professional associations, producers of PET
35 drug products, and other interested parties. A first draft version of this guidance was issued in
36 April 2002 in conjunction with revised preliminary draft proposed regulations.
37
38 FDA's guidance documents, including this guidance, should not be viewed as establishing legally
39 enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic
40 and should be viewed only as recommendations. The use of the word should in Agency
41 guidances means that something is suggested or recommended, but not required.
42
1
This guidance has been prepared by the PET Steering Committee in the Center for Drug Evaluation and Research
(CDER) at the Food and Drug Administration (FDA).
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43
44 II. BACKGROUND
45
46 Section 121(c)(1)(A) of the Food and Drug Administration Modernization Act of 1997 (the
47 Modernization Act) directed the Food and Drug Administration (FDA) to establish current good
48 manufacturing practice (CGMP) requirements for positron emission tomography (PET) drugs.
49 Concurrently with the issuance of this draft guidance, FDA is proposing such requirements under
50 21 CFR Part 212. In 1999, FDA published a preliminary draft of the proposed PET CGMP
51 regulations.2 The FDA received comments on the preliminary draft proposed regulations at a
52 public meeting on the subject on September 28, 1999. The FDA made changes in the working
53 draft in response to the public comments. In 2002, a revised preliminary draft of the CGMP
54 regulations3 was published in conjunction with a first draft of this guidance.4 The FDA received
55 comments on the preliminary proposed rule and the draft guidance at a public meeting on May
56 21, 2002, and in writing after the meeting and has taken all comments into consideration in
57 revising the proposed rule and this draft of the guidance. This second version of the draft
58 guidance provides more details for discussion purposes on acceptable approaches to complying
59 with the proposed regulations should they be published in final form.
60
61 As directed by Congress in the Modernization Act, to help in developing the proposed regulation
62 and this draft guidance, we closely examined the operations of many PET drug producers,
63 including not-for-profit institutions and commercial manufacturers. Since the Modernization Act
64 became law, significant changes have occurred in PET drug production in the United States. The
65 number of PET production facilities has increased, as has the number of facilities where PET
66 scans are performed. The business of PET drug production has changed as well. Historically,
67 PET drug products were produced by academicians and researchers at PET production facilities
68 located in universities and similar not-for-profit institutions. An academically oriented PET
69 production facility usually produces small amounts (a few doses per day) of a few PET drug
70 products for on-site patient use and a larger variety of PET drug products for clinical
71 investigation and academic research.
72
73 An increasing number of PET production facilities are now operated by for-profit corporate
74 entities that contract with academic and medical institutions (many of which have not-for-profit
75 status) to manage the production of PET drugs at those institutions. Most of these PET drug
76 products are administered on site, although often there is some distribution to other local or
77 regional hospitals. In addition, a growing number of independent PET production facilities are
78 not affiliated with any university or hospital. These for-profit, often contractually managed, and
79 independently operated PET production facilities distribute PET drug products to significantly
80 greater numbers of patients, sometimes hundreds of miles from the production site.
2
See FDA's Web site at www.fda.gov/cder/fdama/212draft.htm and notice of availability, 64 FR 51274; September
22, 1999.
3
See FDA’s Web site at www.fda.gov/cder/fdama/cgmpdpr.pdf and notice of availability, 67 FR 15344; April 1,
2002.
4
See FDA’s Web site at www.fda.gov/guidance/4259dft.htm and notice of availability, 67 FR 15404; April 1, 2002.
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81
82 Our review of PET drug production has lead to the conclusion that a PET drug producer’s status
83 as either a not-for-profit or for-profit entity has little bearing on the quality of PET drugs that it
84 produces and distributes for administration to patients, or on the methods, facilities, and controls
85 that a PET production facility needs to ensure product quality. Instead, production and CGMP
86 differences among PET drug producers are primarily a function of the size, scope, and
87 complexity of their production operations. We have also found that implementing certain
88 production standards and controls can ensure the production of quality PET drugs, regardless of
89 differences among the various PET production facilities. The Agency believes that the welfare
90 of a patient undergoing a PET scan should not depend on where a particular PET drug was
91 manufactured.
92
93 The proposed regulations on CGMP requirements contain what we believe are the minimum
94 standards for quality production of PET drugs at all types of PET production facilities. We have
95 designed the CGMP regulations to be sufficiently flexible to accommodate not-for-profit,
96 academically oriented institutions as well as commercial producers.
97
98 The proposed regulations also incorporate principles from the United States Pharmacopeia (USP)
99 general chapter on PET drug compounding. The USP contains standards that are of significant
100 regulatory importance for PET drugs. Currently, under section 501(a)(2)(C) of the Federal Food,
101 Drug, and Cosmetic Act (the Act), a compounded PET drug is adulterated unless it is produced
102 in compliance with USP compounding standards and official monographs for PET drugs.
103 Section 121(b) of the Modernization Act added this provision as a safety net during the time it
104 takes the Agency to develop the final regulations. Under section 121(b) however, section
105 501(a)(2)(C) of the Act will expire 2 years after the date on which we establish approval
106 procedures and CGMP requirements for PET drugs. At that time, compliance with the final
107 version of the regulation will be required. Nevertheless, the USP general chapter on PET drug
108 compounding largely reflects the consensus views of the PET community and FDA on how to
109 properly produce PET drug products. Consequently, we believe it is appropriate to incorporate
110 many of the principles and concepts in the USP general chapter into the proposed CGMP
111 requirements.
112
113 Proposed § 212.5(b) specifies the CGMP requirements for investigational, research, and
114 approved PET drugs. Proposed § 212.5(b)(1) states that the regulations in part 212 apply to all
115 PET drug products for human use, other than research and investigational PET drug products.
116 We believe that it is appropriate to have less detailed CGMP requirements for investigational and
117 research PET drugs to allow more flexibility during the development of these drugs. We also
118 recognize that many investigational PET drugs may not have commercial potential. Therefore,
119 proposed § 212.5(b)(2) states that the regulations in part 212 do not apply to investigational PET
120 drugs for human use produced under an investigational new drug application in accordance with
121 part 312 and research PET drugs that are produced with the approval of a Radioactive Drug
122 Research Committee (RDRC) in accordance with § 361.1.
123
124 Instead, proposed § 212.5(b)(2) states that, for investigational and research PET drugs, the
125 requirement under the Act to follow CGMP is met by producing drugs in accordance with
126 Chapter <823> of the 26th edition of the USP (2003). Chapter <823> sets forth requirements for
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127 PET drug production, including control of components, materials, and supplies; verification of
128 procedures; stability testing and expiration dating; quality control; and sterilization and sterility
129 assurance. Because most PET drug producers are very familiar with the requirements in Chapter
130 <823>, adopting the Chapter <823> provisions as the CGMP requirements for investigational
131 and research PET drugs should greatly facilitate producers’ compliance with those requirements.
132 Although the provisions in Chapter <823>, including those on documentation, are generally less
133 specific and explicit than the requirements in proposed part 212, we believe that they are
134 adequate to ensure that investigational and research PET drugs are produced safely under
135 appropriate conditions, consistent with section 501(a)(2)(B) of the Act.
136
137 Although we propose that USP Chapter <823>, rather than part 212, would constitute the
138 minimum CGMP requirements for investigational and research PET drugs, FDA would retain
139 the authority to inspect facilities where investigational and research PET drugs are produced to
140 verify compliance with Chapter <823>. However, as with inspection of investigational studies
141 of non-PET drugs, we generally would conduct inspections of facilities that produce
142 investigational or research PET drugs only on a for-cause basis (i.e., when we become aware of a
143 potential safety concern related to the production of an investigational or research drug).
144
145 PET drugs, other than investigational and research PET drugs, would have to meet the
146 requirements of proposed part 212. PET drug products that would have to be marketed under an
147 approved new drug application (NDA) or an approved abbreviated new drug application
148 (ANDA) would have to be produced in accordance with proposed part 212.
149
150
151 III. PET DRUGS AND CGMP REQUIREMENTS
152
153 A. What is a PET Drug?
154
155 PET is a medical imaging modality that requires the use of a unique type of radiopharmaceutical
156 drug. A PET drug exhibits spontaneous disintegration of unstable nuclei by the emission of
157 positrons (+). PET drugs are used to provide dual photon positron emission tomographic
158 images. The radionuclide is generally produced by a particle accelerator (e.g., a cyclotron) and
159 has a short half life. Currently, a batch, or lot, of a PET drug typically consists of one multiple-
160 dose vial containing the PET drug product in a sterile solution. A sample from the vial, which is
161 representative of all doses to be administered, is tested to verify that the batch or the lot conforms
162 to all established specifications.
163
164 A PET drug product is typically administered to patients within a few minutes to a few hours
165 following preparation. Because of the short half life of the radionuclide and the mode of
166 production, PET drug products have unique storage, shipping, and handling concerns. Under
167 Section 121 of the Modernization Act, PET producers must comply with the standards in the
168 USP General Chapter <823> Radiopharmaceuticals for Positron Emission Tomography-
169 Compounding, until FDA establishes approval procedures and CGMPs for PET drug products.
170
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171 B. What is CGMP?
172
173 Current good manufacturing practice (CGMP) is a minimum standard that ensures that a drug
174 meets the requirements of safety and has the identity strength, quality, and purity characteristics
175 it is represented to possess. The Agency is proposing CGMP regulations that would require
176 manufacturers of PET drugs to follow certain CGMP requirements. CGMP is demonstrated
177 through written documentation of procedures and practices. The documents and practices may
178 be similar or identical to documents and practices requested by other oversight bodies (e.g.,
179 Nuclear Regulatory Commission and state and local agencies). Documents produced for others,
180 where appropriate, can be used to provide the documentation of compliance with CGMP
181 requirements. However, because of institutional, local, or state differences, some of these
182 documents may not have sufficient overlap to address the issues in this guidance. Therefore, to
183 ensure uniformity for all patients and human subjects, where overlap does not exist, we
184 recommend that PET producers develop supplemental documentation.
185
186 C. Distinguishing Between PET Drug Production and the Practice of Pharmacy
187
188 FDA regulates the production of PET drug products. Section 121 of the Modernization Act
189 directs FDA to establish appropriate approval procedures for PET drugs pursuant to section 505
190 of the Act as well as appropriate CGMP requirements. In the course of developing these
191 approval procedures and CGMP requirements, a question has been raised concerning how to
192 distinguish PET drug production from the practice of pharmacy (regulation of which FDA has
193 traditionally deferred to State and local authorities).
194
195 FDA has determined that the production of a PET drug product includes all operations to the
196 point of final release of a finished dosage form, and these activities would be subject to CGMP.
197 A PET drug product may be released to a hospital, institution, imaging facility, nuclear
198 pharmacy (e.g., pharmacy bulk packages for use in accordance to USP <1> Injections), or other
199 entity or part of an entity. After a finally released PET drug product is received by the receiving
200 facility, FDA generally regards subsequent dispensing of a patient-specific dose and use of the
201 drug product to be part of the practice of medicine and pharmacy. FDA generally will defer to
202 State and local authorities concerning regulation of these activities. In general, a routine FDA
203 inspection to ensure compliance with CGMP would focus on activities up to and including the
204 point of final release of a PET drug product.
205
206 In the following sections, the draft guidance introduces each section by identifying the relevant
207 requirements from the proposed regulations. The section then provides more detailed current
208 thinking. Certain CGMP requirements in the proposed regulations are self-explanatory and have
209 not been further clarified in this guidance.
210
211
212 IV. PERSONNEL RESOURCES
213
214 A. Regulatory Requirements
215
216 Proposed 21 CFR 212.10 would require a PET production facility to have a sufficient number of
217 personnel with the necessary education, background, training, and experience to enable them to
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218 perform their assigned functions correctly. Each center also would have to provide adequate
219 resources, including equipment and facilities, to enable their personnel to perform their
220 functions.
221
222 The following section of the guidance addresses personnel. Guidance on resources (facilities and
223 equipment) is provided in Section VI.
224
225 B. Organization and Staffing
226 We recommend that staffing levels correspond to the size and complexity of the operation of the
227 PET production facility and enable a PET production facility to satisfactorily complete all
228 intended tasks in a timely manner before administration of a finished PET drug to humans. We
229 recommend that the responsibilities and assigned duties of all staff be clearly identified in written
230 policies.
231
232 For a PET production facility that typically produces one or two batches of a product daily, it
233 may be adequate to employ one or two persons to accomplish all production and quality control
234 functions. We recommend the PET facility demonstrate that the production and quality control
235 functions can be consistently accomplished in a timely and appropriate manner before
236 administration of a drug to humans. One individual can be designated to perform the production
237 as well as quality control functions, provided he or she is highly qualified in the performance of
238 all such functions (i.e., has a degree, documented training, and significant experience in the
239 technical area).
240
241 Under current CGMP regulations in 21 CFR Part 211, FDA normally requires second-person
242 checks at various stages of production as well as test verification. In a PET production facility
243 with only one person assigned to perform production and quality control tasks, it is
244 recommended that that person recheck his or her own work. Self-checks involve the
245 confirmation of the operator’s own action and would be documented. Examples of self-check
246 activities include reviewing batch records (e.g., review the batch record to ensure that all
247 finished-product test results are within the acceptance criteria) before release of the drug product
248 for distribution and verifying calculations in analytical tests.
249
250 At a PET production facility that produces multiple PET drugs, we recommend the staffing level
251 be adequate to perform all quality assurance functions and to prevent mix-ups and cross
252 contamination.
253
254 C. Personnel Qualifications
255
256 As mentioned above, each person performing an activity or a function in the production and
257 quality control of a PET drug product would have to have the appropriate education, training,
258 and experience related to that function and should be trained in CGMP relevant to their assigned
259 tasks. We recommend that PET production facilities have adequate ongoing programs or plans
260 in place for training employees in new procedures and operations and in the areas where
261 deficiencies have occurred.
262
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263 We recommend PET production facilities maintain an updated file (e.g., curriculum vitae, copies
264 of degree certificates, certificate of training) for each employee.
265
266
267 V. QUALITY ASSURANCE
268
269 A. Regulatory Requirements
270
271 Proposed 21 CFR 212.20 would require PET production facilities to have a quality assurance
272 function. Under the proposed regulations, the following activities are defined as the
273 responsibilities of the quality assurance function:
274
275 Oversee production operations to ensure that PET drug products have adequately
276 defined identity, strength, quality, and purity
277
278 Examine and approve or reject components, containers, closures, in-process
279 materials, packaging materials, and labeling used in the production of PET drug
280 products to ensure that all these meet their current specifications
281
282 Examine any procedure affecting production, testing, and specifications
283
284 Review production records for accuracy and completeness
285
286 Ensure that all errors are investigated and corrective action is taken
287
288 B. The Activity and Responsibility of the Quality Assurance Function
289
290 The quality assurance function in a PET production facility typically consists of execution and
291 oversight activities.
292
293 We recommend that the execution of quality assurance functions include the following:
294
295 Examine and evaluate each lot of incoming material before use to ensure that the material
296 meets its established specifications
297 Review the production batch records and laboratory control records for accuracy,
298 completeness, and conformance to established specifications before authorizing the final
299 release or rejection of a batch or lot PET drug product
300
301 We recommend that the oversight of quality assurance functions include the following:
302
303 Approve procedures, specifications, process, and methods
304 Ensure that personnel are properly trained and qualified, as appropriate
305 Ensure that PET drugs have adequately defined identity, strength, quality and purity
306 Investigate errors and ensure that appropriate corrective action is taken to prevent their
307 recurrence
308 Conduct periodic audits to monitor compliance with established procedures and practices
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309
310 For PET production facilities currently producing one or two PET drugs, employees located at
311 the facility can perform both the daily execution and oversight functions.
312
313 On the other hand, a commercial PET firm managing multiple production facilities may choose
314 to have an entity located outside the PET production facility help to achieve the objective of
315 manufacturing oversight and more efficient management. For example, a corporate quality
316 assurance/quality control department, or consultants, can provide oversight.
317
318
319 VI. FACILITIES AND EQUIPMENT
320
321 A. Regulatory Requirements
322
323 Proposed 21 CFR 212.30(a) would require that a PET production facility have adequate facilities
324 to ensure the orderly handling of materials and equipment, the prevention of mix-ups, and the
325 prevention of contamination of equipment or product by substances, personnel, or environmental
326 conditions.
327
328 Proposed 21 CFR 212.30(b) and (c) would require that all equipment that would reasonably be
329 expected to adversely affect the strength, quality, or purity of a PET drug, or give erroneous or
330 invalid test results when improperly used or maintained, is clean, suitable for its intended
331 purposes, properly installed, maintained, and capable of repeatedly producing valid results.
332 Equipment would have to be constructed so that surfaces that contact components, in-process
333 materials, or drug products are not reactive, additive, or absorptive so as to alter the quality of the
334 PET drug product.
335
336 B. Facilities
337
338 1. General
339
340 The design of the PET drug production facility should promote orderly operations during
341 the production process and protect the product from contamination originating from
342 personnel and surrounding areas. To achieve this, a facility should contain adequate
343 work areas suitable for the intended tasks (e.g., area for analytical testing, aseptic
344 manipulation, chemical production, radiochemical production, and component storage)
345 and to allow completion of all production-related tasks in an orderly manner. Potential
346 sources of contamination include particulate matter and chemical and microbiological
347 materials.
348
349 Phases of production with the potential for microbiological contamination should be
350 performed under environmental conditions that minimize the possibility of such
351 contamination (e.g., in a laminar airflow workbench (LAFW), or barrier isolator system).
352
353 The placement of equipment and materials should be carefully evaluated to promote
354 efficient operation and eliminate errors, mix-ups, and cross-contamination. All
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355 equipment used in production (e.g., particle accelerator, synthesis units, or other
356 specialized equipment) should be appropriately located and housed (e.g., with shielding)
357 so that all the work areas during the normal course of production are easily accessible.
358
359 We recommend that related work areas be organized and proximally located so as to
360 promote efficient operation and eliminate the potential for errors in the production and
361 control operations. Access to work areas, production and testing equipment, components,
362 containers and closures, and the PET drug products, should be restricted to authorized
363 personnel.
364
365 In most PET production facilities, the same area or room can be used for multiple
366 purposes. For example, the production (e.g., radiochemical synthesis), laboratory
367 operation (e.g., release testing), and storage of approved components, including
368 containers and closures, can be located in the same room. Components that are approved
369 for use as well as those that are under quarantine can be stored in the same area or on a
370 different shelf in a cabinet, provided each lot is properly labeled as to its status and
371 contents and organized in a manner that avoids mix-up or unintended use. Rejected
372 components, containers and closures, and other materials should be kept separate from
373 quarantined or approved materials.
374
375 As the complexity in a PET production facility increases (production of multiple PET
376 drug products), it is important to develop the appropriate level of control required to
377 prevent mix-ups and contamination). Separate and well-defined areas or rooms may be
378 warranted for each independent function of the operation, such as production, testing, and
379 storage of components. It is also important to consider what impact a greater number of
380 personnel and activities could have on the aseptic processing portion of the process.
381
382 2. Aseptic Processing Area
383
384 An aseptic work area should be suitable for the assembly of the aseptic components
385 required for the preparation of a sterile PET drug product. We recommend that air
386 quality in the aseptic processing area be controlled to limit the presence of
387 microorganisms and particulate matter. Critical activities in the production and testing of
388 a PET drug product that expose the PET drug product or the sterile surface of the
389 container/closure system to the environment should be conducted within an aseptic
390 workstation (e.g., a LAFW or barrier isolator). Examples of such activities include the
391 aseptic assembly of sterile components (syringe, needle, filter and vial) for sterile
392 filtration of the PET drug product, and sterility testing of the finished PET drug product.
393 We recommend that the following precautions be taken to help maintain the appropriate
394 air quality of the aseptic workstation:
395
396 The aseptic workstation is sanitized before each operation.
397
398 Items within a laminar airflow aseptic workstation are kept to a minimum and
399 not interrupt the airflow.
400
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401 Operators wear clean lab coats and sanitized gloves when conducting an
402 aseptic manipulation within the aseptic workstation.
403
404 Gloved hands are frequently sanitized or changed when working in the aseptic
405 workstation. Gloves are examined for damage (tears or holes) and replaced if
406 they are compromised.
407
408 The surface of nonsterile items (e.g., test tube rack, and the overwrap for
409 sterile syringes, and filters) are sanitized and wiped with an appropriate
410 disinfectant (e.g., sterile 70 percent isopropyl alcohol) before being placed in
411 the aseptic workstation.
412
413 We recommend that conditions in the room where aseptic manipulations are conducted
414 not present a challenge to the operating capability of the aseptic workstation. For
415 example, the room should not be carpeted nor have overhanging pipes or hanging light
416 fixtures. All areas of the production and processing room should be easily accessible for
417 cleaning. Surfaces of the walls, floors, and ceilings in the aseptic work areas should be
418 easily cleaned. Cleaning should be performed frequently to ensure consistent control of
419 the environmental quality. In addition, the aseptic processing area (e.g., LAFW) should
420 be situated in the section of the room with the lowest traffic and lowest activity. Cartons
421 and boxes should not be stored or opened in the production area to minimize ingress of
422 dust and particulate into the aseptic work area.
423
424 C. Equipment
425
426 1. Production Equipment
427
428 Equipment used in the production, processing, or packaging of a PET drug product would
429 have to be appropriate for the performance of its intended function and not contaminate
430 the product. We recommend that each piece of equipment be suitably located to facilitate
431 its use, cleaning, and maintenance. We also recommend that each PET production
432 facility establish and follow written procedures that address the following issues, where
433 applicable:
434
435 Assignment of responsibility and frequency for cleaning and maintenance of
436 equipment
437
438 Description of cleaning and maintenance procedures in sufficient detail to include
439 disassembly and reassembly of equipment
440
441 Protection of clean equipment from contamination prior to use
442
443 Inspection of equipment and calibration, if indicated, prior to use
444
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445 We recommend that each PET production facility select suitable cleaning agents and
446 cleaning techniques and ensure that their cleaning operations not contaminate the drug
447 product.
448
449 We recommend that newly installed equipment be qualified before first use to verify that
450 it was installed correctly and is capable of operating as intended. Normally, the
451 equipment vendor verifies that the equipment is installed correctly (installation
452 qualification (IQ)) and operates according to specifications (operational qualification
453 (OQ)). Before the equipment is used for production, personnel in the PET production
454 facility should verify that the equipment, when operated under actual production
455 parameters or selected method, produces consistent results within established
456 specifications (performance qualification (PQ)).
457
458 We recommend developing a preventive maintenance schedule with sufficient frequency
459 to ensure the correct performance of the equipment. Where needed, calibration should be
460 performed prior to the use of the equipment for the intended task. We recommend
461 facilities follow calibration checks recommended by equipment vendors unless the PET
462 production facility has determined that more frequent calibrations are appropriate. Major
463 repairs or upgrades in equipment may warrant requalification. We recommend not using
464 malfunctioning or incorrectly operating equipment until repairs or corrective action have
465 been made and the equipment has been found to operate correctly. All qualification,
466 calibration, and maintenance activities should be properly documented, including the date
467 of such performance and who performed them.
468
469 FDA recognizes that, after they become subject to the requirements of the final CGMP
470 regulations, a number of PET production facilities may continue to use existing
471 equipment. If they do, PET production facilities would have to make sure that the
472 existing equipment is working properly and is being maintained and calibrated according
473 to written procedures.
474
475 We recommend that PET production facilities establish procedures to check the correct
476 functioning of the equipment that is developed in-house. Representative equipment is
477 discussed below to illustrate how it might be controlled in a PET production facility.
478
479 a. Automated radiochemical synthesis apparatus
480
481 The apparatus enables the PET production facility to carry out the production
482 process reliably and reproducibly. The provisions contained in the USP General
483 Chapter <1015> Automated Radiochemical Synthesis Apparatus can help ensure
484 proper functioning of a synthesis apparatus.
485
486 Prior to the production of a PET drug product each day, we recommend that the
487 operator should conduct a performance check to ensure the following:
488
489 The synthesis apparatus has been cleaned/flushed according to the established
490 procedures.
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491
492 All appropriate tubing, reaction vessels, purification columns or cartridges,
493 and other materials have been replaced and connected as required.
494
495 The monitoring and or recording devices (e.g., temperature, pressure, flow
496 rate) are functioning properly.
497
498 When the process is under microprocessor control, the operator ensures that
499 the system is functioning and recording correctly and that the correct program
500 and operational parameters are used.
501
502 b. Aseptic Workstation
503
504 The aseptic workstation should provide an appropriate environment for aseptic
505 procedures. Examples of workstations include a laminar air flow workbench
506 (LAFW) or barrier isolator system. We recommend that an integrity test be
507 conducted at installation (including after each change of the high-efficiency
508 particulate air (HEPA) filter) to ensure proper performance. We recommend that
509 certification (integrity testing of the HEPA filter) of the aseptic workstation be
510 performed when the unit is initially installed and at least every 6 months
511 thereafter to ensure the desired air quality. More frequent testing may be
512 appropriate if air quality is found to be unacceptable, for example, as part of an
513 investigation into a finding of sterility failure in a PET drug, or if leakage or
514 decrease in optimal airflow is found.
515
516 We recommend that a qualified operator change the prefilters in the aseptic
517 workstation periodically in accordance with written procedures and preventive
518 maintenance schedules. Some laminar flow hoods are equipped with easily
519 readable static pressure gauges that indicate when the pressure builds up behind
520 the filter because of the clogging of the filter. We recommend that the filter be
521 changed when clogging is detected.
522
523 We recommend laminar airflow velocities be monitored periodically at the work
524 surface as well as at the HEPA filter face to ensure adequate uniformity of flow
525 throughout the critical area. We recommend that operators be trained on the
526 importance of minimizing objects and equipment within the critical area so
527 laminar airflow is not disrupted. We recommend that microbiological monitoring
528 (e.g., using settle plate) in the LAFW be conducted during sterility testing and
529 critical aseptic manipulation.
530
531 c. Electronic or analytical weight balance
532
533 We recommend that written procedures, if not already available, be developed,
534 describing the proper use of the balance, assessment of accuracy, and a schedule
535 for calibration. We recommend that performance be checked by weighing two or
536 more standard weights on each day of use. We recommend that the calibrated
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537 weights used for assessing daily performance bracket the range of the weights
538 being measured. We also recommend that the balance be fully calibrated
539 periodically, or upon failure to meet daily performance checks (see USP <41>
540 Weights and Balances).
541
542 d. Dry-heat ovens
543
544 If glassware and heat-stable materials are depyrogenated and sterilized on-site, we
545 recommend that the PET production facility demonstrate and document that the
546 depyrogenation cycle will achieve at least a 3-log reduction of an endotoxin
547 challenge, as measured by a bacterial endotoxins test. A suitable challenge study
548 usually involves random placement of endotoxin indicators in a representative
549 oven load of materials. Suitable endotoxin indicators include glass vials that
550 contain 1,000 to 10,000 Endotoxin Units.
551
552 e. High performance liquid chromatograph (HPLC)
553
554 When an HPLC is used for purification of a PET drug, we recommend the
555 operator ensure that the system is working properly and there is no bleeding of
556 unintended materials (e.g., column material) into the mobile phase.
557
558 f. Temperature recording device
559
560 We recommend that the temperature and humidity (where appropriate) of the dry
561 heat oven, refrigerator, freezer, and incubator be recorded on each workday when
562 in use. Automated recording devices are recommended for ease of documentation
563 and for recording any deviations.
564
565 2. Quality Control Equipment
566
567 We recommend that PET production facility have the appropriate equipment to
568 adequately perform each quality control function that it intends to perform.
569 Representative quality control equipment can include:
570
571 a. Gas chromatograph (GC)
572
573 Prior to each day of its use, the analyst should make sure that the GC system is
574 functioning correctly by conducting system suitability testing. At least one
575 injection of the standard preparation (reference standard or internal standard)
576 should be done before the injection of test samples (see USP General Chapter
577 <621> Chromatography).
578
579 b. High performance liquid chromatograph (HPLC)
580
581 We recommend that the HPLC system have detectors suitable for the intended
582 purpose and be of sufficient sensitivity. Prior to each day of its use, the analyst
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583 should make sure that the HPLC system is functioning correctly by conducting
584 system suitability testing (see USP General Chapter <621> Chromatography and
585 FDA reviewer guidance, Reviewer Guidance Validation of Chromatographic
586 Methods (November 1994). At least one injection of the standard preparation
587 (reference standard or internal standard) should be done before the injection of
588 test samples.
589
590 c. Dose calibrator
591
592 We recommend a dose calibrator be used to measure the radioactivity of PET
593 drug products. Accuracy and linearity should be assessed at installation and at
594 appropriate intervals thereafter. The instrument should be calibrated in
595 accordance with nationally recognized standards or the manufacturer's
596 instructions. System suitability testing should include a constancy check with a
597 suitable high-energy radionuclide standard source.
598
599 d. Radiochromatogram scanner
600
601 We recommend that a radiochromatogram scanner (or equivalent equipment that
602 provides a radiochromatogram) be used to measure radioactivity distribution in
603 the developed thin layer chromatography plate (e.g., instant thin-layer
604 chromatography (ITLC), paper or plate). The scanner should have sufficient
605 sensitivity and spatial resolution for the intended discriminatory and quantitative
606 objective. Manufacturer recommended checks and maintenance should be
607 performed on the radiochromatogram scanner (see USP General Chapter <821>
608 Radioactivity).
609
610 e. Multichannel analyzer (MCA)
611
612 A multichannel spectrometer coupled to a calibrated sodium iodide scintillation
613 detector (or preferably with the higher resolution germanium lithium
614 compensated, Ge (Li) detector) can be useful to determine radionuclidic purity
615 and to identify the radionuclide. The overall system should have sufficient
616 sensitivity and resolution for the intended purpose (see USP General Chapter
617 <821> Radioactivity). Adequate calibration using National Institute of Standards
618 and Technology (NIST) traceable standards and preventive maintenance should
619 be performed at intervals specified in a written procedure and as recommended by
620 the equipment manufacturer. More frequent intervals should be used if problems
621 in the operation of the MCA are encountered.
622
623
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624 VII. CONTROL OF COMPONENTS, CONTAINERS, AND CLOSURES
625
626 A. Regulatory Requirements
627
628 Proposed 21 CFR 212.40(a) and (b) would require PET production facilities to establish,
629 maintain, and follow written procedures for the control of components, containers, and closures.
630 There would have to be appropriate written specifications for components, containers, and
631 closures.
632
633 Proposed 21 CFR 212.40(c) would establish the minimum standards for controlling components,
634 containers, and closures from receipt to consumption.
635
636 Proposed 21 CFR 212.40(d) would require that components, containers, and closures be handled
637 and stored in a manner that prevents contamination, mix-ups, and deterioration.
638
639 Proposed 21 CFR 212.40(e) would require that PET production facilities keep a record of each
640 shipment of each lot of components, containers, and closures that they receive.
641
642 B. Control of Components, Containers, and Closures
643
644 The written procedures would have to specify how each material (components, containers, and
645 closures) will be selected and controlled in PET production facilities. Procedures should cover
646 the life cycle of a material, from time of receipt to ultimate consumption. The process for
647 procurement and use of materials should include the following elements, where applicable:
648
649 1. Vendor Selection
650
651 We recommend only qualified vendors be used. A vendor is qualified when there is
652 evidence to support its ability to supply a material that consistently meets all quality
653 specifications. We also recommend that PET production facilities ask the vendor to
654 report any major changes in the manufacture of an item. It is preferable to have more
655 than one qualified vendor for a component. A vendor should be replaced if there is an
656 indication that it is supplying unsatisfactory materials.
657
658 2. Receipt of materials
659
660 We recommend that each lot of material be checked upon receipt to determine that
661 the order was filled correctly and arrived in good condition. Each lot should be
662 logged in and assigned a new identification code number. The code number would be
663 used in the disposition of that lot. Sufficient information should be documented to
664 enable the PET production facility to have full traceability of each lot. We
665 recommend that, before release for use, incoming materials be segregated and placed
666 under quarantine and labeled as Quarantined. A lot can then be inspected, sampled,
667 and tested, if applicable.
668
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669 3. Acceptance, release, and storage of materials
670
671 Analytical results in the certificate of analysis (COA) for each lot of incoming
672 material should be inspected against the PET production facility's current
673 specification sheet to ensure that acceptance criteria are met. Where appropriate,
674 certain components described below (see Acceptance Testing) can be tested to
675 confirm their identity before they are accepted and released for use in the production
676 of a PET drug product.
677
678 Materials that meet a PET production facility’s specifications can be approved and
679 released for use. Such release should be recorded and the examination and testing
680 data maintained. It may be helpful to have a component logbook to record
681 information such as receipt date, quantity of the shipment, supplier's name, lot
682 number, expiration date, results of any testing performed, and person responsible for
683 release.5 Approved materials can be labeled Approved with an identifying code
684 number, storage conditions, and expiration date. We recommend that materials be
685 stored under the proper storage conditions and in an area designated for approved
686 materials. If a lot is rejected, we recommend it be labeled Rejected, segregated,
687 properly disposed of, and each of these actions be documented.
688
689 We recommend that items be stored under the conditions recommended by the vendor
690 (e.g., temperature and humidity). Moisture sensitive materials should be stored in
691 desiccated devices in sealed containers. There should be an expiration date for each
692 item. We recommend that PET production facilities have a policy that guides the
693 expiration dating of items, by category. Vendor assigned expiration dates could be
694 used unless the in-house date is sooner.
695
696 4. Acceptance Testing
697
698 a. Reagents, solvents, gases, purification columns, and other auxiliary
699 materials
700
701 We recommend that PET production facilities have procedures in place to ensure
702 that only materials meeting applicable specifications from approved reliable
703 sources are used. The COA and container label for each lot of each shipment of
704 incoming materials should be examined to ensure that all specifications are met.
705
706
707 b. Components that yield an active pharmaceutical ingredient (API) and
708 inactive ingredients
709
710 Under proposed § 212.40(c)(1)(i), for the production of PET drugs where
711 finished-product testing ensures that the correct components have been used (e.g.,
712 production of F18 FDG) PET producers may rely on the certificate of analysis
713 (COA) from the suppliers. Analytical results in the COA for each lot of
5
A sample format for record keeping of incoming components is available at www.fda.gov/cder/regulatory/pet.
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714 component would have to be examined and compared against the PET production
715 facility's current specifications to ensure that acceptance criteria are met. We
716 recommend that PET producers have scientific rationale and supporting data to
717 justify why identity testing is not needed.
718
719 Under proposed § 212.40(c)(1)(ii), for the production of a PET drug where the
720 finished-product testing does not ensure that the correct components have been
721 used, identity testing would have to be performed. When specific identity tests
722 exist, we recommend that they be used.
723
724 The inactive ingredients in PET drugs usually consist of a diluent, a stabilizer,
725 and/or a preservative. Under proposed § 212.40(c)(1)(ii), if a product that is
726 marketed as a finished drug product intended for intravenous administration is
727 used as an inactive ingredient, it would not be necessary to perform a specific
728 identity test for that ingredient. Proposed § 212.40(c)(1)(ii) also states that if an
729 inactive ingredient (e.g., 0.9 percent sodium chloride solution) was prepared on
730 site, an identity test on the components used to make the inactive ingredient
731 would have to be performed before it was released for use.
732
733 c. Commercially available ready-to-use sterile, pyrogen-free, sealed
734 container/closure systems for injections, syringes, transfer sets, and filters
735 used in aseptic process
736
737 We recommend that PET production facilities use reliable sources for these items.
738 Most PET production facilities use sterile and depyrogenated containers (sealed
739 vials with stoppers and crimps) that are commercially available (510K product).
740 Under proposed § 212.40(c)(2), a visual identification of each lot of containers
741 and closures would have to be conducted. We recommend that a COA showing
742 conformance with the established specifications be obtained before accepting a lot
743 of the container/closure system. We recommend that the container/closure system
744 be properly stored under appropriate environmental conditions (e.g., correct
745 temperature, humidity, and sterility).
746
747 If the sterilization and depyrogenation of the container/closure are performed on
748 site, we recommend that the efficacy of each process be demonstrated. We
749 recommend that established procedures be shown to be reproducible and used in
750 such cases.
751
752 5. Handling of components, containers, and closures
753
754 When a lot of material has met all acceptance criteria, the material can be labeled
755 Approved. Under proposed § 212.40(d), approved materials would have to be handled
756 and stored in a manner that prevents degradation or contamination. Unacceptable
757 materials should be promptly rejected, identified, and segregated to prevent their use
758 prior to appropriate disposal.
759
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760 6. Records
761
762 Under proposed § 212.40(e), records would have to be kept for each shipment of each lot
763 of components, containers, and closures that the PET production facility receives,
764 including results of any testing performed.
765
766
767 VIII. PRODUCTION AND PROCESS CONTROLS
768
769 A. Regulatory Requirements
770
771 Proposed 21 CFR 212.50 would require adequate production and process controls to ensure
772 consistent production of a PET drug product that meets the applicable standards for identity,
773 strength, quality, and purity. Under proposed § 212.50(a), PET production facilities would be
774 required to have written production and process control procedures to ensure and document that
775 all key process parameters are controlled and that any deviations from the procedures are
776 justified.
777
778 Proposed § 212.50(b) would require PET production facilities to have master production and
779 control records that document all steps in the PET drug production process. Proposed §
780 212.50(b) also specifies what would be required in the master production and control records.
781
782 Proposed § 212.50(c) would require that a batch production record be generated from the master
783 production record template for each new batch of a PET drug product. Each batch of a PET drug
784 product would have to be uniquely identified, and its batch record would have to include each
785 major production step, weights, and identification codes of components used, dates of production
786 steps, identification of major equipment, testing results, labeling, initials or signatures of persons
787 performing or checking each significant step in the operation, and results of any investigations
788 conducted.
789
790 Proposed § 212.50(f) would require that when the results of the production of an entire batch of a
791 PET drug product are not fully verified through finished-product testing or when only the initial
792 sub-batch in a series is tested, the PET drug producer would have to demonstrate that the process
793 for producing the PET drug product is reproducible and is capable of producing a drug product
794 that meets the predetermined acceptance criteria. Process verification activities and results
795 would have to be documented. Documentation would have to include the date and signature of
796 the individual(s) performing the verification, the monitoring and control methods and data, and
797 the major equipment qualified.
798
799 B. Master Production and Control Records/Batch Production and Control
800 Records
801
802 Master production and control records are the principal documents describing how a product is
803 made. The master production record serves as a template for all batch records, documenting how
804 each batch will be produced. The designated individual should approve the master production
805 and control records, or any changes to them, before they are implemented.
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806
807 We recommend that the master production and control records present logical, chronological
808 step-by-step instructions that document how the PET drug is to be produced.6 Production should
809 be discussed under headings, where applicable, such as accelerator operation, radiochemical
810 synthesis, purification steps, and formulation of the finished product. We recommend the entire
811 production process be pre-established and fully described in the master production and control
812 record. The SOP in performing a specific step can be referenced. The master production and
813 control records would include specifications for each critical step. Critical steps include the
814 process step, process condition, or other relevant parameters that are controlled within
815 predetermined criteria to ensure that the API meets its specification. Under proposed §
816 212.50(b), the master production and control records should include the following:
817
818 The name and strength of the PET drug product in MBq/ml or mCi/ml (strength should
819 be measured at a calibration time immediately after production)
820 If applicable, the name and radioactivity or other measurement of each API as well as any
821 inactive ingredient (e.g., diluent, stabilizer, or preservative) per batch or per unit of
822 weight or measure of the drug product and a statement of the total radioactivity or
823 measurement of any dosage unit
824 A complete list of components designated by names and codes (component code)
825 sufficiently specific to indicate any special quality characteristic
826 Identification of all major equipment used in production of the drug product
827 An accurate statement of the weight or measurement of each component (e.g., batch
828 formula). In the process of producing FDG F 18, for example, multiple components are
829 weighed or measured by volume. The radioactive component should be recorded in
830 terms of radioactivity units.
831 A statement of the action limit on radiochemical yield (i.e., the minimum percentage of
832 yield beyond which investigation and corrective action would be required)
833 Complete instructions (or references) for production, control, and testing of the PET
834 drug. The synthesis of certain PET drugs, such as FDG F 18, involves multiple steps
835 including drying, exposure to organic solvents, heating, pH adjustments, passage through
836 purification media, and sterilizing filtration. We recommend there be a description of all
837 in-process steps and their controls so that the operator can confirm that all steps are
838 completed within specified conditions, where feasible. Controls for movement of liquids
839 or gases should also be provided. For automated radiochemical synthesis equipment, it
840 may be sufficient to reference the equipment manufacturer’s manual that contains a full
841 description of the automated production steps and controls.
842 A description of the PET drug product containers, closures, and packaging materials,
843 including a specimen or copy of each label and all other labeling.
6
The draft guidance for industry PET Drug Applications — Content and Format for NDAs and ANDAs, which was
issued in March 2000, will be available soon in final. Also, a sample format for a batch production and control
record is available at www.fda.gov/cder/regulatory/pet.
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844
845 Proposed § 212.1 defines a batch of a PET drug product as a specific quantity of PET drug
846 product intended to have uniform character and quality. In the case of FDG F 18, a batch
847 normally consists of the PET drug product produced in a single synthesis and purification
848 operation. For ammonia N 13, a batch normally consists of multiple sub-batches having uniform
849 character and quality, that are produced according to a single preparation order during one
850 succession of multiple irradiation using a synthesis and/or purification operation.
851
852 Proposed § 212.50(c) would require the use of a batch record to document the production and
853 testing of each batch. The batch records provide complete traceability and accountability for
854 production and control of each batch. We recommend that information in the batch record
855 (paper, or electronic copy) accurately reflect the information contained in the master production
856 and control records. The control records may be cross-referenced and not be included as part of
857 the batch record. The batch record is therefore a simplified version of the master production and
858 control records that should contain the information needed for a documented history of the batch
859 produced, including:
860
861 Documentation of the execution of each critical production step (e.g., timed events
862 occurred within specifications, heating steps occurred at the specified temperature, and
863 ingredients were properly transferred into the reaction vessel) where feasible, taking
864 radiation exposure concern into consideration. For automated radiochemical synthesis
865 unit, the printout at the end of synthesis documenting the execution of the production
866 steps and controls could be used for the chemical synthesis portion of the batch record.
867
868 A compilation of tests and printouts that led to acceptance of the final product.
869
870 Under proposed § 212.50(c), information specific to batch production and control records would
871 include the following:
872
873 Name and strength of the PET drug product
874
875 Unique identifier or number for each batch (an identifier or number also can be provided
876 for each sub-batch produced)
877
878 The name and radioactivity or other measure of each active pharmaceutical ingredient
879 and each inactive ingredient per batch or per unit of radioactivity or other measurement
880 of the drug product;
881
882 Date and time of production steps
883
884 Identification of major pieces of equipment where identical equipment in the facility can
885 be used
886
887 Actual weights (or measures) and identification codes of components used
888
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889 Labeling (a description of the finished drug product container label and the outer
890 container label should be included)
891
892 Initials or signatures of the person(s) performing and checking each significant step of the
893 operation
894
895 Results of any investigations conducted (this should include documentation of any
896 deviations and follow-up investigations). Reference to the deviation and investigation
897 reports can be indicated if stored separately.
898
899 Results of testing
900
901 Batch records should include documentation that each significant step in the production was
902 accomplished. When entries are made in batch records, an entry should be made directly after
903 performing the activity (in the order performed) and would have to identify the person (signature
904 or initials) making the entry. Corrections to paper entries would be dated and signed or initialed,
905 leaving the original entry still readable. We recommend that each batch record be reviewed and
906 approved for final release (signature/initials and date). For requirements and information on
907 electronic records and signatures, interested persons should refer to Part 11 (21 CFR Part 11,
908 Electronic Records; Electronic Signatures) and the Agency guidance on the scope and
909 application of Part 11, Electronic Records; Electronic Signatures.7
910
911 C. Microbiological Control on Aseptic Processing and Sterilizing Filtration
912
913 Most PET drug products are designed for parenteral administration and are produced by aseptic
914 processing. The goal of aseptic processing is to make a product that is free of microorganisms
915 and toxic microbial byproducts, most notably bacterial endotoxins. The use of aseptic technique
916 and control of microbiological impurities in components can eliminate microbial and endotoxin
917 contamination from PET drugs. Aseptic processing of PET drugs should involve
918 microbiological control over various types of components, as discussed below.
919
920 1. Water
921
922 Production processes that are relatively free of water or have rigorous chemical processes
923 are unlikely to have microbial or endotoxin contaminants. PET production facilities
924 often use Water for Injection, USP (WFI), an approved drug product. Using finished
925 packaged WFI eliminates the need for the PET production facility to verify, maintain,
926 and document a sterile water system.
927
928 Nonsterile water can develop significant microbial growth in a matter of days. We
929 recommend that production processes that are water-intensive have sufficient controls to
930 avoid microbial growth and development of biofilm (bacterial colonization). If nonsterile
931 water is allowed to stagnate in a container or tubing, biofilm will develop. To minimize
7
This draft guidance was issued in February 2003. Once finalized, it will represent the Agency's thinking on this
topic.
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932 their contact with nonsterile water, it is recommended that tubing and glassware be
933 washed, rinsed, and promptly dried.
934
935 2. Glassware
936
937 Glassware and heat-resistant containers are relatively easy to keep free of microbial
938 growth and pyrogens because they can be appropriately wrapped in foil and terminally
939 sterilized by a suitable dry-heat cycle (see Section VI). Control procedures for these
940 items should include prompt cleaning after use, rinsing with purified or WFI water,
941 wrapping in aluminum foil, and depyrogenation by a suitable dry-heat oven cycle.
942
943 3. Transfer Lines
944
945 Transfer lines, which are used for synthesis and transfer of solvents or products, are
946 usually made of durable plastic and are amenable to reuse. Prompt cleaning with organic
947 solvents after use, rinsing with WFI, flushing with a volatile solvent, and drying with
948 nitrogen are measures that help to control microbial contamination. Organic solvents
949 such as ethanol and acetone are useful as a final rinse and are easily dried from containers
950 or lines.
951
952 For PET drugs with a very short half life (e.g., ammonia N 13), sometimes a long fluid
953 line is used to deliver multiple batches of the product solution to a remote area for further
954 processing. We recommend that procedures be established to ensure that these fluid lines
955 are clean and free of pyrogen contamination prior to each use.
956
957 4. Resin columns
958
959 Resin columns are a potential source of microbes and pyrogens because they can be
960 contaminated with microorganisms. If available, the purchase of low-microbial grade
961 resin material may limit bioburden. Material used for preparing resin columns should be
962 suitably processed and rinsed with a large amount of WFI to control contamination. The
963 prepared column should be appropriately flushed. Refrigerated storage is helpful in
964 controlling contamination. We recommend that wet columns not be stored for a
965 prolonged period of time.
966
967 5. Components
968
969 The selection of a reliable vendor and high-quality materials are effective ways to limit
970 the risk of microbiological contamination. Components that support microbial growth
971 during storage should be kept under controlled conditions and periodically assessed for
972 microbial growth/ contamination.
973
974 6. Qualification for aseptic processing
975 Aseptic processing in PET drug production normally consists of, but is not limited to,
976 (1) the aseptic assembly of the container/closure system (syringe, needle, sterilizing
977 filter and vial) and (2) sterile filtration of the PET drug product. The ability of
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978 personnel to perform aseptic processing can be assessed by conducting media fills.
979 Simulations of aseptic manipulations (e.g., the aseptic assembly of the container
980 system, vent connection, and sterile filtration) can be carried out by substituting a
981 bacterial growth medium for the actual drug product. We recommend that an
982 operator complete three successful media fill runs to qualify as a new operator. Each
983 operator can be requalified annually by conducting one media fill run. Only
984 personnel trained in aseptic techniques should conduct aseptic processing.
985
986 7. Sterilizing filtration
987
988 Even if care is taken to minimize microbiological contamination during synthesis, a drug
989 is considered to be nonsterile until it is passed through a sterilizing grade filter.
990 Generally, PET production facilities can use commercially available, presterilized filters
991 to sterilize these solutions, provided that the vendor has been shown to be reliable, the
992 filter is certified as compatible for the product, and it meets acceptable specifications.
993
994 Integrity testing of membrane filters should always be performed postfiltration. This is to
995 ensure that the filter has performed according to specifications. Testing can be
996 accomplished by performing the bubble-point test to show that the integrity of the filter
997 was not compromised during or before use.
998
999 8. Environmental and personnel monitoring
1000
1001 Environmental monitoring is crucial to maintaining aseptic conditions. We recommend
1002 that microbiological testing of aseptic workstations be performed during sterility testing
1003 and critical aseptic manipulation. Methods can include using swabs or contact plates for
1004 surfaces and settling plates or dynamic air samplers for air quality.
1005
1006 D. Process Verification and Computer Control
1007
1008 Proposed § 212.50(f)(1) states that for PET drug production in which every batch undergoes full
1009 finished-product testing to ensure the PET drug product meets all specifications (e.g., F18 FDG),
1010 process verification is not required.
1011
1012 Proposed § 212.50(f)(2) would require that when the results of the production of an entire batch
1013 of a PET drug product are not fully verified through finished-product testing or when only the
1014 initial sub-batch in a series is tested, the PET drug producer would have to demonstrate that the
1015 process for producing the PET drug product is reproducible and is capable of producing a drug
1016 product that meets the predetermined acceptance criteria. Process verification activities and
1017 results would have to be documented. Documentation would have to include the date and
1018 signature of the individual(s) performing the verification, the monitoring and control methods
1019 and data, and the major equipment qualified. The determination not to conduct process
1020 verification should be supported by scientific rationale and data.
1021
1022 1. Process verification under 212.50(f) (2)
1023
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1024 For a PET production facility that has an established history of PET drug production, the
1025 process verification can be accomplished using historical batch records, provided that
1026 there is adequate accumulated data to support a conclusion that the current process yields
1027 batches meeting predetermined acceptance criteria. We recommend that a
1028 comprehensive review of accumulated production, testing, and control data be conducted
1029 according to a written protocol defining the acceptable conditions. The accumulated data
1030 should verify that the process used was consistent and should document all changes to
1031 and failures of the process.
1032
1033 We recommend that new processes or significant changes to existing processes be shown
1034 to reliably produce PET drug products meeting the predetermined acceptance criteria
1035 before any batches are distributed. This verification should be conducted according to a
1036 written protocol and generally include at least three consecutive acceptable production
1037 runs.
1038
1039 Because PET drugs have short half lives, a PET producer may decide to evaluate the
1040 reliability of a new process or a significant change to an existing process to produce a
1041 PET product, meeting the predetermined acceptance criteria concurrently with the
1042 distribution of the batch. Such a decision should be justified in writing, subjected to
1043 quality control procedures, and performed according to a written protocol. Under this
1044 situation, we recommend each batch be processed in strict adherence to the written
1045 procedures, fully tested (except sterility testing), and found to comply with all procedural
1046 and quality test requirements prior to final release.
1047
1048 2. Computer control
1049
1050 Synthesis of some PET drugs can be executed under automated or computer control. We
1051 recommend that the computer program be verified before first use to demonstrate that it
1052 is suitable for its intended purposes and is capable of producing results that meet the
1053 predetermined acceptance criteria. We also recommend that subsequent changes or
1054 upgrades made to the computer program be documented and the process demonstrated to
1055 be capable of producing a PET drug product that meets the predetermined acceptance
1056 criteria. PET production facilities can rely on a certification by the software or system
1057 vendor that the specified software was verified under its operating conditions.
1058
1059
1060 IX. LABORATORY CONTROLS
1061
1062 A. Regulatory Requirements
1063
1064 Proposed 21 CFR 212.60 would require the establishment and implementation of procedures for
1065 testing components, in-process materials, and finished PET drug products. All necessary tests of
1066 materials and products would have to be documented. Each laboratory would also be required
1067 to have sampling and testing procedures designed to ensure that components, drug product
1068 containers and closures, in-process materials, and PET drug products conform to appropriate
1069 standards. Analytical methods and test equipment would have to be suitable for their intended
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1070 uses. Reagents, solutions, and supplies used in testing procedures would have to be adequately
1071 controlled. The preventive maintenance, calibration, and procedures to make sure that the
1072 equipment is functioning properly would have to be documented. A complete record of all tests
1073 related to the production of a PET drug product would have to be kept to ensure compliance with
1074 established specifications and standards, including examinations and assays, as follows:
1075
1076 A description of the sample received for testing, including its source, the quantity, the
1077 batch or lot number, the date (and time, if appropriate) the sample was taken, and the date
1078 (and time, if appropriate) the sample was received for testing.
1079
1080 A description of each method used in the testing of the sample, a record of all
1081 calculations performed in connection with each test, and a statement of the weight or
1082 measurement of the sample used for each test.
1083
1084 A complete record of all data (including graphs, charts, and spectra). For example, a
1085 print-out of the chromatogram with the calculated amounts of each component analyzed
1086 by the test
1087
1088 A statement of results of the tests and their relation to acceptance criteria
1089
1090 The initials or signature of the analyst and the date of the test
1091
1092 B. Laboratory Controls
1093
1094 Under proposed § 212.60, a PET production facility would have to have written test procedures
1095 that describe how to conduct each test of finished products and, where applicable, of components
1096 and in-process materials. Appropriate testing procedures would have to be established to ensure
1097 that PET drug products conform to appropriate standards, including established standards (e.g.,
1098 relevant USP monographs) of identity, strength, quality, and purity. Analytical tests would have
1099 to be suitable for their intended purpose and have sufficient sensitivity, specificity, and accuracy.
1100
1101 We recommend that any new analytical test method be validated, through documented data, to
1102 show that it will consistently yield results that accurately reflect the quality characteristics of the
1103 product tested. The FDA and USP have published information for determining the appropriate
1104 analytical parameters (e.g., accuracy, precision, linearity, ruggedness) that should be used to
1105 validate a new method (see ICH Q2A Text on Validation of Analytical Procedures and USP
1106 General Chapter <1225> Validation of Compendial Methods). On the other hand, validation is
1107 not required for compendial methods.
1108
1109 If a USP analytical test method is used, a PET producer should verify that the method works
1110 under the actual conditions of use.
1111
1112 Most analyses use reference standards. We recommend that PET production facilities establish
1113 the reference standards identified in the analytical procedure or SOP. When a primary reference
1114 standard is obtained from an officially recognized source (e.g., USP), the material usually does
1115 not need further testing if it is stored under conditions consistent with the supplier’s
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1116 recommendations. However, where an official standard is not available or if a PET production
1117 facility establishes its own reference standard, we recommend that data to fully confirm the
1118 material’s identity and purity be established and documented. Documentation such as reference
1119 spectra or other supporting data to prove the identity and purity of the reference standard may be
1120 available from the supplier.
1121
1122 Under proposed § 212.60(f), equipment would have to be routinely calibrated and maintained
1123 according to the established written procedures (see Section VI). We recommend that PET
1124 production facilities verify that the equipment is in good working condition at the time the
1125 samples are analyzed. We also recommend that prior to each day of use of the HPLC and GC, a
1126 system suitability test using reference standards be conducted to verify that the resolution and
1127 reproducibility of the chromatographic system are adequate for the analysis to be done.
1128
1129 We recommend that any reagent or solution prepared on-site be adequately controlled (including
1130 temperature control, if applicable) and properly labeled with respect to identity, composition, and
1131 expiration date.
1132
1133 Raw test data (such as chromatograms, spectra, and printouts) and any calculations performed
1134 can be documented and become part of the batch production and control record. Records should
1135 have information such as the source of the test material, a description of the appearance of the
1136 material, the amount used, test and acceptance criteria, and an entry for data and interpretation of
1137 results. Laboratory controls should be followed and documented at the time of performance.
1138 We recommend that deviation from written procedures be documented and justified. Any out-
1139 of-specification results obtained should be investigated and documented.
1140
1141
1142 X. STABILITY TESTING
1143
1144 A. Regulatory Requirements
1145
1146 Proposed 21 CFR 212.61 would require the establishment of a written stability testing program
1147 for each PET drug product. This program would have to be used to establish suitable storage
1148 conditions as well as expiration dates and times.
1149
1150 B. Guidance on Stability
1151
1152 As with other drug products, PET drug molecules are expected to remain stable during storage.
1153 Although PET drug products have extremely short shelf lives, because of their short half lives
1154 compared to other kinds of drug products, there are stability concerns due to radiation-related
1155 radiolysis. Certain PET drug products (e.g., F18 fluorodopa) can undergo very rapid chemical
1156 changes. Therefore, appropriate parameters should be evaluated to establish and document the
1157 stability of PET drug products under proposed storage conditions. Examples of stability
1158 parameters include radiochemical identity and purity (including levels of radiochemical
1159 impurities), appearance, pH, stabilizer or preservative effectiveness, and chemical purity. We
1160 recommend that appropriate stability-indicating methods that can distinguish degradation
1161 products and impurities be used. Stability testing of the PET drug product should be performed
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1162 at the highest radioactive concentration, and the whole batch volume in the intended
1163 container/closure should be stored. At least three production runs of the final product should be
1164 studied for a time period equal to the labeled shelf life of the PET drug product.
1165
1166 Although stability studies in support of an expiration dating period would be needed for approval
1167 of a PET drug product, subsequent changes to the expiration date could be made without prior
1168 approval (changes would be noted in the annual report for the drug product).
1169
1170
1171 XI. FINISHED DRUG PRODUCT CONTROLS AND ACCEPTANCE CRITERIA
1172
1173 A. Regulatory Requirements
1174
1175 Proposed 21 CFR 212.70 would require that specifications be established and met for each PET
1176 drug product batch, including identity, strength, quality, purity, and, if appropriate, sterility. The
1177 proposed regulation would require the implementation of procedures to ensure that a product is
1178 not released until appropriate laboratory testing is completed, reviewed, and approved by an
1179 appropriate releasing authority.
1180
1181 Proposed 21 CFR 212.71 would require a PET production facility to reject PET drug products
1182 that fail to meet acceptance criteria. Procedures would have to be established to identify and
1183 segregate the product. There would have to be predetermined procedures for investigating the
1184 cause of the problem and preparing a timely report on the occurrence, including a description of
1185 the corrective action taken, where appropriate.
1186
1187 B. Finished Product Testing
1188
1189 Methods of PET drug production may differ from site to site. As a result, there may be specific
1190 impurities to assess depending on the method of production, such as kryptofix in FDG F 18. We
1191 recommend using approved NDA specifications, or the IND accepted specifications. Under
1192 proposed § 212.70, PET production facilities would have to ensure that each batch of PET drug
1193 product meets its established acceptance criteria, except for sterility (see subsection C below),
1194 before it is given final release.
1195
1196 C. Microbiological Tests for Sterile PET Drugs
1197
1198 Sterility testing would have to be started within 30 hours after the completion of PET drug
1199 production. If the sample for sterility testing is held longer than indicated (e.g., over the
1200 weekend), PET producers should demonstrate that the longer period does not adversely affect the
1201 sample and the test results obtained will be equivalent. The samples should be stored
1202 appropriately (e.g., under refrigeration). Verification of equivalent results can be accomplished
1203 by inoculation of USP indicator organism(s) and demonstrate that there is little, if any, loss in
1204 viability of the inoculated microorganism. The USP General Chapter <71> Sterility Tests
1205 provides information about media and incubation conditions.
1206
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1207 We recommend that testing be conducted in a controlled area such as a laminar airflow
1208 workbench (LAFW) with clean-room apparel. Aseptic techniques should be used for sterility
1209 testing. The greatest risk of false-positive results arises in the sampling and transfer of the test
1210 aliquot from the vial to the media. It may be convenient to apply direct inoculation into
1211 commercial media. We recommend that the media be observed on days 3, 7, and 14 after
1212 inoculation, but it is prudent to observe the media more often during the first week of incubation.
1213
1214 The USP Bacterial Endotoxins Test (BET) (General Chapter <85>) should be performed for a
1215 sterile PET drug that is intended for injection. The BET contains gel-clot and rapid photometric
1216 methods for endotoxin measurement.
1217
1218 The product can be distributed under control after a pharmacopeial bacterial endotoxin test is
1219 initiated. However, the endotoxin results should meet the acceptance criteria before
1220 administering the product to humans.
1221
1222 If the result of any bacterial endotoxin test exceeds the acceptance limit, or if a sterility test is
1223 positive for microbial growth, we recommend a complete investigation be conducted
1224 immediately and documented. We recommend that corrective actions based on the results of the
1225 investigations be implemented promptly.
1226
1227 D. Accepting and Releasing a Batch (Lot)
1228
1229 We recommend the designated individual review all laboratory testing and documentation from
1230 the batch record to determine whether or not the PET drug product has met all acceptance
1231 criteria. If the product has met acceptance criteria, the designated individual with quality
1232 assurance function should sign and date the release sections of the batch record and sign a release
1233 for human administration.
1234
1235 In many cases, modifications to this standard procedure for product release may be appropriate.
1236 For example, transportation deadlines may justify a prerelease for distribution before all
1237 elements of testing and review are finalized. Other than sterility testing, all finished-product
1238 tests would have to be completed or in progress at the time of shipment or distribution and PET
1239 drug products can be released for distribution (but not administration) while some tests are
1240 pending. Under proposed § 212.70, these tests would have to be completed prior to final release
1241 for human administration. When it is determined that all acceptance criteria have been met, the
1242 PET production facility should then provide a notice of final release to the receiving facility so
1243 that the dose may be given to the patient. We recommend the establishment of effective
1244 procedures for immediate notification of the receiving facility if there is evidence of an out-of-
1245 specification result. Notification of the receiving facility due to product failure should be
1246 documented.
1247
1248 PET drugs that have a very short half life (e.g., ammonia N 13) can be produced in multiple sub-
1249 batches on the same day. End product testing of the initial sub-batch can be conducted, provided
1250 a sufficient number of sub-batches (beginning, middle, and end) have been demonstrated to
1251 produce a product meeting the predetermined acceptance criteria. For routine production in this
1252 circumstance, the release of subsequent sub-batches can be qualified if the initial sub-batch
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1253 meets all acceptance criteria. In certain cases, testing each sub-batch for certain attributes prior
1254 to release may be appropriate (e.g., for pH determination in ammonia N-13 production method
1255 using Devarda’s alloy catalyst).
1256
1257 E. Conditional Final Release
1258
1259 When one of the required finished product tests cannot be completed due to a breakdown of the
1260 analytical equipment, proposed 212.70 (f) establishes criteria under which PET producers may
1261 still release the drug product for human use. If equipment is properly maintained, breakdowns
1262 should be a rare occurrence. We recommend that PET producers determine if the missing testing
1263 would adversely affect the safety and effectiveness of the PET drug product. Conditional release
1264 should be extremely infrequent. Only products that meets all conditional release criteria would
1265 be able to be released. Conditional release of a PET drug product would not be permitted if a
1266 PET drug producer could not perform a radiochemical identity/purity test on the active
1267 pharmaceutical ingredient of a PET drug product. All activities of conditional release would have
1268 to be documented.
1269
1270 F. Rejection and Reprocessing
1271
1272 Under proposed § 212.71(a), a batch of a PET drug product that fails to meet established
1273 specifications would have to be rejected, and procedures would have to be established to identify
1274 and segregate the product. Proposed § 212.71(b) would require that documentation of the
1275 investigation of a nonconforming product include the results of the investigation and final
1276 disposition of any rejected product.
1277
1278 Under proposed § 212.70 (d), a drug product can be reprocessed if pre-established procedures
1279 (set forth in production and process controls) are followed and the finished product conforms to
1280 specifications before final release. When the option for reprocessing is exercised, we
1281 recommend that the event be documented and conditions described in a brief deviation report.
1282 Examples of reprocessing could include a second passage through a purification column to
1283 remove an impurity, or a second passage through a filter if the original filter failed the integrity
1284 test.
1285
1286
1287 XII. LABELING AND PACKAGING
1288
1289 A. Regulatory Requirements
1290
1291 Proposed 21 CFR 212.80 would require that:
1292
1293 A PET drug product be suitably packaged and labeled to protect the product from
1294 alteration, contamination, and damage during the established conditions of storage,
1295 handling, and shipping.
1296
1297 Labels and packaging operations be controlled to prevent labeling and product mix-ups.
1298
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1299 All information stated on each label be contained in each batch production record.
1300
1301 B. Recommendations on Labeling and Packaging
1302
1303 Regardless of the scope of operation of a PET production facility, we recommend that
1304 appropriate measures be taken to handle labels in a way that prevents mix-ups with any other
1305 labeling materials.
1306
1307 We recommend that PET drug products be labeled with adequate, legible identifying information
1308 to prevent errors during storage, shipment, and use.. Once an NDA or ANDA is approved for a
1309 PET drug product, the label approved in the NDA must be used. Prior to approval of the NDA
1310 or ANDA, the label should be approved by persons responsible for quality assurance procedures.
1311 Labels can be computer generated or handwritten.
1312
1313 Because of radiation exposure concern, it is a common practice to prepare much of the labeling
1314 in advance. For example, an empty product vial can be prelabeled with partial information (e.g.,
1315 product name, batch number, date) prior to filtration of the radioactive product, and upon
1316 completion of QC test, the outer shielded container can be labeled with the required information
1317 (e.g., radioactivity). Alternatively, a string label can be used to label the immediate container
1318 provided that there is a way to associate the label with the vial if the label were to come off.
1319 Different approaches can be used as long as the approach ensures that the required information is
1320 available on the label. A label identical to that affixed to the container shield can be incorporated
1321 into the batch production record. A final check should be made to verify that the correct and
1322 complete label has been affixed to the container and the shield.
1323
1324
1325 XIII. DISTRIBUTION
1326
1327 A. Regulatory Requirements
1328
1329 Proposed 21 CFR 212.90 would require the development of procedures to ensure that the
1330 shipment will not adversely affect the product. PET production facilities would have to maintain
1331 distribution records for PET drug products.
1332
1333 B. Recommendations
1334
1335 PET drug products should be shipped in accordance with labeled conditions (e.g., temperature)
1336 to ensure the identity, purity, or quality of the drug product. For PET production facilities
1337 distributing to outside clients or outside pharmacies, information on the method of shipment and
1338 the contact person at the final destination should be included. We recommend that a system be
1339 put in place by which the chain of distribution of each batch of PET drug product can be readily
1340 determined to permit its recall if necessary. A recall should consist of notifying the receiving
1341 facility, pharmacist, and the patient’s physician, if known. When the receiving facility disposes
1342 of the recalled drug, the PET drug producer can obtain a notification from the receiving facility
1343 confirming the recalled drug has been disposed of and describing the manner in which it was
1344 disposed.
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1345
1346 When the PET production facility ships the final released PET drug product supplied as a
1347 pharmacy bulk package (USP<1> Injections) to a nuclear pharmacy for dispensing into
1348 individual patient doses, FDA generally regards subsequent distribution of the drug product as
1349 part of the practice of pharmacy.
1350
1351
1352 XIV. COMPLAINT HANDLING
1353
1354 A. Regulatory Requirements
1355
1356 Proposed 21 CFR 212.100 would require that procedures be developed and implemented for
1357 receipt and handling of all complaints pertaining to a specific PET drug product, including
1358 review by a designated individual to determine compliance with specifications and to initiate an
1359 investigation into the problem. A file for drug product complaints would have to be maintained.
1360 The file would have to contain the name and strength of the PET drug product, the batch number,
1361 the name of the complainant, the date the complaint was received, the nature of the complaint,
1362 and the response to the complaint. The file would also have to include the findings of any
1363 investigation and followup. A PET drug product implicated in a complaint could not be
1364 reprocessed and would have to be destroyed in accordance with applicable Federal and State law.
1365
1366 B. Recommendations
1367
1368 We recommend that the designated individual be responsible for collecting as much information
1369 as possible about the drug and the nature of a complaint and for completing an investigation of
1370 the matter as soon as possible. Corrective action should be taken immediately if there is any
1371 reason to believe that an adulterated drug was implicated in the complaint. Under proposed §
1372 212.100(c), complaints would have to be maintained in a file designated for that purpose. We
1373 recommend that complaint files be easily retrievable for review and trending.
1374
1375
1376 XV. RECORDS
1377
1378 A. Regulatory Requirements
1379
1380 Proposed 21 CFR 212.110(a) would require that all records be maintained at the PET production
1381 facility or another location that is reasonably accessible to responsible officials of the PET
1382 production facility and FDA investigators.
1383
1384 Proposed § 212.110(c) would require that all records referenced in part 212 be kept for at least 1
1385 year from the date of final or conditional final release of a PET drug product.
1386
1387 B. Recommendations
1388
1389 The regulation would require that records be stored at a PET production facility or another
1390 location that is reasonably accessible. A reasonably accessible location is one that would enable
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1391 the PET production facility to make requested records available to an FDA investigator in a
1392 reasonable period of time during an inspection. The records would have to be legible and stored
1393 in a manner that prevents their deterioration and/or loss.
1394
1395 We recommend that forms for collecting data be kept to a minimum by designing multipurpose
1396 documents and eliminating redundancy, where possible. It is prudent to have as much of the
1397 required information within the batch production record as possible. Records can be kept
1398 electronically.
1399
1400 Other records that would have to be kept include information relating to the composition and
1401 quality of the PET drug product and operation of the production processes, such as laboratory
1402 records, out-of-specification results, master and batch records, distribution records, and
1403 complaint files. Records relevant to materials and PET drug products would have to be kept at
1404 least 1 year from the date of final or conditional final release. Verification reports should be kept
1405 as long as the systems are in use.
1406
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1407
1408 REFERENCES
1409
1410 FDA. Guide to Inspection of Computerized Systems in Drug Processing. February 1983.
1411
1412 FDA. General Principles of Process Validation. May 1987.
1413
1414 FDA. Sterile Drug Products Produced by Aseptic Processing. June 1987.
1415
1416 FDA. Q2B Validation of Analytical Procedures: Methodology. May 1977.
1417
1418 FDA. Q2A Text on Validation of Analytical Procedures. March, 1995.
1419
1420 FDA. Reviewer Guidance — Validation of Chromatographic Methods, November 1994.
1421
1422 FDA. 21 CFR Part 11; Electronic Records; Electronic Signatures. FR Notice 7/21/99 (64 FR
1423 39146).
1424
1425 U.S. Pharmacopeia. <1> Injections. USP 26, NF 21, 2003.
1426
1427 U.S. Pharmacopeia. <71> Sterility Tests. USP 26, NF 21, 2003.
1428
1429 U.S. Pharmacopeia. <85> Bacterial Endotoxins Test. USP 26, NF 21, 2003.
1430
1431 U.S. Pharmacopeia. <621> Chromatography. USP 26, NF 21, 2003.
1432
1433 U.S. Pharmacopeia. <821> Radioactivity. USP 26, NF 21, 2003.
1434
1435 U.S. Pharmacopeia. <823> Radiopharmaceuticals for Positron Emission Tomography-
1436 Compounding. USP 26, NF 21, 2003.
1437
1438 U.S. Pharmacopeia. <1015> Automated Radiochemical Synthesis Apparatus. USP 26, NF 21,
1439 2003.
1440
1441 U.S. Pharmacopeia. <1225> Validation of Compendial Methods. USP 26, NF 21, 2003.
1442
1443
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