Transcript Overview of FDA 21 CFR Part 212 Current Good Manufacturing

Distributed Manufacturing via the SNM
Multicenter FLT IND
Part II
SNM Midwinter
Clinical Trials Network
Albuquerque, New Mexico
February 2, 2010
Sally W. Schwarz, MS, BCNP
Director Clinical PET Radiopharmaceutical Production
Washington University St. Louis
Department of Radiology
§ 212.10 Personnel and Resources: What personnel
& resources must I have?
 Sufficient personnel with necessary education..
 *Responsibilities & assigned duties clearly identified in
written policies
 *Small PET drug production—producing 1-2 batches of
a PET drug daily or weekly—may employ 2 people for
production and quality assurance (QA)
 One individual can be designated to perform production and QA
(highly qualified person)
 Conventional drugs (Part 211) normally require second-person checks
at various stages—for small PET drug operation, can perform
documented self-checks
*Guidance: PET Drugs—CGMP December 2009
§ 212.20 Quality Assurance: What activities must I
perform to ensure drug quality?
(a) Production operations:
– ensure that each PET drug meets the requirements of
the act (safety, identity & purity)
– PET drug meets required quality & purity
(b) Materials: examine & approve or reject components…inprocess materials…finished dosage forms to ensure
compliance with procedures specifications
(c) Specifications & processes: approve or reject before
implementation..specifications, methods, procedures
(d) Production records: review production record to determine
whether errors have occurred, investigate and take action
(e) Quality assurance: establish & follow written QA
procedures
§ 212.30 Facilities and Equipment: What
requirements must my facilities & equipment meet?
(a) Facilities: adequate to ensure orderly handling,
prevention of mix-ups & prevention of contamination
(b) Equipment procedures:
– Clean
– Suitable for intended purpose
– Properly installed, maintained & capable of producing valid
results
– Document activities
(c) Equipment: not reactive, additive or absorptive to alter
the PET drug
§ 212.40 Control of Components, Containers & Closures:
How must I control components used for PET drug &
containers , closures I package them in?
(a) Written procedures
(b) Written specifications
(c) Examination & testing


Establish minimum standards for controlling components
containers & closures.
If you conduct finished-product testing which ensures correct
components have been used, may rely on COA from suppliers.
Need justification why identity testing is not required.
(d) Components be handled and stored to prevent contamination,
mix-ups & deterioration
(e) Keep a record of each shipment of components
§ 212.50 Production & Process Controls: What
production & process controls must I have?
(a) Written control Procedures: document all key process
parameters are controlled & deviations are justified
(b) Master production & control records





Name and strength of PET drug
Name & amount of other active pharmaceutical ingredient (API)
Components
Identification of all major pieces of equipment used
Statement on minimum percentage yield allowed
(c) Batch production & control record created for each new
batch
§ 212.60 Laboratory Controls: What requirements
apply to laboratories where I test components, inprocess materials & finished PET drug products?
(a) Written procedures
(b) Established specifications & standards
(c) Analytic methods, sensitive, specific, accurate &
reproducible
(d) Equipment suitable for purpose, and
(e) Complete record of all data e.g. a print-out of the
chromatogram with calculated amounts of each
component analyzed
(f) Test results and relation to acceptance criteria
(g) Initial or signature of analyst and date performed
§ 212.61 Ensure Stability Through Expiry What
must I do to ensure the stability of my PET drug
products through expiry?
 Establish written stability testing program
 Program used to establish storage conditions and expiration
time
 *Parameters to evaluate:
 Radiochemical identity & purity (including levels of radiochemical
impurities
 Appearance
 pH
 Stabilizer effectiveness
 Chemical purity
 * Perform stability testing at highest radioactive concentration
 * Withdraw sample from the intended final container/closure
*Guidance: PET Drugs—CGMP December 2009
Finished Product Testing
*Guidance: PET Drugs—CGMP December 2009
*Noncritical attributes (perform periodic quality indicator
test [PQIT]): perform on predetermined interval rather
than every batch
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Radionuclidic purity
Low-level nontoxic impurities
Class 3 residual solvents
§ 212.70 Finished Product Testing
Conditional Final Release
 If you cannot complete one or required finishedproduct tests for a batch of PET drug due to
malfunction involving analytical equipment, you may
approve conditional final release
–
–
–
–
Determine all acceptance criteria are met
Retain reserve sample
Promptly correct malfunction, & complete omitted test
May not approve if the malfunction involved performance
of radiochemical identity/purity
§ 212.71 If PET Drug Does Not Conform to
Specifications?
a)
b)
c)
d)
Reject nonconforming product
Investigation
Correction of problem
Reprocessing
§ 212.80 Packaging and Labeling: What are the
requirements associated with labeling & packaging
PET drug products?
• Suitably packaged and labeled to protected from
alteration, contamination and damage
*1. Label to prevent mix-ups
*2 . Due to Radiation exposure : label empty product vial
prelabeled ( e.g. product name, batch number, date)
*3. Outer shielded container labeled
*4. Label identical to the container shield label can be
incorporated into the batch production record
§ 212.110 Records: How must I maintain records of
my production of PET drugs?
(a) Record availability: maintain at drug production
facility or other accessible location to allow
inspection by the FDA
(b) Record quality: legible, stored to prevent
deterioration, readily available for review & copying
by FDA
(c) Record retention period: 1-year from date of final
release, or conditional final release
§ 212.70 Finished Drug Product Controls & Acceptance:
What controls & acceptance criteria must I have for my
finished PET drug products?
a) Establish specifications for each PET drug
b) Establish & document Test Procedures accuracy, sensitivity,
specificity & reproducibility
c) PET Drug conforms to specifications
PET drug batch (sub-batch) may not be released until appropriate
laboratory determination is compete (except sterility), is reviewed
& approved by appropriate releasing authority
d) Sterility testing: innoculate within 30 hours post production
Can exceed 30-hour requirement due to weekend, by demonstrating that
the longer period does not affect the sample
*Verification can be accomplished by innoculation of USP organism
(e.g. E coli) and demonstrate no loss (little) in viability