Transcript United States Pharmacopeia (USP)

Distributed Manufacturing via the SNM
Multicenter FLT IND
Part I
SNM Midwinter
Clinical Trials Network
Albuquerque, New Mexico
February 1, 2010
Sally W. Schwarz, MS, BCNP
Director Clinical PET Radiopharmaceutical Production
Washington University St. Louis
Department of Radiology
US Food & Drug Administration
Modernization Act (FDAMA) 1997
 1997: US Food & Drug Modernization Act (FDAMA)
required revisions to Current Good Manufacturing Practice
(cGMP) for PET Radiopharmaceutical (RP) production
 FDAMA required a new approval path and separate
Current Good Manufacturing Practices (cGMPs) for PET
from cGMPs for drugs
 Prior to adoption of final PET cGMP rule, FDAMA
requires PET Radiopharmaceutical (RP) production to
follow:
 United States Pharmacopeia (USP) PET RP monographs, if
available
 USP General Chapter <823> for Production of PET RPs
USP subcommittee is in process of reviewing/revising
21 CFR Part 212; Final Rule CGMP for PET
December 10, 2009
 Regulation is effective December 12, 2011
 Submission of an NDA or an ANDA required for
all FDA approved PET drugs no later than 2 years
after the enactment date of the Final Rule
– F-18 FDG, F-18 Fluoride, N-13 Ammonia
21 CFR Part 212; Final Rule CGMP for PET
December 10, 2009
The rule §212.5(b) provides that for investigational and research
PET drugs, CGMP would be met by producing PET drugs
 in accordance with Part 212, or
in accordance with USP General Chapter <823>
“Radiopharmaceuticals for Positron Emission Tomography –
Compounding,” May 1,2009, 32nd Edition.
1. PET Drugs produced under Investigational New Drug Application (IND) in
accordance with Part 312 of this chapter or
2. PET Drugs approved through a Radioactive Drug Research Committee
(RDRC) in accordance with Part 361 of this chapter
Overview USP Chapter <823> (32nd Edition)
 Procedures/Process (<823> revision is planned)
– Components, Materials and Supplies
– Compounding Procedure Verification
 Acceptance Criteria
Compounding Procedures
Computers & Automated Equipment Controls
Verification studies (3 consecutive runs)




Stability Testing & Expiration Dating
PET RaPh Compounding for Human Use
Quality Control
Sterilization & Sterility Assurance
Overview USP Chapter <823> (Revision?)
A. Personnel Qualifications
1.
2.
Responsible Person
Aseptic Training (current)
B. Control of Facilities & Equipment
1.
2.
3.
4.
C.
D.
E.
F.
G.
H.
I.
Facilities (current)
Environmental Controls
Aseptic Hood
Compounding & QC Equipment
Control of Components, Materials and Supplies
Compounding Procedure Verification
Stability Testing and Expiration Dating
PET RPh Compounding for Human Use
Quality Control
Sterilization & Sterility Assurance
Reprocessing
FDA Audit
Inspectional Observations (FDA-483)
Inadequate training of personnel
 Failure to train personnel to perform
assigned tasks
No media fill testing performed
A. Personnel Qualifications (add)
1. Responsible person: designated, qualified & trained
person shall be responsible for ensuring that
compounding activities are carried out & properly
completed by qualified & trained personnel
2. Aseptic Training (current)




Didactic training: pass written exam
Training in proper garbing & gloving
Documented visual observation audits of garbing
Media-Fill Test Procedures


–
New preparer: Pass 3 separate Media-Fill Procedures
Annually for personnel who currently prepare (compound)
PET RPh
Any time procedures are changed
Cleansing & Garbing
1.
2.
3.
4.
5.
Dedicated shoes or shoe covers
Head covers
Face masks & eye protection
Hand cleansing procedure
Gowns with fitted sleeves
(sleeve covers)
6. Sterile gloves (disinfect before
entering, then periodically with
sterile 70% IPA )
7. Garb exposed in patient car e
area can’t cross line of
demarcation into compounding
Overview USP Chapter <823> (Revision?)
A. Personnel Qualifications
1.
2.
Responsible Person
Aseptic Training (current)
B. Control of Facilities & Equipment
1.
2.
3.
4.
C.
D.
E.
F.
G.
H.
I.
Facilities (current)
Environmental Controls
Aseptic Hood
Compounding & QC Equipment
Control of Components, Materials and Supplies
Compounding Procedure Verification
Stability Testing and Expiration Dating
PET RPh Compounding for Human Use
Quality Control
Sterilization & Sterility Assurance
Reprocessing
FDA Audit
Inspectional Observations (FDA-483)
 Aseptic workstation is not suitable for aseptic
operations
 Use of non-sterile disinfectant to sanitize LAF
 Frequency of environmental monitoring—does not
reflect the volume of manufacturing operations
 Weekly is not acceptable
 Should “monitor” environment for each set-up of final
product vial
 Can assemble all final product vials for the day, and keep
them in LAF
B. Control of Facilities and Equipment (current)
1. Facilities
2. Environmental Controls
a)
b)
c)
d)
e)
Work area is clean
Aseptic hood located in low traffic area
Clean laboratory clothing worn
Aseptic techniques used
Disinfect final product septum with sterile 70%
alcohol
B. Control of Facilities and Equipment
3. Aseptic Hood (LAF or Isolator)
a) PET RPh final product containers must be
assembled in Class 100 environment (LFH or
Isolator)
b) LFH internal surface is cleaned and disinfected
with sterile disinfectant daily before and after use
a) Gloved hands are disinfected before entering hood
PET RaPh Final Product Vial Assembly
Performed In Aseptic Hood
PET RaPh final product containers
must be assembled in Class 100
environment (LFH or Isolator)
Gloved hands are disinfected before
entering hood
Daily disinfection of surfaces before
use
Microbiological Testing periodically
e.g. weekly (per FDA, NOT monitoring)
Contact plate-surfaces
Settle plate/dynamic air sampler
Airborne, nonviable particle count
less often
FDA Audit
Inspectional Observations (FDA-483)
Frequency of environmental monitoring—
contact plates, touch plates
 Weekly is not acceptable
 Should “monitor” environment for each set-up of
final product vial
 Can assemble all final product vials for the day,
and keep them in LAF
Use of non-sterile disinfectant to sanitize LAF
No media fill testing performed
B. Control of Facilities and Equipment (add)
3. Aseptic Hood (cont’d)
d)
Microbiological monitoring performed periodically




e)
Contact plate-surfaces
Settle plate/dynamic air sampler
Airborne, nonviable particle count less frequently
Frequency of monitoring may be reduced once routine
sterility of drug product is established
Frequency: microbiological testing of the aseptic hood
should be performed after each critical aseptic
manipulation such as set-up of final product vial and
after sterility inoculations
B. Control of Facilities and Equipment (add)
4. Compounding Equipment (current)
a) Equipment used to prepare PET drugs
Properly cleaned
May be processed to remove endotoxin
May be sterilized
Verification of sterilizer performance repeated
periodically
C. Control of Components, Materials and Supplies
 Establish written specifications
Identity, purity & quality of components
Appropriate storage
 Log-in each lot of shipments of components; If no
expiration date, must assign one.
 Determine each batch of components in compliance
with written specifications (procedures, tests, and/or
certificates of analysis)
 Store components in controlled access area according
to established conditions.
D. Compounding Procedure Verification
1. Written acceptance criteria for identity, purity &
quality of each PET drug (If USP monograph exists =
minimum acceptance criteria)
2. Written procedures for compounding



Master file of Written compounding procedures (Outdated copies
retained)
Incorporate 0.22 um for parenteral administration; 0.45 um for
inhalation
Routinely updated at least annually
3. Verification Studies


Three consecutive runs are required initially & for any change
having potential to alter identity quality or purity
Stability testing and expiration dating—meet acceptance
criteria at expiry
E. Stability Testing & Expiration Dating
F. PET Radiopharamceutical (RPh)
Compounding for Human Use
 Inspect compounding area and equipment before use
for cleanliness
 Label final PET RaPh container prior to starting
 PET drug name and lot number
 Compound PET RaPh according to written, verified
procedure with appropriate written batch record
 Use appropriate components
 Responsible individual initials—including each critical step
 Raw analytical data
 Signature & date of individual assuming overall
responsibility
G. Quality Control
 Written QC procedures
 Verification of QC equipment and procedures used
 System suitability testing (Chromatography <621>) must
be confirmed on installation of QC equipment and after
repair (HPLC, GC, analytic instruments)
 Check correct operation on scheduled basis (system
suitability)
 Maintenance performed—written scheduled basis
 Dose Calibrators: Perform applicable tests
• Used to assay bulk radioactivity and dispensed dosages
 Accept or reject PET drug
 Investigate unacceptable QC tests results
 Document outcome
Quality Control Requirements
Pre-Release:
 PET RaPh
T1/2 ≥ 20 minutes (on Batch); T1/2 ≤ 20 minutes ( on QC Sub Batch)
– Post-filtration integrity test of 0.22 m sterile filter (e.g. Bubble Test)
– pH
– Visual inspection
– Radiochemical purity /identity ***
– Radionuclidic identity
– Specific activity
– Residual solvent analysis, and other toxic chemicals
– BET (20 min gel clot, or other recognized procedure)
Post-Release:
 Sterility
 may inoculate test, within 24 h following preparation
Endosafe PTS® System
 PTS® is a software-driven
spectrophotometer for measuring and
documenting endotoxin.
 Unique cartridge containing dry, precalibrated reagents.
 Each cartridge contains duplicate channels
for analysis of sample and positive control.
 PTS® is particularly suited for PET RaPh
because test requires
 ~17-20 minutes
 Requires < 0.1 mL of diluted product
 NO preparation of endotoxin standards.
FDA Audit
Inspectional Observations (FDA-483)
 Failure to audit procedures (SOPs) on regular basis &
update SOPs
 Found production equipment:
 Not qualified
 Not calibrated
 Not properly maintained
 Failure to investigate failed batch & deviations
(should be in writing)
FDA Audit
Inspectional Observations (FDA-483)
 Lack of assurance that QC test results are reliable &
accurate
 QC equipment;
– Not qualified
– Not calibrated
– Not maintained
 No equipment suitability performed (USP Chapter <621>)
 Inadequate reference standards used
 Inadequate QA/QC oversight
H. Sterilization and Sterility Assurance
• Compounding Equipment & Components
– Equipment may be processed to remove endotoxin
– May be sterilized
requires verification of sterilizer
•
•
•


Environmental Controls
Aseptic Hood
Aseptic Technique
Qualification of the Filtration Process
Microbiological Testing of Finished Products
Qualification of Filtration Process
 Sterile Filters:
 COC examined and maintained for each lot of filters
 COA obtained from the company listing microbial retention challenge
 Each lot of filters must be tested for integrity : Acceptance Criteria
 After PET drug production, filter tested for integrity prerelease e.g. Bubble Point Test
 The bubble point pressure is the pressure at which bubbles first
appear from a submerged inlet tube in the receiving vessel.
 Nitrogen gas flow increased until the bubbles appear (e.g. most
filters must reach > 50 psi. *
Nitrogen Gas
* Pressure depends on the filter used
Microbiological Testing of Finished Product
 Innoculated no later than 24 (30) hours after
compounding
 If sterility test fails, an investigation must be
initiated to identify the cause
FDA Audit
Inspectional Observations (FDA-483)
 Lack of assurance that PET drug is sterile
 No growth promotion testing of media performed
 Must have validation data for hold time (eg. 24
hours); assure still have viable product
 Inadequate incubation temperature control
 Automatic sterility re-test without investigation
Class 100 (ISO Class 5)
PET Dose Drawing Station
 Chapter <823> supersedes Chapter <797> for PET RP
compounding, but upon release of PET RP as finished drug
product, further manipulation such as dispensing, contents of
Chapter <797> apply.
PET Dose Drawing Device
In Class 100 Environment
Shielded Dose Calibrator
Thank-you!
[email protected]