Recommended Practices for Manual Aseptic Processes PDA Technical Report 62 Authors:

Transcription

H: Sterile Processing
By: Carol Lampe
Recommended Practices for
Manual Aseptic Processes
PDA Technical Report 62
Recommended Practices for Manual Aseptic Processing
© 2012 Parenteral Drug Association
Authors:
Olivia A. Henderson, Ph.D., Biogen Idec (co-Chair)
Carol Lampe, J.M. Hansen & Associates, Inc. (co-Chair)
James Agalloco, Agalloco and Associates, Inc.
Edward A. Fitzgerald, Fitzgerald Consulting
Thomas Genova, Ph.D., Johnson & Johnson
John W. Levchuk, Food and Drug Administration (retired)
John M. Lindsay, Aseptic Solutions, Inc.
Jeanne E. Moldenhauer, Excellent Pharma Consulting
Robert J. Nolly, University of Tennessee, Pharmaceutical Sciences
Laura A. Thoma, Pharm. D., University of Tennessee, Pharmaceutical Sciences
Contributors:
Mark Birse, Medicines and Healthcare Products Regulatory Agency
Mark Ellison, Medicines and Healthcare Products Regulatory Agency
Andrew Hopkins, Medicines and Healthcare Products Regulatory Agency
Ian Jackson, Medicines and Healthcare Products Regulatory Agency
Terry E. Munson, PAREXEL Consultants
Michelle Rowson, Medicines and Healthcare Products Regulatory Agency
2
1
By: Carol Lampe
Technical Report Purpose
Outline methods and approaches for control
and evaluation of aseptic processing
operations for drug products/medicinal
products which use all or partial manual
procedures.
Image courtesy of pharm.lancasterlabs.com
3
Technical Report Scope
Build upon & supplement, published guidance
which is generally more focused on automated
large-scale operations.
4
2
By: Carol Lampe
Technical Report Scope
The guidance provided in this report may be
applicable to operations including:
Vaccine
preparation
Cell culture
Gene therapy
Investigational
New Drug/IMP
manufacturing
Clinical and
commercial
manufacturing
Pharmacy
formulation
and dispensing
5
Out of Scope
Human intervention into an otherwise
automated filling process. Examples include:
• Reach-ins to remove a toppled vial from the
filling line or to obtain a container for quality
testing
• Aseptic connection made during set-up
• Corrective activities during line stoppages
6
3
By: Carol Lampe
Blanket Statement
• When manual aseptic processing of sterile dosage
forms is required, special consideration must be given
to sterility and verification of processing accuracy:
– Training of Personnel involved in Sterile Preparation
Processes
– Environmental Control and Monitoring Requirements
– Specifications for Sterile and non-Sterile Ingredients and
Components
– Release Criteria for Sterility and Pyrogen Testing.
Note: Refer to the following documents 2004 FDA Guidance on Aseptic Processing, EU GMP
– Annex 1, Ph Eur 5.01.01 “Methods of Preparation of Sterile Products”, and USP
Chapters “Pharmaceutical Compounding – Sterile Preparations– Sterile Preparations” and
“Radiopharmaceuticals for Positron Emission Tomography – Compounding”
7
Table of Contents
1.
2.
3.
4.
5.
6.
7.
8.
Introduction
Glossary of Terms
Buildings and Facilities
Operational Personnel Training and Qualifications
Equipment, Components and Container/Closure
Process Time Limitations
Design of Manual Aseptic Processes
Evaluation of Manual Aseptic Processing – Process
Simulation
9. Conclusion
10. References
11. Additional Reading
8
4
By: Carol Lampe
Definition:
Aseptic Processing
Handling sterile materials
in a controlled
environment, in which
the air supply, facility,
materials, equipment and
personnel are regulated
to control microbial and
particulate contamination
to acceptable levels.
9
What makes MAP special? (1)
• Manual aseptic processing
(MAP) operations differ from
automated operations
• These differences pose unique
operational and evaluation
challenges
Image courtesy of inventionmachine.com
• These challenges must be
considered thoroughly when
designing the evaluation
procedure or protocol for the
MAP operation
10
5
By: Carol Lampe
What makes MAP special? (2)
MAP involves a human
operator performing, at
a minimum, the
container and/or
closure movements
MAP relies heavily on
individual operators’
basic understanding of
microbiology
proficiency
Personnel must be individually qualified
11
People - the Usual Suspects!
Human performance
deviations or failures are
linked to:
• Complex aseptic processing
tasks
• The continuous span of time
during which an operator
carries out repetitive aseptic
activities
• The expected rate of activity
• Change in personnel
12
6
By: Carol Lampe
Goal of Aseptic Processing Evaluation
Prevent the contamination of
sterile materials during their
processing
• Demonstrate that aseptic processing can be
achieved and maintained successfully under the
specified operational configuration, activities, and
conditions
• Same goals for manual or automated aseptic
operations and for small-scale or large scale
operations
13
Other Points
• Personnel performing the manual processes are
located in the surrounding clean area
• Appropriate gowning facilities are required
(consistent with the background environment
requirements)
• Execution of the MAP is usually supported by
sterilization equipment and processes for materials
• Overall flow of MAP facility, personnel and
equipment is consistent with large scale
environments
14
7
By: Carol Lampe
Elements of Training Requirements
Microbiological
Principles
Sterility
Assurance
Aseptic
Practices
Gowning
Practices
Sterilization
15
Risk Management
MAP frequently
involves greater
risks than automated
aseptic processes.
A risk-based quality
management system
is necessary.
“Quality risk management can be an effective
method of identifying and reducing aseptic
processing risk, thus improving the assurance of
sterility, endotoxin control, and subsequent patient
safety.” (PDA Technical Report 44)
16
8
By: Carol Lampe
APS
• Requires operators to perform aseptic interventions
during the simulation that are typically conducted
during manufacturing
• Operators will assemble the sterilized equipment
prior to the media fill
MAP are more susceptible to
Importance of APS
human contamination than
automated aseptic
processing
Interventions during MAP are
frequent; may be complicated
by suboptimal equipment
design.
Note: Aseptic processing simulations are understood to be synonymous with
media fills, simulated product fills, broth trials, broth fills, etc.
17
Manual Aseptic Interventions
• Frequent and may be complicated
• Individuals must demonstrate proficiency in
rigorous MAP requirements regardless of
technology used
− Various challenge tests where operator directly
handles sterile equipment and materials
− Representative of the actual process steps
Intervention: An aseptic manipulation or activity that occurs within the
critical area. This technical report regards interventions as either
corrective or inherent.
18
9
By: Carol Lampe
Equipment, Components
& Container/Closure
MAP is similar to automated lines, but on a
smaller scale:
Sealed package
is supplied to the
APA after
depyrogenation/
sterilization
Requires validated depyrogenation/
sterilization methods
Prep methods prior to depyrogenation/
sterilization similar to automated AP, but
smaller scale
If sterilization/ depyrogenation processes
cannot be used on non-product contact
surfaces, validated sanitization process must
be performed
When sterile containers/closures are
purchased from a commercial source,
procedures should be in place and
implemented to ensure the sterility of these
items are maintained when introduced into an
aseptic environment and used in production.
19
Process Time Limitations
MAP time limitations
more critical than for
Automated AP
Short/non-repetitive
processes time may be
of little relevance
“Worst case” fatigue
evaluation =
APS ≥ duration of longest
period of uninterrupted
task performance
APS at the end of a normal
day’s production can
evaluate the effect of
fatigue on the operator’s
aseptic technique
Repetitive tasks for long periods
fatigue must be considered in both
routine operation and the APS.
The operator’s aseptic technique may
deteriorate with the passage of time.
20
10
By: Carol Lampe
Design of Manual Aseptic Processes
• Sterility assurance to mitigate contamination requires a
holistic approach that encompasses the following:
–
–
–
–
–
Facility
Equipment
Process design
Aseptic practices/validation
Risk Assessment
• Manual Aseptic Processes should be designed to
minimize the impact of personnel
– Process design reduces contamination risk
Aseptic Filling: The part of aseptic processing where a pre-sterilized
product is filled and/or packaged into sterile containers and closed
21
MAP Design Principles:
Unidirectional Air Flow Hood
(1-7)
• Adequate space to perform the work
• Exposed product and product-contact
components remain in First Air
• Aseptic manipulations made in First Air
• Decontaminate or change gloves on a
frequent basis
• Use sterile tools and utensdils
First Air (First Work Location): The work location first in the path of
HEPA filtered air
22
11
By: Carol Lampe
Restricted Access Barrier systems (RABs)
• Variable design
• Items introduced via rapid transfer port
(RTP)
OR
• May resemble manned clean rooms in
design and operation; similar to Unidirectional Air Flow Hoods
Image courtesy of Bayer Healthcare
• Aseptic, not sterile, process enclosures
• Aseptic technique must be followed consistent with the
design of the system (enclosure)
Restricted Access Barrier System (RABs): Aseptic processing systems (ISO 5) intended
to substantially reduce human borne contamination within the aseptic environment where
sterile product, containers, closures and equipment are exposed by the use of separative
devices and defined mechanical features and operating procedures
23
Isolators
• Sealed or supplied with air through a
microbial retentive filtration system (HEPA
minimum) and may be reproducibly
decontaminated
Image courtesy of Amercare, Ltd.
− Closed: Uses only decontaminated (where necessary) interfaces or
Rapid Transfer Ports (RTPs) for materials transfer
− Open: Allows for the ingress and/or egress of materials through defined
openings (“mouseholes”) that have been designed and validated to
preclude the transfer of contamination.
• Isolators can be used for aseptic processing activities, containment
of potent compounds, or simultaneously for both asepsis and
containment
Validation: Establishing documented evidence that provides a high degree of assurance
that a specific process will consistently produce a product meeting its predetermined
specifications and quality attributes.
24
12
By: Carol Lampe
Isolators and RABs
(1-4)
Decontaminate enclosure according validated procedure
Fresh sterile gloves prior to entering enclosure gloves
Use sterile tools and utensils rather than direct contact
with the enclosure gloves
Introduce items and equipment into enclosure via
validated decontamination / sterilization methods and/or
RTPs
Perform as much of the process as possible inside the
enclosure to minimize removal & re-entry of sterile items
25
Evaluation of MAP: Process Simulation
• Process Simulation Design
• Media Sterilization*
• Frequency and Number of
APS Runs
• Observation of the
Process Simulation*
• Media Fill Volume*
• Anaerobes / Inert Gassing*
• Environmental Monitoring
• Execution of the
Simulation
• Pre-Incubation Inspection*
• Incubation Time /
Temperature*
• Post-Incubation
Inspection*
• Growth Promotion*
• Interpretation of Test
Results
*Similar to automated processes
26
13
By: Carol Lampe
Process Simulation Design
•
Supporting Rationale
– Media fill design must simulate routine manufacturing
– Define adaptations to the production process
•
Failure Investigations
– Maintaining the sample
contamination point
fill
sequence
can
aid
in
determining
– Include definition of sample points in the rationale
•
Keep Current
– Update the simulation rationale with changes to process, products,
components, or equipment that could impact acceptability
– Changes will require rationale and support of qualification (3x) or
requalification (1x)
27
Frequency & Number of APS Runs
Operator
Qualification
• Semi-annually or in accordance with the
applicable regulatory requirements
• Initial qualification is typically three replicate
APS studies
• More frequent studies may be required for
infrequent manufacturing operations
Duration of
Runs
• Should meet or slightly exceed the expected
maximum duration of a single working
session by a single operator
Size of Runs
• Dictated by the time period that a single
operator performs the same activity
• Actual numbers of units produced in that time
period should meet or exceed the normal
production quantity
28
14
Interpretation of Test Results
By: Carol Lampe
(1)
• MAP Production lots are typically smaller
standard minimum simulation size of 5,000
units
– MAP simulations in support of container filling must
have a contamination frequency of zero (0) filled
units
– In compositing or formulation simulations, the
simulated bulk material container(s) should be
sterile
29
Interpretation of Test Results
(2)
Technical hurdles in achieving this goal
• Media and simulated product do not match real
product processing characteristics
• Media simulation differences in solubility, pH, filtration
rates, filterability and viscosity
• Reconstituting powdered simulation materials or
adding extra equipment or manipulation increases
contamination risk
• Microbiological medium is designed to support /
stimulate microorganism growth versus processed
product hostile anti-microbial characteristics
30
15
By: Carol Lampe
Conclusion
• This technical report is one of the first attempts to
address the subject of manual aseptic processing
• Manufacturers that use manual aseptic processing to
produce products used in patients must be aware of
the uncertainties associated with a manufacturing
process so heavily reliant on personnel performance
• In new installations, it is strongly encouraged to use
isolation technology to minimize the risk of microbial
contamination from personnel involved in the
manufacturing operations
31
Future Updates
• MAP of non-aqueous drug products
• Additional information on “process time
limitations”
• Additional information on “equipment,
components and container/closures”
32
16

Recommended Practices for Manual Aseptic Processes PDA Technical Report 62 Authors:

Transcription

Similar documents

impianto di produzione acqua sterile tramite filtrazione

Company Image - Greatview Aseptic Packaging Company

1-800-344-2554 www.imiweb.com

PDF - European Association of Hospital Pharmacists

Aseptic Valve Programme GEMBRA

striving for the best

Why Drugs Cost So Much

Sterile Hand Bulb Brochure