Expectations for Early Phase
cGMP
Andra Miller
The Biologics Consulting Group
301-871-1259
CBER’s Expectations for cGMP
Compliance
• GMPs expected throughout clinical studies
• Level of compliance should increase as phases of
study progress (stepwise approach)
• Important early: adequate facility, QC/QA, aseptic
processing, documentation
• GMPs that develop with clinical studies:
– Process validation, Methods validation, Process
controls
Early Phase cGMP
How to define the essential
elements?
How to define?
Early Phase
• Identify critical steps in function of facility
and in process
• Develop controls
Vector Production Facility
Incubator
Supplies
Storage
Hood
Waterbath
Production
In/Out
Final Product
Storage
Vector Production Facility
Training
Cleaning
Monitoring
Incubator
Supplies
Storage
Hood
Waterbath
Production
Equipment
Release testing
DOCUMENTATION
Receipt
Storage
Final Product
Storage
In/Out
Distribution
Documentation
• Procedures
– Standard Operating Procedures (SOPs)
• Facility cleaning
• Manufacturing
• Records
– Log of procedures performed
• Batch production records
• Lab records
• Cleaning log
Procedures
• Standard Operating Procedures- SOPs
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Details of operations/ instructions
Written
Accessible to those doing work
File should be historical- tracks changes to
procedures
– Eventually all functions impacting product
manufacture should be documented in SOP
– Drafted by appropriate organizational unit,
reviewed and approved by QA unit.
Records
• Document accuracy of implementation of
procedure
• Filled out in real time
• QA review and authorization of completed
records on routine basis
Documentation- General
• Must reflect reality
• Must be followed
• SOP Change Control
– Procedure for modifying an SOP- proactive change
• Process, authorization, implementation
• Deviation reports
– Documents a change from SOP that was not proactive
– Record and justify on a separate form- signed
– Store with relevant record
Documentation- General
• Investigation reports
– Documents investigation into reason for
deviation, conclusions and follow-up
– Example: positive sterility
• Quality assurance review and authorization
of SOPs and Records
Importance of Documentation
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Allows control of the Facility
Allows control of Manufacturing Process
Tracking of Product Lots
Reviewed Upon FDA Inspectiondemonstrates control
Vector Production Facility
Training
Monitoring
Cleaning
Incubator
Supplies
Storage
Hood
Waterbath
Production
Equipment
Release testing
DOCUMENTATION
Receipt
Storage
Final Product
Storage
In/Out
Distribution
Training
• Each person involved in preparation of drug
product shall have the education, training or
experience to perform the assigned
function.
• Training should be in particular operation
and cGMPs.
• Anyone entering facility needs training &
supervision (not a research lab)
Training- Procedures
• SOP for training-when, how and content
– Particular operations - individualized
– GMPs – ongoing, repeated
• Training conducted by qualified individual on a
continuing basis
– Formal courses, in-house program, on-the-job
• Personnel at all levels should have appropriate
training
– Management, scientific staff, technical staff,
maintenance/custodial staff.
Training- Records
• Record of training program elements and
materials – serves as documentation and
reference
• Record for each personnel:
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Job description
Training requirements (based on activities)
Documentation of training completed
Curriculum vitae
Cleaning and Sanitization- SOP
• Describe cleaning and sanitization process, agents,
frequency/schedule, personnel responsible
• For Phase I, cleaning agents selected based on
manufacturer’s specifications – no formal
validation
• Gather information on effectiveness to control
organisms in facility via environmental monitoring
(alter as needed).
• Use more than one cleaning agent in program
Cleaning and Sanitization
Records
• Log to verify that cleaning and sanitization
performed according to SOP
• For each individual activity/ room
– Date
– Time
– Signature
Environmental Monitoring
• SOP to monitor:
– Viable and non-viable particulates, surfaces,
personnel
– Methods, Location, Frequency, Responsible
party
– Define alert limits and action limits and
procedure for follow-up
• Records/logs:
– Date, location, method, result, signature
Entering Facility
• Since bi-directional, need SOP for entry and exit
to give temporal separation
– Personnel
– Waste
• Gowning Procedure
– Protective clothing used and order of gowning
– Available for reference
• Records- Log of personnel entering to maintain
control
Receipt and Storage of Materials
SOP
• Record Date of Receipt, Lot number in a Log
• Visual inspection upon receipt
– Damage, proper labeling
• Storage in quarantine, pending release
– Label as to status of material (quarantined)
– Segregate from released materials
• Qualifying materials for use
– Inspection or test as needed (identity, purity, quality) by QC unit
– Must conform to written specification
• Release from quarantine
– Re-label as to status of material (released or rejected)
– Stored with released materials
Receipt and Storage of Materials
Records
• Log for each material received
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Date of receipt
Lot number
Date of quarantine
Result of qualification testing
Release date, signature
Equipment Qualification and
Maintenance
• SOP
– For cleaning, maintenance, qualification for use
• Testing Water bath temperature, and maintenance
• Cleaning procedure and schedule of maintenance for Biosafety
Cabinet
• Records
– Log documenting each activity was carried out
– For each piece of equipment, log recording the batch
processed (date, time, product and lot number)
Manufacturing Process
SOP
• Detailed instructions and protocols for each
step in the manufacturing process
• To assure uniformity from batch to batch
– Documentation of deviations
– Change SOP
Manufacturing Process
Records
• Batch Production Record (BPR)
– Prepared for each batch produced
– Complete information relating to production and
control of each batch
– Documentation that each significant step in
manufacturing, processing, packaging or holding were
accomplished
– Record of materials and equipment used
– Reviewed and approved by QA unit to determine
compliance with SOP prior to release and distribution.
Product Storage and Quarantine
• Written SOP for storage of products,
pending release including:
– Requirements for Quarantine before release by
QC unit
– Requirements for storage under appropriate
conditions so identity, purity, and quality are
not affected
• Records to reflect quarantine of product
pending release (product, lot number, date)
Testing and Release for
Distribution- SOP
• Written procedures for sampling and testing
• QC testing for identity, potency, purity, and
safety
• Established specifications/ acceptance
criteria
• Product must meet specifications for release
Testing and Release- Records
• Laboratory records- include complete data
derived from tests
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Description of sample
Method used, calculations performed
Record of all data
Testing results and signature of “tester”
• Certificate of Analysis listing all tests performed,
specification and result for product- tabular format
• Record of product movement from quarantine to
release status
• QA review and approval for product release
Product Distribution –SOP
• Written procedures describing the
distribution of products including:
– Procedure for oldest approved stock to be
distributed first
– A system by which the distribution of each lot
can be readily determined to facilitate its recall
if necessary
Product Distribution- Records
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Name and strength of product
Description of dosage form
Name and address of consignee
Date and quantity shipped
Lot number
Documentation of receipt by consignee
– Return mail
– Date, amount received, conditions of product and
signature
Product Tracking
• Extends from who was in facility, reagents,
materials, equipment used in production through
storage, release and distribution
• Trace entire product “history”
• Important if any problem occurs
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Assay result
Malfunction of equipment
Patient adverse event
Product recall
• Control over entire process
Summary
• cGMP is important at all phases of development
but can be implemented in a step-wise approach
• Early phase cGMP requires attention to the
facility, documentation and QC/QA.
• Early phase cGMP elements can be defined by
identifying steps in the facility and the
manufacturing process that are critical for control
over the process and seem logically necessary for
production of a safe and consistent product