Process Validation Regulatory

Requirements for Biologics

Conference on
PROCESS VALIDATION
for Biopharmaceutical Manufacturing
October 8-9, 2003
Philadelphia

Elizabeth Leininger, Ph.D.

Process Validation
from a Regulatory Perspective

‹ Regulatory Guidance Documents

‹ Regulatory Expectations
– Purpose of Process Validation
– Validation Life Cycle
– Validation Approached
‹ General Observations
Process Validation: Requirement of cGMP for
Finished Pharmaceuticals (21CFR 210 and 211)

‹ Written Procedures
‹ Process Control
‹ Control Procedures
‹ Validate Performance

→ To assure that the drug products have identity,

strength, quality, and purity they purport or are
represented to possess
Assurance of Product Quality
‹ Selectionof quality parts and materials
‹ Adequate product and process design
‹ Control of the process
‹ In-process and end product testing
Quality Assurance Goal: Production of
articles that are fit for their intended use

‹ Quality, safety and effectiveness must be designed and

built into the product
‹ Quality cannot be inspected or tested into the finished
product
‹ Each step of the manufacturing process must be
controlled to maximize the probability that the
finished product meets all quality and design
specifications

→ Process Validation key element in assuring that these

quality assurance goals are met
 Validation

‹ Establishing DOCUMENTED EVIDENCE which

provides a high degree of assurance that a specific
process will CONSISTENTLY PRODUCE a product
meeting its PRE-DETERMINED SPECIFICATIONS
and QUALITY ATTRIBUTES.

(US FDA Guidance on General Principles of Process Validation, May, 1987)

A Validated Process
‹ Consistently produces a product
– Control of the process
– Minimize product failure
– Meet cGMP
‹ Consistently meets pre-determined specifications
and quality attributes
– Quality built into the product
– Suitable for its intended use
Regulatory Guidance Documents
‹ FDA Guideline on General Principles of Process
Validation (May 1987)
‹ ICH Q7A: Good Manufacturing Practice for
Active Pharmaceutical Ingredients, Section 12
(Validation)
‹ Annex 15 to the EU Guide to Good Manufacturing
Practice (Qualification and Validation)
‹ EudraLex (volume 2B) Part II - Concerning
Chemical, Pharmaceutical and Biological
Documentation for: Biological Medicinal Products
(Section 1.5 Production, 1.8 Process Validation)
Validation Requirements from
Guidance Documents
‹ Critical Parameters/attributes should be identified
during the development stage, and the ranges
necessary for reproducible operation should be
defined.
‹ Critical process parameters should be controlled
and monitored.
‹ Specifications should already be set and approved
prior to the start of the process validation at full
scale.
‹ Testing to the pre-approved specifications is done
with valid assays. Specifications under Change
Control
Validation Requirements from
Guidance Documents (cont.)
‹ Impurity profile must be confirmed.
‹ All equipment, facilities and systems are qualified
before the Process Validation starts
‹ Batches should be the same size as the intended
commercial scale.
‹ A sufficient number of runs should be analyzed,
the number is based on the complexity of the
process.
‹ Validation lots must meet specification
Process Validation Program
PROPOSE, DEFINE & IDENTIFY
‹ Evaluation Studies
‹ Development Studies

CONFIRM
‹ Validation Studies
– Process Validation Protocol
– Critical Process Parameters defined and documented
» Locked Process
– Defined Impurity Profile
– Approved Specifications
– Valid Assays
– Defined number of lots
 Process Validation Development Cycle:
Small Scale & Pilot Plant Activities

Evaluation Studies
•Define Process
unit operations/process steps
•Define operating parameters/
Development process variable
Studies •Identify key/critical operating
Laboratory Models parameters
Pilot Scale •Define product characteristics
& quality attributes

Analytical Methods
Development
Process Validation Development Cycle:
Commercial Scale Activities
Meet established criteria
Validation protocol and specifications

At least 3 consecutive
commercial scale lots Validation report

Pre-approved specifications
Valid analytical assays Validated manufacturing
process
Qualified facilities,
equipment &
systems
 Process Validation Program
[Slide by Chris Joneckis, CBER, FDA (Sept 2003)]

Source/starting material Development Studies

characterization Change Control
Equipment Monitoring/Trending
Raw materials IQ, OQ, PQ
qualification (Statistical Process
Consistency Lots – “validation study” Control PC)
Evaluation studies for
clearance of viruses/
impurities-control of Materials qualification
production scale Analytical Methods
Vaccine/toxin and Assay Qualification
inactivation on
production scale Product Accumulated “Validated
Characterization manufacturing Process”
experience

Discovery Clinical (IND) BLA Post-Approval

Pre-clinical
 Validation Life Cycle
[Slide (modified) by Chris Joneckis, CBER, FDA (Sept 2003)]

Revalidation Evaluation
(propose)

“Validated Development
Commercial Laboratory
Qualified Studies
Manufacturing Scale Model
(identify)
Process”
(monitor) Commercial Pilot
Scale Scale

Maintenance
cGMP validation
Monitor Study
Change Control
(confirm)
Validation Life Cycle
‹ Process and product experience Development Reports
– Define your process (documentation of critical
– Define your product
– Data driven process parameters)
– Identify what’s critical
‹ Process Validation
– Documented evidence of defined
process under control Validation Reports
– Known quality of product
– Confirm what you established
‹ State of Validation
– Maintain thru change control Change Control
– Trending and monitoring
– Revalidation

→Validation must be comprehensive and continuous

Process Validation Approaches
‹ Prospective
‹ Concurrent
‹ Retrospective

‹ GenericClearance Studies
‹ Modular Clearance Studies
Process Validation Approaches:
Prospective Validation

‹ Validation conducted and completed prior to the

distribution of either a new product, or product
made under a revised manufacturing process,
where the revisions may affect the product’s
characteristics
Process Validation Approaches:
Concurrent Validation
‹ Validation which includes all elements of validation
except that the replicate production runs can occur
in conjunction with release of product distribution
‹ Created by CBER
‹ Limited application
‹ Heighten testing
– Increase frequency and or additional testing
Process Validation Approaches:
Retrospective Validation

‹ Validation of a process for a product already in

distribution based upon accumulative production,
testing and control data
Process Validation Approaches:
Generic Clearance Study

‹ Generic Clearance Study: virus clearance is

demonstrated for steps in the purification of a
model mAb and extrapolated to another mAb
following the same purification and clearance
scheme as the model mAb. (PTC mAb, 1997)

‹ Modular Clearance Study: virus clearance is

demonstrated on individual purification steps
(modules) and identical modules can be
extrapolated. (PTC mAb, 1997)
Process Validation Observations
FDA Inspections and 483s
Conference on
PROCESS VALIDATION
for Biopharmaceutical Manufacturing
October 9, 2003
Philadelphia

Elizabeth Leininger, Ph.D.

 Process Validation 483s
Documentation
‹ Site Master Validation Program does not identify production
steps to be validated
‹ Program does not specify time frames for completion of
validation protocols
‹ Process validation limited to retrospective studies; no
prospective or concurrent studies
‹ Validation protocols were not consistently written according
to established procedures
‹ Validation studies are executed prior to approval of the
protocol
 Process Validation 483s
Documentation
‹ Validation Reports includes acceptance criteria that were
not contained in the Validation Protocol
‹ No definition of what constitutes an acceptable validation
‹ Protocol deviations were not always documented,
investigated, and/or corrected
‹ Validation studies are not given independent, final
approval by QA
 Process Validation 483s
Chromatography
‹ No validation for column load volumes for…
‹ No assurance column packing procedure adequately
validated
‹ Maximum number of uses of purification column not
validated
‹ No data to support the between run hold times of the
purification column
Process Validation 483s
Processing
‹ No established validated time limit for processing…
‹ Production time limits have not been established for
inoculum fermentation
‹ No usage limit has been established for ultrafilters used
for…
‹ No validation data to support mixing times used during
addition of excipients
‹ No hold time studies were conducted for buffers and
rinse solutions used in production
Process Validation 483s
Assays

‹ Bioburden method used in both validation and

routine monitoring not validated
‹ Method used to assess protein concentration of
active ingredient not validated
‹ HPLC method used for release and stability testing
before validation was complete
‹ Systems used to identify water, environmental, and
bioburden monitoring isolates not validated
‹ An impurities profile has not been established for
th active ingredient
Process Validation 483s
Equipment
‹ Installation/Operation Qualification of the process
equipment is lacking
‹ Inadequate qualification of vessels used for storage and
transport of sterile bulk product
‹ Inadequate validation of decontamination of fermenters
and media tanks: validation study did not result in all
acceptance criteria being met
‹ Storage/hold time for cleaned production equipment
has not been validated
 Acknowledgments

I would like to give thanks and acknowledgement to

many colleagues whom have contributed to this
presentation by providing input via discussions,
previous presentations and hands-on experience
with process validation.
 Elizabeth Leininger, PhD
Senior Consultant
Biologics Consulting Group
eleininger@BiologicsConsulting.com
(650) 222-4904