VALIDATION

What is the new guidance?

What is a Compliance Policy

Guide?

Explain FDA policy on regulatory issues

CGMP regulations and application commitments.

Advise the field staff on FDAs standards

and procedures to be applied when
determining industry compliance
CPGs may come from a request for an
advisory opinion, from a petition from
outside the Agency, or from a perceived
need for a policy clarification by FDA
personnel.

The Big Disclaimer

It represents the FDA's current thinking

on the topic.
It does not create or confer any rights
for or on any person and does not
operate to bind FDA or the public.
An alternative approach may be used if
such approach satisfies the
requirements of the applicable statute
and regulations.

Process Validation
Requirements for Drug
Products and APIs Subject to
Pre-Market
CPGApproval
490.100

Background

The CPG covers

CDER/CBER/CVM products
Sterile and Nonsterile processes

The CPG does not address methods

and controls designed to ensure
product sterility (e.g. aseptic fill
validation)
Does not cover BLAs or recombinant
protein drug products

Areas of interest

Conformance batch
Validation before PAI
Validation before commercial
distribution
Process analytical technology
API process validation

When is process validation

expected?

Not necessary before an NDA is

approved

Although many prefer to validate the

manufacturing process prior to the
preapproval inspection.

Reduce time to market

Gain additional process information

It is necessary before commercial

distribution

Why Validate?

Quality by design, built in

Cant inspect quality in
Demonstrate control of process
Good science
Good business
Its the law

Process Validation and the

Law

Dosage Forms

Required by CGMPRs (211.100;

211.110)
Enforced as GMP under the FD&C Act
(501(a)(2)(b))

APIs

Enforced as GMP under the FD&C Act

(501(a)(2)(b))

Validated Process

Provides a high level of scientific

assurance to reliably produce
acceptable product

Using rational experimental design

Evaluation of data
From development to commercial
phase

What is expected?

Before commercial distribution

begins, a manufacturer is expected
to have accumulated enough data
and knowledge about the
commercial production process to
support post-approval product
distribution.

There is a new term!!

Conformance Batch

Prepared to demonstrate that,

under normal conditions and
defined ranges of operating
parameters, the commercial scale
process appears to make
acceptable product.

Conformance Batches

Formerly known as validation batches

NDAs may be approved prior to
completion of the initial conformance
batch phase of process validation
The manufacture of the initial
conformance batches should be
successfully completed prior to
commercial distribution

Inspection of validation
activities during a PAI

PAI team will assess any validation

activities whether completed or not
A withhold recommendation will be made if:

Questionable integrity
Demonstrate that the process is not under
control
Firm has not committed to making appropriate
changes
If deficiencies found in already approved
product validations

Inspection of validation
activities - - post-approval

Cover within 1st year of manufacture

at commercial scale if

It is the first drug produced at the site

There were previous problems validating
a similar process for another product
Equipment/process is substantially
different from existing
equipment/processes
Inherently variable/complex operations

Inspection of validation
activities - - post-approval

If a firm has a good validation

history with similar
products/processes

Process validation protocol & report

may be sent to District office for
evaluation

Inspection of validation
activities - - post-approval

If significant deficiencies in
validation efforts are found

Initial conformance batch phase not

completed
Protocol not followed or inadequate
Data shows process not in control

And product has been distributed

Recommend regulatory action

Completion of
conformance batches prior
to
distribution

It is expected for most products

May not be needed for certain
products

Orphan drugs
Radiopharmaceuticals

Completion of
conformance batches prior
toIf product
distribution
distribution is to be

concurrent with release of

conformance batches, FDA will assess:

Basis for justification

Protocol/plan & available data to verify
controls prior to release; eventual process
validation
Post distribution monitoring for problems

Process analytical
technology

For manufacturing processes that

use PAT, it may not be necessary
for a firm to manufacture multiple
conformance batches prior to initial
distribution.
This will be decided on a case by
case basis by FDA depending on
how and the extent PAT is used.

APIs used in other already

approved drug products

Process validation is expected prior

to approval of the application if the
API is already being used in
another drug product and is made
by essentially the same
process/scale
Conformance batches will be
reviewed

APIs: NMEs or new

process

Not having completed process validation and

initial conformance batches will not delay
approval of the NDA
FDA will audit and assess any available process
validation protocols, activities, data, and
information whether or not completed
A withhold recommendation will be made if any
completed API validation efforts include data of
questionable integrity or demonstrate that the
API process is not under control and the firm has
not committed to making appropriate changes.

APIs & Biotech

Some biotech NDAs require

validation information to be
submitted as part of the CMC
section.

Deficiencies in other
validated API processes

If process validation activities are deficient for

an API process similar to that of the API under
inspection and for which a warning letter or
other regulatory action will be proposed, a
withhold recommendation for the dosage form
will be made.
A withhold recommendation will be made if the
API firm has not established or is not following
an adequate initial conformance batch validation
plan/protocol or when the process is not under
control as demonstrated by repeated batch
failures due to manufacturing process variability.

So What Is New?
(nothing really
Wink, wink
Nudge, nudge!!)

So What Is Missing?