Post on 16-Dec-2015
What is a Compliance Policy Guide?
Explain FDA policy on regulatory issues CGMP regulations and application
commitments. Advise the field staff on FDA’s 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 Approval
CPG 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 Can’t inspect quality in Demonstrate control of process Good science Good business It’s 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 to distribution
If product 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.
API’s 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
API’s: 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.