Sec. 490.100 Process Validation Requirements for Drug Products and Active
Pharmaceutical Ingredients Subject to Pre-Market Approval (CPG 7132c.08)
This guidance document represents the Food and Drug Administration's (FDA)
current thinking on this 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.
BACKGROUND:
This Compliance Policy Guide (CPG) explains the Center for Drug Evaluation
and Research (CDER), Center for Biologics Evaluation and Research (CBER), and
Center for Veterinary Medicine (CVM) enforcement policy regarding the timing
of the completion of certain process validation activities for the products
covered by this CPG.
This policy guide covers sterile as well as non-sterile manufacturing processes,
but it does not address the methods and controls designed to ensure product
sterility (e.g., aseptic fill validation). New drug applications for sterile
products include information about the intended sterilization or aseptic processing
procedures. The Centers evaluate this information as part of the application
review process. CDER, CBER, and CVM may also issue assignments to district
offices to audit and assess the filed information as well as any additional
information that demonstrates the adequacy of the sterile process.
This CPG does not address products approved by a Biologics License Application
(BLA) or recombinant protein drug products submitted in a New Drug Application
(NDA).
Validation of manufacturing processes is a requirement of the Current Good
Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (21
CFR 211.100 and 211.110), and is considered an enforceable element of current
good manufacturing practice for active pharmaceutical ingredients (APIs) under
the broader statutory CGMP provisions of section 501(a)(2)(B) of the Federal
Food, Drug, and Cosmetic Act. A validated manufacturing process has a high
level of scientific assurance that it will reliably produce acceptable product.
The proof of validation is obtained through rational experimental design and
the evaluation of data, preferably beginning from the process development phase
and continuing through the commercial production phase. Refer also to the Guideline
of General Principles of Process Validation (May 1987, originally published
by CDER, CBER, and CDRH and presently recognized by CDER, CBER, and CVM).
(Note: The guideline is under revision as of the date of this CPG.)
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. Normally, this is achieved after
satisfactory product and process development, scale-up studies, equipment and
system qualification, and the successful completion of the initial conformance
batches. Conformance batches (sometimes referred to as "validation" batches
and demonstration batches) are prepared to demonstrate that, under normal conditions
and defined ranges of operating parameters, the commercial scale process appears
to make acceptable product. Prior to the manufacture of the conformance batches
the manufacturer should have identified and controlled all critical sources
of variability.
POLICY:
- Conformance batches:
New drug applications may be approved by the Center prior to the 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, except as identified below.
- Inspection of validation activities during a pre-approval inspection:
If a pre-approval inspection is performed, the inspection team should audit
and assess any available process validation protocols, activities, data,
and information, whether or not completed, and report to the firm any deficiencies.
The district should recommend withholding approval of an application if
any
completed validation efforts include data of questionable integrity or
demonstrate that the process is not under control and the firm has not committed
to making
appropriate changes. Refer also to the Center pre-approval inspection compliance
programs for additional guidance.
If during a pre-approval inspection, process validation activities are
found significantly deficient for an approved product made by a process similar
to
that of the subject of the pre-approval inspection and for which a warning
letter or regulatory action will be proposed, the district should recommend
withholding approval of the application.
- Inspection of validation activities during a post-approval inspection:
If the initial conformance batch validation activities for a particular
approved product were not substantially inspected and found satisfactory
during the
pre-approval inspection, the district should cover this activity for the
approved application or a substantially similar process/product during the
next routine
CGMP inspection (see Compliance Programs 7356.002 for human drugs, and
7371.001 for animal drugs).
The district should inspect the firm’s validation
activities for the new product within the first year of manufacture at
commercial scale (if not inspected during the pre-approval inspection)
if any of the following conditions apply:
- the new drug is the first produced by the manufacturing site;
- the firm has had previous problems validating a similar process for another
product;
- the product is manufactured by equipment or process that is substantially
different from equipment or processes previously used by this firm; or,
- the product is made by a process involving inherently variable unit operations
or complex operations or procedures (see Compliance Programs 7356.002
for human drugs, and 7371.001 for animal drugs; and consult further with
the
Center's reviewing office for the product being inspected and/or the
Office of Compliance subject contact for further guidance).
If none of the above conditions apply, the district should evaluate validation
activities for new products during the next routine CGMP program inspection
(7356.002). Alternatively, for sites with a history of successful validation
efforts for related products made by similar processes the district may
request the process validation protocol and report to be sent to the district
office
for audit and assessment. Based on the review of this information, additional
on-site inspection, evaluation, and documentation of the information received
may, or may not be conducted at the district’s discretion unless
directed otherwise.
If a firm’s validation activities for the new product are found to
have significant deficiencies (e.g., the initial conformance batch phase
was not
completed, the protocol was not followed or is inadequate, or validation
data indicates process is not adequate), and one or more batches have been
distributed,
the district office should recommend regulatory action.
Seizure of distributed batches should be considered when there are significant
deficiencies with validation or the evidence demonstrates the product does
not comply with specifications. Injunction should be considered when there
are significant deficiencies or data demonstrating the process is not capable
of producing product meeting the established specifications.
- Completion of initial conformance batch manufacture prior to commercial
distribution:
For some products, the completion of the initial conformance batch phase of
process validation before the distribution of any one batch would require the
manufacture of unneeded batches (e.g., certain orphan drug products), which
would not be in the interest of public health. In addition, the completion
of multiple batches before first distribution may also be impractical for a
product with a very short shelf-life or that is intended for limited use (e.g.,
some radiopharmaceuticals). Therefore, the need to manufacture multiple conformance
batches in advance of initial product distribution may not be needed under
these circumstances. In such cases, product distribution may have occurred
concurrently with the release (or approval for release) of each conformance
batch.
The agency’s evaluation of a firm’s decision to release batches
concurrent with the manufacture of the initial conformance batches should
include review and/or audit and assessment of:
- the firm’s basis for justifying the distribution of individual batches
prior to completion of the initial conformance batches (to include review
of the product/process development effort);
- the firm’s protocol/plan and available data to verify that there
are adequate batch controls and testing prior to release for distribution
of each batch, and provides for adequate and timely assessment of the
validity of the process once all initial conformance batches have been manufactured;
and,
- the firm’s program for monitoring distributed batches and provisions
for a rapid response to information suggesting the process is not under
control (e.g., subsequent batch failures, production problems related to
process
design or equipment performance, complaints).
Advanced pharmaceutical science and engineering principles and manufacturing
control technologies can provide a high level of process understanding
and control capability. Use of these advanced principles and control technologies
can provide a high assurance of quality by continuously monitoring, evaluating,
and adjusting every batch using validated in-process measurements, tests,
controls,
and process endpoints. For manufacturing processes developed and controlled
in such a manner, it may not be necessary for a firm to manufacture multiple
conformance batches prior to initial distribution. Agency staff (field
and Center) should discuss the need for conformance batches prior to distribution
with the designated agency contacts when inspecting firms employing these
advanced
pharmaceutical science and engineering principles and control technologies.
The district should consult with the appropriate agency contact before
initiating regulatory action based on insufficient validation under the above
circumstances.
- Active Pharmaceutical Ingredients:
Under the broader statutory CGMP provisions of section 501(a)(2)(B) of the
Act, process validation, including the manufacture of initial conformance batches,
is also expected for Active Pharmaceutical Ingredients (APIs), but the specific
expectations differ somewhat from those required for dosage form products.
Refer to the Guidance
for Industry, Q7A, GMP Guidance for Active Pharmaceutical Ingredients, issued
August, 2001, for details.
If the API for an application under review is already used in other approved
or marketed dosage form products, and is being made by substantially the
same process and scale as for the application under consideration for approval,
the inspection should cover full process validation data and activities
(including
conformance batches), unless covered during a previous inspection of the
API manufacturer. If validation is covered and significant deficiencies are
found,
the district is to recommend withholding approval of the dosage form application
and consider proposing action to address the use of that API in other dosage
form products.
If the API for an application under review is a new molecular entity or
is being manufactured by a process substantially new in design or scale to
the
site of manufacture, approval of the dosage form incorporating the API
is not to be delayed by the performance of initial conformance batches for
the API.
However, the inspection team is to audit and assess any available process
validation protocols, activities, data, and information whether or not completed,
and
report to the firm any deficiencies. The district should recommend withholding
approval of an application 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.
Some biotech NDAs include information about the validation of the manufacturing
process for the API, and this information is reviewed in conjunction with
the other chemistry, manufacturing, and controls information in the application.
In these cases, the inspection team should audit the accuracy and completeness
of the data and information submitted to the application. Potentially objectionable
findings should be handled consistent with the applicable compliance program
and include consultation with the Center reviewer and/or compliance officer
before making any formal objection to the firm.
If during a pre-approval inspection of the API manufacturer, process validation
activities are found significantly deficient for an API made by a process
similar to that of the API under inspection and for which a warning letter
or other
regulatory action will be proposed, the district should recommend withholding
approval of the dosage form application. The district should also recommend
withholding approval 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.
If batches have been distributed, the district should consider recommending
an appropriate regulatory action.
NOTE: This compliance policy guide (CPG) also applies to pre-market approval
applications submitted to the Center for Veterinary Medicine (NADAs or ANADAs).
The CPG reference may be found at Sec. 638.100 (7125.38).
Issued: 08/30/1993
Revised: 03/12/2004