CHAPTER 56 -- DRUG QUALITY ASSURANCE
SUBJECT: Inspections of Licensed Biological Therapeutic Drug
Products |
IMPLEMENTATION DATE |
|
*Revision note: This program is being reissued as a
CDER program due to the transfer of certain biological products to CDER's
jurisdiction effective FY04. This
reissued program retains most of the instructions and procedures from the
prior version published by CBER: 7341.001. (CBER may continue this same program under
their program number (7341.001) for products remaining under their
jurisdiction.) Products regulated as human drugs by
CDER prior to the transfer of certain biological products from CBER are
subject to the existing Compliance Program for these products, 7356.002,
only.* |
COMPLETION DATE |
|
DATA
REPORTING |
||
PRODUCT CODES |
PRODUCT/ASSIGNMENT
CODES |
|
57YY- |
56002M GMP
Inspections 46832M
Pre-license Inspections |
|
FIELD REPORTING REQUIREMENTS:
Domestic Inspections: A copy of each establishment inspection
report (EIR), including endorsement and classification, should be submitted to *CDER, Office of Compliance
Division of Manufacturing and Product Quality (DMPQ), Investigations &
Preapproval Compliance Branch (HFD-322).* Exhibits should not be included unless
specifically requested. A copy of the coversheet and endorsement should be sent
to HFC-100. The complete original
report, including exhibits, should be sent to the home district for filing.
Foreign Inspections: The complete original EIR, including
exhibits, should be forwarded to *CDER Division of Manufacturing and Product Quality (DMPQ),
Investigations & Preapproval Compliance Branch, Foreign Inspection Team
(FIT), HFD-325, regardless of classification.* A copy of the coversheet and endorsement
should be sent to HFC-100.
PART I - BACKGROUND
FDA is
responsible for ensuring that biological products are safe and effective and in
compliance with the law and FDA regulations.
Biological products are licensed under the provisions of Section 351 of
the Public Health Service Act (42 USC) (PHS Act).
Licensed
therapeutic products are regulated under both the Federal Food, Drug and
Cosmetic Act (FD&C Act) and the PHS Act.
For those therapeutic products that meet the definition of a drug under
the FD&C Act, the manufacture of these products must be performed in
accordance with the cGMP regulations in 21 CFR Parts 210 and 211. As the products are also biologicals,
manufacturers must also comply with the applicable regulations in 21 CFR Parts
600-680.
Technical
advances over the last 15 years have greatly increased the ability of
manufacturers to control and analyze the manufacture of many
biotechnology-derived therapeutic products.
Specified biotechnology-derived products, defined in 21 CFR 601.2, are
exempted from complying with certain biologics regulations and are not required
to be submitted for lot release. These
products are (1) therapeutic synthetic peptides of 40 or fewer amino acids; (2)
therapeutic DNA plasmid products; (3) monoclonal antibodies for in vivo use;
and (4) therapeutic recombinant DNA-derived products.
*This program covers both specified and
non-specified therapeutic biological drug products now regulated by CDER, but
formerly regulated by CBER under this same program.*
Technology
While the
specifics of each manufacturing operation may be different, the manufacture of
therapeutic biological products has a number of common elements. The processes usually begin with a master
cell bank (MCB), which is derived from a single cell or colony and is stored to
assure genetic stability. The MCB
provides source material for the working cell bank (WCB), which is used to
initiate the production batch.
One
method of propagating sufficient cells to manufacture product is through
fermentation. Fermentation is the
process of multiplying the cells from the WCB into a quantity sufficient to
extract the desired product. Cells from
the WCB are inoculated into medium to begin fermentation. After a number of passages in small vessels
(usually flasks), the inoculated medium is added to a fermentation vessel,
usually a bioreactor. At the conclusion
of the fermentation process, the cells are subject to a variety of purification
steps, designed to remove extraneous cellular material and/or media components
and inactivate or remove any adventitious agents. Purification can include filtration,
chromatography, extraction, and enzyme digestion. The resulting final bulk product may be
filled in this form, further diluted and filled, or lyophilized before filling.
Team Biologics
In October
1998, responsibility for conducting biennial inspections of therapeutic product
manufacturers was transferred to the ORA Team Biologics/Core Team. The Core Team will also be primarily
responsible for handling any enforcement actions that result from inspections
performed under this program, in accordance with the procedures set forth in
the Team Biologics case processing procedure.
The Core Team will ensure that the home district is advised of
activities related to facilities in their areas and may solicit assistance from
the home district in carrying out the inspections or enforcement activities.
Pre-license
inspections are the responsibility *of CDER*, and will include a field investigator whenever
possible.
PART II - IMPLEMENTATION
A.
Objectives
This
program has the following objectives:
B.
Program
Management Instructions
Firms
covered under this program include all licensed manufacturers of biological
therapeutic drug products, including biotechnology-derived products.
Work
planning for these inspections will be coordinated by Team Biologics. Each facility and its biological products are
to be covered in a single, comprehensive inspection that assesses the adequacy
of all-significant processes and systems.
The inspections should be performed on at least a biennial basis, or
more often if circumstances, such as the firm's compliance history, so warrant.
The
inspections will be conducted using a team approach whenever possible, with an
ORA Team Biologics/Core Team investigator leading and a *CDER* product reviewer
participating. The inspection team may
include other ORA or *CDER*
members, as necessary, to assure appropriate coverage of the facility. If *CDER* on-site participation is not possible, the
Core Team will proceed with the inspection with other ORA members, as
necessary.
Historically,
there have been individual inspections for each therapeutic class. At some firms, this has resulted in a
burdensome number of redundant inspections.
This program departs from this practice, in that there will be one
inspection of a facility to cover all products.
If a company makes products reviewed by multiple divisions in *CDER*, the Center may
send individuals from each division, but they should try to stagger the
attendance of the additional persons to keep the number of individuals at the
firm at one time to a reasonable level.
PART III – Inspectional
Every
effort should be made to inspect each licensed firm at least once every two
years or more frequently if the firm’s compliance history so warrants.
A.
Inspectional
Procedures
Review
and use applicable sections of Compliance Program 7356.002, Drug Manufacturing
Inspections; Compliance Program 7356.002A, Sterile Drug Process Inspections;
and Biotechnology Inspection Guide. If
there are differences between the instructions in this program and the above
referenced documents, investigators should follow the instructions in this
program when conducting inspections of manufacturers of licensed biological
therapeutic products.
Manufacturers
of licensed biological therapeutic drug products are subject to the regulations
in 21 CFR Parts 600-680 and Parts 210 and 211.
Manufacturers of licensed products must also conform to the conditions
in their approved license applications and supplements. If it is necessary to verify the content of a
license application or supplement, contact CDER for assistance.
B.
Inspection
1.
Components
Manufacturers
who purchase components from outside sources are required to establish adequate
quality requirements and specifications for such components. The licensed manufacturer is ultimately
responsible for ensuring that components conform to specifications and are
acceptable for use. This may be done
through inspections, sampling and testing, and/or through certificates of
analysis from the supplier. Validity of
the certificates should be established by the manufacturer through experience,
historical data, testing, and/or audits of the supplier.
For
components received from outside sources, either purchased or otherwise
received, verify that:
Animal
source material must meet the applicable requirements of 21 CFR 600.11. Investigators should ensure that tests and
specifications for materials of animal source that may potentially be
contaminated with adventitious agents (e.g., mycoplasma, Bovine Spongiform
Encephalopathy for bovine-derived products, and others) as described in a
license application are performed. If
the license application includes certification supporting freedom of substances
from adventitious agents, this should be confirmed during inspections.
Acceptance
activities must be documented. Verify
that the manufacturer has defined methods, e.g., inspections, tests, and other
verification tools (certificates of analysis and/or supplier audits), to ensure
that components conform to all specifications prior to release for use in
manufacturing and that acceptance activities are documented in the batch
record.
Review
the manufacturing SOPs and batch records for a representative number of lots to
ensure that acceptance criteria are met for all components.
The
storage conditions for the MCB and WCB should be clearly defined. Ensure that the storage conditions have been
maintained. If the storage requirements
specify temperature limitations, ensure that there is documentation of the
temperature and determine if there is a working alarm system in place if the
temperature deviates from the established one.
Ensure
that the WCB has been characterized and met specifications before use. If any WCB that did not meet specifications
was used, determine which lot(s) of product was manufactured from the WCB and
the disposition of the product.
Ensure
the firm has records to show the origin and history (number of passages) of the
MCB and WCB.
Review
the records for inventory and handling of the WCB and ensure they are adequate
to protect the integrity of the cells.
Ensure the firm has records to show which WCB is used to initiate a
production batch.
If
the firm has generated a new MCB from a WCB, ensure that there is an approved
license application or supplement for this.
Ensure that the new MCB is tested and properly characterized.
The
firm should have well-established acceptance criteria for all materials. If buffers or media are prepared prior to
use, determine if the firm has established holding times and conditions,
validated the holding times and conditions, and has records to show the
conditions are met.
Ensure
that the firm has adequate written specifications and procedures describing the
receipt, handling, sampling, and storage of containers and closures, especially
those that need to be sterile and/or pyrogen-free.
Review
procedures for accepting/rejecting final product containers and closures from
the vendor. Determine whether the firm
conducts vendor audits and, if so, how and with what frequency.
Review
the procedures and controls used by the firm to verify and ensure suitability
of containers and closures. Evaluate
procedures used by the firm to validate the container/closure systems. Report any changes in container/closure
systems that have not been validated.
Review
SOPs for reconciliation of final containers.
Ensure
that depyrogenation and sterilization procedures for product containers,
closures, and components are appropriately validated, and routinely
followed. Equipment used for these
processes (stopper processors, tunnel sterilizers, ovens, autoclaves) should be
properly maintained and re-qualified periodically.
2.
Manufacturing
a.
Aseptic/controlled
process
Therapeutic
products are manufactured in a controlled environment. The entire process does not have to be done
under aseptic conditions, but the firm must have established the point in the
process where aseptic controls begin.
Observe
the aseptic processes directly, when possible, and evaluate aseptic
technique. Evaluate all connections and
transfers to ensure that they are made in an aseptic manner.
Review
all cleaning and sanitization procedures for the aseptic core and evaluate
whether the cleaning agents are used according to results of validation studies
and whether surfaces are monitored to demonstrate continued efficacy. If filling needles are re-used, the cleaning
should be validated.
If
the duration of filling is lengthy, determine if time limits have been set and
validated to ensure that the duration of the fill does not affect the potency
of the product and its susceptibility to microbial contamination. An SOP should be in place for interruption of
the fill, should it occur.
Some
bulk products are held after sterile filtration prior to filling. Determine whether the holding period and
storage conditions have been validated.
Procedures
must be in place for limiting access to controlled and classified areas.
Determine
if the sterilizing filters were validated for product compatibility and
microbial retention and are adequate for their intended use. Evaluate validation of sterilization of
filters. Ensure that filters are
evaluated prior to use to ensure they meet specifications. Integrity testing should be performed on
filters post-fill and results should be in keeping with manufacturer's and
validated specifications.
Review
the program in place for training operators.
In addition to training in the manufacturing process, the operators
should also be trained in proper gowning technique. Written procedures for gowning should be in
place and followed.
Evaluate
the firm's aseptic processing areas (filling and lyophilization) using 21 CFR
211.42(c)(10), the Guideline on Sterile Drug Products Produced by Aseptic
Processing, and the *Draft
Guidance for Industry – Sterile Drug Product Produced by Aseptic Processing –
Current Good Manufacturing Practices as guides*.
Determine
whether Class 100 conditions have been validated and are maintained in areas in
which sterile product and components, including container/closure systems, are
exposed. When alert limits are exceeded,
microbial identification should be performed.
Products
must be maintained in a controlled environment throughout the process and have
specified action and alert limits for which the firm can provide a meaningful
rationale. Bioburden alert and action
levels should be established for intermediates.
Ensure that the manufacturer has established microbial specifications
and a monitoring program to include identification of the types of
microorganisms present.
Investigators
should examine the system to determine if there are any ports of entry for
adventitious agents.
b.
Endotoxin
levels
There
is often no step to remove endotoxin from the product, so it must be controlled
from the beginning of the process. If
there is a step in the manufacturing process to remove endotoxin, it is usually
early in the process, so the remainder of the process must be carefully
controlled against contamination.
Investigators should review the manufacturing facility and process for
potential opportunities for contamination.
Review the firm's procedures to monitor the bioburden level throughout
the manufacturing process to ensure the level is controlled.
Ensure that:
·
Production
is performed in a controlled environment that prevents an increase in the
product’s microbial load beyond its design specifications;
·
Procedures
to prevent equipment or product contamination by any substance that could
reasonably be expected to have an adverse effect on product quality are in
place and followed; and
·
Precautions
are taken to prevent contamination or cross-contamination in areas in which
operations for the preparation of cell banks and product manufacturing
processes which are capable of promoting microbiological growth are monitored
for bioburden on a routine basis.
c.
Fermentation/Bioreactors
The
fermentation process includes inoculation of the initial vessel with the WCB
and scale-up. Often the early passages
are conducted in open vessels under laminar flow. The larger vessels are generally closed
systems.
Examine
the connections between vessels. If the
system is closed, review the connections to determine there is no break in the system. Review the batch records and ensure that all
steps in the process are recorded.
d.
Disruption
and harvest
Disruption
(when appropriate) and harvesting of the product is done using either chemical,
physical, or enzymatic means. Review the
batch records to determine if the firm is using the approved method. All essential parameters should be
documented.
e. Purification
Purification
is generally performed using a combination of column chromatography, filtration
and centrifugation. Ensure that the method
being used is the same as the approved process and that all steps are
documented in the batch record.
f. Viral inactivation/removal
For
products derived from cells of human or animal origin, viral
inactivation/removal should be performed, in accordance with the process in the
approved license application. In some
manufacturing operations, there will be a specific viral inactivation/removal
step; in other operations, viral inactivation/removal will be accomplished by a
step or steps in the manufacturing process that are not specifically considered
to be viral inactivation/removal steps.
Report
on the viral inactivation/removal steps used by the manufacturer. Ensure that the parameters specified in the
batch record were achieved such that the validated process for viral
inactivation/removal is accomplished. If
changes were made to the process, which did not require submission of a
supplement to *CDER*,
ensure that the changes were validated.
g. Lyophilization
Review
and observe, when possible, transfer of product to the lyophilizer. This transfer should be done under Class 100
conditions, or as otherwise approved by *CDER*.
Ensure the lyophilization process is performed in accordance with
validated parameters, including the placement of products in the lyophilizer.
If
the vials are overlaid with gas (usually nitrogen) evaluate the firm's
procedures for integrity testing of sterilizing filters, sterilization, and
replacement, and ensure that the procedures used have been validated.
3.
Validation
a.
Process
Validation
data for the manufacturing process are generally reviewed during application
review, as are the validation data to support changes that are reported in
prior approval supplements. Ensure that
any changes in the process made since the approval of the application for which
a supplement is not required have been validated in accordance with a protocol,
and that the validation process is adequately documented.
b.
Computer
If
the firm uses computer systems to control any part of the process, ensure that
software for computers or automated data processing systems is validated. If the firm is using a computerized
record-keeping system, assure that the integrity of the records is maintained. The systems should be such that the records
cannot be overwritten to disguise failing results. Document any computer systems the firm uses
for control of the manufacturing process.
c.
Shipping
Ensure
that shipping conditions have been validated, including containers and
methods. If the firm has contract manufacturers
that perform some or all of the manufacturing steps, ensure that the shipping
conditions for the partially processed materials have been validated and the
validated processes are followed and documented. The shipper must assure the product is maintained
at the proper temperature during shipment and must have records to demonstrate
this.
4.
Testing
and Laboratory controls
A large
component of every GMP inspection is the inspection of the laboratory. Laboratory equipment and procedures must be
qualified and validated. Required
testing is defined in the regulations and in the approved license
application.
Review
the records of in-process testing and ensure that all test results are
recorded. If in-process material failed
a test, determine the disposition of the material. If the material was used in a finished
product and released, review the records of the justification for releasing the
product and ensure the firm had adequate justification. The firm must have records to show whether
the product has passed or failed acceptance criteria.
Review
and evaluate the firm's methods for sampling and testing products for identity,
potency, safety, sterility, and conformance with final specifications. Ensure that the firm is using test methods,
which have been appropriately validated for all products on which they are
used. Review raw testing data and
compare to those reported into the batch production records. Review the SOPs for investigating product
test failures and ensure they are adequate and being followed. Determine if reference standards for testing
are in date and on a suitable schedule for determining continuous suitability
for use. Review laboratory records for
the results of tests and their comparison with established standards. Observe the performance of key tests for
adherence to approved procedures.
Investigators
should review a laboratory's quality management procedures and enough raw data
to be assured that data are authentic and reliable. The investigators should assure:
·
Data
are reliable/ complete, and authentic.
·
Data
were generated in accordance with GMPs, including documentation and review.
·
Laboratory
equipment is properly calibrated and qualified.
·
Analysts
and supervisors are adequately trained.
·
Appropriate
application of statistical methods, including averaging.
Retesting
may be allowed under strictly defined conditions. If a manufacturer performs retesting, ensure
there are procedures in place to determine when retesting is appropriate, how
retesting should be performed (sampling, duplicates), and how results should be
interpreted. The procedure may not
permit testing to be performed an infinite number of times. A manufacturer may also retest a sample or
collect an additional sample if an investigation shows that the original test
or sample collection should be invalidated.
5.
Environmental
controls/monitoring
There
should be a comprehensive environmental monitoring program, which includes
monitoring for non-viable and viable air particulates, surface viables and, in the
aseptic filling areas, personnel.
Procedures should address frequencies and locations for monitoring,
alert, and action limits for each area, and corrective actions to be taken when
limits are exceeded. Actions taken when
limits are exceeded should include adequate investigation into the source of
the problem, potential impact on the product, and measures taken to prevent
recurrence.
Generally,
less frequent monitoring is acceptable in areas in which upstream steps are
performed. There, steps may be performed
in unclassified, but "controlled" environments (ones with some level
of particulate controls). As the process
moves further downstream, more frequent monitoring is expected. Monitoring should be performed during
production.
Determine
whether the firm has procedures in place for adequate environmental monitoring
and if the procedures are followed and if the procedures describe what to do
with any affected product. Determine
what steps the firm takes if action or alert limits are exceeded and review any
investigations performed. If the limits
were exceeded during any production runs, determine the disposition of the
product.
Review
the schedule and procedures for media fills.
Review the records for the media fills performed since the previous
inspection. If there were any
excursions, determine what corrective action the firm took.
Evaluate
the firm's media fill procedures and test results. Ensure that all operators and shifts are
covered. Determine if media fills
encompass all events occurring during normal operations. Determine if all package sizes are
represented. This may be done by
bracketing of large and small size containers, particularly when vial openings
are similar for many sizes represented.
Worst case assessments, including any manual manipulations, transport,
loading and unloading, or maintenance functions should be included. If product is lyophilized, this process
should be mimicked during media fills (media should not be actually run through
the lyophilization cycle during a media fill).
Determine the alert and action levels, and evaluate whether the action
taken when these levels are reached or exceeded is appropriate. If excursions occurred, determine whether
investigations were conducted and appropriate corrective action taken. Determine the frequency of media fills after
the initial validation.
6.
Cross
contamination
Cross-contamination
may be a significant concern in a facility that manufactures more than one
product. The firm's method for
separating the products, either by space or time, should be reviewed to ensure
there is no potential for cross-contamination.
If equipment is not dedicated to one product, records of cleaning and
cleaning validation should be reviewed.
If personnel work in more than one area, the employees should be trained
to ensure that they take adequate precautions to prevent cross-contamination
when they pass from one area to another.
7.
Non-conforming
product
a.
Investigation
Determine
if the manufacturer has established and implemented procedures for control of
nonconforming product that include a determination of the need for an
investigation, and a written evaluation of the investigation, if conducted.
Request
a list of all failed final and in-process lots, and a list of all
deviations. Determine whether any lots
that failed to meet any specifications have been released. This includes any lots or portions of lots,
including components or raw materials, that have been rejected either
in-process or during finished product testing for failing to meet any or all of
the product's specifications.
Review
records for proper disposition of nonconforming products to assure that use of
nonconforming product has not resulted in the distribution of unsuitable
products. Document and report on any
distribution of out-of-specification products.
For
biotech products, the manufacturer should conduct an investigation when the WCB
does not generate necessary growth when used according to established
procedures or if usage deviates from the established schedule. If these events occurred, report on the
investigation conducted and the findings.
b.
Reworking/reprocessing
A
firm may rework or reprocess a product or in-process material that fails to
meet specifications. Inspections should
emphasize the investigation into the non-complying result as well as the
corrective action resulting from the investigation.
A
manufacturer may also blend or pool product to recover clinically useful and
economically valuable material. It is
unacceptable to blend lots to reduce the level of adulterants, e.g., endotoxin,
below action limits, unless a manufacturing step designed to reduce the
adulterants is used, and the process is validated.
It
is unacceptable for material from final containers in which bacterial growth
occurs to be used for further manufacturing.
*Determine whether the manufacturer has
established and maintains procedures for reworking/reprocessing.*
Report
on any reprocessing/reworking, i.e., re-pooling, blending, etc. that is
performed. Identify the products that
undergo such procedures; the conditions under which such procedures are
performed; and who approves the reprocessing plan. If failed lots are reworked, determine if the
firm conducted and documented an investigation to determine the cause of the
failure before reprocessing the product.
c.
Complaints
The
firm must have written complaint handling procedures, which should include
obtaining information such as the identity of the complainant and of the
complaint product, the lot number, and factors that contributed to the alleged
deficiency.
When
reviewing complaints, check for Adverse Event Reporting (AER) reportable
events. Determine if the appropriate
reports were filed with FDA within the time frames required in the regulations.
Review
complaints received since the last inspection.
Ensure that all communications involving product deficiencies that meet
the definition of a complaint are treated as such and are reviewed, evaluated,
and investigated unless a similar complaint has been investigated and another
investigation is not necessary.
Ascertain
the firm's basis for determining the significance of complaints and how the
follow-up is conducted. Determine if
oral and telephone complaints are documented.
Review
and analyze complaints to identify existing and/or potential causes of
nonconforming product or other quality problems. Determine if the firm has performed a
sufficient complaint investigation.
If
defective product is returned to the firm, determine the disposition of the
product and if the firm has a procedure for this process.
d.
Recalls
Determine
if the firm conducted any recalls since the last inspection. If the firm did conduct any recalls,
determine the disposition of the affected products. If the firm did not report the recall to FDA,
collect attachment information as described in the Regulatory Procedures
Manual. If the recall was due to *a manufacturing deviation,
determine if the firm filed a product deviation report.*
e.
Product
deviations
21
CFR 600.14(a) requires manufacturers of licensed biological products to
promptly notify FDA, of deviations in the manufacture of products that may
affect their safety, purity, or potency.
If
another location handles product deviation reporting, include in the EIR the
name and address of the location and the name of the person responsible for
handling them. Collect copies of any
SOPs that describe how the location being inspected interacts with the office
responsible for handling these reports.
Ensure
all product deviations that occurred were reported to FDA. If confirmation of their submission to FDA is
needed, contact *DMPQ,
Investigations & Pre-approval Compliance Branch, HFD-322.*
f.
Adverse
Experience Reports (AERs)
21
CFR 600.80 requires that serious, unexpected adverse experiences associated
with the use of a biological product in humans be reported to FDA within 15
days of initial receipt of information or periodically, depending on the
seriousness of the adverse reaction.
Review
records of adverse events received by the manufacturer and ensure that reports
have been submitted to FDA as required.
If there are questions or concerns regarding the seriousness of, and
therefore the reporting requirements for, an adverse experience, contact *DMPQ, Investigations &
Pre-approval Compliance Branch, HFD-322.*
8.
Changes
to be reported
Licensed
manufacturers are required to conform to the standards established in their
license applications as well as applicable sections of the regulations. 21 CFR 601.12 requires that manufacturers
inform FDA about important changes in the product, production process, quality
controls, equipment, facilities, responsible personnel, or labeling, from that
in the approved license application. (See references 4, 11, and 12).
The type
of notification is based on the potential risk of the change having an adverse
effect on the safety or effectiveness of the product. In general, changes which have a minimal
effect on the safety or effectiveness of a product may be implemented before being
reported to FDA; however, manufacturers are required to include such changes in
annual reports to the agency. Data
relevant to changes reported in annual reports (i.e., validation data) must be
made available during FDA inspections.
When a
change has a moderate potential to have an adverse effect on the safety or
effectiveness of a product, a manufacturer must submit a license supplement
describing the change. If FDA does not
advise the manufacturer within 30 days of submission of the supplement that the
change requires approval prior to distribution of the product, the manufacturer
may distribute product manufactured using the change.
When a
change has a substantial potential to adversely affect the safety or
effectiveness of a product, product manufactured using that change cannot be distributed
until FDA approves a license supplement describing the change.
Request a
list of changes or modifications made to products, processes, quality control,
equipment, facilities, systems, and/or responsible personnel that have not been
submitted to FDA as either a supplement or in an annual report since the last
inspection, and include it as an exhibit in the report.
Review
any changes, which the manufacturer has determined do not require a supplement
and that have not yet been included in an annual report to FDA, and describe
them in the inspection report.
Determine if changes have been validated, when appropriate. If there is any question as to whether or not
a change should have been reported, or whether a change should have been
submitted in a supplement instead of an annual report, contact *DMPQ, Investigations &
Pre-approval Compliance Branch, HFD-322.*
9.
GMP
a.
Equipment
Ensure
that key equipment and procedures (those that could affect product quality,
e.g., autoclaves, heat treatment baths, filling equipment and product contact
surfaces, filling and closing of containers, lyophilizers, depyrogenation
equipment) used by the firm are suitable for their intended uses. Determine if periodic *requalification* of the
equipment is performed. Evaluate the
adequacy of the equipment *qualification*.
Ensure
that the firm has SOPs for operating the equipment and that the instructions
are readily available to the personnel performing the operations.
Key
equipment should be appropriately cleaned and tagged as to status, identified,
calibrated, inspected or checked, *qualified, and requalified* when necessary, according to a
written program.
Determine
if the firm has maintenance schedules in place and, if so, that the schedules
are followed.
For
columns used in purification steps, ensure the firm has procedures in place for
cleaning and storage of the column housings and column media and that the
procedures are followed. There should be
an established life span for each column type (i.e., number of runs or months
of use). Ensure that columns are not
used beyond their established life span.
i.
Cleaning
Review
SOPs for equipment cleaning procedures and determine if they are validated and
followed. The validation should have
included an evaluation of the cleaning efficacy of dedicated equipment and
assurance that detergents, if any, are removed during cleaning. The firm should have established residual
limits and be using an assay appropriate to detect any contaminants. For multi-use equipment, the cleaning
validation should have established that there is no carry-over between products
such that the safety and efficacy of subsequent products is compromised. There should be periodic monitoring of the
validated cleaning procedure to ensure continued cleaning effectiveness.
ii.
Calibration
Calibration
should be performed according to a prescribed schedule conforming to the
equipment manufacturer's recommendations.
All
testing, measuring, and monitoring equipment should be calibrated, periodically
checked for accuracy, and recalibrated according to an established
schedule. Determine the frequency, and
the source of the standards used.
Verify
that calibration procedures include specific directions and limits for accuracy
and precision, and provisions for remedial action.
Examine
records of major manufacturing equipment calibration, checks, inspection,
maintenance, cleaning, sanitizing, and use; and laboratory equipment
calibration.
b.
Buildings
Manufacturers
must establish and maintain procedures to adequately control environmental
conditions where they could reasonably be expected to have an adverse effect on
product quality. Lighting, ventilation,
temperature, humidity, air pressure, filtration, airborne contamination, and
static electricity are among many conditions to be considered for control. Environmental monitoring must also be
performed where appropriate to the operation; see Section B.5.
Observe
the state of repair of the facility and determine whether the firm has a
program for updating facilities and ensuring that changes to systems are
validated/revalidated, as appropriate, and that modifications to the facilities
are approved by *CDER*,
when appropriate, and do not adversely affect production areas and product
safety.
Determine
whether cleaning and disinfecting practices, particularly for manufacturing
areas, sterile filling suites, and the aseptic core area are adequate and
validated.
Examine
the procedures and areas for segregating and storing raw materials; quarantined
rejected, in-process, and released products.
Make
certain that buildings:
·
Are
appropriately constructed to prevent, reduce, and control potential
contaminants and support the environmental control program;
·
Have
sufficient space for manufacturing, receiving, packaging/labeling, storage,
etc.; and
·
Are
designed to allow proper cleaning, maintenance, and other necessary operations.
Review
procedures for controlling and monitoring pressure differentials, humidity, and
temperature. Procedures should include
actions to be taken when results are not within established limits. Ensure that the impact of out-of-limit
results on the product is adequately addressed.
i.
Spore-forming
products
If
the firm uses spore-forming products, these materials must be physically
segregated from areas in which non-spore-forming materials are processed. This requires, at a minimum, the building in
which the spore-forming organisms are processed be either a separate building
or be physically separated from other processing areas; that there is a
separate entrance; and that the equipment used in the processing areas for the
spore-forming organisms be used exclusively in that area.
ii.
Water
systems
Review
water system diagrams and inspect the system to determine that the diagrams
adequately reflect the current as-built conditions. While inspecting the system, look for dead
legs and evidence of leaks. All valves
and connections should be of sanitary design.
Source water used to feed the water treatment system should meet EPA or
comparable potable drinking water standards as directed in the USP. If the source water is from a municipal
source, records of EPA tests provided by the municipality may be accepted;
however, periodic testing of identified parameters should be conducted to
ensure that the water meets standards as it enters the firm.
Determine
the source of water and how and with what frequency incoming water is sampled
and tested. All water treatment
components, e.g., sand filters, carbon filters, deionizing units, and reverse
osmosis units, should be maintained according to manufacturer's specifications,
and periodically monitored to ensure proper performance. Ensure that SOPs for maintenance,
replacement, regeneration, and/or sanitation of water treatment components are
in place and followed and that all instruments, gauges, meters, etc., are
routinely calibrated.
Water
that is within the USP's current water for injection (WFI) specifications is
generally used in production of therapeutic drug products. Purified water may be used in upstream processing
and for initial rinses of downstream equipment.
Potable water may be used as an initial rinse for upstream equipment.
If
the WFI system is not a continuous flow design, review the firm's procedures
for batching and discarding the water.
Review
the firm's procedures and controls for the production, monitoring, and testing
of all types of water used and determine if the water quality meets appropriate
specifications. Determine how alert
levels were established, i.e., were they based on historical data? Determine if the data-generated is monitored,
and ensure that procedures include appropriate actions to take when alert and
action levels are exceeded.
Ensure
that all water storage tanks are equipped to prevent microbial
contamination. Evaluate replacement
procedures and determine if integrity testing of filters is performed after
use.
iii.
Clean
in Place (CIP) and Sterilization in Place
(SIP)
systems
For
CIP systems, there should be proper control of cycles and periodic evaluation
of cleaning efficacy. SIP may also be
used in downstream processing areas for sterilization of equipment. As with CIP, there should be proper control
of cycles and periodic evaluation of the adequacy of the sterilization.
Determine
which equipment, containers/closures, etc., are cleaned and which are
sterilized by which process. Evaluate
the firm's validation procedures for all CIP/SIP processes.
iv.
HVAC
systems
The
HVAC system should be designed to provide containment or product protection
when and where necessary. Negative
pressures may be maintained during upstream processing to provide
containment. Positive pressures should
be maintained in downstream processing areas and the aseptic core. Separate air handling units, or single pass
air, should be used in post-viral inactivation areas and the aseptic core.
All
HEPA filters should be validated and should be recertified at least
annually. Recertification should include
integrity testing of the HEPA filters with an appropriate challenge aerosol,
e.g., dioctyl phthalate
(DOP)
or an alternative aerosol that has been determined to have similar or
acceptable physical characteristics for detection of leaks; air velocity
studies; particle counts, and in aseptic areas, laminarity.
c.
Quality
Control
Manufacturers
are required to establish a quality control unit that has the responsibility to
approve or reject all components/ packaging, drug products, labeling, etc. Ensure that the facility has a quality
control unit, document the responsibilities of the QC unit, and evaluate whether
the QC unit is effective in carrying out its responsibilities. Review and evaluate the firm's quality
assurance and quality control procedures and programs.
Review
pertinent SOPs, e.g., final product/check-off sheet found in batch records,
change/repair controls, alert/action limits and corrective actions taken.
Determine
whether specification and procedure changes, changes in work instructions, and
other instructional procedures are made through formal processes and controls.
d.
Personnel/Training
Determine
whether personnel are sufficient in number with the necessary background,
training and experience to correctly perform all required functions; and
whether training procedures are established to ensure all personnel are
adequately trained to perform their assigned responsibilities and to be aware
of the potential effects of their improper job performance. Look for any examples of personnel failing to
perform or inadequately performing a task.
If the facility is a multi-use one, employees that are not dedicated to
one operation or area must be trained in all the areas in which they operate.
Ensure
that employees are trained prior to performing a task and review documentation
of training. If training is performed
in-house, review the qualifications of the instructors and the process for
evaluating the success of the training.
e.
Waste
processing
Review
the firm's procedures for disposal of manufacturing waste. The procedures should include provisions for
inactivation of infectious agents and holding conditions. The procedures should protect against
cross-contamination. The firm should
also have procedures for handling accidental spills.
f.
Labeling/packaging
Labeling
requirements applicable to biotechnology-derived drug products are found in 21
CFR 201, as well as various sections of Parts 610 and 660. Specific wording for labeling is reviewed and
approved by *CDER*.
Ensure
that products are labeled as approved by *CDER*.
Labeling
deficiencies should not be included on Form FDA 483s unless inclusion of the
observation has been approved by *CDER*. Contact *DMPQ, Investigations &
Pre-approval Compliance Branch, HFD-322* if there appear to be labeling
deficiencies in the firm's products.
10.
Records
Records
required by the cGMP regulations must be maintained at the manufacturing
facility or at another location reasonably accessible to responsible officials
of the manufacturer and to FDA investigators.
For facilities that maintain records electronically, see also section
B.3.b. (Computer).
a.
Master
production
The
master production record contains the documentation necessary to produce the
drug product.
The
master production record should have complete manufacturing and control
instructions, sampling and testing procedures, and specifications for the product. It should also include information about the
container, closure, and packaging materials, including labeling.
Ensure
that the master production record contains or references the procedures and
specifications that are current on the manufacturing floor.
b.
Batch
Records
Verify
that batch records representing individual lots exist for all finished products
manufactured, and that the records show the processes, tests,
reworking/reprocessing the drug went through from the beginning of
manufacturing to distribution and reflects that all operations, processes,
etc., described in the master production record were accomplished.
Review
batch production and control records of representative lots manufactured since
the last inspection for completeness and for review and approval by the quality
control unit before release of each lot.
Ensure that the batch records reflect the actual process being
performed, and that the process being performed is the same as that which was
validated.
c.
Distribution
Review
distribution records cross-referenced to final inspection and release and
quarantine record to verify that no obsolete, rejected, or deteriorated product
was used or distributed.
Ensure
that distribution records contain or make reference to the location of the name
and address of the initial consignee, identification and quantity shipped, date
shipped, and control/lot numbers used.
d.
Stability
Stability
records are required to support labeled dating periods. Ensure that stability records show that the
final products and their individual components were tested using standardized
panels and that real time stability is evaluated at appropriate storage and
shipping temperatures, using specimens with varied reactivities in the readable
range. Verify that the firm retains
samples and performs testing, where appropriate, for the entire dating period.
11.
21 CFR
610.2(a) states that a manufacturer may be required to send samples of any lot
of any licensed biological product together with protocols showing results of
applicable tests on the lot to *CDER*; and that upon notification by the Director, *CDER*, a manufacturer
shall not distribute a lot of a product until it is released by the Director.
In a
notice published in the Federal Register in December 1995, the Agency
eliminated the requirement for routine lot release for specified biotech
products. Manufacturers must still
ensure that the products meet the manufacturer's lot release specifications
prior to distribution. *CDER* may require that
these products be submitted for *CDER* lot release if a manufacturer demonstrates an inability to
consistently manufacture product in accordance with specifications.
Some
manufacturers of biological products have, through approved license
supplements, received exemptions from lot release and are on a
"surveillance" program.
Manufacturers on surveillance are required to submit samples and/or
protocols to *CDER*
at specified intervals, but they may market their products without receiving
lot release. If a regulatory action is
taken against a manufacturer whose products are not currently subject to *CDER* lot release, its
product (s) may be removed from surveillance status.
Review
representative lot release test records, especially for those products on
surveillance or exempt from lot release, to ensure that all specifications have
been met. Check-whether any lot has
failed to be released and if so, the reason for failure and the disposition of
failed lots. For products that are
subject to FDA lot release, review records to ensure that products were not
distributed prior to release of the lots by FDA.
C.
*Sample Collection
CDER may request sample collection and
will provide specific instructions. If
official samples are not requested, but the inspection team believes their
collection is warranted, contact the Branch Chief, Case Management and Guidance
Branch (HFD-326), 301-827-8941, for guidance prior to collecting samples.
Collect any samples of a potentially
biohazardous nature in accordance with IOM section 145.
If significant deviations are noted,
collect a documentary sample in accordance with section 405.2 of the IOM.*
D.
Reporting
1.
Record
any deviations from GMP, AER, or other applicable regulations on the FDA Form
483, Inspectional Observations.
2.
Notify
ORO and *CDER/OC *immediately
if a potentially serious health hazard exists.
3.
Briefly
report on all major areas or systems investigated as outlined in this part,
regardless of findings. If the
inspection is a follow-up to a violative inspection, report on the implementation
of the firm's promised corrective actions.
4.
The
ORA Core Team investigator, as lead, will coordinate the preparation of the
report. The report will be endorsed,
classified, and submitted in accordance with agency policy and procedures. Reports should be submitted within
established agency time frames.
5.
Domestic
inspections: Send a copy of each establishment inspection report, including
endorsement and classification, to *CDER *(see Part VI, Program Contacts). The exhibits should not be included unless
specifically requested. The original
EIR, including endorsement and exhibits, should be forwarded to the firm's home
district. A copy of the coversheet and
endorsement should also be sent to ORO, HFC- 100. The home district will be responsible for
releasing the EIR under FMD 145 and for filling any FOIA requests.
Foreign inspections: The original EIR, endorsement, and exhibits should be sent to *CDER/OC/FIT, HFD-325*. A copy of the endorsement and coversheet should also be sent to ORO, HFC- 100. *CDER* will be responsible for releasing the EIR under FMD 145 and for filling any FOIA requests for the EIR.
PART IV - Analytical
No field
analyses are projected under this program.
Routine
sample collection under this program is not anticipated. Consult with *CDER* program contact identified in Part VI before
collecting samples for agency analysis, except for documentary samples for
interstate commerce.
PART V – REGULATORY/ADMINISTRATIVE
STRATEGY
It is
essential to promptly evaluate any violative conditions observed during an
inspection in order to ensure product safety and effectiveness. This evaluation and any resultant
recommendation for action will be conducted using the procedures set forth in
the Case Processing SOP established for Team Biologics/Core Team.
Regulatory
/Administrative Follow-Up
Significant,
documented deviations from the law, regulations, or license may warrant
regulatory and/or administrative action.
Such deviations may include the following violative conditions found
during inspections of licensed biotechnology-derived therapeutic products (this
list is not intended to be all inclusive):
1.
Organization
and Personnel [211.22 - 211.34 and 600.10]
2.
Buildings
and Facilities [211.42 - 211.58 and 600.11]
3.
Equipment
[211.63 - 211.72 and 600.11]
4.
Control
of Components and Drug Product Containers and Closures [211.80 - 211.94]
5.
Production
and Process Controls [211.100 - 211.115]
6.
Holding
and Distribution [211.142 - 211.150]
7.
Laboratory
Controls [211.160 - 211.176]
8.
Records
and Reports [211.180 - 211.198]
9.
Changes
to an Approved Application [601.12]
10.
General
Biological Products Standards; Identity [610.14]
11.
General
Biological Products Standards; Purity [610.13]
A firm's
written corrective action plan in response to an FDA Form 483 does not preclude
consideration of regulatory or administrative action. If voluntary action is not appropriate or
accomplished, or the deviations pose a threat to the consumer, regulatory
and/or administrative action should be recommended. As stated above, the evaluation of inspection
findings and any resultant recommendation for enforcement action should be
conducted in accordance with the procedures set forth in the Team Biologics
Case Processing SOP.
The
decision on the type of action to recommend should be based on the seriousness
of the problem, the most effective way to protect the consumer, and the
regulatory history of the establishment.
It is essential that the importance and relative availability of the
product (s) as well as the potential adverse effect of GMP deviations on the
finished product (s) be considered in determining appropriate regulatory and/or
administrative action. Available options
for regulatory actions include Warning Letter, license revocation and
suspension, seizure, injunction, prosecution, recall order. The Regulatory Procedures Manual should be
used, as a reference to assist in determining which regulatory action is
appropriate. For additional assistance,
the *CDER/DMPQ *may
be contacted.
Warning letters: *CDER concurrence must be obtained for all Warning Letters
issued under this program.*
PART VI – REFERENCES AND PROGRAM CONTACTS
REFERENCES
1.
Federal Food, Drug and Cosmetic Act, as Amended.
2. Public
Health Service Act, Biological Products.
3. Title
21, Code of FederalRegulations, Parts 211, 314, 600, 601, 610.
4.
Investigations Operations Manual (IOM).
5.
Regulatory Procedures Manual (RPM), Chapter 4, Advisory Actions; Chapter 5,
Administrative Actions; Chapter 6, Judicial Actions; and Chapter 10, Other
Procedures.
6.
Compliance Policy Guides, Subchapter 130; Subchapter 200; and Subchapter 400,
section 480.100.
7.
Compliance Program Guidance Manual, CP 7356.002, Drug Process Inspections; CP
7356.002A, Sterile Drug Process Inspections; and CP 7356.002F, Bulk
Pharmaceutical Chemicals.
8.
Guidance for Industry: Changes to an Approved Application for Specified
Biotechnology and Specified Synthetic Biological Products, CBER, July 1997.
9.
Guideline on General Principles of Process Validation, May 1987.
10.
Guideline on Sterile Drug Products Produced by Aseptic Processing, Center for
Drugs and Biologics and ORA, June 1987.
*11 Draft Guidance for Industry –
Sterile Drug Product Produced by Aseptic Processing – Current Good Manufacturing
Practice, CDER, CBER, and ORA, August 2003
*
12.
Guideline for Submitting Documentation for the Stability of Human Drugs and
Biologics, CDER, CBER.
13. Guide
to Inspections of Dosage Form Drug Manufacturers - CGMPs, ORA/ORO/DFI, October
1993.
14. Guide
to Inspections of High Purity Water Systems, ORA/ORO, June 1993.
15. Guide
to Inspection of Bulk Pharmaceutical Chemical Manufacturers, September 1991.
16. Guide
to Inspection of Pharmaceutical Quality Control Laboratories, July 1993.
17. Guide
to Inspection of Microbiological Pharmaceutical Quality Control Laboratories,
July 1993.
18. Guide
to Inspection of Validation of Cleaning Processes, July l993.
19.
Biotechnology Inspection Guide.
20. Guide
to Inspections of Lyophilization of Parenterals, ORA/ORA/DFI, July 1993.
21.
Points to Consider in the Manufacture of Recombinant DNA Derived. Products,
Monoclonal Based In Vitro and In Vivo Products, CBER.
22. FDA
Policy for the Regulation of Computer Products, CDRH.
23.
Biosafetv in Microbiolocrical and Biomedical Laboratories. DHHS.
24.
25. Team
Biologics/Core Team Case Processing SOP, Operations Group.
PROGRAM CONTACTS
*CDER
Send copies of reports and questions
regarding the instructions in this program (except as otherwise directed):
Branch Chief
Division of Manufacturing and Product
Quality
Investigations & Preapproval
Compliance Branch (HFD-322)
11919 Rockville Pike
301-827-8942; fax 301-827-8909
Otherwise, please refer to the main
program, 7356.002, for contact information.*
PART VII – CENTER RESPONSIBILITIES
Inspection
Profiles and Information
*The Investigations & Preapproval
Compliance Branch (HFD-322) *is
responsible for providing appropriate background material, including license
and lot release information and copies of applicable correspondence and
reports, to investigators prior to scheduled inspections. This office will also serve as the point of contact
for any technical questions raised during inspections, and will be responsible
for ensuring the investigators receive responses in a timely manner.
Program
Review and Evaluation
*CDER* will monitor this program and evaluate reports of
inspections. Results of evaluations will
be shared with the field, ORA/ORO, and interested *CDER* units. *CDER* will also coordinate and/or prepare an annual review and
evaluation of this compliance program.