CHAPTER 56 -- DRUG QUALITY ASSURANCE
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SUBJECT: Inspections of Licensed Biological Therapeutic Drug
Products |
IMPLEMENTATION DATE |
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*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 |
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DATA
REPORTING |
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PRODUCT CODES |
PRODUCT/ASSIGNMENT
CODES |
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57YY- |
56002M GMP
Inspections 46832M
Pre-license Inspections |
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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