[Federal Register Volume 60, Number 132 (Tuesday, July 11, 1995)]
[Notices]
[Pages 35750-35753]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-17022]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 95D-0164]
FDA Guidance Document Concerning Use of Pilot Manufacturing
Facilities for the Development and Manufacture of Biological Products;
Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a guidance document concerning the use of pilot
facilities for the development and manufacture of biological products.
The guidance document, entitled ``Center for Biologics Evaluation and
Research; Use of Pilot Manufacturing Facilities for the Development and
Manufacture of Biological Products; Guidance,'' provides guidance by
the Center for Biologics Evaluation and Research (CBER) to
manufacturers of biological products to clarify the licensing
requirements for the use of small scale and pilot facilities for the
development and manufacture of biological products. These facilities
are sometimes collectively referred to by industry as pilot facilities.
This guidance document is intended to provide increased flexibility for
industry without diminishing public health protection.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857. Comments should be identified with the docket
number found in brackets in the heading of the document. Two copies of
all comments are to be submitted, except that individuals may submit
one copy. The comments received are available for public examination in
the Dockets Management Branch between 9 a.m. and 4 p.m., Monday through
Friday.
FOR FURTHER INFORMATION CONTACT: Jean M. Olson, Center for Biologics
Evaluation and Research (HFM-630), Food and Drug Administration, 1401
Rockville Pike, suite 400 South, Rockville, MD 20852-1448, 301-594-
3074.
SUPPLEMENTARY INFORMATION: CBER recognizes that development of
important new biological products is expensive and time consuming, and
that companies must be able to forecast and evaluate their expenditures
for this process. Constructing a new facility to manufacture a product
that has not been fully tested in clinical trials could result in a
company being unable to recover a major capital expenditure if the
product is not ultimately brought to market. CBER also recognizes that
for some companies the best financial option may be the use of a pilot
facility where a product may be manufactured at a smaller scale than
would be ultimately desired for an approved product.
While CBER does not object to the use of pilot production
facilities for the manufacture of clinical material, many companies are
concerned that these facilities would not be eligible for establishment
licensure. This guidance document is intended to clearly articulate
that pilot facilities are eligible for licensure. The guiding principle
is that an application for establishment licensure can be made for any
facility
[[Page 35751]]
(regardless of the scale of manufacture) which is fully qualified,
validated, operates in accordance with current good manufacturing
practices (CGMP's), and otherwise complies with applicable law and
regulations. In order to further streamline the approval process, the
agency is currently considering changing its procedures to eliminate
the requirement for a separate establishment license for certain well
defined classes of biologic products. Because of recent scientific
advances, both in methods of manufacture and in methods of analysis,
some products developed through biotechnology can be characterized in
ways not historically considered possible. Thus, the agency is
considering allowing ``biotech'' products that are well characterized
to be regulated under a single application. The agency plans to hold a
scientific conference in the fall of 1995, to develop a definition of
well characterized products that may be amenable to regulation under
new procedures.
This guidance document describes the conditions and procedures for
submitting establishment license applications (ELA's) for pilot
facilities and for subsequent transfer of product manufacturing to a
different facility. The guidance document provides information
concerning: (1) Use of a product manufactured in a pilot facility in
clinical trials conducted to demonstrate safety and effectiveness and
optional transition to a different facility; (2) submissions for
approval to use a pilot facility for manufacture of a product; (3)
submissions for approval to use a different manufacturing facility
while a product license application (PLA) for a product manufactured in
a pilot facility and an ELA for a pilot facility are pending; (4)
submissions for approval to use a different manufacturing facility when
a product and pilot facility are currently licensed; and (5) submission
of a PLA based on data obtained from a product made in a pilot facility
when licensure of the product manufactured in the pilot facility and of
the pilot facility is not sought.
The guidance also addresses review timeframes and submission times,
product consistency, data comparing products made in different
facilities, and product availability at the time of product licensure.
In addition, FDA intends to revise the policy statement entitled
``Manufacturing Arrangements for Licensed Biologics'' published in the
Federal Register of November 25, 1992 (57 FR 55544) to accommodate
these procedures.
This guidance document is not binding on either FDA or
manufacturers of biological products and does not create or confer any
rights, privileges, or benefits for or on any person.
Interested persons may submit to the Dockets Management Branch
(address above) written comments on the guidance document. Received
comments will be considered to determine if further revision to the
guidance document is necessary.
The title and text of the guidance document follows:
Center for Biologics Evaluation and Research; Use of Pilot
Manufacturing Facilities for the Development and Manufacture of
Biological Products; Guidance
I. Introduction
Biological products, which generally include vaccines, blood and
blood products, allergenic extracts, and biological therapeutics,
are regulated under section 351 of the Public Health Service Act
(the PHS Act) (42 U.S.C. 262), as well as the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321). The PHS Act requires that
biological products be propagated or manufactured and prepared at an
establishment holding an unsuspended and unrevoked license. Lack of
clarity about licensing requirements has led some applicants to make
major investments in large scale manufacturing facilities before
initiating the clinical trial(s) necessary to demonstrate the safety
and effectiveness of their products. Such investments can result in
significant financial loss if the product is not ultimately brought
to market. In this document, the Center for Biologics Evaluation and
Research (CBER) is providing guidance to manufacturers and
developers of biological products to clarify licensing procedures
for the use of pilot facilities for the manufacture of biological
products. CBER considers a pilot production to be a procedure and
facility fully representative of and simulating that to be applied
on a full commercial scale. For example, the methods of cell
expansion, harvest, and product purification should be identical
except for scale of production. These facilities are sometimes
collectively referred to by industry as ``pilot facilities'' and
will be referred to as ``pilot'' in this document. These facilities
are to be distinguished from facilities used in research and
development that may not operate under appropriate current good
manufacturing practices (CGMP's).
II. Background
CBER recognizes that development of important new biological
products may be expensive and time consuming and that companies must
be able to forecast and evaluate their expenditures for this
process. Constructing a large scale facility to manufacture a
product that has not been fully tested in clinical trials could
result in a major capital loss if delays occur or the product is not
ultimately brought to market. CBER also recognizes that for some
companies, the best financial option may be the use of a pilot
facility where a product may be manufactured at a smaller scale than
might be eventually desired for an approved product. While CBER has
not objected to the use of pilot facilities for the manufacture of
clinical material (provided such manufacture is in compliance with
requirements applicable to investigational drugs), many companies
are concerned that these facilities and the product manufactured in
them would not be eligible for licensure. An application for
establishment licensure can be made for any facility (regardless of
the scale of manufacture) that has been fully qualified and
validated, that operates under CGMP's, and that otherwise complies
with applicable laws and regulations. This guidance document
describes the conditions and procedures for submitting such
application(s) and for subsequent, optional transfer of product
manufacturing to a different manufacturing facility.
III. Guidance
The following provides information on the submission of product
license applications (PLA's) and establishment license applications
(ELA's) and investigational new drug applications (IND's) for
products manufactured in a pilot facility.
1. Use of a product manufactured in a pilot facility in clinical trials
conducted to demonstrate safety and effectiveness and optional
transition to a different facility.
IND's for all products should include information that describes
where the material for the clinical trial(s) used to demonstrate
safety and effectiveness is or was manufactured. Data submitted in
support of licensure of a biological product can be obtained using a
product manufactured in a pilot facility. In the event that a
product manufactured in new facilities and/or scaled-up processes or
facilities is intended to be used at a later date for either
completion of the clinical trial(s) demonstrating safety or
effectiveness or for licensable product, the time tables, new
locations, and processes should be identified in the IND. A protocol
for comparing products should also be submitted. Data which compares
a product made in a new facility or with new processes to a product
used in earlier clinical studies should be submitted to the IND
before including the new product in the clinical trial(s). If the
product made in the new facility or by the new process will not be
used in the clinical trials used to demonstrate safety or
effectiveness, the data comparing the two products should be
submitted in the IND, PLA, or PLA supplement. A description of any
manufacturing changes that were made as a result of using a new
facility or new processes and stability data should also be
submitted to the IND or PLA as appropriate.
2. Submissions for approval to use a pilot facility for manufacture of
a product.
Information and data submitted in the PLA should be obtained
using a product manufactured in the pilot facility. The ELA should
include a completed Form FDA 3210; Application for Establishment
License for Manufacture of Biological Products (FDA
[[Page 35752]]
Form 3210), which describes the pilot facility. If the facility is
already licensed, an ELA supplement that contains information
specific to the new product should be submitted. The facility and
equipment, regardless of scale, should have undergone appropriate
qualification and validation and should be in compliance with
applicable regulations, including, but not limited to, 21 CFR parts
210, 211, 600 and 820. A pre-license inspection will be conducted
prior to the approval of the PLA and ELA or ELA supplement. The PLA
and ELA may be submitted at different times, provided a statement is
included in any PLA or ELA submission confirming that the facility
is ready for inspection and indicating the approximate date for the
companion application submission. CBER intends to review PLA's and
ELA's submitted at different times under the normal timeframe
targets of the managed review process (from the date of receipt at
CBER, 12 months for standard applications, 6 months for priority
applications, and 6 months for supplements). Because CBER issues the
ELA and PLA concurrently, timing of submission of the companion
applications should be carefully considered. CBER intends to
consider failure to submit a companion application within 6 months
of receipt of a standard application or 3 months of receipt of a
priority application to be grounds for issuing a not approvable
letter to the applicant.
3. Submissions for approval to use a different manufacturing facility
while a PLA for a product manufactured in a pilot facility and an ELA
for a pilot facility are pending.
In this case, a PLA for a product made in a pilot facility and
ELA for the pilot facility are under review as outlined in section
III. 2 of this guidance. FDA's inspection of the pilot facility may
or may not have occurred. The applicant is now requesting licensure
of a different facility in addition to, or in lieu of, licensure of
the pilot facility. The following information should be submitted to
the pending PLA: a description of manufacturing changes which have
occurred, data comparing products made in the new and old
facilities, and documentation of process validation and stability
data for a product manufactured in the new facility. CBER intends to
consider the submission to be a separate PLA filing that will be
assigned a new reference number and a 6-month review timeframe. A
new ELA that contains a completed ELA Form 3210 describing the new
facility should also be submitted. If the new facility is already
licensed, the applicant should submit a supplement to the approved
ELA with the information specific to the new product. A statement
confirming that the new facility is ready for inspection should be
included in the new PLA filing and the ELA or ELA supplement at the
time of submission. Concurrent review of the pilot facility will
continue unless the applicant is no longer requesting approval to
market lots manufactured in the pilot facility. If the applicant
does not wish to pursue licensure of lots made in a pilot facility,
a request may be made in writing that the pending ELA for the pilot
facility be withdrawn; however, FDA may still conduct an inspection.
In this case, lots manufactured in the pilot facility could be used
in other clinical trials but could not be marketed. CBER intends to
review the ELA for the new facility within new application
timeframes under the managed review process. As such, CBER intends
to issue a new reference number and review priority applications
within 6 months, standard applications within 12 months, and
supplements within 6 months. CBER intends to review the new PLA
filing within 6 months. An inspection of both facilities will be
performed if the applicant requests licensure of both. Applicants
should specify which establishment is a higher priority for
licensure and CBER may choose to concentrate its resources on
reviewing the application for that facility first. Either
combination of product and establishment may be licensed when all
information has been reviewed and found to be acceptable. The pilot
facility and product may be eligible for licensure before the new
facility and product are ready for approval. In regard to the timing
of submissions, it should be noted that CBER's timeframe for review
of a new ELA may be longer (12 months for standard application and 6
months for priority application under the managed review process)
than that for review of the new PLA filing. CBER intends to consider
failure to submit a companion application within 6 months of receipt
of a standard application or 3 months of receipt of a priority
application to be grounds for issuing a not approvable letter to the
applicant.
4. Submissions for approval to use a different manufacturing facility
when a product and pilot facility are currently licensed.
A supplement to the approved PLA for a product made in a pilot
facility and an ELA or ELA supplement for the new facility should be
submitted when the applicant wishes to obtain licensure for a
different facility and product manufactured in it. The PLA
supplement should contain information on a product manufactured in
the new facility, including a description of manufacturing changes
that have occurred. (See ``Changes to be Reported for Product and
Establishment License Applications; Guidance'' (60 FR 17535, April
6, 1995)). Data comparing products made in each facility, and
process validation and stability data for a product manufactured in
the new facility should also be provided. If a new ELA is submitted,
it should contain a completed ELA Form 3210 that describes the new
facility. If the proposed facility is already a licensed facility,
an ELA supplement should be submitted that contains information
specific to the new product. A statement confirming that the
facility is ready for inspection should be included with each
submission. CBER intends to review PLA's, ELA's, and supplements
according to the timeframe targets of the managed review process (6
months for manufacturing and facility changes) and intends to
approve ELA's and PLA's or supplements concurrently, when all
information has been reviewed and found acceptable. CBER intends to
consider failure to submit a companion application within 6 months
of receipt of a standard application or 3 months of receipt of a
priority application to be grounds for issuing a not approvable
letter to the applicant.
5. Submission of a PLA based on data obtained from a product made in a
pilot facility when licensure of the product manufactured in the pilot
facility and pilot facility is not sought.
CBER will allow submission of a PLA based on data obtained from
clinical trials using a product made in a pilot facility when the
pilot facility is not intended to be licensed. In order to verify
data comparing a product made in a pilot facility and used in the
clinical trials to a product made in the facility to be licensed,
the pilot facility should be available for inspection up to the time
the applicant obtains licensure of the product in the new facility.
A product used in clinical trials to support licensure can be made
in a facility for which the applicant does not intend to seek
licensure, but only a licensed product made in a licensed facility
may be marketed. The PLA should contain information and data on a
product manufactured in the pilot facility and a statement that the
pilot facility is ready for inspection at the time of submission. An
inspection of the pilot facility may be performed in some cases.
Stability data from a product made in the pilot facility, if
representative of a product manufactured in the facility intended to
be licensed, can be used in support of a proposed dating period. A
separate, original ELA for the facility intended for licensure may
be submitted concurrently with the PLA or after review of the PLA
has begun. The ELA for the facility intended for licensure should be
submitted when a product in support of approval has been
manufactured, a product is available for review, and the facility is
ready for inspection. If submission of the ELA occurs after PLA
review has begun, an accompanying PLA supplement containing data
comparing products made in both facilities should include stability
data, process validation, and a description of any manufacturing
changes (see Guidance (60 FR 17535)). CBER intends to review each
ELA and PLA under the current timeframe targets of the managed
review process (from the date of receipt at CBER, 12 months for
standard and 6 months for priority applications; 6 months for
manufacturing supplements). While an ELA and PLA need not be
submitted concurrently, applicants are reminded that CBER intends to
approve ELA's and PLA's concurrently. CBER intends to consider
failure to submit a companion application within 6 months of receipt
of a standard application or 3 months of receipt of a priority
application to be grounds for issuing a not approvable letter to the
applicant.
6. Demonstration of product consistency and data comparing products
made in different facilities.
When manufacture of a product is transferred from a pilot
facility to a different facility, a demonstration of product
consistency, data comparing the two products, and process validation
should be submitted in the PLA supplement or amendment to the IND.
Retention samples from the pilot facility should be stored under
[[Page 35753]]
controlled conditions in sufficient quantity to conduct the side-by-
side testing of products. Applicants are encouraged to discuss with
CBER what data are necessary to compare products, as such data may
range from analytical testing to full clinical trial(s).
7. Review timeframes and submission times
There may be cases where applicants wish to submit an ELA for a
pilot facility prior to submitting a companion PLA. A statement that
the facility is ready for inspection at the time of submission
should be included. FDA ordinarily intends to inspect at the time
the facility is manufacturing the product for which licensure is
sought. It is possible that, in some cases, inspection of the
establishment could take place before the submission of the PLA. It
is also possible for the ELA to be submitted after the PLA as
discussed above.
CBER intends to review PLA's and ELA's submitted at different
times under the normal timeframe targets of the managed review
process (from the date of receipt at CBER, 12 months for standard
and 6 months for priority applications; 6 months for supplements).
CBER intends to issue the appropriate action letter (approved,
approvable, or not approvable) to complete its action on any
application.
Applicants should be aware that submitting the ELA and PLA at
separate times will not necessarily reduce the approval time when
compared to concurrent submission. Early submission of applications
may, however, allow earlier feedback from CBER on deficiencies in an
application that can be addressed by the applicant sooner than would
otherwise be possible. In all cases described above, CBER intends to
approve PLA's, ELA's, or supplements concurrently.
In cases of shared manufacturing arrangements (see 57 FR 55544
at 55545), the PLA's for the intermediate product(s) and end product
should be submitted concurrently in order for a complete review of
the product to occur, since determining the approvability of the end
product will depend upon information in the intermediate product
PLA's. The ELA's may be submitted at different times from the PLA's.
Applicants should consider carefully the consequences of the
timing of any submission on the use of CBER resources. It is
expected that applicants will use the flexible submission times in
cases of need. Applicants should recognize that the filing of
submissions which are premature or incomplete will result in
unnecessary resource commitments by CBER and the applicant. It is
therefore recommended that applicants do not submit an ELA before
favorable preliminary data or information from clinical trials of
the product is available. For products intended for use in serious
and life-threatening diseases, applicants should consider submitting
the ELA and PLA concurrently to prevent a situation from occurring
where otherwise approvable product cannot be approved because the
facility is not yet ready to be licensed.
If a scenario exists that is not covered in this guidance
document, the applicant should seek guidance by contacting the
appropriate applications division in the Offices of Therapeutics
Research and Review, Blood Research and Review, or Vaccines Research
and Review, or the Division of Establishment Licensing.
8. Availability of product at the time of licensure
If an applicant requests licensure for a pilot facility, this
choice may affect the amount of product available at the time of
approval. For important new products for use in treating serious and
life-threatening illnesses, the ramifications of limited
availability of the product at the time of approval should be
assessed by the applicant.
Dated: June 26, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-17022 Filed 7-7-95; 10:53 am]
BILLING CODE 4160-01-F
