DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration 

[Docket No. 95D090164]

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

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 (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 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 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.