[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