Federal Register / Vol. 69, No. 191 / Monday, October 4, 2004 / Notices 59257

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003D–0380]

Guidance for Industry: Process 

Analytical Technology—A Framework 

for Innovative Pharmaceutical 

Development, Manufacturing, and 

Quality Assurance; Availability

AGENCY: Food and Drug Administration, 

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug 

Administration (FDA) is announcing the 

availability of a guidance entitled 

‘‘Guidance for Industry: PAT—A 

Framework for Innovative 

Pharmaceutical Development, 

Manufacturing, and Quality Assurance.’’

The guidance explains a science-based, 

risk-based framework, ‘‘Process 

Analytical Technology, or PAT,’’ to 

support innovation and efficiency in 

pharmaceutical development, 

manufacturing, and quality assurance. 

This framework is founded on process 

understanding, with the goal of 

facilitating innovation and risk-based 

regulatory decisions by industry and the 

agency. Working with existing 

regulations, this guidance describes a 

regulatory approach that will enable the 

agency and the pharmaceutical industry 

to address technical and regulatory 

issues and questions anticipated during 

the implementation of PAT.

DATES: General comments on agency 

guidance documents are welcome at any 

time.

ADDRESSES: Submit written requests for 

single copies of the guidance to the 

Division of Drug Information (HFD–

240), Center for Drug Evaluation and 

Research, Food and Drug 

Administration, 5600 Fishers Lane, 

Rockville, MD 20857. Send one selfaddressed adhesive label to assist that 

office in processing your requests. 

Submit written comments on the 

guidance to the Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. Submit 

electronic comments to http://

www.fda.gov/dockets/ecomments. See 

the SUPPLEMENTARY INFORMATION section 

for electronic access to the guidance 

document.

FOR FURTHER INFORMATION CONTACT:

Chris Watts, Center For Drug 

Evaluation and Research (HFD–

003), 5600 Fishers Lane, Rockville, 

MD 20857, 301–443–5197; or

Dennis Bensley, Center for Veterinary 

Medicine (HFV–143), Food and 

Drug Administration, 7500 Standish 

Pl., Rockville, MD 20855, 301–827–

6956; or

Robert Coleman, Office of Regulatory 

Affairs (HFR–SE150), Food and 

Drug Administration, 60 8th St. 

North East Atlanta, GA 30309, 404–

253–1200, ext. 1295.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of 

a guidance entitled ‘‘Guidance for 

Industry: PAT—A Framework for 

Innovative Pharmaceutical 

Development, Manufacturing, and 

Quality Assurance.’’ The guidance 

explains a science-based, risk-based 

framework, ‘‘Process Analytical 

Technology, or PAT,’’ that supports 

innovation and efficiency in 

pharmaceutical development, 

manufacturing, and quality assurance. 

The framework is founded on process 

understanding, which can be used to 

facilitate innovation and risk based 

regulatory decisions by industry and the 

agency.

Conventional pharmaceutical 

manufacturing is generally 

accomplished using batch processing 

with laboratory testing conducted on 

collected samples to evaluate quality. 

This conventional approach has been 

successful in providing quality 

pharmaceuticals to the public. However, 

today significant opportunities exist for 

improving pharmaceutical 

development, manufacturing, and 

quality assurance through innovation in 

product and process development, 

process analysis, and process control. 

Unfortunately, the pharmaceutical 

industry generally has been hesitant to 

introduce innovative systems into the 

manufacturing sector for a number of 

reasons. One reason often cited is 

regulatory uncertainty, which may 

result from the perception that the 

existing regulatory system is rigid and 

unfavorable to the introduction of 

innovative systems. In August 2002, 

recognizing the need to eliminate the 

hesitancy to innovate, FDA launched a 

new initiative entitled ‘‘Pharmaceutical 

Current Good Manufacturing Practices 

for the 21st Century: A Risk-Based 

Approach.’’ Development of this 

guidance was part of that initiative.

Pharmaceutical development and 

manufacturing is evolving with 

increased emphasis on science and 

engineering principles. Effective use of 

pharmaceutical science and engineering 

principles and knowledge, throughout 

the life cycle of a product, can improve 

the efficiencies of both manufacturing 

and regulatory processes. FDA’s 

initiative is designed to do just that 

using an integrated systems approach to 

regulating pharmaceutical product 

quality. This approach is based on 

science and engineering principles for 

assessing and mitigating risks related to 

poor product and process quality. The 

desired future state of pharmaceutical 

manufacturing may be characterized as 

the following: (1) Product quality and 

performance achieved and ensured 

through the design of effective and 

efficient manufacturing processes, (2) 

product and process specifications 

based on a mechanistic understanding 

of how formulation and process factors 

affect product performance, (3) 

continuous real time quality assurance, 

(4) regulatory policies and procedures 

tailored to recognize the level of 

scientific knowledge supporting 

products and processes, (5) risk-based 

regulatory approaches that recognize the 

level of scientific understanding of how 

formulation and manufacturing process 

factors affect product quality and 

performance, as well as, the capability 

of process control strategies to prevent 

or mitigate the risk of producing a poor 

quality product. This guidance is 

intended to facilitate progress to this 

desired state.

II. Comments Received on the Draft 

Guidance

In the Federal Register of September 

5, 2003 (68 FR 52781), FDA published 

a document announcing the availability 

of a draft version of this guidance. The 

draft guidance was issued with the goal 

of soliciting comments from the public 

on related issues. The agency received 

a number of comments on the draft 

guidance, and those comments were 

considered carefully as the guidance 

was finalized. A number of changes 

were made to the guidance. Most of 

them were of an editorial nature. The 

following three substantive changes 

were made to the guidance as a result 

of the comments: (1) The scope of the 

guidance was expanded to include the 

Center for Drug Evaluation and 

Research’s Office of Biotechnology 

Products, (2) links were established to 

ASTM Technical Committee E55 

entitled ‘‘Pharmaceutical Application of 

Process Analytical Technology,’’ and (3) 

the section on process understanding 

was moved forward to emphasize the 

guidance’s focus.

This guidance is being issued 

consistent with FDA’s good guidance 

practices regulation (21 CFR 10.115). 

The guidance represents the agency’s 

current thinking on this topic. It does 

not create or confer any rights for or on 

any person and does not operate to bind 

FDA or the public. An alternative 

59258 Federal Register / Vol. 69, No. 191 / Monday, October 4, 2004 / Notices 

1FDA has verified the Web site address, but FDA 

is not responsible for any subsequent changes to the 

Web site after this document publishes in the 

Federal Register.

approach may be used if the approach 

satisfies the requirements of the 

applicable statutes and regulations.

III. Electronic Access

Persons with access to the Internet 

may obtain the guidance at either http:/

/www.fda.gov/cder/guidance/index.htm

or http://www.fda.gov/ohrms/dockets/

default.htm.

Dated: September 28, 2004.

Jeffrey Shuren,

Assistant Commissioner for Policy.

[FR Doc. 04–22203 Filed 9–29–04; 1:51 pm]

BILLING CODE 4160–01–S

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES

[Docket No. 2003D–0382]

Food and Drug Administration

Guidance for Industry on Sterile Drug 

Products Produced by Aseptic 

Processing—Current Good 

Manufacturing Practice

AGENCY: Food and Drug Administration, 

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug 

Administration (FDA) is announcing the 

availability of a guidance for industry 

entitled ‘‘Sterile Drug Products 

Produced by Aseptic Processing—

Current Good Manufacturing Practice.’’

This guidance explains FDA’s current 

thinking on manufacturing of sterile 

drug products produced by aseptic 

processing in the context of complying 

with certain sections of the current good 

manufacturing practice (CGMP) 

regulations for drug and biological 

products. This guidance is issued with 

the goal of providing clear and 

consistent communication of regulatory 

expectations to promote voluntary 

compliance with current FDA 

requirements.

DATES: General comments on agency 

guidance documents are welcome at any 

time.

ADDRESSES: Submit written requests for 

single copies of the guidance to the 

Division of Drug Information (HFD–

240), Center for Drug Evaluation and 

Research, Food and Drug 

Administration, 5600 Fishers Lane, 

Rockville, MD 20857; or the Office of 

Communication, Training and 

Manufacturers Assistance (HFM–40), 

Center for Biologics Evaluation and 

Research, Food and Drug 

Administration, 1401 Rockville Pike, 

Rockville, MD 20852–1448. Send one 

self-addressed adhesive label to assist 

that office in processing your requests. 

Submit written comments on the draft 

guidance to the Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. Submit 

electronic comments to http://

www.fda.gov/dockets/ecomments. See 

the SUPPLEMENTARY INFORMATION section 

for electronic access to the guidance 

document.

FOR FURTHER INFORMATION CONTACT:

Richard Friedman, Center for Drug 

Evaluation and Research (HFD–

320), Food and Drug 

Administration, 11919 Rockville 

Pike, Rockville, MD 20852, 301–

827–9031; or

Robert Sausville, Center for Biologics 

Evaluations and Research (HFM–

624), Food and Drug 

Administration, 1401 Rockville 

Pike, Rockville, MD 20852–1448, 

301–827–6201; or

Robert Coleman, Office of Regulatory 

Affairs (HFC–240), Food and Drug 

Administration, 5600 Fishers Lane, 

Rockville, MD 20857, 404–253–

1295.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of 

a guidance for industry entitled ‘‘Sterile 

Drug Products Produced by Aseptic 

Processing— Current Good 

Manufacturing Practice.’’ This guidance 

explains FDA’s current thinking on 

manufacturing of sterile drug products 

produced by aseptic processing in the 

context of complying with certain 

sections of the CGMP regulations for 

drug and biological products (21 CFR 

parts 210, 211, and 600 through 680, 

respectively).

In the Federal Register of September 

5, 2003 (68 FR 52782), FDA announced 

the availability of a draft guidance 

entitled ‘‘Sterile Drug Products 

Produced by Aseptic Processing—

Current Good Manufacturing Practice.’’

The draft guidance was finalized after 

consideration of received public 

comments. Consistent with the 

objectives of FDA’s CGMPs for the 21st 

Century initiative, this guidance 

provides updated information regarding 

CGMP expectations for aseptic 

processing facilities, reflects the latest 

science in the area of sterile drug 

quality, and promotes innovations in 

manufacturing that achieve increased 

sterility assurance. Through this 

guidance, FDA hopes to facilitate a 

higher assurance of process consistency 

and promote better contamination 

prevention practices.

Sterile drug products are a high 

priority in FDA’s risk-based 

inspectional program. These drug 

products are generally of high 

therapeutic significance. Clarifying 

relevant regulatory standards for sterile 

drug products will help reduce the 

incidence of manufacturing problems 

with this class of pharmaceuticals, thus 

facilitating the ready availability of 

these therapeutically significant 

pharmaceuticals and avoiding drug 

shortages.

This guidance document is the 

product of extensive public input. FDA 

first published a preview of its current 

thinking in the form of a concept paper 

on September 23, 2003. We presented 

our CGMP approach for aseptic 

processing at the Advisory Committee 

for Pharmaceutical Science on October 

22, 2002. At this meeting, the concept 

paper was discussed in a public forum 

and critiqued by the advisory 

committee’s members as well as a panel 

of invited aseptic processing experts. 

The advisory committee meeting 

yielded a number of issues that 

provided impetus for further discussion. 

In December 2002, an aseptic processing 

working group was formed under 

Product Quality Research Institute 

(PQRI) to address these issues. The 

working group, composed of 41 

prominent aseptic processing experts 

from industry, academia, and FDA, 

prepared technical recommendations on 

the guidance document. The PQRI 

Steering Committee forwarded the 

working group’s final report to FDA on 

March 19, 2003, and it was 

subsequently posted on PQRI’s Web site 

(www.pqri.org).1 The draft guidance was 

published on September 3, 2003.

The advisory committee and PQRI 

Working Group recommendations 

provided valuable contributions and 

many of these recommendations have 

been adopted in the guidance.

II. Comments Received on the Draft 

Guidance

A number of comments were received 

on the draft guidance, most of which 

concerned the need to further enhance 

the precision of guidance provided on 

certain topics. As a result, many 

clarifying changes were made. Major 

changes include the revision of the 

Sterility Testing section of the guidance 

to clearly emphasize and reference the 

United States Pharmacopeial Sterility 

Test <71>. In the guidance, table 1 

entitled ‘‘Air Classifications,’’ which