PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance: Guidance for Industry | Guideline Explorer

Description

This guidance is intended to describe a regulatory framework (Process Analytical Technology, PAT) that will encourage the voluntary development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance. Working with existing regulations, the Agency has developed an innovative approach for helping the pharmaceutical industry address anticipated technical and regulatory issues and questions.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

1

specified biologics

Biologics regulated by CDER and CVM within the scope of this guidance.

Stakeholders

1

manufacturer

Entity required to conduct postmarket surveillance; entity responsible for submitting postmarket surveillance plans; Entity holding the approved PMA, HDE, or cleared 510(k); The entity responsible for conducting postmarket surveillance and submitting reports.; Entity that can use the checklist as a reference for submissions.

Regulatory Context

Regulatory Activities

8

Real time release

Ability to evaluate and ensure quality of product based on process data

CBE

Changes Being Effected supplement

CBE-30

Changes being effected in 30 days supplement; Reporting category for facility and equipment changes.

PAS

Prior Approval Supplement required for high-risk changes.; Prior Approval Supplement reporting category for manufacturing process changes

CMC review

PAT team approach for CMC review

CGMP inspections

analyzing these data has affected the frequency of CGMP inspections

new drug application

intended submission of the application; submission of a new drug application

abbreviated new drug application

Approved application for which an annual report is required.; approved application for drug products

Document Types

3

Batch records

Executed batch records should be provided for master files

PDA Technical Report No. 33

Evaluation, Validation and Implementation of New Microbiological Testing Methods

comparability protocol

A comparability protocol can be submitted to the Agency outlining PAT research

Attributes

4

process understanding

The framework is founded on process understanding to facilitate innovation.

Critical quality and performance attributes

Measured during processing to ensure final product quality.

Critical quality attributes

Impurity profile, polymorphism, particle size

Process end point

Achievement of the desired material attribute rather than a fixed time

Technical Details

Substances

2

drug substances

documentation of identity, strength, quality, purity, and potency

Raw materials

Specification changes to raw materials

Testing Methods

4

laboratory testing

Used when necessary to determine if a product is illegitimate

Multivariate tools

Tools for design, data acquisition, and analysis within the PAT framework.

Statistical design of experiments

Multivariate mathematical approach for identifying multi-factorial relationships

Process simulation

Tool used in conjunction with knowledge management systems

Processes

7

CMC review

Chemistry manufacturing and control review as part of the regulatory implementation strategy.

batch processing

Conventional pharmaceutical manufacturing is generally accomplished using batch processing.

Continuous Manufacturing

Considerations for batch selection in continuous processes; Stability data package requirements apply to CM processes; Manufacturing process impacting batch selection for stability; Alternative to batch processes for drug production; Manufacturing process referenced in ICH Q13

Real time release

A gain in efficiency likely to come from the PAT framework.

At-line measurement

Sample analyzed in close proximity to the process stream.

On-line measurement

Sample diverted to a side stream for analysis.

In-line measurement

Sample analyzed directly within the process stream without removal.

Standards & References

External Standards

10

ASTM E1325-02

Standard Terminology Relating to Design of Experiments

ASTM E 456-02

Standard Terminology Relating to Quality and Statistics

ASTM D 6299 - 02

Standard Practice for Applying Statistical Quality Assurance Techniques

ASTM D 4855 - 97

Standard Practice for Comparing Test Methods

ASTM D 3764 - 01

Standard Practice for Validation of Process Stream Analyzer Systems

ASTM E2363-04

Standard Terminology related to PAT

ORA Field Management Directive No.135

preoperational review of a PAT manufacturing facility

Compliance Policy Guide Sec. 130.300

FDA access to results of quality assurance program audits and inspections

Pharmacopeial specifications

Generally address only chemical identity and purity of raw materials.

ASTM International

develops standards meeting consensus criteria

Specifications

2

Design space

Defined for blending process parameters

regulatory specifications

mechanistic basis for establishing regulatory specifications

Related CFR Sections (4)

21CFR211.165§ 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on sRead full regulation →
21CFR99.3§ 99.3 Definitions.
(a) Agency or FDA means the Food and Drug Administration.Read full regulation →
21CFR211.110§ 211.110 Sampling and testing of in-process materials and drug products.
(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be establiRead full regulation →
21CFR211.100§ 211.100 Written procedures; deviations.
(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, inRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Quality control unit failed to exercise its responsibility

101

Failure to conduct at least one test to verify the identity of each component

95

Failure to establish adequate written procedures for production and process control

88

Failure to thoroughly investigate any unexplained discrepancy or failure of a batch

56

Failure to have appropriate laboratory determination of satisfactory conformance to final specifications

56

Failure to establish an adequate quality control unit

49

Failure to test samples of each component for identity and conformity

47

Failure to establish laboratory controls

36

Failure to thoroughly investigate any unexplained discrepancy

28

Failure to test samples of each component for identity

25

Recent Cases

Related Warning Letters (10)

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics