PDA Standard Practice for Quality Risk Management of

Aseptic ProcessesA Technical Report No. 44 Update

TR 44 QRM for Aseptic Processing Background

• QRM identified as key information need at 2005 Annual Meeting

• Task force formed to meet this need

• TR 44 published in 2008

Followed in by PDA TR 54 1-6 seriesQRM for Biopharmaceutical Manufacturing

(2012 – present)

… and working on PDA ANS-003 Standard Practice for

Quality Risk Management of Aseptic Processes(2020 - ?)

First effort to assist reader in implementing, assessing and managing the unique risks associated with aseptic processing.

TR 44 Report Overview

Presented in four sections:

1. QRM concepts – aligned with ICH Q9

2. Unique aspects of aseptic processing QRM

3. Model preparation, use, and helpful hints

4. Support information – examples, glossary, references and bibliography

Key inputs to TR 44

• Departure from Tech Reports that present best practice of mature technology

• Implementation of FMEA based model

• Focus on unique aseptic processing hazards/risks

• Lack of sterility/sterility assurance

• Endotoxin contamination

Key outputs from TR 44

• Severity is always high and constant

• Detection can be relatively unreliable

• Occurrence is likelihood that a failure will occur to extent that it will result in unwanted event

• Objective is process improvement

• Evaluation of residual risk and continuous review/assessment are essential

• Numeric models may be subjective and ineffective

• Method should not make the decision – instead, it should provide information needed to make informed decisions

DETECTION

O

C

C

U

R

R

E

N

C

E

LOW MEDIUM HIGH

H

I

G

H

M

E

D

I

U

M

L

O

W

Status of QRM in Aseptic Processing Today …

Limited use and perceived value to aseptic processing

Focused on compliance rather than scientific information

“Check the box” and predetermined outcome approaches

Subjectivity without evidence

Need for improvement

Regulatory update

Waldron 2018

• Manufacture of sterile products using principles of QRM to ensure contamination is prevented in final product. QRM applies to document in its entirety …

• Processes, equipment, facilities and manufacturing managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality.

• QRM priorities should include good design of facility, equipment and process … then implementation of well-designed procedures, with monitoring systems

• Where alternative approaches are used, these should be supported by appropriate rationales and risk assessment and should meet the intent of this Annex.

If regulators expect industry to use QRM to justify current approaches …

then QRM can be used to justify improved approaches.

Annex 1 Update: QRM in the February 2020 Draft Revision (12)

9

QRM objective is unclear

Regulatory focus

Aseptic processes are complex and variable

The challenge of aseptic processing QRM

Correlations difficult to find

Processes perceived as inherently risky

Advantages

• Defined pathway

• Diverse/balanced task force

• Industry and regulatory acceptance

• Drives dialog and consensus

• Accelerates change

• Strict rules

• Participation less flexible

• Works best with accepted, standard method

• Must be concise and comprehensive

• Additional vetting and approval process

Challenges

Why develop ANSI Standard for QRM of Aseptic Processes

ANSI is an accrediting body that endorses standards developed by individual organizations for worldwide adoption. PDA is an ANSI certified standards organization

Standard Practice for Quality Risk Management of Aseptic Processes

Project Description and intent:

• Use lessons learned from TR 44 and TR 54, Aseptic Process Points to Consider, Annex 1 revision review, and industry input to develop a useful standard and/or set of standards for the application of Quality Risk Management principles to Aseptic Processing, taking into consideration the unique aspects of Aseptic Process assessment, performance, failure impact, detection, and correlation of observation to desired outcome.

• Create a practical standard to guide industry and regulators seeking to apply or evaluate Quality Risk Management principles in decisions related to the planning, design, qualification, operation, monitoring, and investigation of various aspects of Aseptic Processing.

PDA/ANSI proposal

Criteria for a Successful Standard

People will use the standard to improve aseptic process control.

• Influence contamination control strategies to prevent contamination.

• Increase understanding of aseptic processing and interdependencies.

• Provide an approach for identifying and ranking contamination risks for non-experts and decision makers.

Standard preparation “Rules”

✓Useful ✓Read and followed✓Unique to aseptic processing✓Evidence based✓Applicable to all aseptic processes✓Address current and future lifecycle

issues

• Aseptic processing and microbiology experts

• QRM experts

• Regulators

• General Interest participants

• PDA support team

Task force must be balanced: Standard should be:

Provide standard approaches and guidance to industry and regulatorsthat increase the understanding and use of QRM principles to make scientifically valid decisions needed to improve aseptic manufacturing processes for and prevent microbiological contamination of sterile healthcare products.

Vision and scope

Key decision:

Develop an aseptic processing standard that uses QRM principles or

develop a QRM standard that is useful for aseptic processing

2. Aseptic Processing

Needs

2. QRM Fundamentals

& Principles

6. Other Points to Consider

7. Glossary & Support

Information

1. Scope

and Vision

3. Tools and Methods

Development

4. Aseptic Processing Usefulness

5. Aseptic ProcessingExamples

Sub-teams

QRM fundamentals sub-team role

• Present what reader should know, understand, appreciate, and practice to manage risk

• QRM principles• Basic

• Aseptic process specific

• Objectivity, communication, removal of bias

• How to establish, use, and maintain QRM principles

Aseptic processing sub-team role

• Identify industry needs • Cover process lifecycle, design, validation, operation, monitoring, improvement,

process controls, technology selection

• Align with Annex 1 revision

• What poses risk to product sterility and how to use this information?

• Confirm usefulness of tool for aseptic processing

• Select and present (non-prescriptive) examples to illustrate use of tool

EQUIPMENT UTILITIES FACILITY

MATERIALS PERSONNEL PROCESS

Use fundamentals and needs to find or create a tool to assess the contamination risks common to aseptic processing

Tool development sub-team role

Is there a tool that currently addresses Aseptic Processing needs?

Build a New Aseptic Processing Risk Assessment tool

• Evaluate entire suite of Aseptic Processing Controls

• Controls ranked according to ability to:

• Eliminate

• Prevent

• Reduce

• Detect

• Criteria based on reliable evidence

• Detection linked to prediction

failure modes

Concluding thoughts

1. New therapies and modern technologies reshaping aseptic processing2. Traditional process control may not be sufficient3. Improvement is needed4. We are not changing fast enough5. A QRM standard approach can accelerate change

More to come …

Thank you

Stay safe and be well

hbaseman@valsource.com(561) 676-3940