Biotech Regulatory SME Corner

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Approach to Sterility


Gamma-Irradiation: Sterilization Validation Approach for Allegro™ Single-Use Systems with Sterile Claim

Pall’s Allegro single-use systems (SUS) are sterilized by gamma irradiation following the ISO standard 11137-2 ‘Sterilization of health care products – Radiation – Part 2: Establishing the sterilization dose’ and/or ISO/TS 13004 ‘Sterilization of health care products – Radiation – Substantiation of selected sterilization dose: Method VDmaxSD’ to support the sterile claim as given for these products. A sterile claim can be made when a Sterility Assurance Level (SAL) of 10-6 has been proven.

FAQ: How are the Principles of Sterility Assurance Levels (SAL) Applied to the Sterilization of Liquids by Filtration?

There is no regulatory requirement to perform process-specific bacterial retention studies on pre-filters or bioburden reduction filters. Although this is somewhat up to the interpretation of individual regulators, there are no published regulations or guidances that specifically state this as a requirement.

Is there a Regulatory Requirement to Perform Process-Specific Bacterial Retention Studies on Pre-Filters?

Sterilization techniques based on bioburden destruction by heat or irradiation require a statistical validation of the sterilization process, as the efficiency is based on a combination of various factors, including: the intensity of exposure (temperature or irradiation level); time of exposure; and bioburden reduction factor to be attained.

What are the Main Elements of an Effective Biotechnology Supplier Change Management Process?

In a global manufacturing and business environment, change management requires close coordination between technical, business, quality, and regulatory functions across geographies. In designing effective change management processes, suppliers also need to consider end user applications, as well as regulatory requirements to help minimize risk to customer’s operations, drug product or ultimately patient safety.

Continuous Processing


Quality and Regulatory Considerations for Continuous Bioprocessing Overview

Over the past decade, biopharmaceutical manufacture has been constantly intensified to provide high productivity in highly flexible production suites at minimal cost. One of the most powerful tools to achieve intensification is seen in continuous manufacture: an interconnection of specific unit operations that enables highly automated manufacture in smaller, more flexible and better scalable plants. With first companies moving towards GMP manufacture with continuous principles, the regulatory aspects need to be highlighted. This article explains the regulatory position towards continuous manufacture and shows what challenges are being addressed today.

Process Characterization Approach for Continuous Downstream Bioprocessing

Continuous downstream processing systems are specially developed to deliver a high specific productivity to enhance manufacturing efficiency. The immediate consequence of this is that even at laboratory scale, these technologies exhibit quite significant throughputs and hence process characterization may consume significant amounts of material.

Equipment Design for Continuous Bioprocessing

Fully closed systems are critical for the successful and bioburden-controlled implementation of continuous bioprocessing platforms. This document reviews some essential points in equipment design for continuous bioprocessing.

Batch Definition and Traceability in Continuous Bioprocessing

A continuous manufacture platform operates with interconnected unit operations over an extended amount of time compared to the step-by-step operating approach of a batch process. How to define a batch or lot is therefore one of the most frequently asked questions when dealing with continuous processing. This article describes how current batch and lot definitions are applied to continuous processing and shows how traceability of lots can be assured.

Automation and Control in Continuous Bioprocesses

Continuous bioprocessing is a key enabler for Process Intensification in the biopharmaceutical industry. A continuous platform connects multiple systems that are operating simultaneously, and therefore requires a robust automation platform for real time process monitoring and decision making. This article shows how early adopters of continuous bioprocesses have automated platforms and gives examples of how the concepts of Industry 4.0 align with continuous bioprocessing.

Quality by Design in Continuous Bioprocesses

For well over a decade, the FDA has advocated for Quality by Design (QbD) in pharmaceutical processes to assure product quality throughout the science- and risk-based design and execution of the manufacturing process. For process characterization within the QbD framework, continuous processing relies largely on the same fundamentals as todays batch operations. This article shows how QbD can be applied to continuous manufacture while mainly relying on small-scale batch experiments for the design of experiments testing.

Extractables and Leachables


List of Available Extractables Reports for Pall-Manufactured Components

Pall Biotech recognizes the need for standardized extractables data, such as those proposed by the BioPhorum Operations Group (BPOG) and United States Pharmacopeia (USP) <665>, which support risk assessment requirements and facilitate qualification of single-use systems. Please find a list of our currently available extractables reports.

BPOG/ USP <665> Sample Extractables Report

This sample report is intended to illustrate the type of information communicated in Pall USP <665> and BPOG extractables reports

Impurities Risk Assessment Calculator

This is our impurities risk assessment calculator using the BPOG and USP <1665> approaches. BPOG and USP have linked the low, medium or high-risk determinations with an expected level of supporting data to support risk assessment and qualification for the vast majority of bioprocess applications.  This tool simplifies calculation of the low, medium, or high-risk score based on knowledge of the component, bioprocess, and application condition. 

Industry Interest Groups


Is Pall Biotech Actively Involved with Industry Interest Groups?

Pall Biotech has historically been involved with numerous industry interest groups, and it continues to be a critical activity for our company. This document highlights the current groups of interest.

What is the BPSA? Is Pall Biotech Involved with the BPSA?

The Bio-Process Systems Alliance, or BPSA, is the only industry interest group which focuses solely on single-use technologies and is open both to end users and suppliers. Pall Biotech has been supporting the BPSA since its inception in 2005.

What is BPOG? Is Pall Biotech Involved with BPOG?

The BioPhorum Operations Group, abbreviated as BPOG, is a global cross industry collaboration between developers, suppliers, and manufacturers to the biopharmaceutical industry. Collaborative efforts are focusing on driving biotech industry improvements to enable the production of safer and more cost-effective drugs. Pall Biotech is a member of two phorums: Technology Roadmapping (TR) and Supply Partner (SP).

Integrity of Single-Use Systems


What are The Current Practices for Assurance of Integrity of Single-Use Systems (SUS)?

The Bio-Process Systems Alliance (BPSA) developed a recommended approach in the technical guide: Design, Control, and Monitoring of Single-Use Systems for Integrity Assurance (July 2017). The current ways to assess and demonstrate proper assurance of integrity of SUS are based on risk assessment.

Many suppliers and end-users of SUS follow this approach to define their strategy for assurance of integrity of SUS and their associated practices.

Test Methods to Check a Single-Use System (SUS) for Leaks

This document discusses the most commonly used non-destructive test methods for checking a SUS for integrity, along with the destructive methods that can also be used during qualification steps, routine destructive sample testing, for investigation or for post-use testing.

New ASTM Standard: E3251- 20 Standard Test Method for Microbial Ingress Testing on Single-Use Systems.

The standard practice outlined in this document applies to microbial ingress risk assessment of a SUS or its individual components that require integrity testing either by the assembly supplier or the end user of the assembly, based on a potential risk of a breach to the product or manufacturing process.

New ASTM Standard Practice for Integrity Assurance and Testing of Single-Use Systems

This standard practice provides useful recommendations on how to manage integrity of SUS, with an approach following quality by design (QbD) and quality risk management (QRM) principles. Integrity assurance is associated in this document to microbial integrity and bioburden control (risk to product quality) as well as liquid product loss (risk to operator and environment).

Best Practices For Successful Filter Integrity Testing Using The Water Intrusion Test (WIT) Method

The purpose of this document is to present the collected best

methods/practices to give filter end users the best possible chance of performing a successful WIT. It presents the factors that influence the WIT, the most common reasons for “false failure” results associated with the WIT, and how to overcome them.

Wetting and Flushing of Pall Microbially-Rated Filter Cartridges and Capsules

This guide will discuss general considerations on filter preparation for use, flushing information for wetting and the flushing installation procedure.

Pre-Use Post Sterilization Integrity Test - PUPSIT


What is the Position of the Regulatory Authorities on PUPSIT?

This document will discuss the positions of the following Regulatory Authorities, Europe, USA, China, Japan on Pre-Use Post Sterilization Integrity Test (PUPSIT), including detailed extracts and references.

What is Pall’s Position on PUPSIT?

Pre-Use Post Sterilization Integrity Test (PUPSIT) is applicable in Europe, as indicated in the EU-GMP guidelines intended for Sterilized Filters (2009, Vol 4 Annex 1, paragraph 113).

 A post sterilization integrity test provides meaningful data about filter integrity, Pall Biotech therefore advocates and supports the application as recommended in the guideline.

PUPSIT Risk Assessment

With Annex 1 currently under revision, Pre-Use Post-Sterilization Integrity Testing (PUPSIT) requirements have become an important topic of discussion. Key points that should be considered during a risk assessment are discussed.

Particle Management in Single Use Systems

Particles management for single-use systems (SUS) is not always an obvious consideration. There are currently no standards or regulations directly applicable to SUS. The specification for the SUS used in a pharmaceutical process must be derived from the regulations applicable to the drug product in its final container. Here is a list of what Pall Biotech feels are the most important regulations and guidance documents on this topic. These references provide deeper insight and help to understand the main elements of this complex and evolving subject in more detail.

New BPSA 2020 Particulates Guide Particle Management in Single-Use Systems

This document provides an overview of the BPSA Particulates Guide which recommends to suppliers and end-users of SUS for how to best manage particles from single-use systems. It describes current industry best practices and concludes with a list of considerations for further improvement

New ASTM Standard Practice for Extraction of Particulate Matter from the Single-Use Systems

This article provides details of the new ASTM E323-20 Standard Practice and includes a brief description of the document’s scope and its content.

Sterile Filter Validation


Should a Pre-Filtration Bioburden Be Determined Prior to Sterile Filtering a Solution?

the United States, the FDA’s Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice (cGMP) [1] document states “The manufacturing process controls should be designed to minimize the bioburden of the unfiltered product”. No specific bioburden limits or sampling frequencies are stated. In contrast, the EU guidelines to cGMP state specifically that pre-sterilizing filtration bioburden must be < 10 CFU/100 mL, and as per Annex 1, aseptic processed drugs subjected to sterilizing filtration and terminally sterilized drugs under parametric release must have pre-sterilization bioburden determined for every batch [2].

Application of Pall’s Sterility Optimization by Assessment of Risk (SOAR) Program

The purpose of Pall’s SOAR program is to evaluate the risk to sterility of any given set of processing conditions prior to performing formal filter validation studies. This is important, as it allows the end user to fully explore the proposed filter design space at the time of filter selection. While not every process fluid or sterile application may need this detailed level of understanding, there are significant benefits to considering this during Phase 2 clinical trials. The program is split into the three main areas: process optimization; high risk fluids; and test method development and optimization.

When Should Filter Validation Be Performed?

Although it is widely recognized that product and process related filter validation studies must be performed for aseptic processing, there is no specific guidance that categorically states when such filter validation studies should be performed. Consequently, the decision when to perform filter validation is determined largely by the end-user. Risk mitigation is central to Quality by Design (QbD) and Quality Risk Management (QRM), and increasingly, ways are sought to build quality into production steps, to reduce risk to the patient. With respect to aseptic processing, this includes a thorough understanding of the design space for sterile filtration.

During Filter Validation, Can Pall Perform One Set of Testing to Cover Both Gamma and Steam Sterilization?

Although Pall will readily accommodate specific end user requirements for filter validation testing, in accordance with the guidelines indicated in PDA Technical Report 26, Pall recommends that test filters be sterilized using the same method as used in the customer process. A filter that is gamma irradiated may produce a different extractables profile compared to a steam sterilized filter of the same membrane type and configuration. Consequently, to cover these potential chemical differences, two sets of extractables testing would be required.

Evaluation of Monodispersion in Brevundimonas Diminuta Suspensions

Although Pall will readily accommodate specific end user requirements for filter validation testing, in accordance with the guidelines indicated in PDA Technical Report 26, Pall recommends that test filters be sterilized using the same method as used in the customer process. A filter that is gamma irradiated may produce a different extractables profile compared to a steam sterilized filter of the same membrane type and configuration. Consequently, to cover these potential chemical differences, two sets of extractables testing would be required.

Selection of a Surrogate Solution for Bactericidal Process Fluids

The purpose of this paper is to outline the approach for performing bacterial retention testing on bactericidal fluids, and to provide the scientific rationale for selection of a surrogate solution when the process fluid is determined to be bactericidal.

Meeting Regulatory Requirements for Vent Filtration on Water for Injection (WFI) Tanks

Water systems for the production, storage, and distribution of purified water are critical points in pharmaceutical production plants. A key concern of regulatory authorities is the installed vent filter on high purity water-holding tanks. This document provides Pall’s technical recommendations to meet current regulatory requirements on the topic. 

Question Based Review Approach as Part of Quality by Design

Risk mitigation is central to Quality by Design (QbD) and Quality Risk Management (QRM); one way of capturing the aspects of science and risk for product quality is to adopt a Question based Review – Quality Overall Summary (QbR-QOS) approach. This document provides details about this approach and describes its advantages and benefits to the applicants.

How to Select Worst - Case Parameters for Process - Specific Filter Validation Studies

Points to Consider When Performing Virus Filtration Validation Studies

Virus filtration is widely accepted as being a robust method for virus removal in the production of biotherapeutics. However, successful validation requires careful planning and selection of the virus panel to include in the testing, as well as the worst-case process parameters to simulate. Here we review some points to consider for a successful virus filtration validation and achieve first time success.

Risk Mitigation for Adventitious Agents in Biotechnology Products

Biotechnology products derived from cell lines are inherently at risk of contamination by adventitious agents. Adventitious agents that are of concern in most biological manufacturing bioprocesses are mainly viruses and bacteria (including mycoplasma). Although contamination of bioreactors and biologic therapeutics is rare the consequences can be catastrophic. Therefore, regulatory agencies worldwide mandate testing for adventitious agents in each lot/batch of material in adherence with current Good Manufacturing Practices (cGMP). 

Regulatory Framework for Virus Safety

Virus safety is of critical importance in the manufacture of biotherapeutics. There is a regulatory expectation that through careful sourcing and screening of raw materials, implementation of appropriate virus removal or inactivation steps in the manufacturing process, and appropriate testing of product throughout the manufacturing process, patient safety can be assured. Further, any processing steps with virus clearance claims must be validated.