The revised European Union good manufacturing practice (EU GMP) Annex 1 guidance document (1), which was published on Aug. 25, 2022 and came into effect on Aug. 25, 2023, is a more detailed and comprehensive guideline that aims to enhance process understanding and incorporate new innovative tools. The updated Annex 1 also takes into account changes in regulatory and manufacturing environments. However, it is important to examine how the requirements for liquid sterilizing grade filtration within the revised Annex 1 align with technological advancements and contamination control assurance. This paper aims to review technology advances in filtration and identify areas that require clarification in the Annex 1 guidelines.

Sterilizing-grade filtration is a widely used method for sterilizing biologics, and it has become increasingly prevalent due to improvements in filter and membrane stability, advanced integrity tests, new design and chemistry features, and process validation activities. These advancements have significantly increased the reliability of aseptic processing steps using sterilizing grade filters, necessarily so; as for most biologics, sterile filtration is the only means of sterilization.

Modern sterilizing-grade membrane filters are designed and built to meet the strict requirements of the biopharmaceutical industry and regulatory authorities. These filters have undergone continuous optimization and development, resulting in several important features:

 Filters can withstand high temperatures of up to 134 °C, making them suitable for sterilization by in-line steam or autoclaving even for multiple cycles. The temperature/differential pressure profile has been established, which supports the appropriate operating conditions during steam sterilization, preventing any damage.

 Single-use assemblies utilize filter capsules. These filters are resistant to gamma irradiation up to 50 kGy. The gamma irradiation method is validated to show proof the assembly is sterilized, and the assembly and filter membrane are compatible with the sterilization method, without damage.

 Even when used straight out of the box, these filters release extremely low levels of extractables, which have been published and are detailed in qualification documentation from the filter manufacturers.

 Modern sterilizing filters can withstand 25,000 pulsations at a pressure difference of 70 psi (5 bar), ensuring their durability and reliability. Such tests are performed by filter manufacturers to assure the product robustness.

 Most filters have been optimized to greatly reduce the amount of unspecific adsorption, which is of importance to avoid the retention of target proteins or other important fluid components, for example polysorbate.

 Some filters are designed to provide the highest possible volume of filtration, effectively reducing the cost per liter of filtered material. Highly asymmetric and heterogenous double layer filter designs are throughput focused filter types.

 Some filters are engineered to achieve the most efficient flow rates, which can reduce processing times or the required filtration area. In this case, the filters have a high pleat density and therefore effective filtration area and are typically single layer membranes.

 Sterilizing grade filters must be tested for their integrity using non-destructive methods such as diffusive flow, pressure decay, or bubble point tests. These tests have been successfully used for decades and are a reliable must-do test post-use.

 The filters come with comprehensive qualification documentation, which lists a multitude of tests, for example, endotoxin release, Plastic Class VI, etc., ensuring that they meet the necessary regulatory standards.

 The filters undergo process validation specific to the drug product being filtered under process conditions, confirming their compatibility, performance, and retentivity.

Every sterilizing-grade filter is individually integrity tested by the filter manufacturer, as a release criterion for the product.

The filter suppliers also recommend necessary shelf-life data for filtration and single-use assembly products and validate the packaging and transportation of these components to assure the product are not damaged.

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is principal consultant, BioProcess Resources LLC

When referring to this article, please cite it as Jornitz, M. Filtration Clarification Needs in Annex 1. 

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Misalignment around liquid filtration requirements and contamination control assurance still persist despite the revisions to Annex 1.

Filtration Clarification Needs in Annex 1

The adoption of single-use technologies (SUTs) in biopharmaceutical manufacturing reduces manufacturing costs, increases the manufacturing line flexibility, and improves the speed and efficacy of the line changeovers or the batch turnaround times. The closed manufacturing systems also facilitate production of a safe and regulatory-compliant product. SUTs are used throughout the biopharma manufacturing process flow, the single-use filter capsules, tubing, and connectors being the most widely used in the final fill/finish applications of the injectable preparations. The single-use bioreactor bags and buffer storage bags are used for upstream applications. This paper reviews the drivers for adoption of SUTs and how the risks from the use of these technologies can be overcome in a planned, proactive, and compliant manner. 

The adoption of single-use components emerged from the mid-1980s. Initially, blood bags replaced glass bottles and soon became available with a plastic tube or two as well as connectors, valves, and vials for taking biological samples. The polyvinyl chloride blood bags used for blood donations were more than just bags. Evolving from these examples are the current single-uses systems (SUS) that are gaining wider use in the biopharmaceuticals industry, especially for the production of specialized and/or small-batch biopharmaceutical drugs. These SUS are the alternatives to the systems made of relatively inflexible stainless-steel vessels and reactors, hard piping, valves, and so on. Such fixed systems must be cleaned and sterilized between batches, a relatively labor and energy-intensive operation. The adoption of aseptic connectors, tubing, mixers, storage bags, and sampling bags and usage of capsule filters in a wide range of applications in the late 1990s lead to the “plastic factory” concept in the 2000s. The technology was further expanded to the upstream and downstream unit operations in the biopharma industry, such as the bioreactors, chromatography, virus removal filtration, concentration, and purification steps. This expansion has evolved over time to the current-day concept of closed continuous processing technology, which is almost completely based on SUTs and assemblies (1,2).

Single-use or disposable bioprocessing equipment is now used for ≥85% of pre-commercial scale (i.e., preclinical and clinical) biopharma manufacturing and is increasingly being adopted for commercial product manufacturing, according to an industry survey (3). The leading reasons cited in the survey as being “very important” for the adoption of SUS include a decrease in the risk of cross-product contamination, cited by 46.2% survey respondents; eliminating cleaning requirements, cited by 41.2% of respondents; reducing time to get facility up and running, cited by 44.1% of respondents; and reduction in capital investment in facility and equipment, cited by 40.4% of respondents.

A study found that SUTs, when adopted, required 87% less water (primarily by reducing steaming in place [SIP], cleaning, and changeover between batches), 21% less labor (primarily by reducing cleaning in place [CIP] activities), 38% less space, and 29% less energy (4). According to industry sources (5), SUS lower operating costs by offering 46% water and energy reductions, a 35% more favorable carbon dioxide footprint due to lower facility emissions, and a 40% lower initial investment cost. The technology allows biopharma manufacturers to push products to market faster by increasing throughput and making scalability easier (5). The availability of this technology has made new biopharma companies adopt SUS, as it requires less upfront capital investment and enables quick advancement of development efforts towards new products (6).

1. Rathore, A. S.; Agarwal, H.; Sharma, A. K.; Pathak, M.; Muthukumar, S. Continuous Processing for Production of Biopharmaceuticals. 

 (8), 836–849. DOI: 10.1080/10826068.2014.985834.
2. Klutz, S.; Magnus, J.; Lobedann, M.; et al. Developing the Biofacility of the Future Based on Continuous Processing and SUT. 

, 120–130. DOI: 10.1016/j.jbiotec.2015.06.388
3. Langer, E. S.; Rader, R. A. Biopharmaceutical Manufacturing is Shifting to SUS. Are the Dinosaurs, the Large Stainless-Steel Facilities, Becoming Extinct? 

 online, Oct. 23, 2018.
4. Lim, J.; Cox, S.; Leveen, L.; Monge, M.; Sinclairm A. The Environmental Impact of Disposable Technologies. 

.
5. Single Use Support. Pioneering Biopharma. 

 (accessed Jan. 21, 2024).
6. Das, S. The Appeal of Single-use Tech. 

Ramesh Raju Mavuleti*, rrajum@gmail.com, is head of operations, Validation Services India; Subhasis Banerjee, PhD, is principal technical application expert, Bioprocessing APAC; and Tathagata Ray, is consultant, Global Strategy Deployment; all at Merck Life Sciences Pvt, Ltd.; K. Vasantakumar Pai, PhD , is professor and chairman, PG Department of studies & research in Industrial Chemistry, Kuvempu University; K. Sreedhara Ranganath Pai, PhD, is professor, epartment of Pharmacology, Manipal Academy of Higher Education; and Somasundaram Gopalakrishnan, is senior consultant, Global Biopharm Center of Excellence, Merck Pte. Ltd.

*To whom all correspondence should be addressed.

When referring to this article, please cite it as Mavuleti, R. R.; Pai, K. V.; Pai, K. S. R.; et al. Review of SUT Adoption in Biopharma Manufacturing. 

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Manufacturing

The evolution of therapeutic modalities drives the adoption of single-use technologies.

Review of SUT Adoption in Biopharma Manufacturing

The use of quality-by-design (QbD) principles, supported by standard processes and tools, are well established across industry for delivering enhanced understanding of pharmaceutical drug product and manufacturing processes as well as ensuring regulatory expectations are met. A key pillar of QbD is quality risk management (QRM), which positions risk assessments at the intersection of numerous pharmaceutical processes, acting as a lynchpin, driving control strategy development, technology transfer, supporting regulatory submissions and lifecycle management of manufacturing processes. The primary objective of this article is to explore the use of digital risk assessment platforms and their advantages.

Risk assessments are an essential element within the QbD framework and play a vital role in identifying and controlling product quality risks across the product life cycle. Risk assessments systematically dissect both product and process designs based on potential hazards, aiming to identify risks and quantify their criticality to craft effective risk mitigation and control strategies. Moreover, they help to prioritize the experimental strategy focusing on the process steps with a high number of critical parameters to establish the optimal modeling strategy. The overarching goal of a risk assessment is to provide decision-makers with a comprehensive understanding of the drug product and manufacturing process, facilitating informed decision-making and the implementation of risk mitigation strategies. There are various risk management techniques described in International Council for Harmonisation (ICH) Q9, including basic risk management facilitation methods, failure mode and effects (criticality) analysis (FMEA and FMECA), fault tree analysis (FTA), hazard analysis and critical control points (HACCP), hazard operability analysis (HAZOP), and preliminary hazard analysis (PHA). FMEA, in particular, is a widely used tool for identifying, assessing, and analyzing risks used to prioritize work packages to ensure the development of safe and effective medicines.

Traditional risk assessment workflows using spreadsheets or word-processors can be laborious and have limited capacity to connect with the vast volumes of data generated by organizations, including product specific understanding. This leads to challenges with leveraging prior knowledge, which in turn can result in unwanted inconsistencies between risk assessments for a single product or across multiple products of the same modality. While these risk assessments are acknowledged for their inherent value, they are limited in scalability and susceptible to human errors. The resource-intensive nature of these assessments results in the generation of large datasets that prove complex to maintain and analyze using traditional techniques, leading to knowledge silos.

In response to the evolving landscape, pharmaceutical companies have developed risk assessments embedded with prior knowledge, often stored in a collection of spreadsheets and written report templates. However, these encounter the same challenges that extend beyond their effectiveness, posing limitations on knowledge sharing. The current paradigm of risk assessments operating primarily in this traditional, siloed, unintegrated format results in significant challenges associated with collaborative risk management across disciplines, groups, and even regulatory agencies, making the need for a more integrated and collaborative digital approach evident.

is scientific leader, QbD and digital platforms, medicines development and supply at GSK Upper Providence, Collegeville, PA, USA.


is scientific leader, QbD and digital platforms, medicines development and supply at GSK Upper Merion, King of Prussia, PA, USA.


is head vaccines projects CMC statistics technical R&D, Projects, and Digital Sciences at GSK, Rixensart, Belgium.


phil.j.borman@gsk.com, is director and senior fellow, QbD and digital platforms, medicines development and supply at GSK, Stevenage, UK.


When referring to this article, please cite it as Borman, P. Digitalization of QbD Risk Assessments. 

Quality by Design

Quality-by-design risk assessment workflows can be laborious and have limited capacity to connect with vast volumes of prior knowledge generated by organizations. Their digital transformation can improve efficiency, reduce human errors, and facilitate integration within a much broader digital ecosystem.

Digitalization of QbD Risk Assessments

This article is a sequel of the article published in the Parenteral Drug Association’s 

Journal of Pharmaceutical Science and Technology 

(1) and provides industry with additional options and thoughts on meeting quality risk management (QRM) needs for the manufacture of sterile and microbiologically sensitive products. Part 1 of this article resulted in considerable industry response with respect to its utilization and increasing opportunities to address current technology needs and regulatory challenges. This response includes the use and refinement of the method for new applications. In this second article, the authors discuss and present more application scenarios where the Intervention Risk Evaluation Method (IREM) can be used for effectively assessing and mitigating risks of human interventions and improving the overall sterility assurance level of the final products, further refining and aligning the method with industry needs and regulatory expectations.

Although performing effective risk assessments has long been considered as beneficial for the design, performance, and evaluation of aseptic processes, as well as a strong regulatory expectation, it continues to be an area of concern and a challenge for pharmaceutical companies. With the advent of advanced therapy medicinal products (ATMPs), complex aseptic formulations, and modern manufacturing technologies, objective, data-driven risk assessment is becoming even more important to assess the risk of interventions in a more holistic way and with true representation of actual shopfloor conditions in any given line. This need reflects the current expectations of global regulators as defined in the contamination control strategy (CCS) and QRM sections of European Union and Pharmaceutical Inspection and Co-operation Scheme (PIC/S) Annex 1 guidance and regulations (2,3).

One key aspect that differentiates IREM from other risk assessment tools is that it empowers those performing aseptic processing activities to design their own risk assessment model and establish a mitigation strategy for themselves. IREM involves the people from the shopfloor or cleanroom who are responsible for performing the process control activities. This helps identify the core risk elements and risk mitigation steps. As such, it creates a better sense of awareness and ownership by those individuals for mitigating those risks.

This article focuses on manual or semiautomatic aseptic processes, which have come into significant use due to expansion of ATMP manufacturing and other complex biopharmaceutical manufacturing processes, and aseptic compounding that requires manual aseptic manipulations during these processes. The need for guidance to identify and mitigate aseptic processing risks for ATMPs and certain other manual operations has become a significant concern in the industry. The authors present a case study to illustrate the use of an IREM to evaluate the risks posed by interventions during aseptic compounding. The IREM team is encouraged to use a keyword approach to choose risk factors and ranking criteria that are meaningful and fit the circumstances at the site. In the following case study and in the previous article, five risk factors were identified as opposed to the three identified in early IREM publications (4).

The factors and associated criteria selected may not necessarily be optimal or applicable to other teams and other sites and are not meant to present prescriptive or exclusive risk factors and ranking criteria. However, they are still defendable, have a scientific basis, and are meaningful for the determination of relative risk ranking and mitigation for this site and circumstances. It is important that, for this site and circumstances, the risk factors and ranking criteria are applicable, have a defendable and scientific basis, and are meaningful to the assessment team. The flexibility of allowing the team to choose its own risk factors and criteria helps ensure that the company will use the IREM to its full potential, to establish and mitigate the line-specific risk factors, and not merely go through the formality of a risk assessment exercise.


The figures and tables for this article may be accessed below:

Figure 1: Aseptic compounding process flow in a conventional laminar flow hood with rigid barriers used in this case. [Figure courtesy of the authors]

TABLE I. Definition of risk level for each risk factor.

TABLE II. Risk Class-A based on duration and complexity.

TABLE III. Risk Class-B based on proximity and human exposure.

TABLE V. Final Risk level based on operator skill/experience.

TABLE VI. Risk levels and mitigation actions. CAPA is corrective and preventive actions.

TABLE VII. Risk ranking based on current intervention status.

TABLE VIII. Risk ranking based on mitigated intervention status (hypothetical).

Subrata Chakraborty is founder and CEO at GxPFONT Consulting, INOVR. Hal Baseman is COO at ValSource.

®
Quality and Regulatory Sourcebook eBook
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Pages: 14-24

When referring to this article, please cite it as Chakraborty, S. and Baseman, H. Intervention Risk Evaluation and Management in Aseptic Manufacturing–Part II. 

Aseptic Technologies

IREM can be used for effectively assessing and mitigating risks and improving the overall sterility assurance level in all types of aseptic processing lines. 

Intervention Risk Evaluation and Management in Aseptic Manufacturing–Part II

Regulatory submissions are a critical step in bringing new drugs and medical interventions to market, and the success of these submissions heavily relies on the quality and fitness of the data presented within the submission package to regulatory bodies. Recent FDA analysis shows that 32% of study data in submissions had significant issues with data conformity. If a submission is rejected due to non-conformance with study data requirements, it does not progress to the FDA Electronic Submissions Gateway, nor does it enter FDA electronic document rooms, which is where the official FDA review process begins. Out of the new new molecular entity (NME)/investigational new drug (IND) applications that successfully pass the study data conformance screening, only 50% are approved by FDA on their first submission. There is then a median delay of 435 days to approval following the first unsuccessful submission, which in turn postpones the availability of crucial new medications to patients. The stringent requirements set forth by regulatory bodies such as FDA and the European Medicines Agency (EMA) are not just procedural hurdles, they are essential safeguards to ensure the integrity of the clinical trial process, patient safety, and drug efficacy.

The rapid advancements in medical science and data technology result in both opportunities and challenges in maintaining the highest standards of data quality. As the industry navigates through the complexities of clinical trials, the importance of accurate, reliable, and robust data cannot be understated. Data must accurately reflect the clinical trial’s findings, as inaccuracies can lead to incorrect conclusions about a drug’s safety and efficacy, ultimately affecting patient health and public safety. This is why adherence to standards such as those provided by the Clinical Data Interchange Standards Consortium (CDISC) are essential to ensure that data are consistent, interpretable, and can be efficiently reviewed by regulatory bodies such as FDA. Moreover, complete and comprehensive data are crucial; any gaps can lead to delays as outlined in this article, as well as questions from regulatory bodies to add to these potential delays as they are resolved. Equally important is ensuring that the data remains current and relevant to the specific investigational drug and its intended use, as outdated or irrelevant data can skew the assessment of a drug’s profile. These elements collectively uphold the integrity of data, which is fundamental in the decision-making process of drug approval and, ultimately, in safeguarding public health.

Maintaining data quality is fraught with challenges. These can range from technological limitations in data capture and storage to human errors in data entry and analysis. The complexity of clinical trials, involving multiple sites and varying patient populations, adds another layer of difficulty. The following highlights the main issues each of these challenges can bring:

 Modern clinical trials are inherently complex, often spanning multiple countries and involving diverse patient populations. This complexity can lead to inconsistencies in data collection methods and difficulties in aggregating and standardizing data across different sites.

 While technological advancements have streamlined data collection and analysis, they also present challenges. Ensuring compatibility between different data systems and protecting against data breaches and corruption are significant concerns. Additionally, as technology evolves, so must the methods and protocols for data management to stay current and effective.

 The role of human error cannot be underestimated. Misinterpretation of data, incorrect data entry, and failure to follow protocols can all lead to compromised data quality. This underscores the importance of comprehensive training and rigorous oversight throughout the data collection and analysis process.

Each of these challenges requires a tailored approach to mitigate risks and ensure integrity and quality of data in regulatory submissions.

Claude Price is head of Clinical Data Management at Quanticate.

When referring to this article, please cite it as Price, C. The Importance of Quality Data for Regulatory Submissions. 

Regulatory submissions are a critical step in bringing new drugs and medical interventions to market, the success of which heavily relies on the quality and fitness of the data presented to the regulatory bodies.

Quality and Regulatory Sourcebook, March 2024 eBook

Filtration Clarification Needs in Annex 1

Review of SUT Adoption in Biopharma Manufacturing

Digitalization of QbD Risk Assessments

Intervention Risk Evaluation and Management in Aseptic Manufacturing–Part II

The Importance of Quality Data for Regulatory Submissions