Guest Column | November 21, 2018

Quality Risk Management And The Draft Annex 1 Revision — What To Expect

By Hal Baseman and Kelly Waldron, Ph.D., ValSource, LLC


Part of the ValID Insight series, a timely look at issues and insights shaping the regulated pharmaceutical industry worldwide

The PIC/S (Pharmaceutical Inspection Convention/Co-operation Scheme) Inspectors Working Group is preparing to finalize the EMA (European Medicines Agency) Annex 1, Manufacture of Sterile Medicinal Product, guidance/GMPs. The revision, an overhaul of the 2008 version of Annex 1, went out for public comments in January 2018, with comments due for submission by March 20, 2018.

According to MHRA (U.K. Medicines and Healthcare products Regulatory Agency) and PIC/S committee representatives, over 6,200 comments were received during the comment period. The Parenteral Drug Association (PDA) submitted approximately 100 general and specific comments, prepared by an expert committee with input from PDA membership.

The revision attempts to clarify many issues and concerns specific to aseptic processing of sterile medicinal products, and it addresses some aspects of terminal sterilization of medicinal products, as well. Here are a few takeaways from our review of the draft. Our commentary is informed by recent presentations and discussions at PDA conferences in Washington, DC; Berlin, Germany; and Bethesda, Maryland.

Quality Risk Management (QRM)

The use of QRM principles and risk-based approaches are prominent expectations throughout the draft Annex 1 revision. Risk-based approaches are mentioned 43 times in the draft. As noted at the PDA/FDA Joint Regulatory Conference in Washington, DC, this September, the PIC/S working group is emphasizing the need for risk-based approaches in all aspects of sterile product manufacturing. Interestingly, the working group is considering removing specific preferences for risk-based approaches in individual sections of Annex 1. Instead, they favor a strong statement in the introduction, expressing expectations for universal application of QRM principles and risk-based approaches for process design and decision making. The PIC/S working group is considering doing so because individual references to QRM may give the wrong impression — namely, that where QRM is not specifically mentioned, QRM is not needed.

Whatever the final wording, the message is clear: European health authorities’ inspectors will seek scientifically sound, unbiased risk assessments, and the use of QRM principles in the planning, design, control, monitoring, operation, and investigation of sterile product manufacturing processes. The industry must be prepared to develop and employ those QRM principles and risk management methods.

Clarity Of Intent And Language

PDA‘s comments expressed concern over the use of terms left open to individual company and inspector interpretations, as this heightens the potential for confusion. Terms such as “encouraged to,” “in alignment with,” “typically,” “in consideration of,” “should,” “may,” “can,” “be sufficient,” “appropriate,” “optimized,” “similar,” and “suitable” are difficult to objectively define. These terms make it difficult for companies to distinguish between regulatory options and requirements. In addition, PDA suggested that the working group replace outdated terms with newer, more scientifically accurate terms. Examples include replacing SAL (sterility assurance level) with PNSU (probability of non-sterile unit), non-viable particulates with total particulates, environmental levels with limits, and laminar air flow with unidirectional air flow.

Prescriptive Controls

An overall concern industry expressed about Annex 1 revision is the inclusion of prescriptive and specific methods for process control that appear to be contrary to alternate methods that  could stifle the use of new, novel methods. These prescriptive controls include methods such as:

  • Settling plates for environmental monitoring
  • PUPSIT (pre-use, post-sterilization integrity testing) for mitigation of sterilizing filtration assembly related defects and masking effects
  • Endotoxin-free feed water for clean steam
  • 70oC WFI (water for injection) recirculation systems
  • 5.0-micron total particle monitoring for critical clean spaces.

These controls appear throughout the draft revision as suggestions and examples. It is not clear if they will be interpreted as requirements. For that reason, wherever possible, the use of prescriptive recommendations should be limited, and instead the use of QRM principles and flexibility in risk-based approaches encouraged.

PUPSIT (Pre-Use, Post-Sterilization Integrity Testing)

PUPSIT has been a concern of industry for several years. Although the requirement for pre-use integrity testing of the “sterilized” filter has appeared in previous versions of Annex 1, the enforcement has increased since the last version in 2008. PUPSIT is a test designed to mitigate situations when a sterilizing filter passes initial integrity testing but then becomes defective during sterilization — and that defect is no longer detectable during end-of-use integrity testing. Material in the solution being filtered can clog a hole in the filter, thus blinding or masking the defect.

Performing such a post-sterilization, pre-use integrity test requires complex line and valving installation downstream of the sterilized filter assembly and line. This increases risk of contamination. Does the benefit of uncovering a relatively rare masking effect outweigh the risk of the downstream assembly and intervention?  Some health authorities say yes; many companies say no. The draft revision allows the use of risk assessments to determine the answer to that question. However, some health authority representatives have indicated concern that such risk assessments may be inherently biased to the predetermined outcome of avoiding PUPSIT — and are therefore invalid and non-persuasive.

In the end, the question isn’t whether to perform PUPSIT or not. We should identify and evaluate conditions that pose a risk of filter flawing and masking, and what steps can be taken to reduce or eliminate those risks. Every step introduced into the aseptic process should be assessed for benefit and relative risk to the product and process.

Vapor Hydrogen Peroxide Sterilization Of Indirect Product Contact Surfaces

The draft revision correctly calls for sterilization of indirect product contact parts and surfaces. These are surfaces — such as stopper bowls and tracks — that contact component surfaces, which in turn contact sterile product. These parts and surfaces should be sterilized using a reliable, robust sterilization method.

Many companies currently use vapor hydrogen peroxide (VHP) to sterilize these indirect contact surfaces in isolators, but vapor sterilization may not represent a robust enough sterilization process. In an April 2018 MHRA blog, VHP is presented as an “incredibly fragile” process when used to sterilize these indirect contact parts in isolators. Many health authorities regard VHP as a sanitization, not a sterilization, method. Companies argue their current isolators are not designed for alternate sterilization approaches, and whatever the weakness, VHP sterilization or decontamination of an isolator is still better than the use of conventional lines. In other words, it is good enough. The risks associated with VHP sterilization or decontamination effectiveness for isolator interiors are outweighed by the benefits of using of isolator technology for sterile filling. The issues with the robustness, effectiveness, and reliability of the VHP sterilization method result in part from equipment and sterilization process/cycle designs.

Companies should use QRM principles to establish reasonable expectations for the sterilization of critical process surfaces. Isolators and processes must be designed to meet aseptic process needs.

Aseptic Process Simulations (APS)

The draft revision to Annex 1 correctly sets an expectation for a target of zero contaminated units for APS. This clarifies a longstanding point of confusion and interpretation for defining media fill failure. It further implies that contaminated units should be investigated, and a cause identified and corrected with a CAPA (corrective and preventive action).

The draft still implies that APS design should cover the full duration of the associated process, which in these authors’ opinion is incorrect. Industry comments note that aseptic process simulations are just not sensitive enough, nor are they designed to demonstrate, validate, or set aseptic process durations. Key process variables of cleanroom environmental quality and the effect of cleanroom personnel fatigue cannot be simulated during a media fill and should not be attempted.

Aseptic process simulations are not an effective way to validate cleanroom performance. This is due to the difficulty of running media fills at the various ranges and levels of environmental performance that might be encountered during production. Cleanroom environmental quality can be better demonstrated through proper design, qualification, and monitoring. Any material changes in the cleanroom environment over time should not be validated through media fills, but instead corrected to regain control.

Likewise, the effect of personnel fatigue on the aseptic process cannot be simulated by merely having operators fill media across the full duration of a production time. Other variables associated with human fatigue, including amount of sleep, distractions at home, physical condition, and so on must be taken into consideration. The effects of fatigue should be addressed through proper ergonomic process and barrier system design, rather than through media fills. In these authors’ opinion, Annex 1 places too much emphasis on the APS at the expense of preventive controls, such as facility, equipment, process design, and the human interface.


Although not a technical or QRM issue, it is difficult to contemplate the effect of the Annex 1 revision without considering the political impact of Brexit, given the level of participation, leadership, and guidance provided by the MHRA representatives on the working group. No one — at least no one at the levels of health authorities that most of us deal with — knows what effect Brexit will have on the finalization and implementation of the Annex 1 revision. We have been told that public health continues to be a major priority and that efforts are underway to ensure that any risks to public health resulting from Brexit are minimized. Because of Brexit, the EMA is moving its headquarters from London to Amsterdam, which has resulted in a loss of personnel and a delay in nonessential activities, including the issuance of guidance. However, we have been told that special considerations are being given to the finalization of the revision to Annex 1.

At this point, the PIC/S working group is sticking to its end-of-2018 or Q1 2019 estimated release of the updated Annex 1. There had been some speculation about a second commenting period for the revised revision. That seems unlikely with the logistical and resource issues posed by Brexit. Perhaps more import is the role that the MHRA, as principal contributor to many sections, will have on the interpretation and implementation of the revised document. Time will tell how the evolving political climate will influence the final document.


This latest revision to Annex 1 strongly encourages the use of QRM principles and risk-based thinking in the design and implementation of sterile product manufacturing processes. This is a welcome development, due to an industry need for more effective process control methods. Traditional methods for sterile manufacturing process control may no longer be the most effective means to provide process and product quality confidence. Suboptimal process control activities waste valuable resources, reduce focus on more valuable efforts, and do little to improve patient protection. Typical one-size-fits-all GMP requirements have their place, but certainly not at the expense of more product- and process-specific control strategies developed using sound science and risk-based thinking.

The use of modern control strategies, developed using QRM principles, is essential if the industry is to move forward with innovative, effective process control strategies. For this to happen, companies must employ QRM principles throughout the product lifecycle, including during manufacturing activities. And where risk-based assessments and approaches are unbiased, scientifically sound, and data-based — and avoid predetermined outcomes — regulators must be open to the alternate approaches that result.

It is equally essential that steps be taken to ensure regulators and inspectors governed by the revised Annex interpret and apply the principles and recommendations in a consistent and predictable manner. Companies will then have the confidence to develop, suggest, and implement more effective QRM based approaches.

There should be no debate that those responsible for the planning, design, validation, operation, and quality of sterile product manufacturing for products distributed throughout the European market should be preparing now to develop and implement scientifically sound and effective risk-based approaches to decision making.

About The Authors:

Hal Baseman, COO and a principal at ValSource, LLC, has over 40 years of experience in pharmaceutical operations, validation, and regulatory compliance. He has held positions in executive management and technical operations at several drug manufacturing and consulting firms. He is the immediate past chair of the PDA Board of Directors, former chair of the PDA Science Advisory Board, former co-leader of the PDA Process Validation Interest Group, and co-leader of the PDA Aseptic Processing Points to Consider task force, as well as a long-time member of the PDA Training Research Institute faculty. Baseman holds an MBA in management from LaSalle University and a B.S. in biology from Ursinus College. He can be reached at

Kelly Waldron is a senior consultant with ValSource and a member of the Pharmaceutical Regulatory Science Team (PRST) at the Dublin Institute of Technology. She has expertise in the development and implementation of innovative approaches to quality risk management (QRM), as well as in various quality functions in the pharmaceutical, biopharmaceutical, and medical device industries, including quality system design, quality strategy and planning, deviations/investigations, CAPA, change management, audit and inspection programs and response, stability programs, and design control. She has a BA in biology from Boston University, an MBA in pharmaceutical management from Fairleigh Dickinson University, and a Ph.D. in pharmaceutical regulatory science from the Dublin Institute of Technology. She can be reached at