Innovative Approaches to Sterile Product Manufacturing and the Application of Risk in the Design of Processes

The manufacturing of sterile drug products remains challenging.  Regulators and industry continue to identify the same types of process failures year in and year out.  The industry should always be seeking ways to improve.   This need for process improvement has led to the introduction of many exciting and encouraging innovations and ideas, including the use of:

  • Advanced aseptic filling/packaging systems, i.e. barrier systems, isolators, and closed RABS (restricted access barrier system), BFS (blow-fill-seal),  FFS (form-fill-seal), automation and robotics, closed vial filling
  • More effective statistical process capability and control metrics, Quality Risk Management and assessment techniques
  • Risk-based, scientific lifecycle approaches to process and system validation
  • Innovative sterilization techniques, i.e. E-beam surface sterilization
  • Single-use drug manufacturing and filling systems
  • Ready to use components, stoppers, over-seal/caps
  • Real time and rapid microbiological monitoring and testing
  • Post Aseptic Lethal Treatment

These items represent technology that will help companies meet the regulatory and manufacturing challenges of modern sterile product packaging.  However, it is important to realize that these approaches will not have as much success as possible, without a better appreciation for aseptic processing risk and process control.     

The Concern

Lack of sterility and lack of sterility assurance continue to be significant reasons for product recalls and regulatory citations.  Producing a sterile drug product is one of the most challenging parts of pharmaceutical manufacturing [1].  From 2004 to 2010, three quarters of drug product recalls involved sterile drug products and of these sterile product recalls, approximately 80% were due to lack of sterility assurance [2].  Regulators, including the U.S. FDA consider sterility related manufacturing issues to be a significant risk to drug product shortages, patient safety and public health [3].  This was well illustrated in 2012, by the contamination related issues uncovered at New England Compounding Pharmacy in Framingham, MA and Ameridose - Westborough, MA, which led to a lethal meningitis outbreak [4].  In 2004, the MHRA shut down PowderJect, a vaccine manufacturer in Liverpool England, leading to the inability of Chiron to adequately supply flu vaccine in the U.S. [5].  Most recently, problems at Hospira and Ben Venue sterile drug product manufacturing sites, resulting from conditions at sterile product manufacturing facilities and lapses in GMPs, were noted as reasons for sterile product rejections and product shortage [6].   

In June of 2012, at the PDA Innovation & Best Practices on Sterile Technology Conference, FDA National Expert Investigator, Rebecca Rodriquez gave an informative presentation on sterile product validation and cGMP deficiencies cited in Warning Letters, including issues related to:

  • Media Fills
  • Personnel
  • Microbiology laboratory
  • Environmental monitoring
  • Cleanroom qualification
  • Disinfectant qualification
  • Visual inspection
  • Investigations
  • Sterilization of equipment [7]

No one should have been surprised by the items presented.  These seemed to be the same issues sterile drug product manufacturers have been grappling with for years.  At times, it appears not much has changed.  Many companies still rely on conventional cleanroom filling operations, relying on gowned personnel performing interventions,  environmental monitoring to provide evidence of clean room and personnel performance, aseptic process simulations to in part provide confidence of sterility, and personnel/material flows to prevent contamination.  

This is not to say that the industry is not moving forward.  As noted earlier, the use of advanced aseptic processing technologies, designed to reduce or eliminated the impact of personnel and the environment on product quality, is growing, with increased use of closed isolators and RABS filling systems, automation, robotics, closed vial filling and such [8, 9].  However, based on the recent sterility related issues and regulatory criticism, it would be difficult to say that we are there yet.   As stated earlier, more improvement is needed.

Aseptic Process Risk

Is aseptic processing risky?  A colleague once pointed out, aseptic processes may be hazardous, but if properly controlled, then they are not necessarily risky.   This is an important concept.  By merely defining a process as risky, the focus tends to rest on the inherent hazards of the process, rather than what actions and improvements to the process are needed to reduce the risk. 

Having said this, identifying process risk is the first step to improving the process.  However, the determination of aseptic process risk does involve some challenges.   Risk is defined as the combination of the probability of occurrence of harm and the severity of that harm [10].  Since we are concerned with risk to patient safety, risk can be mitigated if the hazard is detected and kept from harming the patient.  

Reducing this concept to a formula:

Risk = Severity X Occurrence X Detection

Severity:  The principle hazard associated with aseptic processes is loss of sterility.  The harm to the patient from this hazard is infection.  This harm is undoubtedly severe, therefore the severity of this sterile product manufacturing hazard should always be considered as high [11].

Occurrence:  Occurrence is defined as the likelihood that the cause of the failure will happen, resulting in harm to the patient and that it happens in such a way that does cause the failure.  Note: the definition is not just the probability of a process failure.  It is the probability of failure of a process step to the extent that it will result in loss of sterility. 

To illustrate, consider two process failures.  One is a non-integral operator’s glove and the other is a non-integral sterilizing filter.  The hole in the glove is more likely to occur, yet the hole in the filter is much more likely to result in contaminated product.  If we were strictly calculating probability of failure, then we might incorrectly rank the glove as a greater risk than the filter.   

To further complicate the ranking of aseptic processing risk, we are dealing with relatively rare occurrences.  Sterility failures, while severe in their impact, are still relatively infrequent.  Therefore, quantifying the correlation between a cause and result is difficult [11].

Detection:  Detection of the failure reduces risk, because it allows for the product to be rejected before it can reach and harm the patient.*  The most direct method for detecting sterility of a drug product is sterility testing.  However, sterility testing is limited by sample size and sensitivity, and current sampling plans are not very effective at determining if the product is sterile. 

[Footnote: * The exception would be the rejection of the product resulting in an essential drug shortage.   In this case, the detected failure could still potentially harm the patient.]  

Indirect methods are no better.  Environmental monitoring is more effective at determining the condition of the cleanroom environment, but since the correlation between the condition of the environment and the rate of product contamination is imperfect, it is not a good predictor of product sterility.   Human or video observation of aseptic processing is a good way to identify lapses in operator technique, but without a better understanding of the correlation between technique lapses and product contamination, observation will not be effective at predicting product quality.  Therefore, for aseptic processing and sterile product manufacture in general, the current methods of detection of product contamination are not strong.  

For these reasons, quantifying aseptic processing or sterile product manufacturing risk is challenging.  However, understanding the conditions and events which pose a relative risk to the sterility of the product should not be difficult.  Although, one should be cautious when investigating and evaluating the cause of sterile drug product manufacturing failures.   One should not stop at the first plausible cause, but continue to evaluate and address all plausible causes, which cannot be eliminated.  One should also avoid cause and effect misconceptions. 

A common misconception is people-related aseptic processing failures are always the result of people making mistakes.  People are not always the cause of the problem.  Sometimes the process is not properly or optimally designed to reduce the effects of human behavioral variables.  A widely held belief among sterile product manufacturing companies is personnel related and aseptic processing/technique failures are thought to be the most significant contribution to sterility failures.  Therefore, training is the strategy often used for controlling/minimizing risk [12]. 

Is this always true?  Is the operator performing the task the problem or is the task the problem?   To help answer that question, let’s consider a frequently asked aseptic process simulation study duration design question:  How long should an aseptic process simulation or a media fill last?   The answer is:  It should last long enough to capture or address all relevant process variables.   Therefore, if the process or process conditions change over the length of the fill, then a full duration media fill would be logical [13]. 

But do the process conditions change during the length of the fill?   One reason they might change is operator fatigue.  There is little doubt people get tired.  Human fatigue certainly can be a process variable.  If so, then how can this variable be addressed?  Media fills cannot be used to effectively simulate or test human fatigue.  There are too many variables to predict human fatigue or its effect on process performance outcome.  We can simulate doing a task for a period of time, but this will not account for such variables as physical condition, sleep, stress, cumulative effect of the day’s activities, and so on.  

How should human fatigue variables be controlled?  Rather than through validation studies, they should be addressed through better process design.  The goal should be to reduce or eliminate the potential effect of fatigue on process performance and product quality.  In other words, we can do this by designing the process to eliminate variables.  This is a key concept for aseptic process design and improvement.

A simple example would be lifting trays of sterilized glass vials.  This process step can be an issue if as the operator becomes fatigued, they start to bring the tray closer to their body.   In this case, mitigating the risk of microbial contamination would not involve better training or stronger operators.   More effectively, it might involve changing the process – lightening the trays, using a cart, or a sterilization/depyrogenation tunnel.   

Where the correction of repeated aseptic technique problems, too often, seems to involve retraining, more training, or better training; the effective answer, might be to eliminate the obstacles to successful performance – to assure sterility by designing it into the process.

Conclusion: Sterility by Design

Sterile drug product manufacturing continues to be a concern by regulators and industry.  Lapses in quality and process failures can result in severe patient consequences and drug product shortages, adversely affecting public health.  The significance of aseptic processing risk is due, in part, to the impact of process failure, difficulty of detection, and lack of clear correlation between measurable parameters and desired outcome.  Because there are limited means to effectively measure sterility assurance in aseptic processing, the goal of avoiding microbial contamination should be viewed holistically to optimize to provide the greatest confidence in the overall process.  

Effective and innovative control strategies must be designed and in place to reduce the risk of process failure.  The most effective way to assure sterile drug product quality is through sound process design which identifies process variables, evaluates their relative risk, and reduces or controls their effect on product quality.   

The points brought up in this article represent just a sampling of the factors one might consider when using a risk based approach to designing a sterile drug product manufacturing process. Other aspects might include assessment of equipment and system performance, critical material supplier qualification, human factors and ergonomics, and effective quality metrics.  

This should lead to more innovative advances in technology and quality metrics will likely make sterile drug product manufacturing and packaging more effective and efficient.        


[1]         Taylor, P., Top 5 reasons for a Class I product recall ,  April 21, 2011

[2]         Sutton, S., A Review of Reported Recalls Involving Microbiological Control,, January 1, 2012

[3]          Woodcock J., Wosinska M., Economic and technological drivers of generic sterile injectable drug shortages,  Clinical Pharmacology & Therapeutics, 2013

[4]          Tavernise, S., Amid Purity Questions, Drug Company Recalls Products,, October 31, 2012

[5]          Chiron Will Not Deliver Flu Vaccine,, 11 October 2004 00:01,[Source: ICB Americas]

[6]         Thomas, K., Lapses at Big Drug Factories Add to Shortages and Danger,, October 17, 2012

[7]         Rodriquez, R., Validation of the Aseptic Process and Inspection Trends from a Regulatory Perspective, Parenteral Drug Association: Innovation & Best Practices on Sterile Technology Conference (Session Recordings/Proceedings), June 18-19, 2012

[8]          Akers, J. Environmental Monitoring in Isolators – Time for a New Path Forward, American Pharmaceutical Review, Volume 14, Issue 2, March 2011

[9]          Lysfjord, J., Porter, M., Barrier Isolation History and Trends – 2008 Final Data, Pharmaceutical Engineering, May/June 2009

[10]        ICH Q9, Quality Risk Management,  ICH Harmonized Tripartite Guideline,

Current Step 4 version, November 9, 2005, p. 1

[11]        Technical Report No. 44, Quality Risk Management for Aseptic Processes, PDA Journal of Pharmaceutical Science and Technology, Supplement Volume 62, No. S-1, 2008

[12]       Ahmed R, Baseman H, Ferreira J,, A Survey of Quality Risk Management Practices in the Pharmaceutical, Devices, and Biotechnology Industries, PDA Journal of Pharmaceutical Science and Technology, 2008 Jan-Feb;62(1):1-21

[13]        Technical Report No. 22 (revised 2011), Process Simulation for Aseptically Filled Products, Parenteral Drug Association

Hal Baseman is Chief Operating Officer at ValSource LLC.  He has over 34 years of experience in pharmaceutical sterile products operation, validation, and regulatory compliance.  Hal is Chair-Elect of the PDA Board of Directors, Vice-Chair of the PDA Science Advisory Board, Co-Leader of the PDA Process Validation Interest Group, and is or was Task Force Co-Chair for PDA Technical Reports on Process Validation, Aseptic Process Simulation, and Quality Risk Management for Aseptic Processing. Hal holds an MBA in Management from LaSalle University and a B.S. in Biology from Ursinus College.