What’s new in Aseptic Processing, Validation, and Contract Manufacturing?

By Hal Baseman
Principal & COO
ValSource, llc & ConcordiaValSource, llc

Contract manufacturing organizations need to be aware of the latest technologies, approaches, and philosophies in our industry.  As technology increases and regulatory expectations develop, it is becoming more challenging to stay on the wave of optimal and compliant sterile product manufacturing.  This is a reason many companies are turning to contract manufacturing for aseptic filling and processing.   The past few years have been particularly active when it comes to changes in aseptic processing.  However, the more recent changes have not come yet from technology, but rather from shifts in approach to validation and process control.  It is essential that aseptic processing contract manufacturers remain willing to seek, develop, and utilize innovative technologies, because efficiency of operations is essential to the effective operation of contract manufacturing organization.

In this brief article, I would like to explore the state of aseptic processing in the industry today. 
First, what is the current state of innovation and use of technological advances?  Then, how will the changing regulatory environment alter expectations and perhaps allow for a better level of innovation?

Technological Advances

As an aseptic filling supervisor starting out in this industry some 32 years ago, I may have wondered what aseptic filling would be like 30 years in the future.   I don’t know what I would have imagined, but I am pretty certain I could not have imaged what it has become.  Who would have thought we would still be doing sterile product filling pretty much the same way today that we were doing it back in 1978.   Aside from some isolators and closed RABs, and a sprinkling of robotic operations – most of what we do is pretty much what we did back then. Why haven’t we advanced more?  Who knows?  At an aseptic processing and risk management conference a couple of years ago, three notable exchanges give some insight into the reason for the state of innovation in our industry.(1) 

 Early during the meeting, a presentation was given showing a video of a totally automated, highly advanced food processing aseptic filling line.   At the end an audience member commented that this was obviously a very innovative, cutting edge, but somewhat futuristic technology.  The speaker told the commenter that the video showed nothing futuristic.  The clip was actually many years old, prepared in the 1990’s.  

Later in the day, a panel discussion was held to debate the merits and challenges of operating isolators and RABS filling lines.  Issues associated with positioning of gloves and glove ports in the walls of the isolators, as well as concerns of adequate disinfection of the gloves, were being discussed.   A middle aged member of the audience raised his hand and identified himself as a person who had only recently started to work in the pharmaceutical industry.  Previously, and for most of his career he had worked in the semi conductor and electronics industries.  From that perspective he was quite familiar with the manufacturing isolators they used.  He understood what was being presented as the issues related to use, durability, and disinfection of gloves and glove ports, but what he sincerely wanted to know was we needed gloves in automated pharmaceutical filling isolators in the first place.  The panel member answered that glove ports were needed to provide access to manipulate containers, pick up fallen vials, or un-jam components.   With that the fellow responded, “why not just design and operate your isolator fill lines so vials don’t fall down and components don’t jam up?”  The exchange elicited a few chuckles.

At the end of the meeting, another panel was answering questions about innovation.  The panel was made up of upper management quality and manufacturing people. Many of them had been at such conferences for years, going back to when they were supervisors.  When asked about the reason for the lack of technical innovation in our industry, one of the panelists answered that it was difficult to get “management” to buy in and accept new technologies.  It was then noted that these were the same answers these people and others like them had been giving for some time now.  The difference was that now they were the “management” that supposedly was holding back innovation.  

The three exchanges hint to the reasons of lack of technical innovation in our industry.  First, that we may not know what technology is available or how to use technology from another industry.  Second, we tend to focus on addressing the problem of the moment while not looking at how to prevent it from occurring, a classic underuse of CAPA principles.  And third, we are reluctant to take on the chance on using a technology, because of perceived difficulties getting regulators to accept changes, validating new technology, lack of motivation for manufacturing efficiency.

Times may be changing.  Dwindling product margins, increased foreign competition, and the need for manufacturing efficiency as a result of consolidation of merged operations provide motivation to companies to uncover, develop, and utilize innovative manufacturing technologies.  
There are, of course, technological advances available and happening every day.  There are advances in the earlier mentioned isolation and barrier technology, line automation, closed vial filling, e-beam surface sterilization, rapid microbiology, robotics, disinfection techniques, and process analytical technology (PAT).  There are some more advanced Blow Fill Seal microenvironments and closed parison filling systems which limit open container and product exposure.  There is discussion on Post Aseptic Lethal Treatments such as sub overkill level lethal heat and radiation treatments of aseptically filling products to reduce practical levels of contamination.  

Regulatory agencies, the U.S. FDA included, have encouraged the use of risk based approaches to validation and process control, which will move us away from trying to fit new technology into the traditional check list approaches to validation.  This should provide a more excepting environment for new technology and innovation.

In the remainder of this article, I would like to present two relatively recent developments in the area of validation of aseptic processes as examples of changes in expectation which could signal a shift in approach and use of innovative technologies. 

Changes to cGMPs and Aseptic Process Validation

In December of 2007, the FDA announced proposed changes to the 21CFR part 211, the CGMPs for finished drug products.   These changes included a modification of the wording in part §211.113 adding aseptic processes to the requirement for validation of sterilization processes. (2)

Control of microbiological contamination. (b) Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and sterilization processes.

This seems like a fairly unobtrusive requirement.  Aseptic processes are important to the quality and safety of sterile products.   The assurance of process control is therefore important and validation is a way to assure control of process.  However, this clarification resulted in significant comments from the industry.   Several of the comments focused on the inability to properly perform aseptic process validation studies, in the same way that sterilization, cleaning, or process validation studies could be performed.  Some suggested that it was not possible to validate aseptic processes, not at least in the traditional manner of providing a high degree of assurance that the process would result in a prescribed and predicable outcome. 

The issue results from the lack of aseptic process parameters which can be well correlated to product quality outcome.  In moist heat sterilization, the relationship between the amount of energy delivered to a microorganism and the resultant lethality is understood and almost perfectly correlated to the desired outcome of sterility.  The parameters of time, temperature, pressure, and steam quality can be measured, and their affect on product quality outcome measured and correlated to lethality.   The same can be said for gamma and some forms of chemical sterilization.   In cleaning, the correlation between applying a surfactant or water is easily understood and demonstrated.    The parameters of time, temperature, contact, flow, cleaning solution concentration can be measures and correlated to a desired outcome of prescribed residue levels.   The outcomes are predictable. 

However, in aseptic processing there are not the same well defined parameters.  What would one test or show consistency to environmental results, air flow, room pressurization, aseptic technique, and room temperature/humidity?  All are items which affect contamination, but who knows to what extent or at what point failure occurs.  The correlation between what we can measure in aseptic processing and the desired outcome of sterility is difficult to quantify and measure.

In addition, some in the industry commented that the FDA implied in its preamble explanation that media fills were a way, if not the desired way, to validate aseptic processes.   Some expressed the concern that that the FDA’s wording on media fills might promote companies to rely too heavily or exclusively on media fills as the way to validate the aseptic process.

Even before 1987, when the Guideline for Sterile Drug Products Produced by Aseptic Processing was issued, industry routinely conducted validation studies that substituted microbiological media for the actual product to demonstrate that its aseptic processes were validated. These parts of validation studies are often referred to as media fills.

In September of 2008 the FDA announced the final changes, including the inclusion of the requirement for validation of aseptic processes.(3)  In its response to the industry comments, the FDA noted that the requirement for validation of aseptic processes had always been inherent and understood in the CGMPs, and this modification represented a clarification of existing requirements, rather than a new requirement.  In this response the FDA did acknowledge that validation of an aseptic process might be different than validation of a process with more direct cause and effect correlations.  However, that being said, aseptic processing remains a critical process for manufacturing regulated drug products and therefore the requirement to prove that the process and its variables are adequately controlled or validated remains.  It is important to note that the FDA did offer that media fills were only one part of the validation process.  That they needed to be combined with other means to prove process control and reliability.

Although we acknowledge that aseptic process validation does not provide absolute assurance of product sterility, we do not agree that aseptic processes cannot be validated.…. Media fills, together with operational controls, environmental controls, and product sterility testing, provide a sufficient level of assurance that drugs purported to be sterile are in fact sterile.

The relevance to acceptance of innovation lies in the fact that as the FDA has clarified its expectation that companies perform aseptic process validation, they have also noted that due to the difficulties involved with understanding the relationship between process parameters and desired outcome, aseptic process validation must involve a holistic approach, incorporating more elements than just the successful completion of a series of media fills.  This opens the door for more risk and science based approaches, which we should see evolve.

One example is an FDA website posting from November 2009, in which the answer to What is the acceptable media fill frequency in relation to the number of shifts?  The answer included a clear risk and technology based motivation for using innovative technology.(4)

Certain modern manufacturing designs (isolators and "closed vial" filling) afford isolation of the aseptic process from microbiological contamination risks (e.g., operators and surrounding room environment) throughout processing. For such closed systems, if the design of the processing equipment is robust and the extent of manual manipulation in the manufacturing process is minimized, a firm can consider this information in determining its media fill validation approach.

New Process Validation Guidance (PVG)

On January 24th, 2011 the FDA issued its final version of the revision to the 1987 Guidance on General Principles of Process Validation.   This revision was first issued for public comment in November of 2008.  The industry presented numerous comments to the draft revision.  The FDA appears to have addressed most of the major categories of comments in this final version.(5)

The FDA, through the PVG, encourages companies to use a science and risk based approaches to validate critical processes and to ask and answer the questions:  Do I have confidence in my manufacturing process? What scientific evidence assures me that my process is capable of consistently delivering quality product? How do I demonstrate that my process works as intended? How do I know my process remains in control?(6)  Another way to look at it is that the FDA will expect companies to decide on what approaches to process validation best accomplish the objective of confirmation of process control.   This is a departure from a traditional, documentation focused approach where a series of consecutive batches are run and if they pass – the process is deemed validated.   It should also allow for new approaches which can more effectively be used on new technologies.

The new guidance recommends a true life cycle approach, consisting of three stages or parts.  In Stage 1 process design, process variables are identified which could affect product quality.   Control strategies are developed to assure that process variables do not adversely affect product quality.   In Stage 2 process qualification, the process control strategies and systems which provide and support those control strategies, are tested and demonstrated to be effective.  In Stage 3 continued process verification, the commercial manufacturing process is monitored to assure that it maintains proper performance outcome.  Figure 1 illustrates some of the activities and sequence of the three stage approach.

Table 1: Stages

The three stage approach can be used to support and provide guidance for the effective validation of the aseptic process beyond the use of media fills.   Table 1 suggests some process, control, and monitoring elements which can provide a method to meeting the recommendations of a three stage approach for aseptic processing. 

In Stage 1, the company should determine the optimal process design to control variables. Aseptic process variables include such things as personnel interventions, environmental conditions, component configurations, line speeds, and fill durations.  Stage 2 Process Qualification stays largely the same as the traditional approach, but the information needed to design and prioritize equipment and process qualification studies is largely drawn from the process variables and control strategies gleaned from Stage 1 information.    

In Stage 3, the process performance is confirmed through an analysis of process outcome including process parameter and product quality.   For aseptic processing the process parameters are difficult to determine due to imperfect correlation between measurable parameters and conditions and the desired outcome of product sterility.  However, even imperfect information can still be useful in confirming that eth process is performing properly.    

Conclusion

The aseptic processing industry needs to be more innovative.  It needs to embrace new technologies.  The reasons in the past for reluctance to seek, develop, and use new technologies are becoming less valid.  The commercial climate is right for the use of improved technology. And the regulatory climate is right for the use of more creative and effective ways to validate such technologies.  In the future more aseptic processing will like be handled by contract manufactures and it is important that contract manufactures take the lead in the use of such advances.




References

1. Proceedings of the Parenteral Drug Association (PDA) Risk Management and Aseptic Processing Conference, May 15-16, 2008, Bethesda, MD
2. Federal Register / Vol. 72, No. 232 / Tuesday, December 4, 2007 / Rules and Regulations, p. 68064
3. Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 / Rules and Regulations p. 51919
4. FDA’s “Questions and Answers on Current Good Manufacturing Practices, Good Guidance Practices, Level 2 Guidance Production and Process Controls”.   Question #10. Posted December 3,2009,http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm124782.htm
5. Guidance for Industry, Process Validation: General Principles and Practices, U.S. Department of Health and Human Services, Food and Drug Administration, January 2011, Revision 1
6. Presentation given at the Parenteral Drug Association 2010 PDA/FDA Joint Regulatory Conference by Grace E. McNally, FDA CDER Office of Compliance, Division of Manufacturing & Product Quality, September 15, 2010