The second article describes a roundtable discussion that included responses from questions presented to four RMM vendors. Questions focused on perceived hurdles for RMM implementation, validation challenges, available guidance for statistical analysis and how the industry can accelerate RMM adoption and implementation.
Unfortunately, responses provided by some of the vendors demonstrated a general lack of understanding of current regulatory expectations and quality initiatives, as well as what existing validation guidance documents offer the industry.
For example, when discussing perceived hurdles for RMM implementation, Carrene Plummer of Azbil BioVigilant responded “the greatest hurdle is the lack of well-defined guidelines and regulatory expectations” and that “existing documents aren’t in step with RMMs evolution, either not considering RMMs or not addressing distinctions between them.” Plummer further stated “pharma companies express reluctance in making modifications without knowing if their validation approach will find regulatory acceptance...exacerbating the uncertainty is the ill-alignment of regulatory bodies in what is required for validation.” Jörg Stappert of Greiner Bio-One indicated “manufacturers of biologics are quite reluctant in establishing RMMs due to the lack of clear validation and/or acceptance criteria for these methods.”
Some of these responses are far from the truth and do nothing but continue to perpetuate myths and misconceptions associated with the validation and implementation of rapid methods within our industry. There are well-defined guidelines that address distinctions between methods, validation strategies and the use of statistics, and these are getting better (e.g., the revision to PDA Technical Report No. 33, due to be published within the next month). It should also be noted that for a number of years, companies have successfully validated and implemented RMMs using the guidance provided in TR33, USP 1223 and Ph. Eur. 5.1.6. More importantly, the FDA, EMA and other worldwide regulators have put initiatives and policies in place that encourage the implementation of RMMs (e.g., EMA’s post-approval change management protocol, FDA’s strategic plan that includes the implementation of RMMs, and recent changes to the sterility testing of biologics as specified in the U.S. Code of Federal Regulations). Microbiologists representing these same regulatory authorities have also communicated the quality and technical advantages of RMMs over classical methods at professional meetings and in print. Also, the statement that biologics manufacturers are reluctant to establish RMMs is a gross distortion of the facts. Biologics manufacturers have widely implemented RMMs for in-process in addition to finished product testing (e.g., sterility).
As for regulators accepting validation strategies and approaches, numerous firms have already implemented a variety of RMM technology platforms, such as ATP bioluminescence and solid phase cytometry, as alternatives to compendial methods such as the sterility test. And these same multinational firms have obtained approvals from multiple regulatory authorities, demonstrating that the “ill-alignment of regulatory bodies” may not be as apparent as this article suggests.
Next, the participants stated that existing guidance on the use of statistical methods is, in general, at a high-level and do not apply to specific RMM technologies. I don't disagree with this position; however, it is impossible for any single guidance document to address every existing or potential future technology and what statistical method may or may not be appropriate for use. Fortunately, the revision to PDA TR33 will provide enhanced guidance on the use of statistics during the validation of RMMs, and many of these recommendations originated from firms who have used these same strategies for methods that have been approved by worldwide regulatory authorities and are being used today.
Finally, the vendors commented that the industry should continue to work closely with regulators in developing a meaningful validation and implementation strategy. I agree. Open and honest dialogue between all parties is key to success. Darrick Niccum of TSI summed it up nicely when he stated, “only through open discussion and scientific analysis will appropriate applications for each RMM be identified and promulgated.”