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- Practical Workbook - Quality by Design Applied to Viral Safety of Biologicals: Case studies & workshop discussion summary
- Mass spectrometry as a powerful tool for the characterization of monoclonal antibodies in the context of comparability studies
- Continuous Chromatography: Process Improvement and Debottlenecking Solution for Bioproduction Capabilities
- Protein A Affinity Chromatography for Efficient Fab Purification
- Enabling Higher Post Protein A Product Purity Using Novel Chromatographic Clarification Approach
Even though much progress has been made in the definition of "decontamination", it is still very much in the nature of "cleaning" and "disinfection".
This confusion, particularly in the bio-pharmaceutical realm of infectious antigens and particularly viruses, leads to situations of non-technical mastery, non-compliance and ultimately increased risk of cross contamination between products. All of which stress the importance of clarity in biocontainment.
In the early 2000's, the industry was obliged to remove formalin (CMR), which was widely used as a decontamination reagent. The following points are relevant: (i) historical decontamination exposed the relative ineffectiveness of formalin in the light of current practices; (ii) validating the performance efficiency of decontaminants is difficult (too many external variable factors influencing its performance); (iii) highlighted the need for in-depth performance review of all tools and decontamination processes. These observations are further supported by the polio eradication ambitions conducted by WHO (GAP-III) which also highlighted these gaps and weaknesses.
Nowadays, associated technologies of different decontamination methods (ie, Physics, Thermal, Chemical) Numerous are, and Provide a wide panel of choices That can be employed in the biopharmaceutical industry, and Especially vaccines companies. Accordingly, the duty of mastery and performance validation of decontamination processes is no longer an option (!) HOWEVER, new constraints are emerging and substantial businesses require human and technical resources Impacting the project costs, Perhaps Exponentially running into millions of euros!
This article aims to serve as a "lessons learned" and is based on many years of alternative decontamination investigations. The article also shares the strategy, initially conceived in 2004, which was designed to anticipate the new paradigm of state of the art decontamination. Finally, this article is about to get involved in the subject of misunderstood
It is important to clarify the pharmaceutical definitions of "cleaning" and "disinfection", and further elucidation can be highlighted by examples.
Result of an operation in a limited time, the WITHDRAW ALLOWING of all undesirable inert compounds were contaminated Acquired selon objective laid down surfaces. The result of this operation is limited to the compounds Being present at the time of the operations.
These compounds come from natural environmental sources or from the product handled.
Objective by avocation CLEANING are inert compounds (Production or laboratory's areas)
Result of an operation in a limited time, ALLOWING the WITHDRAW, inactivation or killing all undesirable micro-organisms contaminated by the carried inert media selon objective laid down. The result of this operation is limited to the micro-organisms Being present at the time of the operations (AFNOR NFT 72-101).
These micro-organisms are not specific and come from natural environmental sources.
Objective by avocation DISINFECTION Are The environmental microorganisms (production or laboratory's areas).
The definition of decontamination can flow from the two previous ones:
Result of an operation in a limited time, ALLOWING inactivating, killing or destroying all specific micro-organisms handled selon objective laid down. These micro-organisms are Known and specific.
Objective by avocation DECONTAMINATION are to control of the dissemination of the specific micro-organisms (microorganisms or vaccine products handled in laboratory)
In conclusion, the use of the term as a synonym disinfection of decontamination Has to be prohibited. Finally Cleaning Does not insure disinfection or decontamination. Similarly, disinfection Does not insure decontamination or cleaning.
Strategy of viral decontamination
Considering all of the decontamination technologies (physical techno's, chemical reagents ...) with differing mechanisms, that we will call the "Weapons" (see tables 1 & 2) together with the huge number of viruses, that we will call the "Targets", the list of validations to perform can become unmanageable, lengthy and cost prohibitive.
|Liquids reagents||in depth and / or Surface decontamination|
|gaseous||Mainly Surface decontamination|
|Radiation||in depth and Surface decontamination|
|(Pulsed) Light||in depth and / or Surface decontamination|
|e-beam||(Mainly) Surface Decontamination|
|Thermal methods||Mainly used for decontamination depth|
1 table: Decontamination methods, That we will call the "Weapons"
Fortunately, viruses elicit interesting properties Such as (i) Their Inability to generate resistant mutation contre chemical reagents (Because resistant mutation occurrence can only be Acquired During Their viral replication qui is not the here box) (ii) Their composition with 4 basic compounds, Nucleic acids, Amino acids, sugars and lipids qui Essentially viruses transform in to single chemical targets Rather than "daunting" viruses.
Considering thesis new paradigms of viral properties, possibilities emerge comprenant un "bracketing strategy" to create models virus Representing the worst case scenarios. Obviously, the rule of bracketing can not absolutely generalized, object can be linked to a clear and has strong scientific rational, a list of specific criteria's and aussi linked to a list of viruses regarded. Following in the example, 9 viruses Routinely handled in a vaccine company Will Be Analyzed (3 table).
After HAVING APPROBATION the targets and the weapons, all the "Constraints" shoulds be APPROBATION.
Targets from the side:
The availability of the target (ie: level of concentration, fragility of microorganisms ...), the availability of the biosafety containment, the availability of the methods of quantification: are available, if yes what are their detection limits, their robustness (matrix viro and / or cytotoxicity)?
|Methods / Reagents||Target hand (s) is patterned viral|
|Temperature||Viral envelop, (Glyco) protein's, RNA then DNA|
|Acids / Bases||Viral envelop, (Glyco) protein's|
|Alcohols / Ether||Viral envelop, (Glyco) protein's|
(Cl, O3, H2O2, formalin, b-propiolactone ...)
|Viral envelop (Glyco) protein's, Nucleic Acids|
|Detergents (Ionic / Nonionic)||viral envelop|
|UV / p-Light||Nucleic Acids, (glyco) protein's|
2 table: Decontamination versus modes viral biochemical Elements: impact on viral structure
Weapons from the side:
Are chemical reagent compositions's available? (Ie type and concentration of Each component)? Corresponding neutralizing reagents are available? What is Their Impact on methods of quantification due to cytotoxicity?
Because of the target constraints (susceptibility, level of concentration, expression systems, etc.), one of the following strategies is the most effective method for determining the effectiveness of decontamination parameters. The microorganism model must be derived from minimally 3 main criteria (i) a Risk Analysis with the well-defined rules of bracketing. (ii) The physical availability of the microorganism potential model including the infectious titer level consistent with the final objectives, and iii) the method of quantification used (lower detection limit, Its accuracy at low level, robustness ...).
Aware of all these key elements, the efficiency specifications should be set up. Uniformly and exhaustively, they are lacking (French, European, US, International ones ...) and if provided, are limited and do not cover all the cases, especially for viruses (Table 4). Regarding each mode of decontamination, the regulation specifications are not so clear and often derived from sterility assurance experiences, such as the famous "6 Log reduction".
SPECIFICALLY for viral targets, one can find 4 log reduction of infectious titer using chemical method, in order MOST of the viral cases, it is not considers. This leads us to question what The Following are the right specifications for (i) Surface decontamination, (ii) Liquid waste, (iii) solid waste, (iv) air? Without this guidance, a bibliography study is needed at least.
Most of the time, the effective parameters claimed on the label for the purpose of decontamination are not appropriate because of a vast absence of methodological information and environmental conditions (4 Log reduction linked to a standard ... )
|V||External Spikes: glycoprotein||envelope: |
|Core: protein||Genus: RNA||Conclusions Following The "bracketing strategy" rules|
|poliovirus (Enterovirus)||No||No||And it is||And it is||Viruses group into 1|
Model représentée par Poliovirus
|Hepatitis A (Enterovirus)||No||No||And it is||And it is|
|influenza virus (Flu)||And it is||And it is||And it is||And it is||Viruses group into 2|
Model représentée par Influenza virus
|Measles (Morbilivirus)||And it is||And it is||And it is||And it is|
|M (Rubulavirus)||And it is||And it is||And it is||And it is|
|Rubella virus (Rubivirus)||And it is||And it is||And it is||And it is|
|Rabies virus (Lyssavirus)||And it is||And it is||And it is||And it is|
|Are Fever (Flavivirus)||And it is||And it is||And it is||And it is|
|Dengue (Flavivirus)||And it is||And it is||And it is||And it is|
3 table: List of 9 regarded viruses, That we will call the "Targets"
Based on biochemical structure of Each virus, here we can define 2 models, selon The Following characteristics and the "constraints" which Were APPROBATION in the specific rules set up
Finally the Strategies of Validation Can Be Summarized Such as: The right weapon Against the right target with the best tool box, qui shoulds be defined SPECIFICALLY. In Any case, all (your) the specifications must be set up in sight of Each specific use.
|Specifications of chemical decontamination liquid|
|bactericidal||French Norm||AFNOR NF T-72 170 and 171||Log reduction 5|
|European Norm||EN 1040|
|sporicidal||French Norm||AFNOR NF T-72 230 and 231||Log reduction 5|
|Fungicide||French Norm||AFNOR NF T-72 200 and 201||Log reduction 4|
|European Norm||EN 1275|
|Virucidal||French Norm||AFNOR NF-72 180 T, 181 and 185||Log reduction 4|
|European Norm||NF EN, 14675 / 14476 and 13610|
Specifications for air chemical decontamination
bactericidal Log reduction 5sporicidal French Norm AFNOR NF T-72 281Log reduction 3Fungicide Log reduction 4Virucidal Log reduction 4
4 Table: examples of norms for setting up specification
After more than 10 years' experience, our lesson Learned HAS Provided valuable positive experience. All (our) viruses are linked to validated Their efficient decontamination parameters, in a compliant, coherent and robust system while Realizing savings through our approach. Now Each new potential decontamination reagent is easy to validate and a comprehensive update to our decontamination system for all viruses in Can Be Performed In A Few experiments. Moreover, the strategy has-been vetted with regulatory autorités Increased resulting and in compliance with no significant observations.
The remaining challenge is to educate Who Auditors are not familiar with all viruses Reducing Their preconceived notions of viral complexity thereby Enabling full endorsement of the performance and efficiency of These Approaches and data.