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Microbiological Contamination Assignment: Discussion On Remediation


Task: The assignment is designed to evaluate how well you research, and apply contamination control strategies and remediation.

There is no word limit to this assignment.
The assignment is worth 20% of the subject marks.
All assignment work must be the individuals.
A) The work must be your own and should include a bibliography of
source material. Penalties will apply if students submit the same
B) Useful information on preparing assignments is available in the
External Links folder for this subject.
C) All assignments should be uploaded to Turnitin on the submission date
specified in your student notes. An assignment cover sheet must be
completed and attached to the front of the submitted assignment.
Cover sheets can be found at UTSOnline. You must retain a copy of
your submitted work.

Contamination Control Remediation
The attached document is an FDA warning letter related to product
contamination that was sent to a pharmaceutical manufacturer.
Your assignment is to examine the warning letter and:
1. Identify the type of contamination detected.
2. Identify the source of contamination
3. Identify the route of transmission
4. Propose practical procedures that would ensure that this type of
contamination did not occur again. Categorise these procedures as
prevention or detection strategies.
5. Prepare a response to the FDA detailing the corrective action
necessary to address all the findings detailed in the Warning Letter.


Type of Contamination
The type of contamination examined in the microbiological contamination assignment is microbiological contamination caused by Bacillusthuringiensis or Acinetobacterradioresistens (Ahmed, 2016).

As per the research conducted on this microbiological contamination assignment, the source of microbiological contamination is considered to be the production of foreign proteins as well as molecules which are of low molecular weight by the micro-organisms Bacillus thuringiensis or Acinetobacter radioresistens. The proteins produced by Bacillus thuringiensis are considered to be related to danger either as a part of a financially accessible bug insecticide formulation (purged and at high exposures) or when its administration is oral at enormous dosages. The decontaminated natural endotoxin disconnected from these types of microbes was related to danger when managed parenterally at large portions. Acinetobacter radioresistens possibly was an opportunistic pathogen when an invulnerable traded off individual was contaminated by the entire, live form of the organism (Catellani et al., 2014). 

Route of Transmission
The route of transmission identified in the microbiological contamination assignment is expected to be either through a small number of bacteria that might be present in the system or was introduced during the production process, hence resulting in the growth of the small inoculum. Other routes of transmission include non-host cell by-products, as or a result of faulty high~high limit switches (Croughan, Delfosse and Svay, 2014).

What are the practical procedures for the case scenario of microbiological contamination assignment?
Prevention Strategies:

  1. Risk Assessment: It ought to include the assessment of the well-established actualities identified with the processing occasions, in-process, mass drug substance bioburden and endotoxin outcomes, the nature of the drug substance decided from tests and the system of the decontamination steps utilized in the assembling procedure.
  2. As per the readings used to develop this microbiological contamination assignment, Hazard evaluations of crops to express the far higher groupings of bacillus thuringiensis to prevent drug against its contamination (Croughan, Delfosse and Svay, 2014).
  3. Further appraisal of risk through estimation of potential contamination amount and clearance, toxicology evaluation and a survey of unfriendly occasion data.
  4. Disinfecting of Bioreactors
  5. An option CIP cycle should be developed and assessed to satisfactorily and successfully evacuate the dirt made by the disinfecting procedure under assessment.

Detection Strategies:

  1. Mass drug substance discharge, solidness, and non-routine portrayal testing.
  2. Potential impurity amount, as well as its clearance, should be determined, toxicology appraisal of determined contaminations should be finished, and adverse occasion data should be assessed for the lot.
  3. Explicit investigative testing past routine discharge and stability ought to be performed for the comparing Soliris drug substance lots to confirm whether potential pollutions created were expelled during the decontamination procedure.
  4. Bioreactor Contamination Investigation
  5. It is also mentioned in the microbiological contamination assignment that extra surface sites should be incorporated for investigational purposes to additionally build the capacity to identify potential wellsprings of Bacillus thuringiensis and other spore-formers (Dancer, 2016).

Response Letter
Mr. Leonard Bell,

M.D. Chief Executive
Officer Alexion Pharmaceuticals, Inc.
352 Knotter Drive
Cheshire, CT 06410
March 27, 2013

Amber G. Wardell,
Director of Compliance,
New England District,
Food and Drug Administration,
One Montvale Avenue,
4th Floor, Stoneham,
Massachusetts 02180.

Telephone - 781-587-7484, 781-587-7484
Subject: Response to FDA Warning Letter- March 22, 2013

Dear Ms. Wardell:
A CGMP inspection was held at Alexion Pharmaceuticals, Inc which is located at 100 Technology Way, Smithfield, RI, 352 Knotter Drive, Cheshire, CT 06410, between July 12, 16-18, 20, 24-26 and August 6, 2012. After the inspection ended on August 6, 2012, an FDA warning letter with Form “483” was furnished provided with various observations. Manufacturing of safe just as a healthy product is the main need of Alexion Pharmaceuticals, Inc while the organization is setting aside the effort to keep things directly in various areas. The representatives of our organization are attempting to keep their work steady for quickly looking into and changing the strategies, and distinguishing evidence and usage of office improvements. We have taken the perceptions asserted by the investigators truly and have attempted to take determined actions at the time after the issue of the warning letter to expel the related risks. We have attempted to not be constrained to just the perceptions gave in CMS #352798, moreover, we have attempted to a more extensive look towards every one of the parts of our organization.

The Observations of GMP violations according to FDA's Inspection
As for the specific discernments noted in the March 22, 2013 warning letter provided in this microbiological contamination assignment, if it's not all that much issue note that Alexion Pharmaceuticals, Inc has had systems and tasks which address such observations accordingly for well over a year. Those strategies and tasks are applied to all of Alexion Pharmaceuticals, Inc cGMP just as APIs and are according to the accompanying:

1. Your firm failed to investigate the critical deviations also a failure of a batch for meeting the particulars as well as the relevant quality standards.

Risk evaluations explored in the microbiological contamination assignment presume that the hazard to product quality was low. The data surveyed per SOP QC-0394 and extra testing performed include:

  1. Neither Bacillus thuringiensis nor Acinetobacter radioresistens are viewed as regular human pathogens (Dancer, 2016).
  2. No effect on in-process material or preparing equipment dependent on the test results from the daily practice in-process tests. The qualities of bioburden and endotoxin were all lower than as far as possible:
  • The bioburden consequence of post-filtered was 0 CFU/10mL (announced as < 1CFU/10 mL) (Shintani, 2015).
  • The bioburden results for the pre-testing were each of the 0 CFU/10mL (detailed as < 1CFU/10 mL) (Shintani, 2015).
  • The endotoxin results for all the pre-tests were <1.25 EU/mL, which is the breaking point of quantitation for this example (Shintani, 2015).
  • The bioburden and endotoxin results were accounted for as < 1CFU/10 mL and <0.0625 EU/mL, which is the utmost of quantitation for this example (Shintani, 2015).
  • The last mass product substance bioburden and endotoxin results in met determinations with aftereffects of 0 CFU/10 mL and <0.1 EU/mg, which is the cutoff of quantitation for this example (Shintani, 2015).
  1. The study developed in the microbiological contamination assignment signifies that the company focuses on the culmination of the expository tests on the drug substance part by April 1, 2013. No surprising outcomes were seen that would propose the nearness of bacterial contaminants. The outcomes were predictable with different outcomes from parcels that didn't encounter the diagnostic advance.
  2. In view of the consequent in-process steps, the hazard evaluations likewise exhibited that the probability of remote proteins or low atomic weight particles answered to be delivered by Bacillus thuringiensis or Acinetobacter radioresistens being co-sanitized with the drug is low (Maillard, Sattar and Bradley, 2016).

Further Assessment of Risk
Notwithstanding the components surveyed in SOP QC-0394 and the extra testing examined above, potential impurity amount and clearance wert determined, toxicology appraisal of determined polluting influences finished, and antagonistic occasion data was assessed for the lot.

Worst Case Calculations:

  • The concept of Worst case scenario computations discussed in the microbiological contamination assignment was performed to evaluate the number of potential impurities produced and the freedom of the potential polluting influences. So as to play out an investigation of potential contaminant expulsion following a bioburden testing to initially set up. The in-process bioburden testing was too various to even consider counting (TNTC) for a 10 mL test (Maillard, Sattar and Bradley, 2016). As per the observation from the content created in the microbiological contamination assignment, the unit activity for the test took roughly 15 days. Our working supposition is that it a few microscopic organisms that were either present in the framework or were presented during the procedure, and this little inoculum developed during that stage.
  • A supposition that was made that the microscopic organisms were brought into the framework. Utilizing the Bacillus thuringiensis has expanded the bioburden detailed. In this manner, the utilization of Bacillus thuringiensis speaks to the worst cases. To give a worst-case scenario imaginable, it was expected the entirety of this mass was potential protein contaminations. Drug substance lot bringing about the centralization of 1 pg protein/mL. A limit of 120 mL portion of Soliris would contain close to 15 pg of the contaminant protein as the worst-case scenario estimation. While this speaks to a hypothetical worst-case scenario count, the procedure evacuation information for the drug procedure demonstrates that the genuine expulsion is a few sets of extent higher.
  • The hazard evaluation discussed in the microbiological contamination assignment will be altered to incorporate all discharge, dependability, and extra test results just as the potential pollution worst-case scenario count. The revision will be finished by March 19, 2013 (Rihs, Lee and Stout, 2017).

Toxicology Assessment of Calculated Impurities

  • In light of a worst-case estimation, drug substance lot had a limit of
  • The measure of Bacillus thuringiensis poisons and Acinetobacter radioresistens in the medication part were far beneath any focuses answered to be related with any signs or proof of harmfulness or different discoveries. Bacillus thuringiensis proteins have been related to harmfulness either as a part of an economically accessible bug spray readiness (filtered and at high exposures) or when regulated orally at enormous portions. The decontaminated endotoxin confined from these types of microscopic organisms was related to harmfulness when regulated parenterally everywhere dosages. Acinetobacter radioresistens possibly was an opportunistic pathogen when a safe bargained individual was contaminated by the entire, live life forms.
  • The deliberate drug lot has the last bioburden of 0 CFU/l0 mL and <0.1 EU/mg and negative endotoxin discoveries evaluated contaminations from bioburden at more than l5 pg of Bacillus thuringiensis per 120 mL portion of medication and all-out conceivable human portion level of a scope of 3-8 all out dosages, was surveyed related to the writing search on poisonous impacts of the two microscopic organisms and bacterial segments or protein items (Shintani, 2015).
  • The low centralizations of bacterial protein segment pollution that have been determined as potentially present in the part, are a lot of lower than the enormous portions of Bacillus thuringiensis proteins related with any unfriendly impacts in any in vivo or in vitro examinations. Hazard evaluations of yields that express far higher centralizations of Bacillus thuringiensis presumed that poison crops than communicating any Bacillus thuringiensis from drug represented no part hazard to laborers presented to the harvests or to purchasers of the yields. In this manner, the danger of clinical unfavorable occasions related to the organization of this part of the drug is viewed as extremely low to unimportant.

Adverse Event Evaluation in the context of microbiological contamination assignment
The hazard appraisal directed for a lot according to SOP QC-0394 inferred that the hazard to the drug lot quality was low. Further appraisal of hazard through estimation of potential impurity amount, toxicology evaluation and an audit of unfavorable occasion data supports the underlying outcome of being safe. The organization perceives that FDA expects, in occurrences when in-process bioburden activity limits are surpassed, the relating hazard appraisal ought to evaluate the potential polluting influences produced, for example, non-host cell byproducts, and the procedure polluting influence clearance determined. Moreover, explicit scientific testing past routine discharge and dependability ought to be performed for the relating Soliris drug substance lot to check whether potential polluting influences created were evacuated during the cleansing procedure. The company will evaluate investigative approaches and methods to guarantee desires for chance appraisals are met. Future chance evaluations used for an ideal demeanor of a lot that experience an in-process bioburden activity limit trip will incorporate data to address FDA desires. Alexion will finish the modification of SOP QC-0394, "Bioburden Microbial Risk Management and Assessment'' by March 31, 2013 (Silbergeld, 2017).

2. Your firm has not adequately investigated to determine whether the bioreactor contamination events are linked and has not adequately prevented the reoccurrence of microbial contamination in the drug manufacturing process.


  • The company finished an examination of the bioreactor and the contamination occasions per SOP TMS~0027, " bioreactor Contamination Investigation" and SOP TMS~0028 and Purification Equipment Investigation." The methodology expects examinations to be finished by a cross-useful group of topic specialists from Technical Services, Manufacturing, Facilities, Quality Control, and Quality Assurance. Examinations directed per this SOP are efficient request and assessments of elements to decide root cause(s) or the most plausible root cause(s). The system requires a survey of labor, material, hardware, and natural variables (Silbergeld, 2017).
  • The deviation examinations in April 2011 and in March 2012 recognized the most likely main drivers identified with working methodology. In particular, the potential reason for the April 2011 occasion was an inadequate methodology that didn't distinguish the potential effect of remaining WFI in a ton preceding utilizing. Counteractive action estimates included techniques adjustment related to trustworthiness testing and venting.
  • The organization has drawn in counseling firms to help the examination. Generation in the bioreactors has been suspended to help the culmination of investigational and restorative activities. Starting discoveries recommend incapable routine CIP of non-routine soils added to ineffectual SIP. It is noted in the microbiological contamination assignment that non-routine soils were delivered because of a postponement in assembling for safeguard support. Each bioreactor contamination experienced in July and August 2012 was started after the drawn-out postponement. All proof revealed to date demonstrates that the reasons for the latest contaminations are not identified with the main driver recently recognized. The organization will give a report of the examination to the FDA once it is finished. The reports (or an update of the reports are not finished) will be sent to FDA by May l, 2013. The information gathered during all examinations doesn't show a connection between the bioreactor microbial contamination occasions. The evaluation will likewise decide whether shared characteristics exist between the past and late occasions that require extra deterrent activities. What's more, accessible strains from the past contamination occasions will be contrasted with the living beings disconnected from the ongoing occasions including ecological secludes. The outcomes will be utilized to help substantiate and bar potential underlying root causes for ongoing occasions (Tidswell, Tirumalai and Hussong, 2019).

3. The firm has not adequately assessed necessitation for an increased frequency of a sporicidal agent throughout the clean rooms.


  • Since January 2011, the company has changed its utilization of sporicidal operators on two events because of an exhaustive survey of environmental checking (EM) information. In light of the outing rate and considering the potential effect of generation activities in the context of this microbiological contamination assignment, the recurrence of sporicidal tidying up in the room was expanded.
  • According to the research carried on microbiological contamination assignment, extra surface sites will be incorporated for investigational purposes to additionally expand the capacity to distinguish potential wellsprings of Bacillus thuringiensis and other spore-formers. The extra testing areas were picked to mull over variables, for example, closeness to the bioreactor and equipment, and potential for high staff traffic. This extra testing and checking will be performed for a period sta1ting on May 9, 2013. This could be broadened dependent on the course of the examination concerning the bioreactor contamination occasions which happened in July and August 2012. A notice with information gathered because of the expanded examining will be given as a major aspect of the bioreactor defilement examination reports or update on April 1, 2013 (Wiencek, 2018).
  • An assessment of the recurrence of cleaning with sporicidal operators will be directed assembling effort and archived by means of a hazard evaluation supporting any subsequent activities. The hazard evaluation will be finished by August 31, 2013 (Wiencek, 2018).

From the overall analysis done in the microbiological contamination assignment, we accept that the activity plans and timetables depicted in this reaction letter pass on our duty to keep an eye on the 483 and its related admonition letter in a total way. Changes to approaches and techniques have been joined with the execution of an expansive getting ready venture of all appropriate staff affected by the updates. An invigorated adjustment of our helpful exercises will be given to you freely inside fifteen (15) working days of our receipt of the notice letter.

We furthermore request that the FDA post our Warning Letter reaction on the FDA site. If it’s all the same to you recognize this letter as an endorsement to post on the FDA Internet website.


/S/                               /S/  

Ahmed, A. (2016). Microbiological contamination assignment Microbial toxinology for safer drug industry. Journal of Pharmaceutical Care & Health Systems, 03(04).

Catellani, P., Miotti Scapin, R., Alberghini, L., Radu, I. and Giaccone, V. (2014). Levels of microbial contamination of domestic refrigerators in Italy. Food Control, 42, pp.257-262.

Croughan, M., Delfosse, S. and Svay, K. (2014). Microbial contamination in industrial animal cell culture operations. Pharmaceutical Bioprocessing, 2(1), pp.23-25.

Dancer, S. (2016). Missing a trick? Response to: ‘Disinfectant wipes are appropriate to control microbial bioburden from surfaces’. Journal of Hospital Infection, 92(2), pp.208-209.

Maillard, J., Sattar, S. and Bradley, C. (2016). Missing a trick? Response to: ‘Disinfectant wipes are appropriate to control microbial bioburden from surfaces’. Journal of Hospital Infection, 92(2), pp.209-210.

Rihs, J., Lee, E. and Stout, J. (2017). Microbiological contamination assignment Microbial Contamination of Heater/Cooler Units: M. Chimaera and Beyond. American Journal of Infection Control, 45(6), p.S23.

Shintani, H. (2015). Validation Study on How to Avoid Microbial Contamination during Pharmaceutical Production. Microbiological contamination assignment Biocontrol Science, 20(1), pp.1-10.

Silbergeld, E. (2017). Managing hazards in place: The risks of residual risks. Environmental Research, 158, pp.806-811.

Tidswell, E., Tirumalai, R. and Hussong, D. (2019). Fidelity to Science & Correct Scientific Vocabulary—Microbial Control Versus Contamination Control. PDA Journal of Pharmaceutical Science and Technology, 73(5), pp.510-516.

Wiencek, K. (2018). Effectiveness and Bioburden of Microfiber Mops Used to Clean Healthcare Environmental Surfaces. Microbiological contamination assignment American Journal of Infection Control, 46(6), pp.S32-S33.


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