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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 paper.

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

Microbiological contamination induced by Bacillusthuringiensis or Acinetobacterradioresistens is the sort of contamination that is investigated in the microbiological contamination assignment (Ahmed, 2016).


According to the research done for this biology assignment sample, the creation of foreign proteins and molecules of low molecular weight by the microorganisms Bacillus thuringiensis or Acinetobacter radioresistens is thought to be the source of microbiological contamination. The proteins generated by Bacillus thuringiensis are thought to pose a risk when used as an inexpensive pesticide formulation (purged and at high exposures) or when taken orally in extremely high doses. When administered parenterally in large doses, the decontaminated natural endotoxin that was let loose from these kinds of microorganisms was linked to risk. When an invulnerable traded off individual got infected by the complete, live form of the bacterium, Acinetobacter radioresistens may have been an opportunistic disease (Catellani et al., 2014).

Route of Transmission

The microbiological contamination assignment indicated a pathway of transmission that is anticipated to involve either a small number of bacteria already existing in the system or bacteria that were added during the production process, causing the small inoculum to increase. Non-host cell by-products produced by or as a result of defective high-high limit switches are among the additional channels of transmission (Croughan, Delfosse and Svay, 2014).

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

Prevention Methods:

1. Risk assessment: This should involve a review of the established facts regarding processing times, in-process endotoxin results, mass drug substance bioburden, the composition of the drug substance as determined by testing, and the system of decontamination processes used during the assembling process.

2. According to the readings used to create this microbiological contamination assignment, crop risk assessments to reflect the greater groups of bacillus thuringiensis to protect drugs from its contamination (Croughan, Delfosse and Svay, 2014).

3. Additional risk assessment via estimation of the quantity and clearance of any potential contamination, toxicological assessment, and data analysis of unfavourable event.

4. Bioreactor disinfection

5. A choice To satisfactorily and successfully remove the filth created by the disinfecting technique under examination, a CIP cycle should be devised and examined.

Detection Techniques

1. Widespread drug substance discharge, stability, and irregular depiction testing

2. Potential impurity level and clearance should be established, toxicological evaluation of identified contaminations should be completed, and adverse event data for the lot should be evaluated.

3. Comparing Soliris drug material batches should undergo explicit investigative testing beyond normal discharge and stability to determine whether any potential pollutions were eliminated throughout the decontamination process.
Investigation of Bioreactor Contamination 4.

5. Additional surface sites should be included for investigative reasons to further develop the ability to identify potential sources of Bacillus thuringiensis and other spore-formers, as specified in the microbiological contamination assignment (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-***-**84

Subject: Response to FDA Warning Letter- March 22, 2013

Dear Ms. Wardell:

Between July 12, 16-18, 20, 24-26, and August 6, 2012, a CGMP inspection was conducted at Alexion Pharmaceuticals, Inc., which has offices at 352 Knotter Drive in Cheshire, Connecticut, and 100 Technology Way in Smithfield, Rhode Island. Following the conclusion of the inspection on August 6, 2012, an FDA warning letter with Form "483" was delivered along with a number of observations. Alexion Pharmaceuticals, Inc.'s primary goal is to produce products that are both healthy and safe, despite its efforts to maintain order in numerous sectors. The representatives of our company are making an effort to maintain consistency in their work so that they can swiftly examine and modify the tactics and separate the proof and application of office improvements. We endeavoured to take decisive action to eliminate the associated risks at the time when the warning letter was issued, taking the investigators' assertions of perceptions seriously. In addition to trying to take a more thorough look at each component of our organisation, we have tried not to limit ourselves to only the viewpoints expressed in CMS #352798.

The Observations of GMP violations according to FDA's Inspection

If it's not too much of an issue, note that Alexion Pharmaceuticals, Inc. has had systems and tasks which address such observations accordingly for well over a year. These observations were specifically noted in the March 22, 2013 warning letter provided in this microbiological contamination assignment. All of Alexion Pharmaceuticals, Inc.'s cGMP products are subject to certain procedures and tasks, which are as follows:

1. The key deviations and a batch's inability to meet the specifics and the applicable quality requirements were not investigated by your company.

The microbiological contamination assignment's risk assessments make the assumption that the threat to product quality was minimal. The data collected in accordance with SOP QC-0394 and further testing done include:

1. Acinetobacter radioresistens and Bacillus thuringiensis are not thought of as typical human infections (Dancer, 2016).

2. No impact on materials or preparation tools based on the outcomes of the daily practise in-process tests. Bioburden and endotoxin characteristics were all as low as possible:

• The post-filtered bioburden result was 0 CFU/10mL (announced as 1CFU/10 mL) (Shintani, 2015).

• Each of the pre-bioburden testing's results was 0 CFU/10mL (explained as 1CFU/10 mL) (Shintani, 2015).

• The endotoxin findings for all of the pre-tests were 1.25 EU/mL, which, in this case, is the limit of quantification (Shintani, 2015).

• The results for the bioburden and endotoxin were accounted for as 1CFU/10 mL and 0.0625 EU/mL, respectively, which is the highest level of quantification for this case (Shintani, 2015).

• The final mass product substance yields met determinations with aftereffects of 0 CFU/10 mL and 0.1 EU/mg, which serves as the threshold of quantitation in this example (Shintani, 2015).

1. According to the research conducted for the microbiological contamination assignment, the company is focused on finishing the expository tests for the drug material component by April 1, 2013. There were no unexpected results that suggested the presence of bacterial pollutants nearby. The results were expected, and those of the parcels that didn't experience the diagnostic advance had different results.

2. The risk assessments also showed that there was a minimal likelihood of the medicine being co-sanitized with distant proteins or low atomic weight particles that could be given by Bacillus thuringiensis or Acinetobacter radioresistens (Maillard, Sattar and Bradley, 2016).
Further Assessment of Risk

Apart from the elements analysed in SOP QC-0394 and the additional testing discussed above, it was also determined the amount and clearance of probable impurities, completed toxicological evaluations of identified polluting influences, and evaluated data on antagonistic events for the lot.
Worst Case Calculations:

• The calculations for the worst-case scenario, which were covered in the microbiological contamination assignment, were done to determine the quantity of potential impurities that may be produced and the freedom of the potential contaminating influences. in order to initially set up an examination of suspected contaminant expulsion after a bioburden testing. For a 10 mL test, the in-process bioburden testing was too diverse to even consider counting (TNTC) (Maillard, Sattar and Bradley, 2016). The unit activity for the test, as observed from the content produced for the microbiological contamination assignment, took about 15 days. Our working hypothesis is that a small number of microscopic organisms, either already existing in the framework or introduced during the technique, caused this little inoculum to form at that time.

• It was hypothesised that microscopic organisms were introduced into the framework. The bioburden described has increased as a result of the use of Bacillus thuringiensis. The use of Bacillus thuringiensis speaks to the worst-case scenarios in this way. The worst-case situation conceivable was that all of this bulk might include protein contaminations. One pg of protein/mL is concentrated in the drug material lot. As a worst-case scenario estimate, a portion of Soliris limited to 120 mL would contain close to 15 pg of the contaminated protein. While this refers to a fictitious worst-case scenario count, the medication procedure's procedure evacuation information shows that the actual expulsion is a few sets of extent greater.

• The risk assessment stated in the microbiological contamination assignment will be updated to include all discharge, reliability, and additional test results as well as the worst-case scenario count for potential pollution. By March 19th, 2013, the revision will be complete (Rihs, Lee and Stout, 2017).
Toxicology Assessment of Calculated Impurities

• The maximum quantity allowed for a drug substance lot was ="" li="" style="box-sizing: inherit;">

• The concentrations of Acinetobacter radioresistens and Bacillus thuringiensis toxins in the medical section were considerably below any targets determined to be associated with any signs or evidence of harm or other discoveries. Proteins from the Bacillus thuringiensis have been linked to danger when used either as a filter in a readily available bug spray (at high exposures) or when ingested in large doses. When administered parenterally at consistent dosages, the decontaminated endotoxin contained by these kinds of tiny organisms was linked to harmfulness. When a safe bargained human got contaminated by all the living life forms, Acinetobacter radioresistens may have been an opportunistic infection.

• The intentional drug lot has the most recent 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 range of 3-8 all out dosages, was surveyed related to the writing search on poisonous impacts of the two microscopic organism (Shintani, 2015).

• The small concentrations of Bacillus thuringiensis proteins linked to any unfavourable effects in either in vivo or in vitro tests are much lower than the large concentrations of bacterial protein segment contamination that have been determined as potentially present in the part. Risk assessments of yields with far greater concentrations of Bacillus thuringiensis assumed that poison crops rather than those that transmitted Bacillus thuringiensis from medication posed no threat to harvest workers or yield buyers. In this way, the risk of clinically unfavourable events connected to the structure of this pharmacological component is regarded as extremely low to negligible.

Adverse Event Evaluation in the context of microbiological contamination assignment

The SOP QC-0394-required hazard analysis for a lot implied that there was little risk to the lot's quality of drugs. The underlying conclusion of safety is supported by other risk assessment methods such as possible impurity amount estimation, toxicological review, and an audit of unfavourable occasion data. The company believes that FDA expects the hazard appraisal to analyse any potential polluting influences produced, such as non-host cell byproducts, in situations where in-process bioburden activity limitations are exceeded, and to establish the procedure polluting influence clearance. Additionally, for the related Soliris medication substance lot, explicit scientific testing beyond routine discharge and dependability needs to be carried out to see whether any prospective contaminating influences made were eliminated during the cleaning process. To ensure that requests for chance appraisals are satisfied, the organisation will assess investigative techniques and methodologies. Future risk assessments that are used to determine the optimum behaviour of lots that undergo an in-process bioburden activity limit trip will include information to satisfy FDA requirements. Alexion will complete SOP QC-0394's update "By March 31, 2013, Bioburden Microbial Risk Management and Assessment (Silbergeld, 2017).

2. Your company has not done enough to stop microbial contamination from happening again during the drug manufacturing process and has not done enough to assess whether the bioreactor contamination episodes are connected.

• In accordance with SOP TMS-0027, "Bioreactor Contamination Investigation," and SOP TMS-0028, "Purification Equipment Investigation," the company has completed an examination of the bioreactor and the occasions of contamination "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. Exams conducted in accordance with this SOP are effective inquiries and evaluations of factors to determine the root cause(s) or the most likely root cause (s). The system needs an evaluation of labour, materials, hardware, and environmental factors (Silbergeld, 2017).

•The most likely primary drivers identified with working technique were detected during the deviation examinations in April 2011 and March 2012. In particular, a poor methodology that failed to recognise the possible impact of leftover WFI in a significant amount prior to employing may have contributed to the April 2011 incident. Estimates of counteractive action included adjustments to trustworthiness tests and venting methodologies. To assist with the assessment, the corporation has hired counselling companies. To aid in the completion of research and remediation efforts, generation in the bioreactors has been halted. Initial findings suggest ineffective SIP combined with ineffective routine CIP of non-routine soils. Because of a delay in assembling for safeguard support, non-routine soils were provided, as mentioned in the microbiological contamination assignment. Following the protracted deferral, each bioreactor contamination that occurred in July and August 2012 was initiated. All evidence to date shows that the most recent contaminations' causes are unrelated to the previously established primary driver. Once the examination is complete, the organisation will submit a report to the FDA. By May 1, 2013, the FDA will receive the reports (or an update of the reports that have not yet been completed). There is no correlation between the bioreactor microbial contamination events and the data acquired during all studies. The evaluation will also determine whether there are any shared traits between the early and late instances that call for additional deterrent measures. Additionally, living things isolated from current events like ecological seclusions will be compared to strains that can be found from earlier instances of contamination. The findings will be used to support and rule out putative underlying root causes for ongoing events (Tidswell, Tirumalai and Hussong, 2019).

3. The firm has not appropriately analysed necessitation for an increased frequency of a sporicidal chemical throughout the clean rooms.


• Since January 2011, the corporation has changed its usage of sporicidal operators on two events because of an intensive survey of environmental checking (EM) facts. The frequency of sporicidal cleaning up in the room was increased in response to the outing rate and taking into account the probable impact of generation activities in the context of this microbiological contamination assignment.

• In accordance with the study done for the microbiological contamination assignment, additional surface sites will be included for research to enhance the ability to identify potential sources of Bacillus thuringiensis and other spore-formers. The additional testing locations were chosen to consider several factors, such as proximity to the bioreactor and equipment and potential for heavy staff traffic. Starting on May 9, 2013, additional testing and checking will be done. Depending on the results of the investigation into the bioreactor contamination incidents that occurred in July and August 2012, this may be expanded. The bioreactor decontamination inspection reports or update will include a note with information acquired as a result of the extended examining as one of their main components on April 1, 2013. (Wiencek, 2018).

• Assembling effort will be devoted toward assessing the likelihood of cleaning with sporicidal agents occurring again, and the results will be recorded by way of a risk assessment supporting any following efforts. By August 31st, 2013, the risk assessment will be complete (Wiencek, 2018).


We accept that the activity plans and deadlines described in this response letter discharge our obligation to monitor the 483 and its associated reprimand letter in a comprehensive manner based on the overall analysis performed for the microbiological contamination assignment. All applicable staff members who will be affected by the upgrades have undergone extensive training in conjunction with changes to approaches and tactics. Within fifteen (15) working days of our receiving your notification letter, we will give you a free adjustment of our beneficial exercises.

Additionally, we ask that the FDA publish our response to the Warning Letter on the FDA website. If it's okay with you, consider this letter to be a recommendation for publication on the FDA website.

/S/ /S/


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