Quality Assurance, Clinical Trials and Regulatory Affairs
Quality Assurance, Clinical Trials and Regulatory Affairs
INSTRUCTIONS
You are to provide a critical evaluation of two research articles related to Process Analytical Technology (PAT), Quality by Design (QbD) and/or analytics of quality in pharmaceutical industry, and present a paper critique assessing the chosen articles as an oral presentation, which would be followed by questions (20 minutes in total).
You should plan carefully the structure and content of the presentation before writing. Although there is no limit to the number of slides or diagrams to be presented, you are strongly recommended to practise your presentation to fit within a 15-minute time frame.
The presentation must demonstrate your own critical analysis on the appropriate research papers selected. It is important that you present your information appropriately and clearly to support your discussion on the chosen topic.
You should include the following in your presentation:
• Background information of your chosen topic
• The reasons for selecting the two journal articles for discussion
• Critical evaluation of the selected journal articles, in terms of the analytical methods used (and alternatives that could be used), results and conclusion
• Complete bibliographical details in Harvard format
Total of 15 slides needed. Sample document attached
QUALITY ASSURANCE, CLINICAL TRIALS & REGULATORY AFFAIRS
PJ4018
Francesco De luca
Development and validation of a new HPLC analytical method for the determination of diclofenac in tablets
Bushra Tuwfeeq Alquadeib
King Saud University, Riyadh, Saudi Arabia
Aim and Objectives
Faster analysis of Diclofenac Sodium in pharmaceutical formulations
Development of a new HPLC method for the evaluation of Diclofenac Sodium in tablets
Validation of method
BACKGROUND
Diclofenac is a widely used NSAID (nonsteroidal anti-inflammatory drug)
Treatment of rheumatoid arthritis, musculoskeletal injuries, and post surgery
analgesia
Water insoluble but quickly absorbed by the GI tract if used as the salt form
HPLC has already been used for the determination of Diclofenac in dosage forms but they require time and are expensive
Method Used
Different products selected randomly : Voltaren, Clofen, Voltaic, Rapidus and Rofenac
Chromatografic separation obtained using C18 as stationary phase and a mix of Orthophosphoric acid and Acetonitrile (35:65) as mobile phase
Lidocaine used as internal standard
Running time is 2 minutes
Validation
Fulfill ICH requirements on specificity, linearity, LOD, LOQ, accuracy, precision and robustness.
➢ Specificity
Evaluated to avoid interference from excipients
Placebo and standard solution have been used
No peaks close to the one from Diclofenac Sodium
➢ Linearity
Studied by injecting seven solutions with different concentration of Diclofenac Sodium
A calibration curve was created with each point representing the mean of six determination
Validation
➢ LOD and LOQ
Calculated based on the calibration curve
Value used have been standard deviation of response and slope of the calibration curve
LOQ was 3.9 ng/mL and LOD 13.1 ng/ml
➢ Precision
Six replicates of different concentrations were analysed on the same day to obtain intraday precision
The same procedure has been applied on three different days to obtain inter-day precision
The total precision has been measured using relative standard deviation (<2%)
➢ Robustness
Robustness was studied by changes in the method like using different pH of the mobile phase or wavelength
No big changes in the chromatogram showed this is a robust method for analysis.
Stability Studies
Stability tests have been carried on to test the stability of the sample in the auto sampler during the analysis
Temperature used have been 25°C, 4°C and -35°C for three weeks
Diclofenac Sodium has proven to be stable at 4°C and -35°C but a significant loss of active compound has been registered at 25°C
Results Obtained
New HPLC method for the analysis of Diclofenac Sodium
Faster than the previous ones which focused on acetonitrile as the main solvent
Could be used to estimate the concentration of Diclofenac Sodium in plasma or other biological fluids
Positives
Simple and quick to use analytical method
Validation to ensure that every aspect follows ICH guidelines
Short explanation of every parameter used for validation
Negatives
No direct comparison with data obtained from other analytical methods
Rationale behind the use of this mix of Acetonitrile/Methanol is not explained
No picture of the chromatograms obtained during specificity studies
Determination of apomorphine freebase in
sublingual tablets by proton nuclear magnetic
resonance spectroscopy
Li Tan, Shook F.Chin, Virginia W. Miner, Liang Dong, Suneel Gupta, Steven M.Fields
Aim and Objectives
Provide an analytical technique for the development of Apomorhine sublingual tablets
Development of a 1H NMR method to determine the quantity of Apomorphine freebase and Apomorphine chloride in tablets
Evaluation of specificity and linearity
BACKGROUND
Apomorphine hydrochloride is a dopamine agonist drug used for the treatment of Parkinson’s Disease
The marketed drug is used as a subcutaneous injection multiple times a day
Need for a non-invasive procedure to administrate Apomorphine
Development of sublingual tablets
Apomorphine freebase has high permeability with a plasma profile similar to the subcutaneous injection
The freebase form is unstable in aqueous solution but a mixture of salt and freebase in a solid formulation increases stability
The ratio between freebase form and chloride salt is critical for quality and efficacy
Previous quantification methods
➢ Titration Assay
Described by the US Pharmacopoeia in the Apomorphine monograph
Titration of HCl in the formulation
Cannot determine freebase content
➢ HPLC
Samples must be dissolved in an acidic solution
All Apomorphine gets protonated and it is not possible to distinguish between salt and freebase
➢ Titration + HPLC
Determine salt form by titration and then both forms together by HPLC
Long process that require use of multiple solvents
Development of a 1H NMR method
1H NMR techniques have already been used to determine equilibrium constants by analysis of the chemical shift of particular groups
In this study the chemical shift of NCH3 is considered as an indicator of the ionization state
The chemical shift of NCH3 is proportional to the percentage of freebase form and salt form
A calibration curve has been prepared with solutions containing different ratios of Apomorphine freebase and its chloride salt
The chemical shift of NCH3 in Apomorphine freebase is at 2.908ppm
The methyl amine group is protonated in Apomorphine salt form but it isn’t in its freebase
Chemical shift of the non protonated group is lower because of more shielded protons compared to the salt
Three different solvent systems have been studied:
• Deuterated water (D2O) : Apomorphine freebase is not soluble enough in this medium
• DMSO: proton shift is almost the same in the two forms
• Deuterated Methanol (CD3OD) : high solubility, high polarity, substantial change in the chemical shift
Samples analysed contained different percentages of the two forms :
1) 100% Apomorphine HCL
2) 100% Apomorphine Freebase
3) 75% Apomorphine Freebase (normal content of a sublingual tablet)
1H NMR Results
Method Validation
➢ Specificity
Excipients added to the mixture to evaluate possible interference
No significance change in the chemical shift
Robust method
➢ Linearity
Verify linearity to support future formulation development
Determined from 100% Apomorphine freebase to 0% freebase
Excellent linearity
Conclusion
A new 1H NMR method to analyse mixture of Apomorphine freebase and salt form
Faster and cheaper than previous ones
Specific and robust method that can be used for further development of more Apomorphine formulations
Positives
Improved analysis of a formulation still in development
Clear explanation of method and materials used
Good comparison of different NMR spectra
Negatives
Few information about the calibration curve
Specificity and linearity data have only been stated but no graph or diagram has been shown
Bibliography
Alquadeib, B.T. (2019) ‘Development and validation of a new HPLC analytical method for the determination of diclofenac in tablets’, Saudi Pharmaceutical Journal, 27(1), pp. 66-70. doi: //doi.org/10.1016/j.jsps.2018.07.020.
Tan, L., Chin, S.F., Miner, V.W., Dong, L., Gupta, S. and Fields, S.M. (2016) ‘Determination of apomorphine freebase in sublingual tablets by proton nuclear magnetic resonance spectroscopy’, Journal of pharmaceutical and biomedical analysis, 129, pp. 378-382. doi: S0731-7085(16)30362-4 [pii].
ADDITIONAL INSTRUCTIONS FOR THE CLASS
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- Discussion Questions (DQ)
Initial responses to the DQ should address all components of the questions asked, including a minimum of one scholarly source, and be at least 250 words. Successful responses are substantive (i.e., add something new to the discussion, engage others in the discussion, well-developed idea) and include at least one scholarly source. One or two-sentence responses, simple statements of agreement or “good post,” and responses that are off-topic will not count as substantive. Substantive responses should be at least 150 words. I encourage you to incorporate the readings from the week (as applicable) into your responses.
- Weekly Participation
Your initial responses to the mandatory DQ do not count toward participation and are graded separately. In addition to the DQ responses, you must post at least one reply to peers (or me) on three separate days, for a total of three replies. Participation posts do not require a scholarly source/citation (unless you cite someone else’s work). Part of your weekly participation includes viewing the weekly announcement and attesting to watching it in the comments. These announcements are made to ensure you understand everything that is due during the week.
- APA Format and Writing Quality
Familiarize yourself with the APA format and practice using it correctly. It is used for most writing assignments for your degree. Visit the Writing Center in the Student Success Center, under the Resources tab in Loud-cloud for APA paper templates, citation examples, tips, etc. Points will be deducted for poor use of APA format or absence of APA format (if required). Cite all sources of information! When in doubt, cite the source. Paraphrasing also requires a citation. I highly recommend using the APA Publication Manual, 6th edition.
- Use of Direct Quotes
I discourage over-utilization of direct quotes in DQs and assignments at the Master’s level and deduct points accordingly. As Masters’ level students, it is important that you be able to critically analyze and interpret information from journal articles and other resources. Simply restating someone else’s words does not demonstrate an understanding of the content or critical analysis of the content. It is best to paraphrase content and cite your source.
- LopesWrite Policy
For assignments that need to be submitted to Lopes Write, please be sure you have received your report and Similarity Index (SI) percentage BEFORE you do a “final submit” to me. Once you have received your report, please review it. This report will show you grammatical, punctuation, and spelling errors that can easily be fixed. Take the extra few minutes to review instead of getting counted off for these mistakes. Review your similarities. Did you forget to cite something? Did you not paraphrase well enough? Is your paper made up of someone else’s thoughts more than your own? Visit the Writing Center in the Student Success Center, under the Resources tab in Loud-cloud for tips on improving your paper and SI score.
- Late Policy
The university’s policy on late assignments is a 10% penalty PER DAY LATE. This also applies to late DQ replies. Please communicate with me if you anticipate having to submit an assignment late. I am happy to be flexible, with advance notice. We may be able to work out an extension based on extenuating circumstances. If you do not communicate with me before submitting an assignment late, the GCU late policy will be in effect. I do not accept assignments that are two or more weeks late unless we have worked out an extension. As per policy, no assignments are accepted after the last day of class. Any assignment submitted after midnight on the last day of class will not be accepted for grading.
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Communication is so very important. There are multiple ways to communicate with me: Questions to Instructor Forum: This is a great place to ask course content or assignment questions. If you have a question, there is a good chance one of your peers does as well. This is a public forum for the class. Individual Forum: This is a private forum to ask me questions or send me messages. This will be checked at least once every 24 hours.
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