Assignment Answers: Analytical Method Validation- PHEN604

Assignment Answers: Analytical Method Validation- PHEN604

PhEn604 : Va lidatio n & Re gulatory Issues Distance Learning, Spring 2022
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SECT ION A: CASE ST UDY: SAM PLING PLANS (15 points total)
Instructions: Please answer the following questions in the space provided. For reference tables,
please use the copy of ANSI/ASQ Z1.4 provided with your lecture notes.
The ANSI ASQ Z1.4 and Z1.9 tables are great for picking validation acceptance criteria, but they are
commonly used for normal operations as well. Here’s one example.
Your packaging department orders glass vials once per month for packaging 4 of the com pany’s
liquid products, a 2 -shift / 5 -day operation per week. Each shipment lot consists of 6 pallets, each
pallet containing 32 stacked, shrink -wrapped cases, each packed with 250 vials. Your QC
Department requires the vendor to supply a Certificate of Conformity with each shipment, indicating
that the vials were produced and tested as meeting a number of specifications set forth in the quality
agreement and supply contract.
QC’s master plan requires that they sample and inspect all incoming packagin g component lots
following ANSI/ASQ Z1.4 -2003 R2018 plans and switching rules (identical to the 2008 revision you
received in class), and their SOP for vial inspection requires them to sample and inspect for cracks
and other imperfections considered critic al quality risks (AQL = 0.065%). This company’s QA has an
average risk appetite, employing General Inspection Level II and single sampling plans for AQLbased
inspections, unless specifically required to do otherwise by an SOP or contractual obligation.
1) (1 point each ) For the past 2 years, QC has been inspecting incoming lots of vials and has
never had to reject a batch. Last September, Lot #2021 -35 was received. Following the
company’s inspection rules, identify the following regarding acceptance or r ejection of this lot:
Total Lot Size of vials to be sampled: 180000
Sample Size Code Letter to Use: P
Sampling Plan to Use (Tightened, Normal, Reduced):
Minimum Required # Vials to be sampled:
Minimum # Non -Conformin g Vials to Re je ct Lot:
Maximum # Non -Conformin g Vials to Acce pt Lot:
2) (1 point each ) For Lot #2021 -35, QC found 1 cracked vial among the samples. Following their
master plan, what will this mean for accepting or rejecting the next Lot #2021 -36?
Sampling Plan to Use (T ightened, Normal, Reduced):
Minimum Required # Vials to be sampled:
Minimum # Non -Conformin g Vials to Re je ct Lot:
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Maximum # Non -Conformin g Vials to Acce pt Lot:
QA continues to monitor incoming shipments over the next quarter, following the AQL guidelines, and
identify the following # of defects in each of the next 10 consecutive lots #2021 -37 through 2021 -46:
1, 0, 0, 2, 0, 1, 2, 3, 1, 0.
3) (1 point total ) Your company change Sampling Plans (from that used in Question 2) at some
point during the above inspections.
a) (1/2 point ) What Inspection Plan did they change to, and why (provide full details)?
b) (1/2 point ) If each lot # was tested in numerical order, yielding the above results, for which
Lot #(s) did the Sampling Plan change?
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Sure at this point that there must be a problem, QA sends all rejected lots and those pending
inspection back to the supplier, demanding an investigation. Within a week, the supplier has
identified a subtle but significant problem with a batch of glass th ey purchased from their vendor,
which can occasionally cause vials to crack during shipping and handling. They soon resolve the
issue with their supplier, test a new batch of glass, and provide evidence that several batches of vials
made from the new glas s do not reflect the error.
Given the likelihood that the problem has been corrected, your company’s QA and Operations
authorize receipt of a new batch of new vials (Lot 2021 -53).
4) (1 point each ) Following the company’s inspection rules, identify the following regarding
acceptance or rejection of the incoming vial lot:
Sampling Plan to Use (Tightened, Normal,
Reduced):
Tightened
Minimum Required # Vials to be sampled: 800
Minimum # Non -Conformin g Vials to Re je ct
Lot:
2
Maximum # Non -Conformin g Vials to Acce p t
Lot:
1
SECT ION B: CASE ST UDY: ANALYT ICAL M ETHOD VALIDAT ION (25 points total)
Your lead research scientist Dr. W elby, PhD (he reminds you of his PhDs in Biology, Organic and Inorganic Chemistry,
and Biochemistry at each meeting) has developed and validated a method for the company’s new blockbuster drug,
Melambien. Dr. W elby and hi s staff have completed the chromatographic method validation for the drug and have given
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you, the Director of Quality, the report for review and approval. Below are some of the information included in the report
and questions based on the data presented.
PARAMETER 1: Me thod Line a rity
1. (5 points) Dr. W elby handed you the below data for an HPLC strength assay, and you need to report the maximum
range of concentrations of Melambien across which the method is linear. In other words, what is the widest
concentration range (in g/mL) across which this method meets linearity requirements?
Acce pta nce Crite ria : According to the protocol, the Correlation Coefficient (R) must be > 0.9925 for a given
concentration range in order to consider the method to be lin ear across that range.
Ra w Da ta : The absolute concentration on the column for the active ingredient is 0.50 g/ml. The results are recorded in
the table and are illustrated in the graph below, for which three linear trendline equations were calculated for three ranges,
starting with the entire range of data points (10% -200% of target), and decreasing at the top and bottom ends
progressively to a range of 50% -130% of target.
%a ge of Ta rge t Sta nda rd Are a Count for Re plica te #n Sta tistics (n=5)
Ta rge t g/mL n = 1 n = 2 n = 3 n = 4 n = 5 Me a n Std De v Va ria nce
10% 0.05 73482 102811 92382 83429 118329 94086.6 17355.5 3.01E+08
25% 0.13 140000 135366 129356 130462 139672 134971 4985.12 2.49E+07
50% 0.25 179484 173166 178327 174884 177193 176611 2568.47 6.60E+06
75% 0.38 269225 270437 273303 271352 269384 270740 1671.02 2.79E+06
100% 0.50 358967 354588 348808 350273 352984 353124 3970.5 1.58E+07
115% 0.58 412812 423297 405731 408362 415682 413177 6845.62 4.69E+07
130% 0.65 466657 458257 439056 440372 470938 455056 14736.8 2.17E+08
150% 0.75 480000 472385 503482 470283 505389 486308 16951.9 2.87E+08
200% 1.00 527681 521244 512748 514901 518886 519092 5836.64 3.41E+07
Da ta Re gre ssion Ana lysis:
Best Fit trendline for ran ge 0.0 5 -1.00 g/mL: y = 506451x + 81166, R² = 0.9488
Best Fit trendline for ran ge 0.1 3 -0.75 g/mL: y = 613668x + 43100, R² = 0.9889
Best Fit trendline for ran ge 0.2 5 -0.65 g/mL: y = 700774x + 2976.3, R² = 0.9994
REMEMB ER: S HOW ALL
WORK ON THES E MATH
QUES TIONS FOR FULL OR
PARTIAL CREDIT!
94086.6
134971.2
176610.8
270740.2
353124
413176.8
455056 486307.8 519092.28
90000
190000
290000
390000
490000
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
Target Concentration g/mL
Graph 1: Mean Peak Area @ Target Concentration
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For the concentration range to be regard as linear, the correlation coefficient (R) should be> _ 0.9925 . Using a regression
analysis and the formula of √ R ^2 = R can help in determining the linearity. The following table summarizes the calculation
s.
Range of
concentration
Equation R^2 R = (R2)21/2
0.05 -1.00 Mg/ ml Y=506451 x +
81166
0.94 88 0.9740
0.13 -0.75 mg/ml Y= 613668 x +
43100
0.9889 0.9 944
0.25 -0.65mg/ml Y = 700774x +
2976.3
0.9994 0.99 96
The concentration ranges of 0.13 -0.75 µg/ml and 0.25 – 0.65 µ g/ml meets the protocol of the correlation coefficient
being >_ 0.9925 and therefore will have the wide concentration range.
PARAMETER 2a : Pre cision – Syste m
2. (5 points) Dr. W elby’s report claims that the method is precise on the system. Using the same da ta set provided for
Question #1, determine if the system is precise, and if so, over what range of concentration (in g/mL) of Melambien it
is precise. Provide your answer and the data to support your answer.
Acce pta nce Crite ria : % Relative Standard Devi ation (%RSD = Std. Dev./Mean*100 ) must be ≤ 2% for five replicate
injections of the standard solution.
Answ e r: The pre cision syste m
The a cce pta nce crite ria for the syste m to be pre cise is; the % RSD should be le ss tha n or e qua l to 2% .
The follow ing formula w ill be use d;
RSD = sta nda rd de via tion÷ me a n
% RSD = sta nda rd de via tion÷ me a n × 100
For e x a mple , for a conce ntra tion of of 0.50 mg/ml; the % RSD = 3970.5/ 343124 × 100 = 1.124
% of
ta rge t
Ta rge t Me a n Sta nda rd
de via tion
RSD %
RSD
10% 0.05 94086.6 17355.6 0.18 446 18.446
25% 0.13 134971 4985.12 0.03693 3.693
50% 0.25 176611 2568.47 0.01 454 1.454
75% 0.38 270740 1671. 02 0.00617 0.617
100% 0.50 353124 3970.5 0.01124 1.124
115 % 0.58 413177 6845.62 0.01 656 1.656
130% 0.65 455056 14 736.8 0.03238 3.2 38
150% 0.75 486308 16951.9 0.03485 3.485
200% 1.00 519092 5836.64 0.01 124 1.124
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The %RSD of the concentration of 0.25 mg/ ml, 0.38 mg/ ml, 0.5 mg/ml, 0
58mg/ml and 1.0 mg/ml have %RSD ≤ 2%. Therefore, the system is precise at these concentrations.
PARAMETER 2b: Pre cision – Me thod
Te st De scription: As part of the validation, one analyst ground ten tablets into a powder and weighed the equivalent of
one tablet of the powder into each of two flasks and diluted to volume. The solutions were diluted so the resulting
concentrations were approximately 0.50 g/mL. Each solution was injected three times and the %Label Strength (%LS)
for each injection was calculated against a known reference standard. The results are provided in the table below.
Solution
% La be l Stre ngth
(%LS) Std De v
Sample 1 97 98 102 2.6
Sample 2 99 102 105 3.0
3. (5 points) Is the method precise? Provide your answer and the data to support your answer. The analysis results
are in the table below.
Acce pta nce Crite ria : %LS for each injection must be 100% ± 5%, the mean %LS of each sample must be 100% ±
2%, and the %RSD (formula given above) must be ≤ 3%.
The pre cision me thod
For the method to be considered precise, the %LS for each of the injection must be 100% + or – 2% and the %RSD should
be ≤ 3%.
Formulas, RSD= Standard deviation/ mean
% RSD= Standard deviation / mean × 100
For 0.50 µg/ml= 3970.5/ 353124 × 100 = 1.02%
Solution % label
strength
Standard
deviation
Mean %
RSD
Sample 1 97 98 102 2.6 99 2.62%
Sample 2 99 102 105 3.0 102 2.92 %
For the calculation, of sample 1; the mean = (97+98+ 102)/3 = 99
%RSD = 2.6/99 × 100 = 2.62
Based on the calculations, both methods are within the limit that was stated by the acceptance cretiria which makes
them to be precise .
PARAMETER 3: Accura cy
Te st De scription: Accuracy of the method is determined by calculating the % Recovery of active ingredient in Melambien
from a mixture of excipients spiked with a known quantity of Melambien API, at concentrations spanning ±50% of the
target (at least 5 data points are required). Samples were prepared and run in triplicate at each no concentration level and
results are recorded in the table below.
%age of
Target
Target on
Coulmn
Concentration
(g/mL) Sample #
Amount
Added
(mg)
Amount
Recovered
(mg)
50% 0.25 1 37.35 34.92
2 37.30 35.25
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4. (5 points) Over what concentration range (in
g/mL) is this method accurate? Provide your
answer and the data to support your answer.
Acce pta nce Crite ria : % Recovery or each of three
samples at a given concentration must be within 100%
± 5%.
Note: % Recovery = amount recovered / amount
added * 100)
Note: Rememb er to apply significant figures correctly.
For example, 99.4% rounds to 99% and 99.5% rounds
to 100%.
Accura cy
The a cce pta nce crite ria for the a ccura cy of the give n cre tiria , a tle a st 3 sa mple s w ill ha ve to be ta ke n a nd the
% re cove ry for e a ch of the sa mple should be w ithin 100% + or – 5; % .
%
a ge
of the
ta rge t
Ta rge t on
column
conce ntra tion
Sa mple
#
Amount
a dde d
Amount
re cove re d
Re cove ry
= a mount
re cove re d
/ a mount
a dde d
%
re cove ry
= a mount
re cove re d
/ a mount
a dde d
*100
3 37.29 37.10
75% 0.38
1 55.85 55.57
2 55.80 55.13
3 55.83 55.44
100% 0.50
1 74.45 73.33
2 74.53 72.70
3 74.51 73.39
125% 0.63
1 93.05 91.56
2 92.98 90.75
3 93.10 91.42
150% 0.75
1 111.50 105.81
2 111.58 107.01
3 111.62 107.60
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50% 0.25 1
2
3
37.35
37.30
37.29
34.92
35.25
37 . 10
0.9349
0.9450
0.99 490
93.49
94.50
99.49
75% 1
2
3
55.85
55.80
55.83
55.57
55.57
55.4
0.99498
0.99799
99.5
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100% 1
2
3
74.45
74.53
74.51
73.33
72.40
73.39
0.98495
0.9744
0.98496
99.3
99.30
98.50
125 1
2
93.05
92.98
91.56
90.75
0.98398
0.97444
98.40
98.50
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3
93.10
91.42 0.98195 98.20
150% 0.63 1
2
3
111.50
111.58
111.62
105.81
107.01
107.60
0.94889
0.95904
0.96398
94.90
95.90
96.40
For the conce ntra tion of 0.38, 0.5, 0.63 mg/ml is a s its fit in t he a cce pta nce crite ria a nd the re fore ma king the
me thod to be a ccura te in conce rn w ith the ma tte r sta te s.
ALL TOGETHER…
5. (5 points) Assume that Analytical Method Validation for this assay requires demonstrating only
Linearity, System & Method Precision, and Accuracy. For what range of Melambien concentration
(in g/mL) would this method be validated? Prov ide your answer and rationale.
Concentration Linearity Precision Accuracy Final
validation
0.13 Yes No No No
0.25 Yes Yes No No
0.38 Yes Yes Yes Yes
0.50 Yes Yes Yes Yes
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0.58 Yes Yes Yes Yes
0.63 Yes Yes Yes No
0.65 Yes No No No
0.75 Yes No No No
From the information that is in the table above, it can be assumed that the demonstration of
linearity, system and method precision and accuracy that was obtained previously was an
estimation. The concentration th at is completely complying with all the three methods of analytical
validation parameters is from 0.38 – 0.58 mg/ml and for the concentration range of 0.58 mg/ml for
accuracy had no proofs of validity. The lack of validation was because the amount that was added or
recovered was rath er an assumption as it was not provided. Therefore, the accuracy assumed at the
concentration of 0.5 mg/ml falls between the ranges of 0.38 -0.58 mg/ml.
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SECT ION C: CASE ST UDY: CLEANING VALIDAT ION (25 points total)
Instructions: Please answer the following questions. You should be able to answer the essay -style
questions in 1 paragraph, but use as much room as you need. Show all math work – this will allow
you to get partial credit!
Consider two products that may be processed in a single 50 cubic foot blender that has a product contact
surface area of 750 dm 2.
Highly -potent Product A (Armenantyx, used to treat anxiety) is manufactured with 250 g API in a small 1 mg
tablet, and is produced in batch sizes of at least 200,000,000 tablets. Patient dosage is two tablets of Product
A administered orally every 12 hours.
Product B (Melambien, used to make you feel confident and smart) contains 25mg API in larger 250 mg
tablets, produced in batches of up to 250,000 tablets. Patient dosage is one tablet of Product B administered
orally once per day.
Your company’s Cleani ng Validation VMP specifies that MACO calculations for products such as Product B
must use a Safety Factor of 1,000, and that those products that are toxic or highly potent must use a factor that
translates to ten times the safety to the patient.
You as k your engineers to assess the cleaning procedure after three process validation runs of Product A in
the new blender. In response, your validation engineers watch operators accurately execute approved
cleaning procedure CL -021, which was successfully val idated on other V -Blenders on your site.
After the validation batch, your engineers use suitable practices and methods to swab, analyze, and calculate
the results, which are given in the table below:
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Avg. (n=3) Sw a b
Re sult (Actua l
Amount)
Avg. (n=3) Sw a b Re sult
(Adjustme nt a ssuming
95% Re cove ry)
Conta ct Are a
of Ble nde r
Pa rt
Ca lcula te d
Product Amt
On Ble nde r Pa rt Sw a b
Se t #
Sw a b
Position (mg/dm 2) a (mg/dm 2) b (dm 2) c (mg)
1 Blender Lid, Left 0.03791 0.03990 40 1.596
2 Blender Lid, Right 0.03591 0.03780 40 1.512
3 Outlet Valve 0.02394 0.02520 4 0.1008
4 Inside, Left Side 0.02294 0.02415 333 8.042
5 Inside, Right Side 0.02394 0.02520 333 8.392
Collection M ethod
or
Formula Used:
HPLC Assay for
Product A analyte Calculated by: Column
#3 / 0.95
M easurement
on Drawings
Calculated by:
Column #4 * #5
Footnotes: a) To demonstrate reproducib ility, results in Data Column “A” represent the average of the assay of
3 swab s from areas distrib uted evenly across the b lender component b eing evaluated
b) As an additional safety factor, these data assume a maximum of 95% recovery of the analyte from
each swab (Data Column B)
c) 1.0000 square decimeter ( dm 2) = 15.5000 square inches ( in2)
1) (6 points total ) Assuming these are the only 2 products run on a piece of equipment whose
cleaning you will need to validate:
a) (1/2 points per box ) List in the table below the values for each of the MACO calculation
parameters. Clearly docu ment the calculations you perform for each parameter so I can grade
for partial credit (note: I can’t grade a correct # full credit, either!). Don’t forget to give the
units !
PARAMETER PRODUCT A PRODUCT B
DTD Dose 250 mg
Frequency – twice a day of tablet
taken each time – 2
DT B = 250 mg × 2 times × 2 tablets
= 1000 mg or 1 mg
Dose – 25 mg
Frequency – once a day
No. Of tablets taken -1
MBS
Tablets in each batch
200000000
Weight of each tablet – 1 mg
= 200000000 mg or 200 kg
DT D= 25 mg × 1 time × 1
tablet= 25 mg
Weight of each batch – 250, 000
Weight of each tablet – 250 mg
MRS = 250, 000 × 250
= 62, 500000
SF 10000 = 10 times
1000 ( given )
MDW
1 mg
250 mg
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b) (1/2 points per formula ) In the space below, carefully print the formulas for calculating the
MACO of Product A as the contaminant, and for the MACO of Product B as the contaminant:
Formula:
MACO (A in B)
DTD A × (MBSB / MDWA) / SFA
Formula:
MACO (B in A)
DTDB, × MBS/ MDWA, / SFB
c) (1/2 points each box ) Using the parameter values recorded above in Question 1a) and the
formula you recorded above, calculate the two MACOs and record them in the table below.
Remember, show your calculations. Don’t forget to be careful with the units!
MACO (A in B) 1 mg × (62 500000 mg/ 250 mg) / 10000
= 25 mg
MACO (B in A)
25 mg × (200000mg /1 mg) / 1000 = 5000000 mg
2) (9 points total ) The following questions refer to the correct answers for Part 1, which you have
hopefully provided.
a) (4 points ) Which of the two products is “worst case” for patient safety – Product A, or Product
B? Why?
From the results of the formula that was used, the MACO (A in B) is considered one of the worst
case. MACP (A in B) has less comparison and it can be said that A is less acceptable in B. Similar
results can also be observed in the calculation that are prov ided above which indicate that A has
less amount in the API in the table, the results means the product can be very toxic when used with
large amount of the same concentration in the tablet. Therefore, it can be concluded that the worst
case scenario for the patient safety is product A in B.
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b) (5 points ) Let’s say for another product, Product C, that it can have contamination of Product
B with a MACO of 10kg. When the cleaning study is performed, the results show that the
blender retained an amount of Product B equal to 90% of this MACO value.
Does this mean that the blender is safe for use without re -cleaning (from a patient/consumer
perspective)? Does this mean that the blender is clean? Why or why not?
The blender is safe for use without need for cleaning because the amount of B that can be retained
by the blender is about 90 kgs which is 90% of MACO value of 10 kgs. The blender can not cause
any harm to the patients even though a cleaning study should be performed constantly . Also, the
procedures of cleaning should have regular consideratio n.
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3) (10 points total ) The following questions refer to the validation data presented earlier.
The cleaning validation has three acceptance criteria for validating the procedure:
a) Equipment must be “visibly clean”. Note: your company defines this based on the “average
person’s” visual LOD, which in turn was based on research studies 1 that have approximated
this limit to be 100μg spread evenly over a 4in 2 area).
b) Total contamination of the equipment must be le ss than the MACO for that product as a
contaminant, based on cumulative swab results.
c) No individual location of the cleaned equipment may have >35.0μg/dm 2 per swab.
In this company, Cleaning Validation would pass only if all three of these are met. Expl ain which of
the criteria pass (if any) and which fail (if any) and conclude whether the validation passes or fails.
Justify your answer by comparing the actual obtained results vs. the acceptance criteria.
For visible cleaning ; the acceptance criteria: 100 mg spread evenly over 4 in area.
The results observed : the total amount of the product on blender = (1.596 + 1.512+
0.01008 +8.042+8.392)
= 19.64 mg
The tota l product contact area = 750 dm 3 × 15.5 in 2area
The results are therefore a pass.
B. The total contamination of the equipment;
The acceptance criteria: equipment contamination

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