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Critical Quality Attributes CQAs #Quality by Design- Part 4 — Transcript

by Simplify Pharma · 1,916 words · 354 segments · language en · Watch on YouTube

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0:01Welcome to Simplify Pharma.
0:03In this lecture, we will discuss the
0:05step two of quality by design.
0:08How the concept of critical quality
0:11attributes was developed, what does it
0:14mean,
0:15and how it is beneficial for
0:17pharmaceutical industries.
0:19An effort has been made to simplify it
0:22further.
0:23So, please like and subscribe to my
0:25channel and press the bell icon to get
0:28the new video updates.
0:30If you remember in my last video,
0:33we saw the step one for execution of
0:36QBD, that was to define product profile.
0:39Now, how do we define product profile?
0:41How do we design a product profile?
0:45It is on basis of two things, based upon
0:48the patient needs and the labeling
0:50condition.
0:51So, on that based upon that, there are
0:54two types of product profile. One is
0:56target product profile, which we called
0:58as TPP, and the second one is quality
1:01target product profile, which we called
1:04as QTPP. And if you remember, the TPP
1:07constituted of the entire information
1:10about the drug, starting from usage
1:13information, indication, administration,
1:16dosage form, strength, contraindication,
1:20precautionary warning, adverse reaction,
1:23overdose information, then
1:26information about clinical and
1:28non-clinical pharmacology, clinical
1:30studies, references,
1:32information about storage, handling, and
1:35also about the patient counseling. Then,
1:38the difference between TPP and QTPP,
1:41wherein TPP constitutes the entire
1:44information about the drug product,
1:47starting from description
1:49till the clinical studies, the entire
1:51information.
1:52On the other hand, the QTPP, it
1:54constitutes the information that is
1:57related to the quality of the drug
1:59product, the characteristics that can
2:01affect the quality of the drug product.
2:05So, we can say TPP constitutes the of
2:08the overall information of the drug
2:10product, and QTPP constitutes of
2:14the factors that can affect the quality
2:16of the drug product.
2:19The components of QTPP, they are further
2:22subdivided into critical and
2:24non-critical. Critical factors, they are
2:27based on the severity of harm to a
2:29patient's safety and efficacy
2:32resulting from failure to meet the
2:34quality attributes. So, if the quality
2:37attributes, we fail to meet the quality
2:39attributes, how much harm
2:42they can cause to the patient? Based on
2:45that, we define the critical and
2:47non-critical factors.
2:49For example, if the dissolution
2:50properties assay
2:52or the content uniformity, if there are
2:54variations in these properties, that
2:56will that can cause harm to a patient.
2:59Whereas, the odor, the appearance, the
3:03physical factors,
3:05you know, if there is any change in the
3:07physical factors, the severity of harm
3:09to a patient,
3:11that won't be much severe.
3:14See, when we talk about strength and
3:15dosage form, obviously, dosage form,
3:19it
3:20dosage form is constant, it is fixed.
3:23There cannot be any variation in the
3:24dosage form.
3:25Also, the strength of the product, that
3:28is also fixed. There cannot be any
3:30variation, that's why they come under
3:32non-critical factors.
3:34So, the components of QTPP, they are
3:37again subdivided into variable and
3:39fixed. Variable elements, they may have
3:42a range of acceptable values.
3:45As we can see, dissolution properties
3:48assay, content uniformity, there is a
3:51range because these elements, they vary
3:55based upon other factors. Whereas, the
3:57strength, dosage form, these are the
3:59fixed factors. The strength is not going
4:02to change, the dosage form is not going
4:04to change.
4:05So, coming to the step two of QBD
4:08approach, that is to identify CQA,
4:12critical quality attributes.
4:16Once we are done framing the QTPP, the
4:20second step involves identifying the
4:22important quality characteristics of the
4:25drug product, which can be useful in
4:27regulating the consistency in product
4:30quality. And there comes the picture of
4:33CQA, that is a critical quality
4:36attributes.
4:37It includes
4:39critical parameters that are likely to
4:41change based upon variations in raw
4:44materials and processes.
4:47So, CQAs are nothing but subset of QTPP.
4:51We have to identify a CQA based on the
4:54severity of harm to a patient, patient
4:58safety and efficacy resulting from
5:00failure to meet the quality attribute.
5:04So, based upon this, we identify a CQA.
5:09The potential varieties of CQAs include
5:13the physical attributes, chemical,
5:15biological, microbiological attributes
5:18of the product.
5:20And they are usually kept within
5:21appropriate limit or within appropriate
5:24range distribution to ensure the desired
5:27product quality.
5:29And
5:30they directly affect the product
5:32quality. That's why they are critical
5:34quality attributes.
5:36They can be critical quality attributes
5:38for drug product, drug substance,
5:40intermediates, excipients.
5:43CQAs are subsets of QTPP.
5:47And they have potential to be altered by
5:51change in formulation or process
5:53variables.
5:55Let's take a simple example.
5:57QTPP may include additional quality
6:00attributes of the drug product, such as
6:02strength and dosage form,
6:04which are not part of CQA. Why? Because
6:07they will not change during drug
6:08development process.
6:10The dosage form, for example, we are
6:12making a paracetamol tablet
6:14of 500 mg. See, there can be other
6:17variations. There can be variations in
6:19raw material, there can be variations in
6:21excipients, the process that we use, but
6:25the tablet won't change into injectable.
6:28We are going to manufacture paracetamol
6:31tablet, that is fixed. We are going to
6:33manufacture paracetamol tablet of 500
6:35mg, that's the strength, that is also
6:37fixed. So, these two things are fixed.
6:41Other things, variation should not bring
6:43any change to these two things. That's
6:46why they are not CQA.
6:49However, the QTPP attributes, such as
6:52assay,
6:53content uniformity, dissolution,
6:55permeation flux,
6:57they can be CQA. Why? Because they may
7:01be altered by formulation or process
7:03variables. Other factors can bring
7:06change or variations to these factors,
7:09that's why we can consider them as CQA.
7:13As per ICH guideline Q9, we identify CQA
7:17through risk assessment. But also, we
7:21require prior product knowledge or some
7:24lab data, non-clinical, clinical data,
7:28that is also that also helps in making
7:30the risk assessments.
7:32CQA cannot be controlled directly, but
7:36indirectly through input factors, such
7:38as CME and CPP, that is critical
7:41material attributes and critical process
7:44parameters.
7:45Now, let us see over here, this is an
7:48example. For example, this is a list of
7:50QTPPs. Now, how are we going to identify
7:54a CQA from this list?
7:57First is dosage form.
7:59It won't change. Route of
8:00administration, that will also not
8:02change. Strength, that will also not
8:05change. Weight,
8:07even though it can change because of
8:10change in any raw material or excipient,
8:13but the harm that it can cause to the
8:15patient is not much.
8:17Then comes the pharmacokinetics,
8:19appearance, identity.
8:22All this, the harm that is caused to the
8:24patient is not much. Then, what do we
8:26consider as CQA?
8:29Impurities, dissolution properties
8:31assay, content uniformity. If there is
8:34any variation in these factors, that can
8:37cause harm to the patient, so they come
8:39under
8:41very critical factors.
8:43And that's why they are
8:46they come under the CQA category.
8:50Now, let's take a simple quiz
8:53to understand whether you all have
8:55understood the concept of critical
8:57quality at
8:59Now, I will flash few factors. You have
9:03to take pause the video, take a
9:05notebook, divide into two columns,
9:08whether it is a CQA or not a CQA. I will
9:11flash few factors and you have to write
9:13it down under whether it is a CQA or
9:15whether it is not a CQA.
9:18Let's start, and then after
9:21that, I will flash the result and you
9:23can check whether you have understood
9:25the concept or not.
9:26So, let's start the quiz.
9:29Odor.
9:30You have to write it down
9:32in between the two
9:34columns, whether it is a CQA or not.
9:38Appearance.
9:41Think carefully.
9:43Dissolution properties.
9:47Strength.
9:51Dosage form.
9:55Assay.
9:57Content
9:59content uniformity
10:05So this is a result. You can check your
10:07result whether you have understood the
10:08concept of critical quality attributes.
10:13So as you can see over here order
10:15appearance strength, dosage form They
10:19are not CQA.
10:21Whereas dissolution properties essay
10:24content uniformity
10:26API level These are CQAs.
10:29Now let us understand why.
10:31If you consider order, appearance
10:35These are likely something that if they
10:37fell out of a certain range or a certain
10:39limit they're likely not going to cause
10:42any harm to a patient.
10:44However if the active ingredient level
10:47is decreased or increased
10:49or if there was an increase in
10:51degradation product or the dissolution
10:54properties are changed of the product
10:56all of these could potentially impact
10:59how the drug works in a patient and
11:02could potentially cause harm to the
11:04patient. So that's why all these would
11:07fall in a category of CQA.
11:10Now this is another example how a CQA
11:14document looks like.
11:16There will be key
11:17columns like this in which the first
11:19column is which all QT QTPP elements are
11:22there.
11:23What is the target?
11:25What is the justification for that?
11:27Now this is one I have pulled up from
11:30the FDA website.
11:32Here the author has outlined different
11:34elements that they're concerned about in
11:37the QTPP.
11:39Then they have a column for what is the
11:41target goal
11:42for that element. Then they have also
11:44put in a justification.
11:46Why did they choose that target?
11:49And as you'll see in the QTPP elements,
11:52most of these really focus on things
11:54that are related to the drug product
11:57itself.
11:58So focusing on things like stability of
12:00the product or different quality
12:02attributes such as physical attributes,
12:04identification of the product.
12:07It also focuses on things like container
12:09closure system which would be really
12:11important not only for drug stability
12:14but also for ease of use by the patient.
12:18And as you can see there's one column
12:20whether this QTPP is a CQA or not.
12:25So physical attributes like appearance,
12:27order, size they are not CQA.
12:31Whereas essay, content uniformity,
12:34dissolution
12:36they all fall under the
12:38type of CQA.
12:40Then we can see residual solution,
12:43degradation product they all are CQA.
12:48One more case study we'll see. This
12:50again I pulled up from the internet
12:52wherein this is a research article
12:54quality by design based formulation and
12:57evaluation of fast dissolving tablet of
12:59aspirin.
13:01And as you can see over here the CQA
13:02profile
13:04These are the factors and whether they
13:06are considered as CQA or not and they
13:08have given justification for that.
13:11Physical attributes color, order,
13:12appearance no they are not considered as
13:14CQA. Justification
13:16physical attributes of the formulation
13:19are not directly linked to the efficacy
13:21and safety.
13:23Then we can see hardness, disintegration
13:26yes yes they are considered as CQA. Why?
13:29Because hardness will affect friability,
13:31disintegration, dissolution that can
13:34impact the bioavailability.
13:36Both formulation and process variables
13:38affect the hardness. So you can see
13:42on what basis we can consider a
13:44particular attribute as CQA or not.
13:47There is a justification that we have to
13:49give for that.
13:50There is one more research paper that I
13:52have pulled up from the internet.
13:54This is again uh for a mucoadhesive
13:57extended release tablet.
13:59And as we can see over here
14:01uh the physical attributes they are not
14:03considered as CQA except the hardness
14:06since it is a
14:07mucoadhesive extended release tablet
14:10that may affect the disintegration
14:12that's why. Then other than that drug
14:15content, dissolution, mucoadhesion time
14:17all these are CQAs and there even the
14:20justification is given for that.
14:23Then
14:24for the drug substance and for drug
14:27product for example the paracetamol
14:30drug and the paracetamol tablet how a
14:33CQA is written for both. This is given
14:36in this table.
14:38So this was all about critical quality
14:40attributes.
14:42Please like and subscribe to my channel.
14:44And in my next video we will discuss the
14:47next step. Thank you. Thank you for
14:49watching.

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