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ICH Flashcards

1
Q

What does ICH Q2 cover

A

Analytical Validation

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2
Q

What are the key points in ICH Q2

A

SLARPDQSS

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3
Q

What does ICH Q2 say about specificity

A

Should be done when developing ID, IMPS and Assay tests

Needs to discriminate between closely related structures which might be present

Use reference spectra

Show peak resolutions of two that elute closest together

IMPS can be done by spiking studies

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4
Q

What does ICH Q2 say about linearity

A

Use 5 solution strengths minimum

correlation coefficient, y-intercept, slope of the regression line and residual sum of squares should be submitted

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5
Q

What does ICH Q2 say about Range

A

The following minimum specified ranges should be considered: -

  • for the assay of a drug substance or a finished (drug) product: normally from 80 to 120 percent of the test concentration;
  • for content uniformity, covering a minimum of 70 to 130 percent of the test concentration, unless a wider more appropriate range, based on the nature of the dosage form (e.g., metered dose inhalers), is justified;
  • for dissolution testing: +/-20 % over the specified rang
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6
Q

What does ICH Q2 say about Assay

A

Spiking studies with known qty of DP or impurity have been added.

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7
Q

What does ICH Q2 say about Precision

A

Repeatability
Reproducibility
Intermediate Precision

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8
Q

What is Reproducibility

A

Different labs trial

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9
Q

What is Intermediate Precision

A

The effects of random events on the precision of the analytical procedure.

Typical variations to be studied include days, analysts, equipment, etc

Use of DoE matrix approach recommended.

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10
Q

What are the ICH Q2 requirements for repeatability

A

Min 9 determinations across the range of the trial (3 concentrations, 3 replicates)

Or

Min 6 at 100% of the test concentration

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11
Q

What data is recommended for Precision tests?

A

standard deviation, relative standard deviation (coefficient of variation) and confidence interval

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12
Q

What does ICH Q2 say Robustness is?

A

This is a measure of reliability of analysis against deliberate variation in method parameters

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13
Q

What method parameters should be considered wrt ICH Q2

A

Solution stability
Extraction time
Different columns
Differing pH of mobile phase
Temperature
Flow rate

Do this in method development and then control the bad things found.

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14
Q

What are ICH Q3 A – E?

A

A = Imps in new DS
B = Imps in new DP
C = Solvents
D = Metals
E = Extractables and leachables

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15
Q

What are the three classes of solvents in ICH Q3C?

A

1 – Solvents to be avoided

2 – Solvents to be limited

3 – Solvents with low toxic potential

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16
Q

What level of class 3 solvent is acceptable without justification

A

50 mg per day

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17
Q

When may levels above the PDE be justifiable?

A

Intermittent dosing

Short term dosing (<30days)

Specific indications (life threatening, unmet medical need, rare diseases)

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18
Q

What are the potential sources of elemental impurities?

A

Stuff added deliberately (eg catalysts)

Stuff added by accident (eg from water, the API or excipients)

Stuff added from the manufacturing equipment

Stuff that may have leached from container closure systems

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19
Q

What factors can influence leaching?

A
  • Hydrophilicity/hydrophobicity;
  • Ionic content;
  • pH;
  • Temperature (cold chain vs room temperature and processing conditions);
  • Contact surface area;
  • Container/component composition;
  • Terminal sterilization;
  • Packaging process;
  • Component sterilization;
  • Duration of storage.
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20
Q

What are ICH Q3D class 1 metals?

A

Cd

Pb

As

Hg

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21
Q

What are the ICH Q3D class 2A metals?

A

Co

Ni

V

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22
Q

How do you know whether elements need to be considered in a risk assessment (ICH Q3D)?

A

There’s a table in guideline.

All deliberately added elements need assessing.

Then generally all class 1 and 2A with a few class 3’s for parenteral and inhaled dose forms.

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23
Q

What is ICH Q4

A

Pharmacopoeias

Lists whether various tests are harmonised or not

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24
Q

What is a master cell bank?

A

A single pool of cells prepared from the selected cell clone under defined conditions, dispensed into multiple containers and stored under defined conditions.

The MCB is used to derive all working cell banks

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25
What’s a working cell bank
A pool of cells prepared from aliquots of a homogeneous suspension of cells obtained from culturing the MCB under defined culture conditions
26
With respect to ICH Q5, what information should be supplied to describe the expression construct
To describe the expression construct, the following information should be provided: Coding Sequence: The correct coding sequence of the product should be incorporated into the host cell and maintained during culture to the end of production1. Nucleic Acid Techniques: Segments of the expression construct should be analyzed using nucleic acid techniques123. Other Tests: These analyses should be performed in conjunction with other tests on the purified recombinant protein123. The purpose of these analyses is to assure the quality and consistency of the final product
27
What’s different when stability testing biologics cf small molecule?
Purity is relative and is method dependent. Should be assessed by more than one method. Stability testing for purity should focus on determination of degradation products. Storage temperature generally tightly controlled so don’t need to do standard ranges. Should do accelerated and stress conditions though (for transport excursion and identifying what to look for in longer term studies) Containers typically exclude humidity so if can demonstrate the container does this then don’t need to do different RH’s Stability of freeze dried products after reconstitution should be done.
28
What’s the aim of ICH Q6
the establishment of a single set of global specifications for new drug substances and new drug products. It provides guidance on the setting and justification of acceptance criteria and the selection of test procedures
29
Do the release and shelf-life acceptance criteria need to be the same (ICH Q6)?
Sometimes do it for assay and impurity due to known degradation. In US and Japan they must be the same but you’re allowed tighter “in house” criteria for release. In EU, if they are different then there must be regulatory specification for both release and shelf life if they are different.
30
When might you replace disso testing with disintegration?
If immediate release and highly soluble. Need to have shown during DP development that have consistently rapid drug release.
31
What’s the definition of a specification?
A list of tests and references to analytical procedures with appropriate a/c
32
What specification tests are applicable to all drug substances?
Description Identity Assay Imps
33
What tests are applicable to all drug products?
Description Identity Assay Imps
34
What’s not allowed for an identity test
the test needs to be specific so no to identification solely by a single retention time. Use IR or combination like HPLC/UV diode array, HPLC/MS or GC?MS = OK
35
wrt ICH Q6, What are the other DS tests that could be registered?
Physicochemical properties (pH, melting point, refractive index etc) Particle size Polymorphic tests Water content Inorganic imps Microbial limit testing
36
wrt ICH Q6, What tests are there for polymorphism?
Physicochemical tests – melting point, solid state IR, X-ray powder diffraction, thermal procedures (DSC), Ramen, optical microscopy, NMR Chiral tests
37
wrt ICH Q6, what are the potential tablet release tests
Disso, Disintegration, crushing strength, friability, UDU, water content, microbial limits
38
wrt ICH Q6, what modifications to disso testing
for modified release / extended release: Multiple time point sampling Two stage testing using media in succession. For immediate release with bioavailability concerns: Develop test that discriminates and rejects when bioavailability unacceptable.
39
wrt ICH Q6, What are the potential liquid release tests?
UDU (mass OK for powders for reconstitution) pH Microbial limits Preservative content (antimicrobial or antioxidant as appropriate) Extractables Alcohol content Disso (oral suspensions or pfos) Particle size (oral suspensions or pFos) Redispersability Rheological properties Reconstitution time Water Content
40
wrt ICH Q6, What are the potential liquid release tests?
UDU pH Sterility Endotoxins / Pyrogens Particulate Matter Water content Preservative content (both antimicrobial or antioxidant) Extractables Functionality of delivery system Osmolarity Particle size distribution Redispersibility Reconstitution time
41
Wrt ICH Q6, how do you decide what tests to do
There are a number of flowcharts appended that take the form of a decision tree.
42
What are the DS tests that form a specification for biologics?
Appearance and description Identity Purity and Imps Potency Quantity
43
What are the DP tests that form a specification for biologics?
Appearance and description Identity Purity and Imps Potency Quantity General tests (e.g. osmolarity / pH) Any other additional tests needed
44
What's special about purity testing of biologics?
The absolute purity of biologics is difficult to determine – the results are method dependent. Usually estimated by a combination of methods
45
Where does ICH Q8 get used?
It suggests the contents for 3.2.P.2 (pharmaceutical development) section of the regulatory submission (ref ICH M4)
46
What does ICH Q8 say about overages?
Overage of API to accommodate degradation or extend shelf life is discouraged. Need to justify what you do (expected manufacturing losses)
47
What are the sections of the drug product development section?
1. Components of the Drug product. 2. Drug Product 3. Manufacturing Process Development 4. Container Closure System 5. Microbiological Attributes 6. Compatibility
48
What is a Quality Target Product Profile (QTPP)
It forms the basis of the desigh for the development of the product (high level intended use, route of admin, dose form and strength, container closure, etc
49
What bits of NPI delivery does ICH Q8 mention
QTPP CQAs TRAs Design Space Control Strategy PLM and CI
50
What are the stages of a quality risk management process (ref ICH Q9)
Formal process. Risk Assessment – hazard identification, risk analysis and risk evaluation Risk Control – risk reduction and risk acceptance Output and communicate Risk Review
51
What are some examples of risk management tools (ICH Q9)
FMEA, FMECA, HAZOP,
52
What does ICH Q9 say about approaches to risk-based decision-making?
Structure and formality is scalable. Less structure when high existing knowledge
53
Wrt ICH Q10, what are the stages of the product lifecycle?
Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation
54
What are the aims of a PQS wrt ICH Q10 and how are they achieved?
Achieve product realisation Establish a state of control Facilitate continual improvement Enablers = Knowledge management and quality risk management
55
When product ownership changes, what should management consider (ICH Q10)
The complexity of the change ensuring a. The ongoing responsibilities are defined for each company involved b. The necessary information is transferred
56
What sort of things need to be managed during product discontinuation (ICH Q10)
Retention of documentation and samples Complaint handling and stability Reporting in line with regulatory requirements
57
What are the performance indicators described in ICH Q10?
1) Complaint, deviation, CAPA and change management processes 2) Feedback on outsourced activities 3) Self Assessment processes including risk assessments, trending and audits 4) External assessments e.g. regulatory and customer audits
58
What’s the aim of ICH Q12
It addresses the commercial phase of the product lifecycle (as described in ICH Q10); and it both complements and adds to the flexible regulatory approaches to post-approval CMC changes. It is also intended to demonstrate how increased product and process knowledge can contribute to a more precise and accurate understanding of which postapproval changes require a regulatory submission as well as the definition of the level of reporting categories for such changes
59
What is the status of ICH Q12
Implemented in US and Japan. In process of implementation in other major markets
60
What are ECs (ICH Q12)
EC’s = established conditions. CPPs = ECs
61
How do you change EC’s?
Post approval variation Or via a PACMP or via an approved post-approval regulatory commitment
62
What is a PACMP?
Post-Approval Change Management Protocol This is a system of stating what changes may be made during commercial life and how the change would be prepared and verified. Also defines whether it will just require notification or prior approval.
63
How is a PACMP submitted?
The PACMP may be submitted with the original MAA or subsequently as a standalone submission and can be proposed independent of any prior identification of ECs
64
WRT ICH Q12, if an element of CMC is not an EC, what is it?
Supportive information

QP - the reprise (16 decks)

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