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QP - the reprise > ICH > Flashcards

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
Q

What’s a working cell bank

A

A pool of cells prepared from aliquots of a homogeneous suspension of cells obtained from culturing the MCB under defined culture conditions

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26
Q

With respect to ICH Q5, what information should be supplied to describe the expression construct

A

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
Q

What’s different when stability testing biologics cf small molecule?

A

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
Q

What’s the aim of ICH Q6

A

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
Q

Do the release and shelf-life acceptance criteria need to be the same (ICH Q6)?

A

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
Q

When might you replace disso testing with disintegration?

A

If immediate release and highly soluble. Need to have shown during DP development that have consistently rapid drug release.

31
Q

What’s the definition of a specification?

A

A list of tests and references to analytical procedures with appropriate a/c

32
Q

What specification tests are applicable to all drug substances?

A

Description

Identity

Assay

Imps

33
Q

What tests are applicable to all drug products?

A

Description

Identity

Assay

Imps

34
Q

What’s not allowed for an identity test

A

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
Q

wrt ICH Q6, What are the other DS tests that could be registered?

A

Physicochemical properties (pH, melting point, refractive index etc)

Particle size

Polymorphic tests

Water content

Inorganic imps

Microbial limit testing

36
Q

wrt ICH Q6, What tests are there for polymorphism?

A

Physicochemical tests – melting point, solid state IR, X-ray powder diffraction, thermal procedures (DSC), Ramen, optical microscopy, NMR

Chiral tests

37
Q

wrt ICH Q6, what are the potential tablet release tests

A

Disso,

Disintegration,

crushing strength,

friability,

UDU,

water content,

microbial limits

38
Q

wrt ICH Q6, what modifications to disso testing

A

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
Q

wrt ICH Q6, What are the potential liquid release tests?

A

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
Q

wrt ICH Q6, What are the potential liquid release tests?

A

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
Q

Wrt ICH Q6, how do you decide what tests to do

A

There are a number of flowcharts appended that take the form of a decision tree.

42
Q

What are the DS tests that form a specification for biologics?

A

Appearance and description

Identity

Purity and Imps

Potency

Quantity

43
Q

What are the DP tests that form a specification for biologics?

A

Appearance and description

Identity

Purity and Imps

Potency

Quantity

General tests (e.g. osmolarity / pH)

Any other additional tests needed

44
Q

What’s special about purity testing of biologics?

A

The absolute purity of biologics is difficult to determine – the results are method dependent.

Usually estimated by a combination of methods

45
Q

Where does ICH Q8 get used?

A

It suggests the contents for 3.2.P.2 (pharmaceutical development) section of the regulatory submission (ref ICH M4)

46
Q

What does ICH Q8 say about overages?

A

Overage of API to accommodate degradation or extend shelf life is discouraged.

Need to justify what you do (expected manufacturing losses)

47
Q

What are the sections of the drug product development section?

A
  1. Components of the Drug product.
  2. Drug Product
  3. Manufacturing Process Development
  4. Container Closure System
  5. Microbiological Attributes
  6. Compatibility
48
Q

What is a Quality Target Product Profile (QTPP)

A

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
Q

What bits of NPI delivery does ICH Q8 mention

A

QTPP

CQAs

TRAs

Design Space

Control Strategy

PLM and CI

50
Q

What are the stages of a quality risk management process (ref ICH Q9)

A

Formal process.

Risk Assessment – hazard identification, risk analysis and risk evaluation

Risk Control – risk reduction and risk acceptance

Output and communicate

Risk Review

51
Q

What are some examples of risk management tools (ICH Q9)

A

FMEA, FMECA, HAZOP,

52
Q

What does ICH Q9 say about approaches to risk-based decision-making?

A

Structure and formality is scalable. Less structure when high existing knowledge

53
Q

Wrt ICH Q10, what are the stages of the product lifecycle?

A

Pharmaceutical Development

Technology Transfer

Commercial Manufacturing

Product Discontinuation

54
Q

What are the aims of a PQS wrt ICH Q10 and how are they achieved?

A

Achieve product realisation

Establish a state of control

Facilitate continual improvement

Enablers =

Knowledge management and quality risk management

55
Q

When product ownership changes, what should management consider (ICH Q10)

A

The complexity of the change ensuring

a. The ongoing responsibilities are defined for each company involved
b. The necessary information is transferred

56
Q

What sort of things need to be managed during product discontinuation (ICH Q10)

A

Retention of documentation and samples

Complaint handling and stability

Reporting in line with regulatory requirements

57
Q

What are the performance indicators described in ICH Q10?

A

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
Q

What’s the aim of ICH Q12

A

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
Q

What is the status of ICH Q12

A

Implemented in US and Japan.

In process of implementation in other major markets

60
Q

What are ECs (ICH Q12)

A

EC’s = established conditions.

CPPs = ECs

61
Q

How do you change EC’s?

A

Post approval variation Or via a PACMP or via an approved post-approval regulatory commitment

62
Q

What is a PACMP?

A

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
Q

How is a PACMP submitted?

A

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
Q

WRT ICH Q12, if an element of CMC is not an EC, what is it?

A

Supportive information

QP - the reprise (15 decks)

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