ICH Q11 – Definisjon av startmaterialer– Fleksibilitet og dokumentasjonskrav

Andreas Sundgren

LMI 17. april 2012

Definition of Starting Materials

Non-scientific approach:

• Justification based on complexity/non-complexity of starting materials.

• Justification based on commercial availability

• Focus on number of steps, less focus on the manufacturing process as a whole.

Definition of Starting Materials

Q11 – A scientific approach:

• A starting material should be a substance of defined chemical properties and structure.

• Steps that impact the impurity profile of the drug substance should normally be included in the manufacturing process

• Changes in material attributes or operating conditions that occur near the beginning of the manufacturing process have lower potential to impact the quality .

Starting Material

Active Substance

• No GMP requirements• No detailed

description• MA holder might have

limited access to documentation

• Limited change control

• GMP requirements• Detailed

documentation• MA holder has access

to relevant documentation

• Full change control

Definition of Starting Materials

Starting Material

Manufacturer

Starting material

Active substance

Starting Material Supplier

Starting Material

Manufacturer

IntermediateStarting Material

Manufacturer

Errors in communication

Not samedefined SM

Different quality control standards

Considers their processes confidential

Definition of Starting Materials

Formation of stereochemical center

All significant impurities from Step 4-6

A or D as Starting Material?

Definition of Starting Materials

D acceptable as Starting Material provided that:

• D can be fully identified from tests in the Starting Material specifications.

• Full control of all potential stereoisomers.

Definition of Starting Materials

Indicates that A should be defined as Starting Material

Stereochemistry controlled by the manufacturing process

A or D as Starting Material?

E, F etc

Identity not fully controlled by Specifications

Definition of Starting MaterialsSecond example:

Proposed SM

Concerns regarding (genotoxic) impurities in Step 4

Indicates that the proposed SM (E) should be redefined to D

Definition of Starting Materials

Proposed SMImpurities from the manufacture of D should be insignificant.

All significant impurities from Step 4-6

Information on the manufacturing process for D important?

Definition of Starting Materials

Commercial availability:

• Commodity in a pre-existing, non-pharmaceutical market

• Chemicals produced by custom synthesis are not considered to be commercially available

• If a justification is needed, it is most likely not commercially available

Definition of Starting Materials

Commercial availability:

• A compound that, based on the manufacturing process, is more expensive to produce by an in-house manufacturing process than to buy from a manufacturer using a “specialised” manufacturing process.

• Typically manufactured by well established processes

Definition of Starting Materials

Examples:

Purification

Starting Material Active Substance

”?” One step

R4

R1

R2

R3

CH3

R5

R1

R2

R3

CH3

Insufficient control of impurities

Stereochemistry based on SM man. process

Definition of Starting Materials

Examples:

Typical daily dose is 3g

SM

Latanoprost

O CH3

O CH3

OH

OH

OH

Necessity to include a large part of the manufacturing process within GMP?

Definition of Starting Materials

Examples:

BenzydamineSM

Definition of Starting Materials

Examples: N-nitrosoamine genotoxic?

BenzydamineSM

Indicates that the N-nitrosoamine and control of related impurities should be included in the manufacturing process.

N-nitrosoamine

Design Space & Documentation Requirements

Chapter 6, 7 & 8 in ICH Q11

Should be read in conjuction with Q8, Q9 & Q10

Guidelines discusses approach, not requirements.

Presentation by the ICH Quality Implementation Working Group:http://www.ich.org/uploads/media/Q-IWG_Web_Key_Messages.pdf

Design Space & Documentation Requirements

What is a design space?

• ”…the multidimensional combination and interaction of input varables and process parameters that have been demonstrated to provide assurance of quality.”

• Working within a design space is not considered as a change.

• The Guidelines applicable also to one or two dimensions, e.g. flexibility for one parameter?

Design Space & Documentation Requirements

What is a design space?

• Enhanced approach - Operational ranges for one or more process parameters (forms a Design Space.)

• Traditional approach – Set values for process parameters.

Design Space & Documentation Requirements

Traditional vs. Enhanced?

• …4 kg of NH4Cl is added to the reaction mixture…• …4-5 kg of NH4Cl is added to the reaction mixture…• …NH4Cl is added to the reaction mixture until a pH of

5-6 is obtained…

• …1-8 kg of NH4Cl is added to the reaction mixture…• …NH4Cl (8 kg MAX) is added to the reaction mixture…• …NH4Cl is added to the reaction mixture…

NH4Cl

Traditional?

Enhanced?

Design Space & Documentation Requirements

• The manufacturer / developer possesses much more knowledge and expertise on their own manufacturing processes than any external reviewer.

• The intention with the documentation is to convince any external reviewer that the quality control is sufficient.

• The process description should be still be reproducible.

Design Space & Documentation RequirementsICH Quality Implementation Working Group:

• Design Space need to be clearly presented and justified in regulatory submission

• Design Space need to be described in sufficient details in regulatory filing

• Description should include critical and non critical parameters to assure complete understanding

• Designation of criticality need to be justified in regulatory submission based on QRM and/or experimental results

Design Space & Documentation RequirementsICH Quality Implementation Working Group:

• Critical parameter ranges/model are considered a regulatory commitment and non-critical parameter ranges support the review of the filing

• Critical parameter changes within design space are handled by the Quality System and changes outside the design space need appropriate regulatory notification

• Non-critical parameters would be managed by Quality System

Design Space & Documentation Requirements

Identify Quality Attributes

Critical Quality Attributes?

Identify potentially Critical Process Parameters

Experimental data and/or scientific discussion

Critical Process Parameters?

Design Space & Documentation Requirements

R-enantiomer

Quality Attributes:• S-enantiomer

Potentially Critical Process parameters:• Solvent ratio• Temperature Critical?- Yes

Acceptable limit 0.3%

Design Space & Documentation Requirements

Process Parameter Critical Attribute

Solvent ratio Temperature S-enantiomer

1:3 20°C 0.13%

3:1 20°C 0.41%

1:3 60°C 0.11%

3:1 60°C 0.43%

Design of Experiments at laboratoty scale (10g):

Design Space & Documentation Requirements

Parameters Attribute

Solvent ratio S-enantiomer

1:3 0.13%

1:2 0.18%

1:1 0.25%

2:1 0.38%

Design of Experiments at laboratoty scale (10g):

10:30 10:20 10:10 20:100

0.1

0.2

0.3

0.4

Design Space & Documentation Requirements

Design of Experiments at laboratoty scale (10g):

Impu

rity

Con

tent

(%)

Solvent ratio

Design Space & Documentation Requirements

Parameter Operational Range Target Criticality

Solvent ratio 1:3 to 1:1 1:1 Critical Process Parameter

Temperature 20-60°C 25°C Non-Critical Process Parameter

Should also be included in S.2.2 Description of Manufacturing Process

Design Space & Documentation Requirements

Temperature

Sol

vent

ratio

pH

Second example: Design of Experiments for three process parameters

S-enantiomer above 0.3%

S-enantiomer below 0.3%

Design Space & Documentation Requirements

Temperature

Sol

vent

ratio

Second example: Design of Experiments for three process parameters

Below 0.3%

Above 0.3%

Operational boundaries should be included in section S.2.2 and could be presented as a;

• figure

• function

or

• range

Design Space & Documentation Requirements• Full Design of Experiments on laboratory scale (10 g?)

• Verification on larger scale comparable to commercial scale (100 kg?)– Suitable set of experiments– Equipment comparable to that used at commercial scale– Not necessary to challange the edge of failure

Design Space & Documentation RequirementsSummary of expectations from the documentation:

S.2.6 Manufacturing Process Development• Critical & non Critical Quality Attributes• Critical & non Critical Process Parameters• Based on experimental data unless justified on a rigid scientific

discussion• Verification on commercial scale

S.2.2 Description of Manufacturing Process• Criteria for process parameters clearly depicted• Specified scale and expected yields

Design Space & Documentation Requirements

Scope:In order to enhance the manufacturing process...

Present:10 kg of intermediate is dissolved in 100 L of water and 5 kg of reagent is added. The reaction is stirred at 50ºC for 30 minutes.

The reaction mixure is extracted with 3 ˟ 40 L of ethyl acetate…

Proposed:The intermediate from last step is dissolved in water followed by addition of reagent (Max. 10 kg). The reaction is stirred until completion.

The reaction mixure is extracted with ethyl acetate…

Type IB change in the manufacturing process

Wrong category

Most likely not acceptable

Design Space & Documentation Requirements

Design Space & Documentation Requirements

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