Block 2: Lecture 4: Analytical Method Development and Stability Studies

What is an analytical method?

A prerequisite for all stages of drug product development activities. Begins approximately at preformulation up to commercial production.

Where is an analytical method required for?

• Preformulation data generation

• Identity determination

• Assay of API and drug product

• Impurity and degradation product testing

• Dissolution testing

• Acceptance criteria setting

• Stability studies and shelf life estimation

• Specification development

• Troubleshooting

Name 4 types of analytical tests in pharmaceutical development.

• Identification tests

• Quantitative tests for impurity content

• Limit tests for the control of impurities

• Quantitative tests of the active moiety in samples

What are validation characteristics of analytical methods?

• Accuracy

• Precision (e.g. repeatability)

• Specificity

• Detection Limit

• Quantification Limit

• Linearity

• Range

Sampling analytical methods

• Representative

• Container inertness

• Storage of sample

• Contaminants

• Sample matrix effects

• Separation and purification

Data interpretations analytical methods

• Correct statistics

• Operating parameters of instruments known and established

• Methods described in enough detail

• Reference values provided

• Computers and LIMS (laboratory information management system) systems properly validated

As what is a specification defined?

A specification is defined as a list of:

• tests

• references to analytical procedures, and

• appropriate acceptance criteria

"Conformance to specifications"

The drug substance and/or drug product, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

What is in the contents of specification?

• Description

• Identification

• Assay

• Uniformity of doses

• Drug availability

• Dissolution, disintegration (tablets and capsules)

• Particle size, droplet size (suspension, emulsions)

• Impurities

• Microbiological control (sterility, microorganisms)

Stability

The ability of a product to remain in compliance with its established specification to be the same as it was produced (identity, strength, quality, purity) and to deliver active ingredients at an effective level specified during shelf-life.

Shelf-life

The period of time during which a product remains in compliance with its specification stored under the conditions of the market (period of use and storage).

Expiration date

The period of time printed on the container/package indicating the limit time

allowed to be consumed, since the product remains in compliance with its established specification.

Stability studies

• An integral part of the drug development process

• Take long time to conduct

• Hence very often on the critical path of a drug development project

• High visibility within the R&D department

What information do stability studies provide?

Provide evidence on how the quality varies with time:

• Under influence of a variety of environmental factors

• To establish a shelf life for the drug product and recommended storage conditions.

• Carried out on drug substances, drug products, new dosage forms.

What are the steps involved in the design of a stability study?

• Selection of batches

• Selection of container closure system

• Test procedures and criteria

• Specification

• Testing frequency

• Storage and test condition

• Data evaluation

• Shelf life and expiration date setting

How do you select stability batches?

• Three primary batches of the drug product

• Two should be at least pilot scale batches

• Same formulation as proposed for marketing

• Manufacturing process simulate that to be applied to production batches

• The same quality and meeting the same specification as that intended for marketing

• Drug products should be manufactured by using different batches of the drug substance.

What are 3 testing procedures for the formulation?

• Testing attributes that are likely to change during storage and influence quality, safety, and/or efficacy.

• Analytical procedures validated and stability indicating

• Shelf life derived from consideration of all available stability information

How many times should the product be tested?

For products with a proposed shelf life of at least 12 months,

• Every 3 months over the first year

• Every 6 months over the second year

• And annually thereafter through the proposed shelf life

At the accelerated storage condition

• A minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended.

The long term testing should cover a minimum of 12 months at the time of submission and should cover the proposed shelf life.

Under which storage conditions should a drug product be evaluated?

• That will test its thermal stability

• And if relevant its sensitivity to humidity, light, oxygen

What should the storage conditions and the length ot the studies cover?

Storage, shipment, and subsequent use.

What should you do if long-term studies are conducted and “significant change” occurs at any time during 6 months’ testing at the accelerated storage condition?

• Intermediate storage condition should be applied and evaluated

• The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition.

What is an example of an approach for an evaluation of stability data?

To determine the time at which the 95 one-sided confidence limit for the mean curve intersects the acceptance criterion.

To what extend can the proposed shelf life be extrapolated?

Up to twice the time. It should not be extrapolated more than 12 months beyond the period covered by long-term data.

What should be established for the labeling?

A storage statement should be established for the labeling in accordance with relevant national/regional requirements.

What can be indicated on the label?

One of the following recommendations as to storage conditions can be prominently indicated on the label.

• Store under normal storage conditions

• Store between 2 and 8oC (under refrigeration, no freezing);

• Store below 8 oC (under refrigeration);

• Store between -5 and -20oC (in a freezer);

• Store below -18oC (in a deep freezer)

What are 3 components of process development?

• Technology transfer

• Scale up

• Control strategy

What is a batch?

A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture.

What is and how can you scale-up?

• The process of increasing the batch size.

• From laboratory to pilot scale.

• From pilot scale to production scale.

Pilot Scale

The manufacture of either drug substance or drug product by a procedure fully representative of and simulating that used for full manufacturing scale. For solid oral dosage forms this is generally taken to be, at a minimum, one-tenth that of full production, or 100,000 tablets or capsules, whichever is larger.

A control strategy

A planned set of controls derived from current product and process understanding assures process performance and product quality.

Validation

Documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its pre-determined specifications and quality attributes.

What is the aim of process validation?

• Should establish that quality attributes and process parameters can be consistently met by the process.

• Same batch size as the intended commercial scale batches.

• A minimum of three (3) consecutive batches.

• A process validation protocol and report should be prepared.

What are 3 change control principles?

• Each change requires a review and authorization to keep the system in its original state of “proven suitability”.

• Formal change control guarantees that all changes are evaluated for their effect on product quality or validation status.

• Change control minimizes the risk that changes can have on the quality or process characteristics.