1. Purpose
The purpose of this Procedure is to define the requirements for the retesting and assignment of storage periods for API’s, excipients, intermediates and raw materials.
2. Scope and Applicability
This Procedure is applicable to all API’s, excipients, intermediates and raw materials (herein after termed “materials”) used for manufacturing of formulated products and pure Active Pharmaceutical Ingredients.
3. Definitions
3.1 API (Active Pharmaceutical Ingredient)
Any substance or mixture of substances intended to be used in the manufacture of drug (medicinal) product that when used in the production of a drug becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body. Note: Also known as Bulk drug or Drug Substance.
3.2 Excipients
Any material that is used in the manufacture of a Formulated Product that excludes the active ingredient; an excipient may be used during processing but not be presenting the final formulation, e.g. Water.
3.3 Intermediate
Material produced during manufacture that undergoes further change or purification. Intermediates may or may not be isolated.
3.4 Retest Date
The date after which a material shall be re-examined to ensure that it is still suitable for use. The initial retest date is the date of manufacture plus the initial retest period.
Additional retest dates are calculated from adding appropriate retest periods to the dates of retesting.
3.5 Initial Retest Period
The period of time following manufacture / release testing that a material can be used prior to retesting and the setting of a new retest date, providing the material has been stored under appropriate conditions. For an API, this initial retest period will be registered.
Note: The initial retest period may also be known as the “life to retest”.
3.6 Retest Period
The period of time following analysis that a material can be used prior to further retesting, providing the material has been stored under appropriate conditions.
3.7 Retest
The physical or chemical analysis of a material against a defined testing protocol. The protocol shall consider the specification of the material, any stability indicating tests, plus any additional testing required to support an extension of life (such as microbiological analysis), which may not have been included in the primary specification.
3.8 Expiry Date
The date placed on the container/labels of an API designating the time during which the API is expected to remain within established shelf life specifications if stored under defined conditions, and after which it shall not be used.
Note: API’s may be registered with either a retest date or an expiry date.
3.9 Raw Material
A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or API’s.
3.10 Contractor
An external provider of a service (e.g. manufacturer and/or quality control, product, project or study according to company’s specified (e.g. via Technology Transfer) requirements.
3.11 Vendor
A supplier of materials.
3.12 Reprocessing
Introducing an intermediate or API, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (e.g. distillation, filtration, chromatography, milling) that are part of the established manufacturing process.
Continuation of a process step after an in-process control test has shown that the steps incomplete is considered to be part of the normal process, and not reprocessing.
3.13 Date of Manufacture (API)
The date of completion of the final purification step of the final API, excluding any subsequent physical manipulation steps such as blending, milling etc.
Note: Where an API is subject to a subsequent physical processing step such as blending or milling which involves one or more input batches, the Date of Manufacture applicable to the oldest input batch must be used.
Note: For reprocessed material, the Date of Manufacture is defined as the date of completion of the final purification step of the reprocessed material.
3.14 Date of Manufacture (Intermediate / Starting Material / Excipient)
The date of completion (isolation) of the final processing stage.
Note: For reprocessing, the Date of Manufacture is defined as the date of isolation of the reprocessed material.
4. Responsibilities
4.1 It is the responsibility of the manufacturing site to develop and implement local procedures that comply with this procedure.
4.2 It is the responsibility of each site to put in place procedures for the retesting of materials locally, and/or at certified contractors / vendors / other sites.
4.3 It is the responsibility of each site to ensure that all materials are stored under the correct conditions.
4.4 It is the responsibility of each site to ensure that this procedure is followed by their contractors / vendors.
4.5 It is the responsibility of each manufacturing site to develop and implement local purchasing, and stock management procedures so as to minimize the need for retesting.
5. Guideline
This procedure is based on taking a scientific approach and dealing with materials on an individual basis. All available information shall be gathered and evaluated to provide a sound basis for managing the use of a material beyond its initial retest period. Individual assessments shall be made and documented using the principles contained within this procedure as a framework. Where possible, retesting shall be kept to a minimum.
The procedure has been split into an API section and an excipients, intermediates, and raw materials section to provide clarity.
5.1 API’s
5.1.1 Retest Dating and Initial Retest Periods
Retest dating and the use of retest periods is the standard method of controlling the use of APIs. APIs shall have initial retest periods based on available stability data assigned in accordance with the tightest international product registration requirements. QA & Supply chain Group has responsibility for ensuring this data is included in the relevant documentation. Typically, for new chemical entity Instability studies will support an initial retest period of 12-36 months. The retest period can be formally extended over time using data generated from mature stability study programs.
This is preferable to the long term real-time retesting of material in stock. The retest date shall be calculated from the date of manufacture of the API. Once anapsid has reached its retest date, the API shall not be used until it has been retested, or the retest period extended.
A maximum initial retest period of 5 years shall be given to an API providing supporting stability data is available.
5.1.2 Retesting
Once an API has reached its retest date, it may be retested and a new retest period assigned. Retesting is undertaken on a sample taken from the material stock. The new retest period shall be assigned on the basis of: –
– Available stability data
– Retest data meeting specification / results comparison with previous analysis
– Available retest data from previous batches
– Avoidance of ‘1 batch testing’.
To assure continued suitability, and not rely on 1 batch QC testing, build up of stability profile for the API using extended stability studies. Where limited stability data is available, further supporting data can be obtained such as: –
– Analysis of samples from stock of several batches of similar age an evaluation comparing impurity levels and profiles with original results
– Evaluation of the effect of ageing on the physical parameters of the material.
– Consideration of the final usage form of the product.
– Consideration of the conditions the API has been stored in.
– Consideration of regulatory implications.
Consideration shall also be given to the use of stability indicating methodology. The rationale used to determine the retest period shall be documented. The new retest date shall be calculated from the retest period added to the date of completion of analysis.
It is recommended that retesting shall be conducted by the same laboratory that conducted the initial release testing.
Any extension to the retest dates shall be accompanied by appropriate extensions to the retention periods of batch records and reference samples.
No API shall be used beyond its retest date, until it has been verified that the Aimee’s the specifications and is satisfactory for use.
An API may be retested on more than one occasion. Where an API is retested with limited available additional supporting data, a maximum retest date of 3months from the date of completion of analysis shall be assigned. The rationale used to support this retest period shall be documented and shall include a review of the initial retest life for the material.
5.1.3 Use of API’s Greater than 5 years of Age
The approval of use of an API beyond 5 years shall be considered and evaluated on an individual basis. Beyond 5 years, due to the age of the material, the rationale shall be documented with a higher level of authority than the normal extension of use of anapsid. Section 5.1.2 above shall be applied.
When using API’s greater than 5 years in age, consideration shall be given to: –
* Formulating under experimental program to monitor the affect on manufacturability/material behaviour.
* Placing formulated product on stability.
5.1.4 Expiry Dating
An expiry date can be set instead of a retest date for an API if it is considered more appropriate to do so.
5.1.5 Reprocessing
The normal method of extending the use of an API is to extend its retest life VI retesting. For those API’s which have degraded or are considered inappropriate for further retesting, the material may be reprocessed and a new retest date assigned from the date of reprocessing.
API’s may only be reprocessed following a documented assessment which includes:
* A knowledge of the chemistry. This may include a user trial.
* A knowledge of the process capability to handle the “Out of Specification “component.
* A scientific rationale.
* Any appropriate process validation.
* A regulatory assessment.
If the API has failed specification prior to reprocessing, then an extensive justification of the reprocessing operation is required. Consideration shall be given to validation of the reprocessing operation.
5.1.6 Stability
Formal stability studies shall be conducted for API’s. Data from ongoing studies can be used to extend initial retest periods. Stability studies may be undertaken by the company itself or at a contractor, or a vendor as appropriate / registered.
5.1.7 Changes to Initial Retest Periods
Permanent extensions to assigned initial retest periods may be made where satisfactory evidence is available to support the changes. For an API such evidence is typically data from stability programs but may also include real-time testing of material in stock. Any change must be made via the change management system in order that it is subject to regulatory compliance and to ensure that all relevant documents and systems are updated.
5.2 Excipients, Intermediates and Raw Materials
5.2.1 Retest Dating and Initial Retest Periods
Retest dating and the use of retest periods is the standard method of controlling the use of these materials.
Excipients and Raw Materials shall be assigned an indicative initial retest period and retest date based upon available data on a case by case basis. The initial retest date shall be determined by: –
The retest date assigned by the vendor (either stamped on the container or indicated on the certificate of analysis), assuming storage conditions at the vendor are comparable with those at the receiving site, and that the company specification is comparable with the vendor’s specification. Where available, stability determined by the company or stability data provided by the vendor (where a retest date is not provided by the vendor on the label or on the Certificate of Analysis).
Examination (e.g. analysis, user trials, etc.) of samples from stock of several batches of similar age.
For intermediates a one-off stability study is typically used to determine the initial retest period.
The retest date shall be calculated from the date of manufacture of the material if available.
For raw materials and excipients where a date of manufacture is not available from the supplier, the date of testing or date of release on the Certificate of Analysis maybe used. For non-certified materials, the date of receipt at the site may also be used. Once any material has reached its retest date, the material shall not be used until the material is retested, or the retest period extended.
Over time, retest data from previous batches can be used to redefine the initial retest period.
5.2.2 Retesting
Once an excipient, intermediate, or raw material has reached its retest date, it may be retested and a new retest period assigned. Retesting is undertaken on a sample taken from the material stock.
As ongoing stability data is not typically available for these materials, the new retest period shall be assigned on the basis of:
* (Stability Data – if available)
* Retest data meeting specification / results comparison with previous analysis
* Available retest data from previous batches
The rationale used to determine the retest period shall be documented. If the retest period is extended on the basis of retest data from previous batches, consideration shall be given to the redefinition of the initial retest period.
The new retest date shall be calculated from the retest period added to the date of completion of analysis.
It is recommended that retesting shall be conducted by the same laboratory that conducted the initial release testing
No material shall be used beyond its retest date, until it has been verified that the material meets the specifications and is satisfactory for use.
Material may be retested on more than one occasion. Where a material is retested with no available additional supporting data, a maximum retest date of 3 months from the date of completion of analysis shall be assigned. The rationale used to support this retest period shall be documented.
5.2.3 Expiry Dating
An expiry date can be set instead of a retest date for a material if it is considered more appropriate to do so.
5.2.4 Reprocessing
Reprocessing is unlikely to be undertaken for excipients and raw materials but may occur for intermediates. For the reprocessing of these materials, the same process shall be used as that for API’s. See Section 5.1.5.
5.2.5 Stability
The stability of a material can be determined by either a formal stability study by the evaluation of the retesting data developed over years. Formal stability studies are not typically undertaken for excipients, intermediates or raw materials, although for intermediates a one-off stability study is typically undertaken to determine an initial retest period.
5.2.6 Changes to Initial Retest Periods
Permanent extensions to assigned initial retest periods may be made where satisfactory evidence is available to support the changes. Such evidence may include real time testing of material in stock, data from stability programs etc.
Any change must be made via the change management system in order that it is subject to regulatory compliance and to ensure that all relevant documents and systems are updated.