1. Purpose
The purpose of this guideline is to describe the requirements for the sampling and storage of reference and retention samples under GMP regulations/legislation. Local regulatory requirements that require the retention of additional samples, increased sample quantities or longer retention periods, take precedence over this guideline.
2. Scope and Applicability
This guideline covers GMP samples of Active Pharmaceutical Ingredients (API’s) Raw Materials, Excipients, Intermediates, Bulk Investigational Medicinal Products (Bulk IMP), Packaging Materials and Drug Delivery Systems, and Packaged Investigational Medicinal Products (Packaged IMP) including comparators, related to Clinical Trials. Medical Devices are not included within the scope of this document. Bio-equivalence/bio-availability samples and method validation samples are included within this guideline. Samples are retained to fulfill several purposes; to provide a sample for analytical testing, in order to help investigate deviations/complaints as needed, to provide a sample to the Competent Authority if requested. This guideline applies to all manufacturing and R&D sites and should be applied to contractors sites when working on behalf of the sponsor company.
3. Definitions
3.1 Active Pharmaceutical Ingredient (API)
Any substance or mixture of substances intended to be used in the manufacture of a 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.
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 present in 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 Packaging Material
Any material employed in the packaging of an API, intermediate or formulated product, excluding any packaging material used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.
3.5 Raw Materials
Ingredients, excluding drug substance, which make up the pharmaceutical product. Includes Excipients
3.6 Bio-availability (BA)
This term means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
3.7 Bio-equivalent (BE) drug products
This term describes pharmaceutically equivalent products that display comparable bioavailability when studied under similar experimental conditions.
3.8 Bulk Investigational Medicinal Product (Bulk IMP)
A finished dosage form, for example tablet, capsule, solution, suppository that contains an API usually, but not necessarily, in association with inactive ingredients. It also includes a finished dosage form used as a placebo and modified comparators.
3.9 Comparator
An investigational product used as a reference in a clinical study.
3.10 Container Closure System (CCS)
The sum of packaging components that together contain and protect the active substance or the dosage form. This includes immediate packaging components and secondary packaging components, if the latter are intended to provide additional protection to the active substance or to the drug product.
3.11 Diluents
Diluting agents (vehicles and carriers) are indifferent substances that are used as solvents in the administration of medicinal products.
3.12 Drug Delivery System
An instrument, apparatus or appliance used in combination with a drug product, where the primary pack provides delivery of the drug product.
3.13 Packaged Investigational Medicinal Product (Packaged IMP)
A formulated product which has undergone all stages of production including packaging in its final container.
3.14 Pivotal Bioequivalence Study
A study conducted to demonstrate bio-equivalence between the clinical trial formulation on which substantial evidence of safety and effectiveness has been generated and the proposed sales formulation to support an NDA/MAA.
3.15 Reference sample (Reserve sample)
A sample of a batch of API, excipients, packaging material, or bulk or packaged IMP which is stored for the purpose of being analyzed should the need arise during the shelf life of the batch concerned. The reference sample shall be stored in the same container closure system in which the product is packaged or shipped, or in one that has essentially the same characteristics, (i.e. mimics the container- closure system). The IMP reference sample may be taken after manufacturing or after primary or secondary packaging.
3.16 Reference standard for BE Studies
The drug product against which the test article is being tested. This is either, (1) the drug product that was used in the clinical studies demonstrating substantial evidence of safety and effectiveness for the test article’s claimed indication, or (2) the marketed product in the case where the test article is being compared to the originator/reference product to establish bio-equivalence.
3.17 Retention sample
A sample of a unit from a batch of packaged IMP. It is typically trial specific and stored for visual identification purposes should the need arise during the shelf life of the batch concerned. This sample can be a physical specimen or an electronic file or photograph based on local legislative and regulatory requirements, and may only be required once per trial. 3.18 Test Article for BE Studies The drug product for which a company is seeking NDA/MAA approval or supplemental application, e.g. the proposed sales formulation.
4. Responsibilities
It is the responsibility of each site to have procedures in place which comply with this guideline and with local legislative or regulatory requirements where they are different. The responsibility for the retention of all reference samples lies with the site responsible for analyzing and releasing the materials.
This guideline serves as the agreement between sister sites for the retention of API, unless otherwise agreed in a Quality Assurance Agreement (QAA). It is the responsibility of each site to ensure that contractors have procedures in place to comply with this procedure and local legislative or regulatory requirements where they are different.
These responsibilities must be clearly stated in the relevant QAA between sites and the contractor. The Qualified Person in the EU or Quality Assurance in the US who releases a batch should ensure that all relevant reference and retention samples have been taken. They should also ensure together with the line function that the samples are accessible at all reasonable time to regulatory authorities and the sites, including those held by a contractor.
Reference and retention sample requirements should be clearly stated in the relevant QAA between R&D and Operation sites.
5. Guideline
5.1 General Points
Reference samples of each batch of API, excipient, packaging material and bulk IMP must be retained. The holding of reference samples is for the purpose of potential future evaluation of the quality of batches, and not for future stability testing. Reference samples are for the purpose of analysis, and should be conveniently available to a laboratory with validated methodology. It is expected that all necessary analytical materials and equipment are available, or are readily obtainable, in order to carry out all tests in the specification during the retention period (See Appendix A).
Reference samples are also available for identification purposes. There is no requirement to retain reference samples of both bulk IMP and packaged IMP if they are packaged in the same CCS. For oral solid dosage forms, bulk IMP reference samples should be collected in standard walled HDPE bottles. Additional samples are only required when packaged the first time in a different CCS.
For dosage forms other than oral solids, samples must be pulled for each CCS. Reference samples that need to be placed in foil pouches or similar enclosures to assure sterility, protection from moisture, etc., must be retained in that enclosure.
There is no mandatory requirement to take retention samples (as a physical specimen), when accurately documented robust processes supported by e.g. bar code technology are in place to provide assurance of segregation of products and labels.
5.2 Reference Samples
If a reference sample is taken after the secondary packaging of a IMP, the sample can serve as both a reference and retention sample provided an adequate sample quantity is pulled.
5.2.1 Raw Materials, Excipients, API’s, Intermediates, and Formulated Products (Bulk IMP)
The reference sample for excipients, API’s and bulk IMP should consist of at least twice the quantity necessary for all analytical tests required to determine its compliance with specification, except for sterility and pyrogen testing; where the quantity required to repeat these tests only once should be retained. These samples should be retained as described in Appendix A. There is no requirement to retain raw materials or intermediates. Reference samples need not be taken for excipients such as water, gases or other materials that are highly corrosive or very inflammable unless stated specifically.
5.2.2 Packaged IMP
A packaged IMP reference sample is not mandatory if a bulk IMP reference sample has been pulled in the same CCS, unless required by local regulations. The reference sample should be contained in its primary packaging or in the CCS composed of the same material as the primary container in which the product is distributed.
5.2.3 Comparators and Diluents
Samples of comparators are only required if the comparator is physically manipulated or packaged in an alternative container/closure system. Sampling requirements are per 5.2.1 for bulk IMP. Samples of diluents are only required if they are physically manipulated.
5.2.4 Packaging Material
Reference samples need to be taken from primary and printed packaging materials, unless retained as packaged IMP. Any overprinting, such as batch /lot and expiry date should be included as part of the reference sample. This can be included as a sample retained in the associated packaging documentation.
5.2.5 Storage
Reference samples should be retained and stored under conditions consistent with the product labeling and SLIFE. Reference samples should be securely stored in facilities where the storage conditions are monitored, and segregated from other materials. Samples should be stored in the orientation directed on labeled product.
5.2.6 Location of Samples
Reference samples from batches should be stored at the site of analysis / release. Reference samples from batches manufactured by a third party may be stored at the site of analysis or the site of release. Reference and retention samples should be stored at the premises of a manufacturer authorized to store samples in order to permit ready access by the Competent Authority.
These samples should be taken in accordance with a written agreement between the manufacturing site and importing and/or site of release. The Qualified Person or R&D GMP Quality Assurance in the US releasing the batch should satisfy himself/herself that the arrangements and responsibilities for their storage and access are adequate.
Each packaging site should keep a reference sample of each batch of primary packaging materials, unless the primary packaging material is supplied from a sister Operations.
5.2.7 Inventory List and Sample Transactions
An inventory list of every stored sample should be kept. All sample transactions should be recorded. Samples should be destroyed at the end of their appropriate retention period. A record of the disposal should be retained.
5.2.8 Labeling
All reference samples shall be unambiguously identified with name, code number, control or batch/lot number as well as with sampling date and expiry date if appropriate.
5.3 Retention Samples
Retention samples are examples of packaged IMP and should be retained per Appendix B. The sample can be a physical specimen or an electronic file or photograph based on local legislative and regulatory requirements.
This may be done at the master level with subsequent checks during each packaging or during the first packaging. It is recommended to keep a retention sample of comparator packages which have been over-labeled by a third party prior to receipt by the company.
5.4 Bio-availability and Bio-equivalence
Samples Reference samples of the test and reference articles administered to study subjects are mandatory for pivotal BA and BE studies. These samples may be analyzed to ensure that the BA/BE results upon which regulatory approval of marketing applications are reliable. These samples may be requisitioned by Regulatory Agencies for independent testing to confirm the identity of each article.
Samples should be kept at the testing facility where the study is conducted or at an approved contractor site. The study sponsor should provide the testing facility with a supply of the test article and the reference standard sufficient to complete the study and retain the appropriate number of dosage units as reference samples.
The study sponsor should not separate out the samples to be reserved prior to sending the batches to the testing facility. The testing facility will randomly select the Reference samples from the supply sent by the sponsor. This is to ensure that Reference samples are in fact representative of the same batches provided by the study sponsor for the testing. In general, the testing facility should retain enough quantify to permit regulatory authorities to perform five times all of the release tests required in the application.
To reduce risk, it is recommended that an additional sample of the same size should be maintained by the sponsor. These materials will be retained for testing by the company if necessary, to confirm the FDA test results under conditions specified by the labeling.
5.5 Reference Samples From Batches Used in Analytical Method Bio-batch Validation (For US NDA only)
Retain 4 X samples of the API and drug product proposed for marketing, each sufficient to permit performance of three times each test described in the sponsor’s application until one year after a successful pre-approval inspection.
5.6 Reference and Retention Samples in the Case of Closedown of a Manufacturer
Where a contractor or company sister manufacturing site closes down and the Investigational Medicinal Products (IMP) Manufacturing Authorization is surrendered, revoked, or ceases to exist, it is probable that many unexpired batches of IMP manufactured by that manufacturer will still be in use in clinical trials.
In order for those batches to continue to be used in clinical trials, the manufacturer, in collaboration with the CTA or IND holder should make detailed arrangements for transfer of reference and retention samples (and relevant GMP documentation) to an authorized storage site.
The CTA/IND holder should, in relation to the suitability of the proposed arrangements for storage of reference and retention samples, consult with the competent authorities of each country, as appropriate, in which any unexpired batch has been placed on the market.
6.1 Appendix A Reference Samples
6.2 Appendix B Retention Samples