1. Purpose
The purpose of this procedure is to describe the minimum requirements for the retention of samples and documents under GMP and Medical Device regulations/legislation. Local legislative and regulatory requirements which may require retention of increased sample quantities or longer retention periods, take precedence over this procedure.
2. Scope and Applicability
This procedure covers GMP and Medical Device documentation and Reference/Reservesamples for Active Pharmaceutical Ingredients (API’s), Intermediates, Formulated Products,Starting Materials, Packaging Materials and Finished Products.
(Note: No reference/reservesamples of Medical Devices are required)
This procedure does not include GMP documentation and Reference/Reserve samples relatedto Clinical Trials.
3. Definitions
3.1 GMP Documentation
GMP documentation is any procedure, control, record, distribution or related record, or electronic file that is required to be retained as evidence of compliance with GMP.
3.2 Medical Device
Any instrument, appliance, material or other article, whether used alone or in combination, including the software necessary for its proper application, intended by the manufacturer to be used for human beings for the purposes of diagnosis, prevention, monitoring, treatment or alleviation of disease.
3.3 Medical Device Documentation
Medical Device Documentation is any procedure, control record, distribution or related record, or electronic file that is required to be retained as evidence of compliance to Medical Device Legislation.
3.4 Reference Sample
Is the term used in the GMP of the European Community for samples taken for retention.
3.5 Reserve Samples
Is the corresponding term to reference samples used in the FDA GMP.
3.6 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 effect the structure and function of the body.
3.7 Intermediate
A material produced during steps of the processing of an API which must undergo further molecular change or purification before it becomes an API.
3.8 Starting Material.
Any material used in the production of an API, intermediate or a formulated product, but excluding packaging material. Starting material can be further defined as follows:
Excipient – material used in the production of a formulated product (excluding APIs)
Raw Material – material used in the production of an API or Intermediate. A raw material may be further classified as either a CRM (Contributory Raw Material) or an NCRM (Non contributory raw material) dependant on it’s role in the synthesis
3.9 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.
3.10 Formulated Product
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.
3.11 Finished Product
A formulated product which has undergone all stages of production including packaging in its final container.
4. Responsibilities
4.1 It is the responsibility of each manufacturing site to have procedures in place which comply with local legislative or regulatory requirements.
4.2 It is the responsibility of the lead site to ensure that contractors have procedures in place to comply with local legislative or regulatory requirements where they are different.
These responsibilities shall be clearly stated in the relevant Quality Assurance Agreement (QAA) where one exists.
4.3 The responsibility for the retention of the GMP and Medical Device documentation and Reference/Reserve samples for API’s, Intermediates, Starting Materials and Packaging Materials lies with the company or site responsible for releasing the materials.
4.4 For the Formulated Product the responsibility lies with the company or site responsible for the packaging into primary packaging material, unless otherwise agreed in the Quality Assurance Agreement (QAA).
4.5 For the Finished Product the responsibility lies with the company or site responsible for the packaging into secondary packaging material and for the release to the local market or international markets.
5. Guideline
5.1 GMP and Medical Device Documentation
5.1.1 GMP and Medical Device documentation shall be retained by functions given this responsibility and retained GMP documents shall not be accessible by unauthorized people.
5.1.2 GMP documentation should be readily available for inspection by regulatory authorities and internal audits.
5.1.3 In the case of facility closure/termination of a 3rd party contractual agreement, arrangements must be made for the secure storage and retention of all GMP relevant documentation in accordance with the requirements in Appendix 1.1
5.2 Electronic Data
5.2.1 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use shall be in place and the accuracy and accessibility of Data shall be checked. Electronic data shall be readily retrievable into a written document.
5.3 Retention Period for GMP Documentation
5.4 Retention Period for Medical Device Documentation
5.5 Reference/Reserve Samples
5.5.1 Raw Materials, Excipients, API’s, Intermediates, Formulated Products and Finished Products.
The Reference/Reserve sample shall consist of at least twice the quantity necessary for all tests required to determine its compliance with specification, except for sterility and pyrogen testing; where the quantity required to repeat these tests only once shall be retained.
The Reference/Reserve sample shall be retained and stored under conditions consistent with the product labeling and/or specification requirements.
In the case that there are no conditions given on the label and/or in the specification the samples shall be stored in controlled room temperature.
The Reference/Reserve sample shall be stored in the same primary container enclosure system in which the product is marketed or shipped, or in one that has essentially the same characteristics, (i.e. mimics the container-closure system); it is acceptable to use smaller packs.
Reference/reserve samples of APIs shall be retained as described in the Appendix 1.3.
Reference/reserve samples need not be taken for intermediates. However, intermediate samples are typically taken and retained until stock is consumed and API released.
Reference/reserve samples need not be taken from Raw Materials. However, individual sites may take the decision to keep some materials for investigative purposes. Typically this will be the case for New Product Introduction/Technology Transfer materials or changes in suppliers. Consideration should be given to the criticality of the material in the production process.
Reference/Reserve samples need not to be taken from water, gases or starting materials that are highly corrosive or very inflammable unless stated specifically.
Reference/Reserve samples should be retained in accordance with the retention stated in Appendix 1.2, if the stability of the product permits.
For product marketed in the USA or starting material used for USA marketed product, as a minimum, representative sample lots or batches of Finished Products shall be selected by acceptable statistical procedures. The samples for Finished Products should be examined visually at least once a year for evidence of deterioration unless visual examination could affect the integrity of the samples. The results of the examination should be documented and maintained with other stability data on the Finished Product.
5.5.2 Packaging Material
Reference/Reserve Samples need only be taken from primary and printed packaging materials. For printed and primary packaging material one unit must be retained, unless retained as Finished Product. Any overprinting such as batch code and/or expiry date must be included. This can be included as a sample retained in the associated packaging documentation.
5.6 Sampling
Reference/Reserve Samples shall be taken by personnel and by methods approved by Quality Assurance/Quality Control. The samples should be representatives of the materials from which they are taken.
5.7 Labelling
All Reference/Reserve 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.
5.8 Requirements for the Storage of Reference/Reserve Samples
5.8.1 Storage
Reference/Reserve Samples should be securely stored in accordance with their label require and segregated from other materials. The conditions in the store area must be supervised and recorded.
5.8.2 Responsibility
The storage area shall be supervised by appointed responsible person(s) from the Quality Assurance/Quality Control organization.
5.8.3 Access
Access shall be restricted to authorized personnel only
5.8.4 Release from Store
Whenever a Reference/Reserve sample is required for repeated testing, etc. it can only be released from the store following a written order approved by an authorized person, e.g. the Head of Quality Assurance/Quality Control.
5.8.5 Inventory
An inventory list of every stored sample shall be kept. Any released and discarded sample shall be recorded
5.9 Retention Period for Reference/Reserve Samples
See Appendix 1.3.
5.9.1 Extension of Storage Period
For materials which have been retested and granted a further retest period consideration must be given to assuring the appropriate extension to the storage period of the retained samples and documentation.
5.10 Disaster Plan
Detailed procedures shall be in place describing measures in place to safeguard the archived documents and samples from damage or loss caused by environmental conditions, accident, fire and flood etc and their salvage in the event of such a disaster.
5.11 Disposal of Documentation and Samples
Documents and samples should be destroyed at the end of their appropriate retention period.
Disposal of samples must be in accordance with relevant Environmental, Health and Safety principles. A record of the disposal should be retained. Documents must be disposed of by shredding or incineration.
In the event of a third party contractor being used to dispose of documents and/or samples, this contractor’s activities should have been inspected by authorized QA personnel in order to determine suitability and to ensure that systems are in place to ensure that confidential information/proprietary material is adequately safeguarded before, during and after disposal.
6. Appendix
A2 Medical Device Documentation
Notes
A. “Expiry life” is the time during which the API, Intermediate, Formulated Product or
Finished Product is expected to remain within the established shelf life specifications
if stored under defined conditions.
B. “Retest Date” is the date after which material should be re-examined to ensure that it is still suitable for use. Material can be retested and assigned an additional retest period, at this point consideration should be given to the extension of the storage period for samples and documentation as required
C. For the purpose of this procedure “indefinite” means 30 years.
D. “Full change history” means that any amendments, corrections or deletions can be created from the change history. The other option is to retain each Original Copy as it is superseded by subsequent versions.
E. This list is not intended to be exhaustive.
F. When changes to processes, e.g. cleaning, manufacturing or analytical methodology, occur, and revalidation is required, superseded copies of validation reports shall be retained indefinitely.
G. Retention of Formulated Product samples is only necessary for those sites which release the product as bulk and do not have the finished product on site. In the case of a site having Bulk Formulated Product and Finished Product, only Finished Product needs to be retained.
H. Retention period for Samples of Excipients could also be calculated as “Shelf life + one year or at least five years after the release of the Formulated Product which it was last used in”.