Introduction
This Guidance sets out guidelines for the determination and validation of in-process and bulk product holding times.
Maximum allowable hold times should be established for bulk and in-process drug products (where applicable).
Typically one lot can be used for validating hold times. Data to justify the hold time can be collected during development on pilot scale batches, during process validation, via a historical review of batch data, or as part of a deviation with proper testing.
Recommendations & Rationale for Recommendations
Although there are no specific regulations or guidance documents on bulk product holding times, good manufacturing practice dictates that holding times should be validated to ensure that in-process and bulk product can be held, pending the next processing step, without any adverse effect to the quality of the material. This practice is supported by indirect references made to determining holding times in various FDA guidance documents, FDA regulations as follows:
“If a firm plans to hold bulk drug products in storage…..stability data should be provided to demonstrate that extended storage in the described containers does not adversely affect the dosage form” .
“Stability data also may be necessary when the finished dosage form is stored in interim containers prior to filling into the marketed package. If the dosage form is stored in bulk containers for over 30 days, real-time stability data under specified conditions should be generated to demonstrate comparable stability to the dosage form in the marketed package. Interim storage of the dosage form in bulk containers should generally not exceed six months” .
“When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product.”
This regulation could be interpreted to include the time for holding bulk product as part of the production process. “holding times (includes storage times) studies may be conducted during development or carried out in conjunction with process validation lots and shall be representative of full scale holding conditions” .
Holding time data may be generated in the following situations:
Bulk holding studies may be conducted on product developmental pilot scale batches to demonstrate comparable stability to the dosage form in the marketed package.
Holding data may be generated as part of a process validation study. Data can be collected on the bulk product itself after holding or collected after the held product has been packaged.
For current marketed products, a historical review of product lot release and stability data may be used to substantiate hold times if hold times were not established as part of validation. The longest hold time used for the lots reviewed will become the validated hold time.
In rare cases where normal production batches are held in bulk for periods longer than the standard hold times, due to a delay in initiation of the next stage of processing or packaging, data may be generated to support the extended holding time as part of the deviation investigation.
If the bulk dosage form is shipped in bulk containers prior to final packaging, a simulated study may be conducted to demonstrate that adverse shipping and/or climatic conditions do not affect its stability.
In-process and bulk hold times used in manufacturing should be stipulated in a site SOP or master batch record and should be qualified by supportive data. A holding study should be based on the maximum time the material is expected to be held. Examples of materials that should undergo such holding time studies are:
In-Process Product:
- Granulations
- Granulation solutions
- Dry powder blends
- Tablet cores (prior to coating)
- Coating solutions or suspensions
- Extended-release beads or pellets
Bulk product:
- Bulk tablets (prior to packaging)
- Bulk capsules (prior to packaging)
- Bulk liquid solutions, suspensions and semi-solids (prior to packaging)
Bulk holding studies should be conducted in accordance with an approved validation protocol. Protocols should be executed, test data reviewed, and reports written to ensure that the validation objectives are met.
The product bracketing or matrixing approach may be used to group products with same/similar formulations or combination strength products. For multiple strengths of the same formula, use of lots with the highest and lowest dosage only may be justified for the study. Reasons for excluding a product from a bulk holding study should be justified. Typically, one lot is recommended for bulk holding studies.
Where pilot batches and/or aliquots of in-process or bulk product are used for simulated bulk holding studies, product should be held in containers fabricated of the same or equivalent materials, e.g. AISI 304/316 grade stainless steel, to those used in normal production. The material specifications of the bulk container and closure system (e.g. stainless steel, fiber/PVC drums, LDPE liners, desiccants etc) to be used should be included in the protocol. Representative portions of bulk/in-process material should be stored in these containers to represent normal storage scenarios (e.g. % head space) where feasible. Bulk holding study containers should be stored under similar environmental conditions that are normally experienced in routine operations.
Samples only need to be taken initially (time zero) and at the end of the hold time study. However an intermediate time point is recommended to ensure that data will support a shorter hold time if the end point fails. Intermediate time point sampling should not be performed when exposure to environmental conditions could compromise product.
Testing should include visual, physical, chemical and microbiological analysis, where appropriate. Initial testing of product should use lot release test methods. In-process or bulk release acceptance criteria should be applied to the sample testing. Hold times should be confirmed on completion of the trials. Holding times are considered validated if all physical, chemical and microbial tests are within acceptance criteria at the end of the holding study.
In 21 CFR 211.111, Time limitations on production, it states “Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product.” Upon deviation from the validated hold time, it is acceptable to increase the hold time if substantiated with data that the quality was not impacted. This may require that the lot be placed on stability. Increasing hold times in this manner should be the exception and not standard practice.
A summary report should be issued with an evaluation of the holding time data together with recommended hold time limits to be used in Production. Quality Assurance should review and approve the recommended hold time. It is recommended that current bulk hold studies should be reviewed as part of the annual product review process. Bulk holding studies should be completed according to the following guide.
1) Holding time considerations for Granulations and Powder Blends.
Typically, in-process products such as dried and sized granulations and blends may be held for up to 30 days from their date of production without being retested prior to use. An in-process product that is held for longer than 30 days should be monitored for stability under controlled, long-term storage conditions for the length of the holding period. A representative portion of the granulation/powder blend should be held for the defined hold periods. At the test points, samples should be taken from the storage container and tested. Typically top samples are normally taken from a container. Multiple samples should be taken at each time point if holding can impact product uniformity. Results obtained should be compared with the initial baseline data of the granulation/powder blend control sample results.
Typical tests include the following: Assay; Appearance; Degradation products (where applicable); and moisture content. Where powder blends might have the potential to segregate, consideration should be given to evaluating blend uniformity, particle size, and bulk/tapped density.
2) Holding time considerations for Granulation Solutions, Coating Solutions or Coating Suspensions.
Typically, if these in-process products are used within 24 hours of manufacturing, no bulk holding time studies are deemed necessary. An in-process product that is held for longer than 24 hours should be monitored for physical characteristics and microbial contamination. A solution/suspension should be held for the defined hold period. At the test points, a sample should betaken from the storage container and tested. Results obtained should be compared with the initial baseline data of the solution/suspension control sample results.
Typical tests include the following: Microbial count; Yeast/Mould count; Specific Gravity; and Viscosity.
3) Holding time considerations for Tablet Cores, Extended-Release Beads or Pellets.
Typically, in-process products such as cores, extended-release beads or pellets may be held for up to 30 days from their date of production without being retested prior to use. An in-process product that is held for longer than 30 days should be monitored for stability under controlled, long-term storage conditions for the length of the holding period. A representative portion of the core/bead/pellet should be held for the defined hold period. At the test points, a sample should be taken from the storage container and tested. Results obtained should be compared with the initial baseline data of the core/bead/pellet control sample results.
Typical tests include the following: Hardness; Friability; Appearance; Dissolution/Disintegration; Assay; Degradation Products (where applicable); and Moisture Content.
4) Holding time considerations for Bulk Tablets and Capsules.
Typically, bulk tablets and capsules may be held for up to 30 days from their date of production without being retested prior to use. A bulk product that is held for longer than 30 days should be monitored for stability under controlled, long-term storage conditions for the length of the holding period. Interim storage of the dosage form in bulk containers should generally not exceed six months. At the test points, a sample should be taken from the storage container and tested. Results obtained should be compared with the initial baseline data of the tablet/capsule control sample results.
Typical tests include the following: Hardness; Friability; Appearance; Dissolution (in the case of controlled and extended release products, the establishment of a dissolution profile is recommended); Disintegration; Assay; Degradation Products (where applicable); Moisture Content, and microcount (where applicable).
5) Holding time considerations for Oral Liquids and Semi-Solids (Suspensions, Creams, and Ointments).
Typically, liquid and semi-solid dosage form products should be held for no more than 5 days without a hold time study. Full scale batches should be used for these studies. Samples should be taken from the holding vessel after transfer from the manufacturing vessel, and again at the completion of the holding period. Multiple samples should be taken at each time point if holding can impact product uniformity.
Samples would be taken to prove that product uniformity of actives and preservatives is maintained and that there are no microbiological concerns throughout the holding period. At the test points, samples should be taken from the storage container and tested. Results obtained should be compared with the initial baseline data of the product control sample results.
Typical tests include the following: Active ingredient assay (for bulk uniformity); Preservative; Appearance; Degradation products (where applicable); Microbial count; Yeast/Mould count; pH; Specific Gravity; and Viscosity.
Bulk Product – is that bulk drug product that is stored in bulk containers under manufacturing or warehouse conditions prior to primary packaging.
Bulk Product Hold Time –
1) the elapsed time period from the completion of the last manufacturing step to the start of packaging of the finished product in the primary package. OR
2) the amount of time that bulk drug product is allowed to remain in the bulk container between manufacturing and primary packaging.
Completion of Manufacturing – the time at the completion of the last step of the manufacturing process when the bulk is submitted for Quality Control lot release testing.
Hold Time Study – the collection of data on the stability of a material when stored in bulk containers which are not finished package configurations, and stored under manufacturing or warehouse conditions which may or may not be at ICH conditions.
Initial Testing – lot release (time 0) testing performed on a sample taken at the end of the manufacturing step in question.
In-Process Product – any material manufactured, blended, compacted, coated, granulated, encapsulated, tableted, or otherwise processed that is produced for and used in the preparation of a drug product.
In-Process Product Hold Time – the elapsed time period from the completion of one manufacturing unit operation to the start of the next manufacturing unit operation.
Primary Package – the immediate container or closure system for the product, for example, bottle/cap, and blister/foil backing.
Product Bracketing or Matrixing – the assessment of the effect of multiple parameters, such as strength, batch size, presentation format or other process parameters by using a multidimensional matrix to identify the worst-case(s) and using these conditions during validation instead of including all possible combinations of the variables.