1. Purpose
The purpose of this guideline is to provide guidance regarding the reworking, reprocessing or recovery (salvaging) of formulated products, active pharmaceutical ingredients (API’s) and intermediates used in the processing of APIs.
2. Scope and Applicability
This document is applicable to all commercial products manufactured within A manufacturing facility. Products used or manufactured within R&D facilities solely for R&D purposes are excluded. Local or national Regulations may take precedence over this guideline.
3. Definitions
3.1 Product
Formulated Product, API or API intermediate.
3.2 Re-treatment
Re-treatment is the general term applied to any recovery, rework or reprocess activity.
3.3 Re-processing
Reprocessing is the act of repeating process step(s) that is (are) part of the established manufacturing process for product.
Note: For formulated product reprocessing is carried out on product of unacceptable quality so that its quality may be rendered acceptable. For APIs and intermediates reprocessing can also be carried out on product that meets established specifications e.g. in order to combine smaller amounts.
3.4 Reworking
Reworking is subjecting all or part of a batch of product that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain an acceptable quality product.
3.5 Recovery
Recovery is the introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture.
Note: For APIs and intermediates the isolation (recovery) from previous batches may require additional processing steps in order to render required quality API or intermediate for use in subsequent manufacture e.g. the recovery of API or intermediates from crystallization mother liquors.
3.6 Blending
Blending is the act of deliberately combining product into subsequent batches of the same product.
4. Responsibilities
The Head of the QA Function of the Site or facility is responsible for ensuring that the principles embodied in this procedure are carried out.
The Head of the QA Function is also responsible for ensuring that each failure leading to a re-treatment is fully investigated and the appropriate remedial action to prevent recurrence is completed.
5. Guideline
5.1 General
The re-treatment of products including rejected or sub-standard product should be by exception only. Where the batch integrity has been altered retreatment should not be carried out. If retreatment is used for a majority of batches such processing should be included as part of the standard manufacturing process.
Continuation of a process step after an in-process control test has shown that the step is incomplete is considered to be part of the normal process and is not reprocessing. Retreatment should only be allowed if the quality of the product will not be adversely affected by the retreatment, it is carried out in accordance with a defined procedure, and has been authorized by QA after evaluation of the risks involved, including any possible effect on product shelf life.
Proposals for retreatment of product manufactured at a contractor must be referred to the product Lead Site (site managing the contract or sponsor) for consideration and written approval prior to commencement of the retreatment activities. The need for and extent of the validation requirements of all retreatment procedures should be carefully evaluated for each case of retreatment and approved by QA.
All retreatment procedures that are intended to be a supplement to, or a part of the established manufacturing process should be validated by a prospective approach, or at a minimum by a concurrent approach. Retreatment should be carried out according to a written procedure and batch documentation should provide full traceability of all materials and operations performed.
Out of Specification batches must not be blended for the purpose of meeting specification. Where blending is carried out blended batches must be traceable back to individual batches and the blend must be tested for conformance to specification and have expiry or retest life based on the oldest material used in the blend.
5.2 Suitability for Retreatment
Before a decision is taken to retreat a product its feasibility should be technically assessed and the assessment approved by Quality Assurance. In addition Quality Assurance should also assess any additional control measures and validation work required in addition to the normal release requirements and ensure before hand that the product will comply with all regulatory requirements.
All retreatments should have acceptable implications regarding Safety, Health and Environment. An investigation must be conducted to determine the cause of the retreatment and remedial action shall be taken to prevent recurrence.
Retreated product that fails to meet specification or release criteria should not be retreated for a second time if the failure is the same reason as for the original retreatment. The only exceptions are:
(i) For a failure associated with physical size reduction (e.g. milling and micronising) where further size reduction is permitted
(ii) For API or intermediate reprocessing providing that the reason for the reprocessing failure is understood and there is evidence that further reprocessing will give acceptable quality product.
5.3 Control of Retreated Products
A regulatory implication assessment may be required before any product resulting from a retreatment activity can be considered suitable for sale. Any batch of product that has undergone a retreatment procedure must be clearly identified in its batch documentation prior to the formal documentation review by QA.
Retreated batches whether bulk, formulated or packed stock must conform to all established specifications. Any possible market restrictions imposed by regulatory authorities must be considered before release of the product. Product that has exceeded its shelf life/expiry date should not be retreated under normal circumstances. However, Active Pharmaceutical Ingredients and intermediates may be reprocessed after their allotted retest date according to Procedure ‘Determination of Storage Periods for APIs, Excipients, Intermediates and Raw materials’.
Where applicable, retreatment requests shall be assessed by the local and/or global change management procedures. This includes retreatment activities that involve significant changes to approved manufacturing processes, plant or equipment, e.g. changes to plant configuration or additional stages.
5.4 Additional Testing and Validation Requirements
The following procedures are required depending upon each specific situation.
(a) Where no physical or chemical change to the product occurs, the retreatment process should be validated with sufficient additional testing carried out on each batch to ensure the product meets specification.
(b) Where chemical and/or physical changes occur to the product the retreatment process should be validated with sufficient additional testing to ensure that each batch remains stable, is homogeneous and meets all specification requirements, plus (in the case of tablets and capsules) the dissolution profile is satisfactory.
5.5 API and Intermediate Products
Retreatment of API and intermediates differs from formulated product retreatments in that further purification is often the outcome of an API/intermediate retreatment whereas this is rarely the case with formulated product retreatment. Therefore, subject to any regulatory constraint, it can often be acceptable to retreat APIs and intermediates. The boundary between what constitutes reprocessing and what constitutes reworking may not always be clear. Simple changes to an existing described process the retreatment may be considered as reprocessing however for significant changes the retreatment should be considered as reworking. For example, changing a solvent volume may be considered as reprocessing whereas changing the solvent usually would not be within the written scope of the process and hence considered as reworking. Where reprocessing is selected as the method of retreatment any variations to the existing described process should be justified as part of the evaluation of the retreatment process; see section 5.2.
5.5.1 Blending
Where physical attributes of an API are critical any blending operations must be validated to show homogeneity of the blended batch. If blending of APIs could adversely affect stability blended batches should be included in the stability program for the API. Several activities that are a normal part of API or intermediate processing are not considered to be blending including: the mixing of an API pressure filter heel into a subsequent batch (carryover); mixing of fractions (e.g. chromatography); or using a multi-drop centrifuge and combining drops for drying.
5.5.2 Reprocessing
Blending of tailings (small quantities of isolated API or intermediate) is acceptable and is considered as reprocessing.
5.5.3 Reworking
Since reworking involves a process that may not be covered by the registered process description API or intermediate obtained by reworking may not be used commercially until approval of the authorities has been obtained; see section 5.3.
Any rework must be supported by an appropriate evaluation and documentation demonstrating equivalent quality to that produced by original process; see section 5.2. Concurrent validation allows for a more in-depth assessment of a reworked batch and must be used for any API or intermediate rework unless sufficient batches shall be reworked to allow prospective validation.
Where routine analytical methods are inadequate (eg if new impurities or physical forms are suspected) additional testing methods should be used.
5.5.4 Recovery
Recovery of API and intermediates is acceptable providing that there is an approved procedure for recovery and that the recovered API or intermediate meets a suitable specification for its use. The specification is not required to be same specification as original (un-recovered) API or intermediate provided that it is suitable to control the quality of the finished API (i.e. raw material for formulation) to its established specification.
5.6 Tablet Products
Where the retreatment activity does not alter the physical or chemical constitution of the product, (e.g. check weighing, hand picking), the process should be validated and then testing may be restricted to those tests, which verify that the retreatment has been successful in removing the defect to a satisfactory level.
This will involve a suitable sampling protocol and check test, (e.g. weighing, visual inspection). However, some retreatment procedures may affect the average physical characteristics of the batch, (e.g. check weighing a batch for low weight tablets could alter mean weight), and suitable checks must be carried out in these cases.
When the reprocessing activity is simply a repeat of a previous unit operation, (e.g. re-drying), testing may be restricted to repeating the normal in-process controls applied to that unit operation.
Any retreatment activity that includes altering the chemical and/or physical constitution of the product (e.g. slugging and recompressing, milling and blending with new manufacture, adding extra lubricant, recoating) is not permitted.
5.7 Capsule Products
Similar principles to tablet products, section 5.5, should be applied. Retreatment activities that do not alter the physical constitution include metal checking, check weighing, hand picking and polishing.
5.8 Liquid/Cream Products
Due to physical stability problems, any retreatment of creams or other emulsions should occur within 24 hours of the original processing. If the retreatment involves the remixing and/or refiltering of a simple mixture then additional testing after that stage will usually be sufficient. When a cream or other emulsion requires remixing, usually with a reheat and cool process then some stability testing should be performed on the retreated product. This also applies to re-homogenization processes.
If additional active agents or excipients have been subsequently added to correct an error then additional sampling/testing for the component(s) added must be undertaken. If remixing, re-homogenization etc. are required following the addition then stability testing may be required, as described above. Packed material is sometimes recovered by re-bulking and refilling.
In this case, additional tests for active agent uniformity in the refilled packs should be carried out. If remixing, re-homogenisation etc. has been necessary then stability testing may be required, as described above. Recovery of batch residues from these formulations must not be carried out.
5.9 Sterile Products/Inhalation Products
The only retreatments allowable are:
(i) Re-inspection of ampoules/vials if the material has failed for particulate contamination. Sampling/testing should be increased for the re-inspected batch, according to a defined statistical plan.
(ii) Re-filtration of the bulk solution when filters fail bubble-point tests or other abnormality has occurred during filtration.
Testing must be performed to establish that re-filtration has not resulted in an adverse effect from interaction with filter materials, particularly on active agent and preservative levels.