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Compounded medicines and good manufacturing practice (GMP)

Guide to the interpretation of the PIC/S Guide to GMP for compounded medicinal products

29 May 2017

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Interpretation - production - chapter 5

Topic PIC/S clause Interpretation
Vendor assurance 5.26

There should be a vendor assurance program in place based on risk management principles.

The vendor assurance program for starting materials that are registered or listed therapeutic goods is normally limited to ensuring that products are sourced from a suitably authorised wholesaler, via approved supply routes.

For all other starting materials please refer to the section titled "Requirements for starting materials that are APIs"

Inspection of starting & packaging materials 5.5

Each delivery of materials should be quarantined, physically or by equivalent means, until such time as it has been verified against specification.

Where the component is an approved/licensed finished human medicinal product it should be purchased directly from a manufacturer without repacking or other alteration since initial manufacture, or purchased from a distributor that certifies that it has not been subject to repacking or other alteration since initial manufacture.

There should be a record of incoming materials into the facility.

The incoming inspection should be performed against the approved specification; this would normally only be a visual inspection looking for approved supply chain, integrity of the unit, compliance with the specification, including sterility for containers/closures/devices and indications that the goods may be counterfeit.

However, if the starting material is an API then additional requirements apply. Refer below.

Any component not meeting acceptance requirements must be investigated and rejected.

Requirements for starting materials that are APIs 5.25-5.31

If APIs are received, including those to be used for manufacture of clinical trial products, then full compliance with the PIC/S Guide to GMP requirements is expected.

It is expected that there are systems in place for supplier approval and qualification, material receipt, incoming inspection and testing, approval for use, storage, status labelling, expiry dating, etc.

There should be approved specifications for API starting materials. These should reflect any available pharmacopoeial monograph. If there is no recognised official monograph available then the specification should be based on the supplier's specification and include at least test for identification and assay, as a minimum.

Certificates of analysis, from the manufacturer, should be available for all API starting materials.

Refer also Quality Control.

Starting material traceability 5.29 For all materials, including APIs, excipients, finished product components, packaging components, consumables, there should be a unique identifier for each which should be used for identification and traceability throughout the manufacturing systems and documents in the event of a notified problem/recall.
Checks for auto-compounders (sterile production)

Checks on the correctness of set-up should include:

  • The correct starting material is connected to the correct line. This check should be independent of set-up, and may be either a second operator or automated verification (e.g. barcode linking). Replenishment of starting solutions throughout the process should be similarly verified.
  • Volume delivery checks.
  • Independent check on the required volume for each solution.
  • Reconciliation of starting solutions at the end of the compounding session.
  • Details of remaining manual additions.

The mechanism for setup and checking is extremely important.

Validation of any new equipment should also include a risk assessment.

Reconciliation 5.56

There should be a system in place for the reconciliation of all materials and components used, and partly used, during the compounding operation, prior to release of the batch and before destruction of the used/empty containers.

There should be checks in place to ensure the correct quantities have been used, e.g. weight or volume checks. The additions are checked by the compounding operator and an independent operator in the room prior to addition and reconciled afterwards. Secondary checks may be performed by a second operator or suitably validated electronic system, (Refer Annex 11 of the PIC/S GMP guide for requirements)

There should be adequate controls for the pre-dilution of multiple containers prior to use, e.g. antibiotics, and the practice of sharing starting materials across batches. Reconciliation processes should be checked to ensure that the appropriate control exists for these operations due to the risk of mix-up.

Syringes used to aseptically transfer reconstituted product to the final container, addition of diluents, etc., must be adequately controlled to minimise the risk of mix-up. Such devices must be adequately identified (such as a system to mark, label or identify them) and considered as part of the reconciliation exercise.

Labelling 5.41 & 5.50 Labels should be checked for readability and compliance with GMP at the time of generation and the check recorded on the batch record.
Computerised Systems Annex 11 Full compliance is expected.
Validation Annex 15

In general, full compliance to this Annex is expected.

Due to the nature of the batch sizes some flexibility is allowed with respect to process validation. Operations relating to the compounding of patient specific units should be validated in terms of dispensing accuracy. This should be performed for each device/manipulation combination. A model analyte such as NaCl can be used for the purposes of validation, as the content of the compounded medicine may be analysed and quantified e.g. by titration.

Process validation for products made from APIs or batch manufacture is expected to be performed in full accordance with Annex 15.

Media fills (Process Simulation Tests) Annex 1, 66-70

Process simulation tests should be performed for aseptically produced sterile products as part of initial validation and repeated at 6 monthly intervals and should be representative of the batch sizes manufactured.

Operator media fills must be performed twice per year for every operator involved in aseptic manipulations. These assessments are typically separate from process simulation tests.

Process simulation tests should mimic the number, type and complexity of manipulations taking place in the worst case manufacturing process identified as well as non- routine interventions and events. Usually a matrix approach is taken and this is acceptable. New processes, changes to existing processes, scale of activity, etc. must be assessed to ensure that the previous media fills remain valid.

Batch scale "process simulation" exercises are not the same as "end of session media fills", the latter of which are used in lieu of performing the test for sterility and can be an abbreviated form of a media fill.

For the matrix approach, the process simulation should include the worst case attributes of the products covered by the simulation, including factors such as types of manipulations, number of compounded units, and length of the process and container type.

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