Interpretation - manufacture of sterile medicine products - annex 1

Processes should be designed to include the minimum number of aseptic manipulations necessary. All aseptic manipulations should be performed under unidirectional airflow that is grade A.

Personnel performing manipulations in the Grade A environment should be dedicated to this activity for the duration of the work session. Process design should prevent "swapping" of roles (e.g. with other Grade B operators) as this could create disturbance to the Grade A environment.

Monitoring of the Grade A zone for both non-viables and viables should commence at the start of each work session and continue for the full duration of the session. Non-viable results for a session should be considered for release of products manufactured in that session. Viable results should be monitored and the impact of any out of specifications or out of trends considered in determining whether released product is of the appropriate quality and/or if any corrective action needs to be taken.

The monitoring of lower grade areas should be performed in accordance with Annex 1 requirements.

The PIC/S Guide to GMP requires that for every worker in a Grade A/B area, clean sterile protective garments (including masks and gloves) should be provided at each working session. A working session can be considered to be maintenance of the period of the same operational conditions i.e. personnel, process, and environment. Hence, movement from, i.e. exiting the Grade B cleanroom would necessitate a gown change for re-entry. Storage of sterile cleanroom garments (including hoods, gowns and boots) beyond a working session is not acceptable. Monitoring of gloves and garments used in Grade A and B areas is required to ensure that microbial load conforming to requirements is maintained.

Ampoules should only be used for a single withdrawal immediately after opening and discarded.

The contents of glass ampoules should be filtered prior to dispensing into the final dosage container to ensure any glass particulates have been removed.

Definition: "the bulk transfer of multiple original containers of a sterile staring material into a new (pre-sterilised) container without changing the formulation or concentration of the original starting material".

Aseptic pooling of sterile materials should be minimised and only used where this activity reduces the risk of errors in compounding. The use of aseptic pooling should be justified by a risk assessment which considers the risk to the finished product from the additional aseptic manipulations required for the production of the pool(s).

Aseptic pooling should be treated as a batch operation, which is validated by media fill, described in SOPs and recorded in a batch manufacturing records. Each batch should undergo assessment and release and in the case of pools for immediate use, this release may be concurrent with finished product release.

Any aseptic pool should be given a maximum shelf life, as justified and demonstrated through appropriate validation/media fill studies, and should not be transferred between different work sessions.

The nature of aseptic compounding requires that numerous components including consumables such as syringes, needles, caps together with injection vials, ampoules and intravenous solution bags are introduced into the final preparation area which is normally a Grade A LAF or CDSC. For consumables these are normally enclosed in a primary packet which is opened in a Grade A environment. The outer surfaces of these packets and containers are usually not sterile and may be contaminated with both viable and non-viable particulates. Introduction of such particulates into the Grade A preparation zone poses a risk of contamination of the final product.

Standard practice in compounding is to surface sanitise with suitable disinfectants in a manual process of either "spray" and/or "spray and wipe". The effectiveness in reducing particulates to an "acceptable" level relies on a number of aspects which must be consistently applied. These include adequate exposure to appropriate disinfectants (exposure time and coverage) and adequate wiping with suitable cleaning materials.

It is considered that a sanitisation step be performed at each transfer through each of the final grade changes. i.e. Grade C to B, Grade B to A.  Procedures should be in place to detail exposure time to sanitant, control of materials used for wiping, preparation details for sanitants, in use period for sanitants, wipes and any other cleaning aids, wiping technique.

Sanitants used for early sanitisation steps should be of an appropriate level of bioburden, preferably sterile, and used in such a fashion as to prevent contamination. Wipes used should not shed particles and be sterile when used at the last stage of transfer for aseptic products. Sanitants and cleaning solutions for use in Grade B and A areas should be sterile.

The minimum expectation is that there are two discrete decontamination steps with a spray and wipe performed at both steps and the first decontamination steps should use a sporicidal agent. Manufacturers should ensure that the sanitising agents and processes used do not adversely affect the product and are do not leave any residues that may present any risk of harm to the patient

During any transfer activity measures should be in place to avoid any re-contamination of sanitised articles. Where items are packed in multiple protective layers, such as agar plates, needles, syringes and diluent bags, the inner most sterile layer should only be removed at the Grade B/A interface. Management and handling in the Grade A zone after final sanitisation should minimise the likelihood of recontamination and reflect good aseptic practice. For example, orientation of critical surfaces to a clear stream of HEPA filtered air.

During sanitisation, particular attention should be paid to the rubber septa of vials and break lines of ampoules, which should be subjected to all stages of the sanitisation treatments. Over-seals should therefore be removed at the first sanitisation stage (in Grade C).

Extended storage time of sanitised components is considered to be a risk factor and therefore the storage times of items held between sanitisations steps should be supported by appropriate validation data. Steps should be taken to minimise the exposure of items supplied as sterile prior to entering the Grade A work zone.

Sanitant solutions should be subject to an ongoing monitoring program to demonstrate their suitability.  The effectiveness of sanitants should be validated before use. Sanitants should be demonstrated to be effective against the normal flora encountered in the facility and on process materials.

Sanitisation processes should be validated and used as the basis for sanitisation procedures. Periodic verification of sanitisation effectiveness should be carried out at a frequency based on a risk assessment.

Training to maintain sound practices is required.

Some injectable products are intended for single use only, however, often the full (reconstituted) contents of a container may not be used for a compounded product batch and when another batch is to be made/dispensed for the same product, the reconstituted vial may be retained for subsequent use. This may occur to avoid wastage.

The use of partial vials  may be acceptable if the following are met:

• A risk assessment of the process is conducted to determine the need to utilise partial vials and all controls in place to mitigate any risks associated with their use.
• The container is a vial closed with an elastomeric stopper and is held / stored under appropriate conditions at all times. The vial should not be stored in an area classified less than Grade C and there should be an appropriate and validated* mechanism to return it to the Grade A cabinet.
• Ampoules should not be reused once opened.
• The product is manufactured as a campaign with the patient doses prepared one after the other. The product cannot be left in the cabinet when other different products are being manufactured.
• Batch records must reflect the actual manufacturing process carried out with the appropriate line clearance steps between the manufacture of individual patient doses as required.
• Appropriate checks on the volume drawn up for each patient at the time of manufacture are carried out to ensure that the correct dose is supplied for each patient.
• The use of 'partials' including all manipulations is to be validated via the media fill program.
• The stability (and sterility) of the partial vial has been established based on stability studies.
• The product is not used outside the conditions stated in the 'product information'.
  *The use of partials should be validated taking into consideration the following:
  • The transfer process
  • Container closure integrity
  • Closure type
  • Penetration device
  • The septum is appropriate for multiple entries (usually using a closed system transfer device)
  • The product formulation
  • Eradication of any sources of contamination

Performing the "test for sterility"