Production and In-Process Controls

1 Production Operations

Weighing or measuring of raw materials (solids and liquids) should follow procedures designed to ensure accuracy and to avoid cross contamination.

These may include:

• Specified weighing or measuring areas protected from the environment with controlled access.
• Use of log books or registers to record the usage and cleaning of the weighing, measuring area.
• Cleaning procedures for the weighing ,measuring areas
• Procedures to ensure that materials for different processes are not dispensed concurrently
• Extraction systems to control dust or vapour exposure during dispensing
• A range of appropriately scaled weighing or measuring devices should be available to ensure accuracy of weighing operations. The appropriate scales for specific weights or measures should be defined.
• Flowmeters, for liquids, or weight belt feeder, for solids, may be appropriate for charging or for monitoring continuous production processes.
• Critical weighing and measuring devices should be appropriately calibrated and traceable to certified standards. The calibration should be recorded and performed on a regular basis.
• Regular checks by operational staff that balances are functioning correctly should also be considered.

Not all containers are suitable for subdividing materials. Examples of suitable primary container for sub-dividing solids are

• a plastic bag for smaller quantities or
• plastic bags, liners inside rigid support, or
• loading hoppers for quantities of solids.

Multi-use containers receiving sub-divided material (e.g. loading hoppers) should be clearly identified. Such equipment should be appropriately cleaned according to written procedures.

Companies should define the critical weighing, measuring or subdividing operations which should be witnessed or subject to an equivalent control to the minimum number. This should be based on the known critical parameters which could impact on the quality of the API or intermediate. General non-critical weighing or measuring of materials does not require witnessing.

As was seen in the step 2 document it was intended that such weighing operations should be "supervised", which would not have required the physical presence of a second person. However the word "supervised" suggests that someone more senior in the organisation should carry out this task. To avoid this interpretation the word "witnessed" was chosen to indicate that anyone could carry out this check. However it was not intended that this word should be used within the narrow legal sense of being physically present throughout the operation and a subsequent check would fulfil the requirement.

A typical equivalent control that avoids the need for a second person is a recording system where all weighing or measuring operations are detailed. The critical weights or volumes could be checked at the end of the batch production.

The final check by production that the identity and lot numbers of dispensed raw materials comply with the batch instructions may also include a check of the quantities or volumes of critical measurements. These checks should be clearly defined in the operating instructions for each batch.

Companies should decide which operations other than weighing and dispensing could be considered critical and therefore should be witnessed or subject to additional controls. Examples are :

• Charging of critical raw materials.
• Control of critical temperatures, pressures, times.
• Point of crystallisation of API where this is critical to the control of polymorphs.

Variation in yield is a likely indication that a process is not performing to expectations. Therefore investigation of variations in yields at defined process steps is intended not only to control variations in production efficiency but also to optimise process consistency and assist in assuring consistent product quality.

The expected yield may be defined at designated steps for example key intermediates, the final step of synthesis of the API.

It will be easier to calculate the yield of dried products. When wet products or crude liquids are involved, it may be necessary to calculate the yield after analysis and determination of the percentage of expected product.

In some cases there could be significant batch to batch variations in yield due to different quantities of product remaining in enclosed equipment such as filtration or drying equipment. In these cases monitoring of yield trends or averages over a range of batches may be more appropriate.

Yield definition may also not be practicable in purification steps, continuous production processes or processes with multiple recycle streams (e.g. mother liquors). These processes instead may be assessed for example on a weekly or monthly basis.

The important point is that companies should evaluate the likely yield expectancy and variability and decide what is the expected yield and the likely impact on quality.

Once again there are advantages in defining critical process steps to ensure that the yield investigations are focussed on the steps likely to have an impact on product quality. A deviation is defined as a departure from an approved instruction or established standard.

The guidelines require that ANY deviation to the defined processing steps in the production records should be documented. It may be useful to have an additional page in the production record to allow easy recording of unexpected occurrence or deviation to the standard instructions.

It is then the responsibility of the persons reviewing the completed production records (Production) to decide which deviations could be considered critical and require investigation. The Quality Unit should check the deviation records (not the full production/batch records!) and ensure that critical deviations were investigated (reference 2.22 and 6.72 ICH Q7a).

A critical deviation is defined as a variation to previously established critical parameters or a significant variation to standard operations which COULD affect the quality of the API or intermediate. Critical deviations should always be investigated and corrective actions identified.

Where deviations recur on a regular basis the need for example to re-qualify equipment, retrain operators, redefine the process parameters or to implement other appropriate actions should be considered. This review may be done as part of the Product Quality Review. See section 2.5 Product Quality Review in chapter E.6 ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients)

Examples of deviations are:

• Incorrect charging of raw materials
• Temperature, pressure, vacuum parameters outside defined limits.
• Operating instructions not correctly followed.
• Breakdown of process equipment or failure of utilities.
• Equipment out of calibration.
• Production records not adequately completed.
• Temporary alteration to defined production instructions
• In Process Control Limits not achieved.
• Alternative production equipment used at short notice.
• Extraneous contamination of API and intermediates
• Any other unplanned event.

Defining the process status of equipment is intended to assist the process operators and supervisors to properly control their operations and avoid the miss-use of equipment.

In particular the following examples should be well controlled:

• The batch number and process in operation
• The cleanliness status of equipment
• Equipment under maintenance, Out of Service or Out of Calibration

Colour coded labels for material for reprocessing or reworking may be appropriate.

The Quality Unit should clearly identify material for reprocessing or reworking and ensure that the appropriate procedure for reprocessing or reworking has been approved before the production unit consider using these types of material.

• The appropriate control of materials requiring reprocessing or reworking could be quarantine (see 10.11), computer controlled, specific labelling, locking of equipment or other appropriate measures.

2 Time Limits

Time limits are one of many indications for product quality. Therefore deviations have to be assessed. Examples of possible deviations of time limits for processing steps are:

• extended drying or distillation times beyond what is normally observed due to faulty equipment,
• interruption to normal production due to external events e.g. fire alarm or power failure or public holiday.
• Use of raw materials or intermediates beyond documented storage times.

An appropriate storage area for intermediates held for further processing should be defined. The storage area should protect the materials from the risk of external contamination or cross contamination with other materials and from extremes of temperature and relative humidity.

Intermediates which will be stored for any significant period should either be tested again prior to use or have a retest or shelf life period established.

The retest or shelf life period can be determined by:

• Bibliography.
• Information of the manufacturer
• Based on the experience of the company when re-testing products that have been stored during a certain time.
• A simple analytical check of material kept under standard storage conditions. (This does not need to comply with ICH Q1A.)

Special care should be taken with the storage of wet intermediates, to assess the likelihood of degradation.

3 In-process Sampling and Controls

The most common examples of in-process controls are:

• pH control, reaction completion, crystallisation, and batch drying checks. In these and other cases the in process control data assists with process monitoring
• The acceptance criteria are not intended to be specification checks unless there is a direct relationship with product quality.

The approval of critical in-process controls could be carried out as part of the master production instruction approval. Any deviations from pre-established limits for critical in process controls should be investigated and reviewed by the quality unit.

Sampling is required to be scientifically sound. This is a common sense approach to a potentially critical procedure. Samples are used to monitor the process and the results of the sample predefines the disposition of the material being processed. The integrity of the sample predefines the integrity of the analysis. Sampling procedures are therefore a highly important part of GMP

The importance of sample integrity should not be overshadowed by the focus upon the result.

Scientific sound sampling procedures should be developed by considering the following issues:

• Sample size: at least enough to undertake check testing if designated a critical test requiring OOS investigation.
• Sampling method: should be demonstrated to provide representative samples of the whole batch. Particular care is required for sampling of solids and slurries. Simple dip pipes can be used for homogeneous liquids while more complex systems including re-circulation loops may be used for slurries. Sampling of solids is best done from a falling goods stream. Sampling out of bags or drums should be done carefully to ensure representative samples obtained for particle size distribution and analysis when these parameters are critical.
• Sampling procedure: should provide sufficient instruction to ensure that truly representative samples are obtained. Details should include flushing, re-circulation and cleaning of samplers (sampling equipment).

Particularly for critical steps and sampling of the API itself evidence should be available that the sampling methods allow a representative sample to be taken.

Where there is a risk that the batch is not homogeneous for example tray drying of an API a blending step to improve homogeneity should be considered.

Although the sampling regime SQR of n+1 is a common but not the only practice within the industry it is recognised that other statistical approaches can be suitable (e.g. ISO 2859 Sampling procedures for inspection by attributes is an alternative reference).

Sampling tools should be controlled by a cleaning procedure and should be adequately stored when not in use to avoid contamination.

Care should be taken to minimise the risk of external contamination during in process sampling. For example in situ sampling probes should be considered when sampling the final API or protective covers should protect the area where the process equipment will be opened. As a minimum the area around the sampling point should be well maintained with no evidence of flaking paint, rust, dust or other possible sources of contamination.

Procedures should be in place to protect the integrity of in-process control samples, for example: flushing of in situ sampling probes to ensure a representative sample is taken.

In-process sample containers should be clean, clearly labelled with product name or code, date, time, batch number, step number, operator name, if relevant.

In-process tests that require OOS should be clearly identified/designated and these should be critical tests only.

4 Blending Batches of Intermediates or APIs

As written the guidance on blending applies to both chemical and physical property specifications. The intention is that each individual batch should conform to both chemical and physical property specifications.

Care should be taken when setting specifications for intermediate steps or for API's not to include unnecessary limits if a further processing step e.g.: re-crystallisation as part of the process, milling or micronisation will result in product which complies with the final specifications.

5 Contamination Control

Where significant carryover occurs between batches and particularly in the case of filter or dryer heels, it should be demonstrated that no unacceptable build-up of impurities or, where applicable, microbial contaminants is occurring (see 5.23 ICH Guide). This will also assist in determining the frequency of cleaning of equipment which is dedicated to the long term manufacture of one product.

A wide range of production facilities exist from modern multi-purpose facilities designed to minimise risk of cross contamination to older facilities which rely on procedural controls to minimise cross contamination.

It is recommended that companies review existing facilities and define the controls required to minimise cross contamination particularly as the process moves to the final API isolation.

Some of the risks which should be assessed are as follows:

Where more than one product is manufactured simultaneously in one production area or building strict procedures should be in force to avoid for example the misuse of raw materials and intermediates during processing operations.

• Generally such charging areas should be clean and tidy with no evidence of for example flaking paint or rust, or dripping water from service pipework should be in the vicinity of the charge area.
• Where intermediate is isolated in open production areas, adequate distances should be maintained between equipment for different processes for example filters or dryers

Wuth regard to avoid contamination the clauses below have potentially wide impact on API manufacturers.

• Charging of solids and liquids at the final step of API's should be controlled to avoid cross contamination.
• Solids loading systems which avoid opening of reactors to the environment may be appropriate for the final API.
• Segregation of the isolation areas for the final API including controlled access by personnel should be considered.
• Where the API is exposed to the external environment for example during sampling of the final reaction mixture, off loading of filters or dryers then building controls and procedures should be in place to avoid the risk of external contamination.
• No microbiological monitoring of isolation areas and equipment for APIs used in oral solid dosage forms is required unless a microbiological quality is specified.
• Classified Rooms, if applicable, and control of microbial contamination are only essential when stipulated by the requirements of the drug product process.
• The key requirement is that building controls and procedures are in place to avoid contamination at any of the steps after purification of the API.