Manual – 038 Cleaning and Cleaning Validation of API Plant and Equipment

 5.1 General

The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps. Likewise, for cleaning the stringency and validation requirements should increase from early steps to final steps reflecting the risk to the quality of the API and subsequent drug product.

The specifics of API manufacturing (multi step processing, chemical reactions, complex plant and equipment with difficult access) mean that specific guidance is required to ensure effective cleaning and validation.

5.2 Guidance for Cleaning API Plants

5.2.1 Design for Cleaning and Product Accommodation

The first activity in ensuring API plants can be effectively cleaned is to ensure cleaning is actively planned for in the plant/equipment design. Good design for cleaning should be built into plant/equipment specifications. For new plants a list of potential hot spots should be included in the hand over documentation.

Trial cleaning can be conducted prior to production cleaning to generate information on how easily the plant/equipment can be cleaned. Trial cleaning can be used to collect data for a specific cleaning procedure and to identify hot spots. The results of trial cleaning should be evaluated to help establish optimal cleaning procedures. The justification for any cleaning approach should be based upon an understanding of the impact that each identified hot spot will have.

A new accommodation of a product into an existing plant should take account of the attributes of the product and the capability and design of the plant with respect to cleaning. For example, dedicated production areas should be considered when material of high pharmacological activity or toxicity is involved (e.g., penicillin, certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.

5.2.2 Cleaning Methods

Cleaning methods must reflect actual equipment usage, be documented and be carried out to pre-determined acceptance criteria. Typical cleaning methods include water rinses, acid/base rinses, refluxing solvent washes, high pressure water jets, manual cleaning, rinsing via spray ball, solvent re-circulation (via filtration) and detergent cleaning. This list is not exhaustive and where possible individual processes should also be designed to maximize ‘in process’ cleaning (e.g. solvent rinsing via spray ball following the process through the plant/equipment). Cleaning should be carried out as soon as practicable after completion of processing.

Cleaning agents (e.g. detergents) may be used provided sufficient information is known about their formulation and toxicity to allow ACQ calculation. The carry-over limits should also reflect the fact that cleaning agents should not be part of the process or product formulation and as such the acceptable residue levels will be low.

By their nature detergents are highly soluble and residual levels should be reduced and minimized, taking into account the analytical methods available for quantification. Where the API or residue being cleaned from the equipment is more toxic and less soluble than the detergent, a bracketing approach may be justified, i.e. that analysis for guiding substance only is undertaken. The justification must be documented in the appropriate validation documentation.

5.2.3 Dedicated, Multi-purpose, and Mobile Plant and Equipment

For dedicated plant or equipment, cleaning need not be applied between every batch but as appropriate to the process, the length of the production run and the time between batches. The minimum acceptance criteria must be removal of gross contamination.

In some circumstances cleaning to visibly clean may be required (e.g. degradation of product residues, health considerations). Multi-purpose equipment must be cleaned between manufacture of different materials to prevent cross-contamination. Acceptance criteria must reflect the relative risk of cross contamination of API (see Section 5.2.4).

In an API manufacturing plant mobile equipment is often an essential component to configure the plant to fit the need of specific processes. Mobile equipment also increases the complexity with respect to cleaning and hence requires rigorous control.

If the mobile equipment is dedicated: Such equipment must be unambiguously identified as dedicated for its use, preferably with permanent equipment labelling, in addition to the general status labelling. Individual equipment records are not necessary and the records of use, cleaning or maintenance can be part of the batch record. Cleaning acceptance criteria are (as for other dedicated equipment) removal of gross contamination or visibly clean (if required for technical or health reasons). If the mobile equipment is multipurpose:

There should be separately maintained records of equipment use, cleaning or maintenance with the appropriate cross-references to batch records. Such equipment must be considered as a part of the total equipment train with respect to risk for cross-contamination and cleaning, i.e. when assessing the acceptable ACQ and verifying the level of cleanliness all mobile equipment must be included.

When configuring more than one item of mobile equipment (individually cleaned to a specified limit for different products) into the same equipment train an assessment must be made as to the suitability for use of the equipment both as individual items and as part of the overall equipment train.

Mobile equipment, including spare parts, that has been cleaned and is not infuse must be stored to prevent contamination (e.g. in cabinets providing a clean environment, or by sealed covers or other appropriate means). Small items (e.g. sight glasses) are not considered as separate items of equipment and are cleaned along with the equipment that they are connected to.

5.2.4 Establishment of Acceptance Criteria for Carryover Limits

5.2.4.1 Application of a risk based approach to product changeovers (risk levels)

In order to prevent cross contamination of API that will be incorporated in dosage form for administration to patients, residues must be quantified after cleaning and ACQ specified. The ACQ is determined to ensure that the level of residue after cleaning will not have a clinically significant pharmacological or toxicological effect at the maximum daily dose of the subsequent product. The choice of the guiding substance(s) must be recorded and justified.

Typically, it will be the last material prepared in the vessel, though other components of the contamination matrix should be considered, e.g. catalysts, toxic reagents, solvents, degradedness or by-products of the last material. The amount of a specific contaminant actually presents in the equipment to be used for the manufacture of an API is determined by summing the amount present in the rinse washes or swabs of all the equipment to be used in the manufacture.

For the calculation a worst-case assumption is taken that the amount of contaminant remaining is equal to the amount that has been recovered by swabbing or rinse analysis. It is not necessary to add results from rinses and swabs, unless they are measuring separate parts of the equipment train, in the calculation of residual guiding substance(s).

The most appropriate method to give the final result should be selected based on consideration of the equipment, guiding substance properties and knowledge of the cleaning procedure (see section 5.2.5.3). Surface area calculations for plant must be documented Three risk levels need to be considered depending on the type of changeover.

The flowchart (Appendix 1) shows the changeover scenarios within and between two synthetic sequences and the associated risk levels. The table (Appendix 2) shows the recommended minimum acceptance criteria to apply for each risk level.

Appendices 1 and 2 provide the context for the subsequent sections and should be read before proceeding to section 5.2.4.2. In some cases, the assessed risk level for a particular changeover may be higher than that indicated in the general guidance.

To reflect the higher risk level, it may be necessary to apply tighter acceptance criteria than that specified in Appendix 2

5.2.4.2 Calculation of ACQ for a Level 2 Change Over

5.2.4.3 Use of ACQ for a Level 0 or 1 Change Over (see Appendix 2)

Generally, it is not possible to use the calculation approach for level 0 or 1because therapeutic dose information is not available. However, in some circumstances a calculated ACQ, or where this is not possible a more stringent, may be applied to level 0 or 1 changeovers.

Examples:

Changeover of plant between the manufacture of a crude and pure API from the same series (general guidance risk level 0) where the crude process uses a highly toxic reagent or metal catalyst. In such circumstances an ACQ may be calculated using the API therapeutic data and the reagent/metal toxicological data.

Change over from a pure API to a crude API from another series (general guidance risk level 1). Data may be available for both APIs to enable calculated ACQ for comparison with the default minimum acceptance criteria of100ppm.

5.2.5 Inspection, Sampling and Determination of Residue

5.2.5.1 Inspection and Sampling Plan

Due to the complexity of a chemical plant an effective plan must be devised and documented prior to inspection and sampling. Key to this activity is an understanding of the plant layout and equipment paying particular attention to hotspots. A critical assessment of the equipment and its configuration to assess all potential hot spots should be performed.

This assessment of hot spots should involve Bathe plant engineer, the plant operator, the production manager and include a review offline diagrams alongside physical plant inspection. For new plants a list of potential hot spots should be included in the hand over documentation. For new plant or product, it may be necessary to sample all hot spots.

Where experience has been built up over several cleaning batches that demonstrate the potential hot spots are adequately cleaned, a reduced level of sampling may be applied. For example, where there are a number of similar pieces of equipment it may be appropriate to select the worst case based on experience and use these as the indicator for cleanliness (e.g. selecting the worst 4 out of 10 ball valves).

The inspection and sampling plan must be clearly documented and approved by Quality Assurance prior to any sampling activity being performed.

5.2.5.2 Inspection to Confirm Plant and Equipment is Visibly Clean

Where required (see ‘Establishment of Acceptance Criteria for Carryover Limits’ section 5.2.4) sites shall implement cleaning procedures to clean plant to visibly clean. These procedures should be established prior to validation.

It is recognized that assessment and achievement of visual cleanliness is more difficult for API plants than for drug product plants due to the plant design and the harsh nature of chemical processes that often lead to stains. Such surface marking is acceptable as long as it can be established that any mark is due to abstain.

Procedures shall be established to determine whether visual markings due to staining. Such procedures should include both physical and chemical steps to attempt stain removal (patch test), detailed documentation of the stain, review of stain records (which may include diagrams and/or photographs) and assessment of the impact of stain removal, worsening or the appearance of new stains after further processing.

In some circumstances visual inspection can be used as part of a quantitative calculation to determine if plant has passed an ACQ limit (for level 1 and 2cleans). In such cases (e.g. the removal and inspection of a valve) the level of contamination that can be assessed as visibly clean must be quantified and worst-case figure assumed in any subsequent calculation.

The assessment of whether or not ‘visibly clean’ has been achieved is a critical activity when visibly clean status is required. Sites should implement documented visual inspection procedures capable of consistently assessing whether or not visibly clean has been achieved. Sites must ensure staff responsible for inspection and assessment of visual cleanliness are trained. Such procedures should include the following:

* Instructions on preparation for visual inspection (including engineering work to prepare for inspection, health considerations, plant condition (e.g. plant must be dry), allocation of trained inspection resource, review of plant use and cleaning and familiarization with hot spots).

* Instruction on how to carry out a visual inspection (including equipment to be used, areas to be inspected and documentation to be generated).

* Instruction on how to follow up a failed visual inspection (including investigation into the cause of the failure (e.g. stain, poor cleaning or physical damage), follow up action (e.g. physical cleaning), and assessment of suitability for use (e.g. in the case of a stain).

5.2.5.3 Sampling Methods

The most suitable sampling method or combination of methods should be chosen to verify, validate and/or monitor the effectiveness of cleaning on a case by case basis. The two most commonly used methods of sampling are swab sampling and rinse sampling although other approaches can be taken if scientifically justified (e.g. the use of placebos and the use of coupons (test pieces made of the same material as the plant).

The advantage of rinse sampling for API cleaning is that it contacts the vast majority of the many inaccessible and difficult to clean surfaces in API plant that cannot be swabbed (e.g. transfer lines, condensers, vapour uplifts and small inaccessible vessels).

If well designed (taking account of solubility in the wash solvent and the kinetics of dissolution i.e. how much time is required for effective dissolution of residue) rinse sampling will give the best picture of the amount of residue remaining in the plant (with the exception of certain hot spots e.g. ball valves).

The advantage of swabbing is that it directly samples the surface and measures the actual residue left on the equipment. Additionally, residues that are ‘dried out ‘or insoluble can be sampled by physical removal. Swabbing can be particularly effective in sampling hot spots where the action of refluxing solvent washes maybe ineffective (e.g. vessel roofs, complex manifolds and ball valves).

It is unlikely to offer any advantage over rinse sampling for large surfaces well contacted by solvent rinse washes (e.g. vessel side and base walls) and can be impractical in much API plant (e.g. transfer lines). The greatest risk of carryover of residue comes from material hold up in hotspots.

The first step in an effective sampling plan is to identify potential hot spots (see section 5.2.5.1) and to ensure these are closely monitored (see appendix 1 –typical hot spots in API plant). Risk assessment may be a suitable approach to identify which hot spots to sample and inspect or test. In some cases, it may be most effective to remove and clean such hot spots or to replace them with like-for-like clean equipment (e.g. transfer pumps or ball valves). During the establishment and validation phase a combination of rinse sampling with inspection and swab sampling (and/or removal and physical cleaning) of hot spots must be used. After validation the effectiveness of cleaning should be monitored with at least rinse sampling (final wash only) and visual inspection.

Following cleaning validation, inspection and swab sampling (and/or removal and physical cleaning) of selected hot spots may be retained. When selected as a sampling technique, swabbing procedures should define the area to be monitored, use of any solvents, details of the technique and equipment to be used and how a quantitative residue result is then derived, taking into account the area to be swabbed, recovery from swabbing, size of equipment etc.

These procedures should be sufficiently detailed to ensure adequate consistency in the swabbing technique between analytical method validation and on plant sampling in addition to thorough training for all staff involved in swabbing. Surface area calculations for plant must be documented.

5.2.5.4 Analysis

For commercial manufacture the analytical methodology must be appropriately validated and documented in order to provide the appropriate limits of detection and quantification for the material to be determined.

Qualitative methods are generally not acceptable. Analytical methodology should take into account the method of sampling, proven level of recovery from swabs and surfaces, and other materials present in the sample matrix (i.e. solvents, swab extractives, cleaning agents, other products, etc.). R&D should supply appropriately validated analytical methods to Operations. These methods should be formally transferred. For analysis of clean samples non-specific techniques such as Total Organic Carbon (TOC) determination or Absorption may be applied for certain products, providing there is scientific justification that these will give worst-case results (i.e. they could detect additional contamination).

5.2.6 Engineering Cleaning

Engineering cleaning may include routine as well as non-routine cleaning activities in a production plant before and after equipment maintenance, equipment modification or new installation of equipment. The purpose of engineering cleaning is to clean plant and equipment to fulfil both health and GMP requirements.

Health requirements are typically around ensuring safe condition of plant and equipment prior to entry or engineering work. Health requirements are outside the scope of this guideline and are not covered. From a GMP perspective the acceptance criteria outlined section 5.2.4 apply where engineering cleaning is undertaken as part of product changeover.

In addition to these further criteria should be applied to ensure that no material from engineering work (e.g. grease, metal shavings, dust) is carried over into subsequent product. Typically, these criteria must include visibly clean but may also include other criteria (e.g. a limit for the residue on evaporation of a solvent rinse). Where engineering work is carried out separately from a product changeover (e.g. For breakdown maintenance) the acceptance criteria need only ensure no materialism visibly carried over from the engineering work into product (i.e. visibly clean applies).

5.2.7 Justification for Campaign Lengths

The campaign length for the manufacture of a single intermediate or API and hence the cleaning interval should be defined and agreed prior to the start of manufacture. The cleaning interval should be no longer than one year unless there is evidence to support an extension or limit to the interval. For end of campaign cleans normal acceptance criteria apply.

Where cleaning is required within a campaign manufacturing a single intermediate or API the plant will be treated as dedicated plant (see section 5.2.3). In all cases there should be an assessment justifying the proposed campaign length. The assessment should take into account both development and manufacturing experience and where possible incorporate stability, impurity and degradation profiles. For processes where the initial assessment indicates a risk of instability, e.g. temperature, moisture or light sensitivity, a monitoring regime should be established.

Typical areas that lend themselves to such testing are pressure filter heels and mill bag filters. The cleaning interval may be changed providing that there is sufficient supporting data. However, the campaign length must never exceed the retest period of the product. Where the cleaning process has been validated, the cleaning interval shall be considered an integral aspect of the validation status and as such any change must be managed under the appropriate change control system. As with the validated status of the process and plant, the campaign length should be periodically reviewed by Production and Quality Assurance.

5.3 Guidance for Cleaning Validation

Cleaning for commercial manufacturing processes should be validated. Validation should be directed to situations or process steps where contamination or carryover of materials poses the greatest risk to API quality (for example, in early production it may be unnecessary to validate equipment cleaning procedures where residues are removed by subsequent purification steps).

The degree of validation or cleaning required may be determined by risk assessment. The validation cycle should include an initial period of cleaning process establishment prior to formal validation. Cleaning process establishment is key to developing effective cleaning processes and can take a significant amount of time due to the complexity if API plant/equipment and the materials used in manufacture.

Establishment of a documented and QA approved cleaning process must be completed prior to formal validation. During the establishment phase the clean status of plant and equipment must be verified.

5.3.1 Cleaning Validation Requirements

Cleaning validation requirements vary according to the changeover type and the subsequent risk to API contamination.

Figure: Cleaning Validation Requirements

5.3.2 Cleaning Validation Documentation Requirements

There must be a documented cleaning process approved by QA prior to validation. The validation must be documented (e.g. in a validation program/protocol and report). The detailed requirements for the validation documentation must be described in site policies and procedures.

5.3.3 Bracketing Approach for Cleaning Validation

For a multipurpose plant it is acceptable to use a bracketing approach for cleaning validation. Bracketing may be applied to the guiding substance(s) and/or the plant.

5.3.3.1 Bracketing of Guiding Substances

If bracketing the guiding substances all of the substances contacting the equipment must be reviewed and a representative substance or substances selected. The selection of a representative substance(s) for cleaning validation must include worst-case example(s) based on solubility, difficulty of cleaning, potency, toxicity, stability and ACQ.

5.3.3.2 Bracketing of Plants and Equipment

Bracketing of identical equipment items may be an acceptable approach if justified. Bracketing of plants may be used for identical plants with the same configuration, if justified, however this is likely to be more difficult than for individual equipment items.

Any justification of bracketing plant or equipment should include consideration of equipment age, surface condition, equipment usage and guiding substances. Bracketing of non-identical plant or equipment is not recommended as small changes may significantly affect ease of cleaning and the location of hot spots.

5.3.4 Revalidation

Validated cleaning procedures must be periodically monitored and reviewed. Sites must have procedures detailing how to carry out this review and at which frequency (based on the frequency of cleaning and changeovers).

Site change control systems must include a review of the validation status for validated cleaning procedures when changes are made which could impact on that status (e.g. modifications and part replacement). The validation status of the cleaning procedures may be reviewed as part of Product Review processes.

Appendix 1 – Product Changeovers and Risk Levels

* See section 5.2.4.3Each box represents the process to convert to the named intermediate or API. The envelope for the cleaning is all the equipment used to manufacture the named intermediate or API. The guiding substance is likely to be the intermediate/API manufactured at that stage of the process (e.g. Conversion too Intermediate 2, the equipment will be contaminated with intermediate 2 or a chemical used in this step)

Appendix 2 – Risk Level Minimum Acceptance Criteria

Appendix 3 – Typical API Plant Hot Spots

 – Baffles with thermites

 – BRO valves

 – Discharge assemblies/valves on pressure filters

 – Pressure filter spray rings, door seals, inlets and vent lines

 – Pipe manifolds

 – Tight bends

 – Dead legs

 – Long pipe runs

 – Condensers (particularly carbon block)

 – Sampling systems (including dip legs, valves and pumps)

 – Agitators (particularly where cladded)

 – Valves (particularly ball valves and butterfly valves)

 – Uplifts/charge chutes etc.