In the past, cleaning or cleaning validation problems were often pointed out by the authorities. A simple and standard cleaning approach can be used in the pharmaceutical industry in absence of specific know-how in order to initiate a reflection about cleaning.
Insufficient or inadequate cleaning can have various consequences. From a health point of view, an absence of good cleaning can lead to contaminated drugs with a risk for patients, but also for the workers within the pharmaceutical company due to a lack of correct protection. The ecological problems can be summarized in pollution risks. The regulatory issues are linked with warnings from agencies up to possible authorization withdrawn. Economic problems start with a diminution of production and stock shortage which imply increased internal costs and financial loss. In addition, image problems for a company exist when patients must return medications to the pharmacy as in the case of batch recall. Agencies can increase inspections due to a lack in confidence, and financial institutions could rate a company as a higher risk due to profit diminution and poor predictability of the potential benefits.
A clean product, surface, apparatus, fluid, or gas is one “with an acceptable and predefined level of contamination.”9 Contamination is defined as “the presence of contaminant” and contaminant means “a solid, liquid, biological, or gaseous matter, a microorganism, or any combination of these likely to alter in any way the health or safety of workers, patients, product or process.”9 Cleaning and cleaning validation are continuous processes from the beginning of development until full production and included periodic revalidations. EU GMP annex 151 stresses that “Facilities, systems and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation.”
One main problem is when a first batch of a new product must be manufactured, for example, for the first clinical trials. According to EC 20/2001 guidelines, clinical trial material needs to be produced under GMP conditions, and typically pilot plants are multi-product facilities. It is obvious that “Non-dedicated equipment should be cleaned according to validated cleaning procedures between production of different pharmaceutical products to prevent cross-contamination.” 11 As a general concept, until the validation of the cleaning procedure has been completed, the product contact equipment should be dedicated.8 A highly potent or allergenic product emphasizes those problems.
The aim of this article is to bring some idea about a general concept to approach cleaning and cleaning validation for a new compound.
CONTAMINATION AND CLEANING
Contamination is a process with three main factors: the source of contamination (i.e. previous API or excipients, cleaning agents), the vector (for example, unclean apparatus or co-workers), and the receptor (for example, the next batch). Numerous solutions exist to break the links between the factors, and cleaning is one of the most critical. Cleaning should be efficient in all parts of the equipment, but also in rooms and for all the parts or places in which contamination could exist. Some zones which are not easy to clean (O rings, U-bend, etc.) are often called critical points that are defined as “zones or spots in systems on which an absence of control will bring an unacceptable risk for security.”9
To determine a cleaning strategy for a new chemical entity entering in phase 1 development, some information is needed first:
- Characteristics of the products: toxicities, and solubility degradation products that might appear during the cleaning, etc.
- Characteristics of the equipment: presence of cleanin- place (CIP), ease of dismantling or access without risks, compatibility of the material with the cleaning
- Characteristics of the production: use of specific apparatus, plan of utilization
- Possible cleaning processes: cleaning agents including type of solvents; mechanical actions including the type of cleaning (CIP, COP, manual); possible contact duration, possible temperature of the cleaning solvent, and time elapsed between end of production and cleaning
Before any cleaning strategy is decided, a standardized approach must be set up within the company. This approach includes the use of a standard template for the cleaning procedure that must be adapted to each case as a new procedure or as specific instructions, and include a full checklist of all the points to take into consideration. The idea of a standard approach is presented in Figure 1.
- Characteristics of the products to be cleaned: physico-chemical, toxicity, risk assessment, etc.
- Cleaning type: manual, clean out of place with dismantling instructions, or clean in place
- Type of detergent and solvent: including T°, concentration/ dilution, rinsing instructions with the choice’s rational, cleaning agent and solvent composition, and their approval as well as the presence of a method to detect their traces
- List of equipment, rooms, and utensils to be cleaned: including non-trivial ones such as co-workers clothing. For each operation of the process, a list of all the possible parts in contact with the products should be established including equipment, rooms, products (with their toxicity), surfaces in contact with possibilities of leachability (O rings, for example), type of contact (direct, indirect), flow of personal materials, products, and equipment
- Cleaning process: including time between end of production and cleaning, safety procedures for co-workers, and its critical parameters
- Rinsing process: including type and quality of solvents, for example, WFI water for equipment dedicated to sterile production
- Sampling type: rinse or swab, the placebo approach being not recommended. The sampling technique selected should be capable of detecting both insoluble and soluble residues with a good recovery. For swabbing, the choice of swab material and solvent are important: no interference, good dissolution properties, no particle release, safe for co-workers and equipment. For rins ing, the procedure must include at least: the type, volume, temperature of solvent, maximum time elapse during the cleaning and rinsing (to avoid over dried contaminant), and contact time with the solvent. For both techniques, the recovery must be calculated.
- Sampling procedure: including, when appropriate, the site of sampling and its justification, number of sample, surface, solvent type, volume, etc.
- Sample handling and identification: including time between sampling and analysis
- Analytical procedure and its validation: As stated in annex 15 of the European GMP1 “Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant.” Validation of the analytical method might follow ICHQ2,6 for example, for rinse water and TOC. The validation reference must include the fact that TOC is validated and adapted for the traces of the compounds under consideration.
- Limits: with a rationale of the limits and the interpretation of results including non-conformity management
- List of all procedures, protocol and references: existing within the company about cleaning
For a new product limit definition is not simple. For existing and well known drug, limits are defined in the Canadian Guideline (2) or PIC/S:10
“ Carry-over of product residues should meet defined criteria for example the most stringent of the following criteria (i, ii, iii):
(i) NMT (Not More Than) 0.1% of the normal therapeutic dose of any product to appear in the maximum daily dose of the following product;
(ii) NMT 10 ppm of any product to appear in another product;
(iii) No quantity of residue to be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible.
(iv) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limits should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.”
In the case of a new agent without any known daily dose (for example, for the first clinical batch), the first step is to consider the NOEL (no observable effect level) and calculate the first dose to be administered in humans. Based on this expectation, a 0.1% rule can be applied in a first attempt.3,5 In the case of a formulation used both for adults and children, the worst case scenario (children) is often taken into account to calculate the limits.
Before any production on the real plan for a new chemical entity, cleaning and recovery testing should be performed, for example, on coupons of the various materials used in production over a range of concentrations (low, medium, high). A recovery of 95% can be considered as good, in the case of lower recovery, the reason of the poor recovery must first be found.
VALIDATION OF CLEANING
As in all processes, cleaning validation is mandatory and must verify the effectiveness for removal of all moieties including product residues, degradation products, preservatives, excipients, and cleaning agents. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. As presented in EU GMP annex 151, validation of cleaning processes should be based on a worst-case scenario including challenge of the cleaning process (usage of reduced cleaning parameters such as overloading of contaminants, over drying of equipment surfaces, minimal concentration of cleaning agents, and minimum contact time of detergents) to ensure that the cleaning process is able to work in all cases. At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.1 The interest of a validation is to reduce the analytical monitoring in the routine phase.2,7
For first trials, specifically non-toxic compounds can be used, such as colorants or riboflavin which can be visually detected at low traces. In the case of highly potent drugs (substances either toxic or hazardous), products which simulate the physicochemical properties of the substance to be removed should be considered, for validation purpose before the final test, instead of the substances themselves.1 In the case of a series of compounds exhibiting similar characteristics (follow-up products or products of the same series), cleaning procedures for products and processes which are very similar do not need to be individually validated, this could be dependent on what is common, equipment and surface area, or an environment involving all product-contact equipment. In addition, raw materials sourced from different suppliers may have different physical properties and impurity profiles. When applicable, such differences should be considered when designing cleaning procedures, as the materials may behave differently.
Special attention must be paid to providing information to co-workers. As defined in the WHO GMP11 “The manufacturer should provide training in accordance with a written programme for all personnel whose duties take them into manufacturing areas or into control laboratories (including the technical, maintenance and cleaning personnel) and for other personnel as required.”
For a new compound which exhibits allergenic properties or which is a highly potent drug, dedicated equipment and plants should be anticipated as described in the above mentioned guideline but also in ICH Q7A8 “The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures are established and maintained.”
For a new chemical entity, the main problem is often to produce the first GMP batch in facilities which are not dedicated. In the case of non-adequate cleaning or an absence of cleaning validation, the plant should be considered as dedicated until the absence of contaminant is proven. The entire problem with new chemical entities is to make a good risk assessment analysis before any operation in GMP plants.
- Annex 15 to the EU Guide to Good Manufacturing Practice, July 2001
- Canadian Health Products and Food Branch Inspectorate Guidance Document, Cleaning Validation Guidelines, June 2002
- David C., Naumann B., Hecher L., Setting health based residue limits for contaminants in pharmaceuticals and medical devices, Quality Assurance: Good Practice, Regulation and Law, 1992, Vol I, No. 3, pp 171-180
- FDA, Current Good Manufacturing Practices
- Fourman G. and Mullen M., Determining cleaning validation acceptance limits for pharmaceutical manufacturing operations, Pharmaceutical Technology, (April 1993) pp. 54-60
- ICH Q2(R1), Validation of Analytical Procedure: Text and methodology, November 2005
- ICH Q9 Quality Risk Management, June 2006
- ICHQ7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients, August 2001
- NF EN ISO 14644 Clean Rooms
- PIC/S Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-sterile Process Validation, Cleaning Validation (PI 006-2), July 2004
- WHO, cGMP, 2007