INTRODUCTION:

Cleaning-In-Place (CIP) and Sterilization-In-Place (SIP) are systems designed for automatic cleaning and disinfecting without major disassembly and assembly work. Additionally, a well designed CIP system (employing double seat valve (block and bleed) technology and a bit of process integration) will enable you to clean one part of the plant while other areas continue to produce product. Furthermore, a modern CIP system will not only save money in terms of higher plant utilization but also due to significant savings in CIP liquid (by recycling cleaning solutions), water (the system is designed to use the optimum quantity of water) and man-hours.

The technology of CIP (Cleaning-In-Place) and SIP (Sterilization-In-Place) is obviously important to many industries including food, dairy, beverage, nutraceutical, biotechnology, pharmaceutical, cosmetic, health and personal care industries in which the processing must take place in a hygienic or aseptic environment.

The most effective way to implement Cleaning In Place technology is to design it into a process. It involves the additional of spray systems, tank cleaners, nozzles, and seals in order to automate the cleaning process.

Advantages of CIP Cleaning-In-Place

The addition of automation to the cleaning cycle, in effect, converts batch pharmaceutical processes to a continuous operation of production cycles and cleaning cycles. Cleaning In Place technology has the advantages of:

• Reducing cleaning cycle times
• Optimization of the use of detergent and water
• Avoiding the necessity for manual cleaning

• Improved operational hygiene and cleaning efficiency due to reproducible cleaning processes
• Improved product quality, recovery and purity due to enhanced plant hygiene
• Reduced expenditure of time and personnel for manually performing the cleaning tasks
• Reduced pollution and production costs through the effective use and reuse of water, cleaning chemicals and boiler condensate
• A safer, more consistent method of plant sanitation

Cleaning Validation Overview

1.Objectives

n  Assurance of product purity, safety, efficacy and quality

n  Prevention of product cross contamination by byproduct, residual product, microbial residue and residual detergent

2When cleaning validation is required

• Introduction of new equipment/product
•   Manufacturing/cleaning process changes
•   Raw material/cleaning agent  changes

3Good system design
4.Comprehensive Master Validation Program
5.Effective cleaning process development
6.Adequate analytical technique
7.Justifiable acceptance criteria – product specific (How Clean is Clean?)
8.Continuous data monitoring and evaluation

•  Acceptance criteria adjustment as necessary

9.Routine review of deviations, excursions and change control related to cleaning process parameters, equipment, and materials
10.Re-validation as required

n  Define what and how to revalidate

n  Define when to revalidate

11.Application of validation lifecycle management

Cleaning Validation Lifecycle Management

Cleaning Cycle Development

Elements to consider

Design/Construction complexity of equipment

•   Adequate design/structural complexity and  configuration
•   Material and Surface
•   Non-Reactive and cleanability
•   Compatibility with detergents
•   Stage of Manufacturing Process
•   Upstream
•   Down stream  Increased Risk
•   Drug product
•   Structural/design complexity
•   Size and process piping configuration for CIP
•   Potential dead leg/space
•   Adequate turbulence
•   Adequate slope
•   Nozzle design and locations
•   Branch piping orientation

Characteristics of residuals/product to clean

Understand (Bio)chemical characteristics of Product(s)

•   Product matrix
•   Type of active molecule (e.g., protein, DNA, peptide, small molecule)
•   Excipients/Process related components
•   Product matrix is a critical element for:
•   Cleaning process design

•   For the determination of a detergent and process parameters

Physicochemical characteristics 

•   Solubility with medium (e.g., water, organic solvent)
•   Reactivity is a critical element for the determination of process parameters
•   Degree of a reaction with a detergent or medium at different conditions.
•   Degradants
•   Chemical state
•   Liquid
•   Semi-solid
• Solid

Microbe static property

•   Critical for detergent selection

Toxicity/Pharmacological potency

• Critical for acceptance criteria

Potential product and/or component degradants after reaction with a detergent

•  Critical for acceptance criteria

 Cleaning agents

Selection of a Cleaning Agent

•   Depending on the particular type of chemicals (soils) to remove considering:
•   Chemical/Physical nature of the molecule (soil) to remove
•   Reactivity
•   Physicochemical characteristics of the molecule
•   Chemical state of soils
•   Biological soils – alkaline
•   Blending of other cleaning components with alkaline detergent enhances cleaning effects.
•   Builders – the group of complexing agents that enhance the cleaning effect and the effect of surfactant
•   EDTA, polyphosphate, NTA, citrates
•   Surfactants –several types based on the ion characteristics of the active group
•   Anionic, cationic, non-ionic and amphoteric
•   Anionic and Non-ionic: used as components for detergent
•   Cationic and amphoteric: used in the formulations of disinfectants for their microcidal effect
•   Surface tension – capillary action
•   Complexing agents – complexing with minerals and inorganic components
•   Sequestering agent – prevention of scale formation (crystallization of water hardness)
•   May reduce the need for acid cleaning following the base cleaning
•   Deformers
•   Oxidizing agents –H₂O₂
•   Corrosion inhibitors – Silicates
•   Application parameters for cleaning agents
•   Type of cleaning agent
•   Depending on the type of soils to remove
•   Concentration
•   Effectiveness
•   EH&S consideration
•   Temperature
• Contact time

Type of Detergent

Type of cleaning process (Automated vs. Manual)

Selection of Cleaning Process

•   Automated vs. Manual
•   Automated CIP and/or COP
•   Consistency and reproducibility
•   Readily validatable
•   Better process control
•   Manual
•   Inconsistency
•   Hard to validate
•   Inadequate for most of the state-of-the-art facilities

Types of CIP (Clean-in-place)

•  Portable CIP
•   Simple control and non re-circulation
•   Multiple-Tank Re-use CIP
•   Separate tanks for detergents (Acid, Base) and washing solution (e.g., water)
•   Re-circulation and re-use of detergents and washing solution
•   May not be adequate for biopharmaceutical in terms of prevent cross contamination (e.g., viral contamination)
•   Single and multiple-tank single use CIP
•   Appropriate for Biopharmaceuticals: re-circulation
•   Relatively easy for validation but depending on number of pumps, valves, and the complexity of cycle
•   High degree of cycle flexibility

COP (Clean-out –of place)

Cleaning Out of Place is defined as a method of cleaning equipment items by removing them from their operational area and taking them to a designated cleaning station for cleaning. It requires dismantling an apparatus, washing it in a central washing area using an automated system, and checking it at reassembly.

•   Used for miscellaneous fittings and parts out of the main equipment (disassembly)
•   A single open tank for rinsing and washing
•  Re-circulation of detergent using a detergent feed pump
•  Appropriate cycle development

Manufacturing process

 Selection of appropriate method(s) is a key for successful cleaning validation

• Routine and validation
•  Methods must be validated for
•  Sensitivity (LOD/LOQ)
•   Specificity
•   Precision
•   Accuracy

Examples of methods widely used in biopharmaceutical cleaning process

Analytical methods and their sensitivity

  Depending on the types of analytes

• Proteins
•  Organic compounds
•   Inorganic compounds
•   Other biological contaminants
•   Adversary agents
•   Mycoplasma, virus
•   Residual host bacteria
•   Type of analytical methods
•   Specific
•   Multi-product equipment
•   Potent product
•   Toxic or potent degradants or contaminants
•   Non-specific
•   Broad application
•   Holistic evaluation
•   Selection of methods based on the nature of analytes

Validation Approach

•  Development of Validation Master Plan to describe:
•   Objective, scope, references, responsibilities
•   Nature of products (dosage form and therapeutic areas) – all products
•   Manufacturing process
•   Include equipment list
•   Cleaning system and process for each type of equipment

Cleaning Validation Prerequisites

•  Ensure that all cleaning process equipment are adequately qualified.
•  Draft a cleaning SOP based on the development study.
•   Prepare P&ID for each piece of equipment and define sampling locations and/or methods.
•  Ensure that analytical methods are validated.

Clean room

A cleanroom is an environment, typically used in manufacturing or scientific research, that has a low level of environmental pollutants such as dust, airborne microbes, aerosol particles and chemical vapors. More accurately, a cleanroom has a controlled level of contamination that is specified by the number of particles per cubic meter at a specified particle size. The air entering a cleanroom from outside is filtered to exclude dust, and the air inside is constantly recirculated through high-efficiency particulate air (HEPA) and/or ultra-low penetration air (ULPA) filters to remove internally generated contaminants. Staff enter and leave through airlocks (sometimes including an air shower stage), and wear protective clothing such as hoods, face masks, gloves, boots and coveralls. Some cleanrooms are kept at a positive pressure so that if there are any leaks, air leaks out of the chamber instead of unfiltered air coming in. Some cleanroom HVAC systems control the humidity to low levels, such that extra equipment (“ionizers”) are necessary to prevent electrostatic discharge (ESD) problems.

GMP EU classification

Federal Standard 209D Class Limits

Clothing of appropriate quality for Personnel in case of Sterile Production

Clothing of appropriate quality:

–     Grade D

• hair, beard, moustache covered
• Protective clothing and shoes

–     Grade C

• Hair, beard, moustache covered
• Single or 2-piece suit (covering wrists, high neck), shoes
• no fibres to be shed

–     Grade A and B

• Headgear, beard and moustache covered, masks, gloves
• No shedding of fibres, and retain particles shed by operators

Blow Fill Seal (BFS)

The Blow-Fill-Seal system is an innovative production system to produce products where forming the container and filling the solution takes place at the same time and sealing is accomplished immediately under aseptic conditions. A direct-blow forming machine incorporating sophisticated forming technology and high-performance filling machine with time pressure method are combined that forms the container and fills the solution at the same time. Blow-Fill-Seal technology refers to the manufacturing technique used to produce small, (0.1mL) and large volume, (500mL +) liquid filled containers.

Process of BFS

The process begins with the Extrusion of plastic granules in the form of a hot hollow pipe of molten plastic called a parison.

The following step is the Blow moulding of the container from the plastic granule. The parison is closed between the mould, and the container gets formed either by blowing sterile compressed air or by vacuum or by using vacuum as well as blowing. The container assumes the shape of the cavity in the mould. The container thus produced is open from the top and in its top part, the plastic is still hot and in molten state until the subsequent steps of filling and container sealing.
The subsequent step is Filling of the formed container from the top, which is still open (and still in a “hot molten” state). Filling nozzles enter from the top of container and filling is done. Filling nozzles are specially designed and constructed to facilitate automatic cleaning and automatic sterilization. Additional functions of filling nozzles are to blow the bottles and also to provide an exhaust path for air in the container. The filling process can be carried out under a shower of sterile filtered air to avoid contamination during filling. The blower on the sterile air shower can have variable pressure which can be made to change automatically so as to maintain constant air pressure under various situations. The sterile air shower is validated at certain air pressure, and an automatic device can maintain the same pressure by automatically modulating the speed of the blower.

The next step is Sealing the top of the container, which is still open and in a hot molten state. The top gets pressed between head moulds and as a consequence, the top part of the container gets formed, sealed and at the same time, gets cooled. The result is a hermetically sealed container.

ISO (International Organization for Standardization)

ISO (International Organization for Standardization) is the world’s largest developer and publisher of International Standards.

ISO is a network of the national standards institutes of 163 countries, one member per country, with a Central Secretariat in Geneva, Switzerland, that coordinates the system.

ISO is a non-governmental organization that forms a bridge between the public and private sectors. On the one hand, many of its member institutes are part of the governmental structure of their countries, or are mandated by their government. On the other hand, other members have their roots uniquely in the private sector, having been set up by national partnerships of industry associations.

Therefore, ISO enables a consensus to be reached on solutions that meet both the requirements of business and the broader needs of society.

ISO 14000

Every organization determined to embrace ISO 14000 should have a supporting policy manual, procedures, data collection forms, etc. The ISO 14000 family addresses various aspects of environmental management. The very first two standards, ISO 14001:2004 and ISO 14004:2004 deal with environmental management systems (EMS). ISO 14001:2004 provides the requirements for an EMS and ISO 14004:2004 gives general EMS guidelines.

An EMS meeting the requirements of ISO 14001:2004 is a management tool enabling an organization of any size or type to:

• identify and control the environmental impact of its activities, products or services, and to
• improve its environmental performance continually, and to
• implement a systematic approach to setting environmental objectives and targets, to achieving these and to demonstrating that they have been achieved.

Similarities Between ISO 9000 and ISO 14000

ISO 9000 is concerned with quality management and meeting customer quality requirements, achieving control of processes, and encouraging continuous improvement while ISO 14000 is concerned with environmental management. Both standards outline a solid, traditional management approach. The ISO 14001 standard uses the same fundamental systems as ISO 9000 such as document control, management system auditing, operational controls, recordkeeping controls, management policies, audits, training, and corrective and preventive actions.

Differences Between ISO 9000 and ISO 14000

The ISO 9000 standards have been developed specifically to address customer requirements and expectations regarding product quality. ISO 9001 sets out the requirements for organizations whose business processes range from design and development, to production, installation and servicing. ISO 9002 is applicable for organizations that are not involved with design and development. ISO 9003 is the appropriate standard for organizations whose business processes do not include design control, process control, purchasing or servicing, but rather use inspection and testing to ensure that final products and services meet specified requirements. With ISO 14000, organizations respond to much more than just customer requirements. Multiple external stakeholders who influence the environmental aspects of an organization often must be satisfied. Examples of external stakeholders under ISO 14000 include: Federal, State and local regulators; the surrounding community; and special interest groups.

A quality system will include evaluation of suppliers and review of customer contracts.  An environmental system will include methods of evaluating environmental impacts and systems for responding to emergencies.

Calibration and validation

A calibration is a process that compares a known (the standard) against an unknown (the customer’s device). During the calibration process, the offset between these two devices is quantified and the customer’s device is adjusted back into tolerance (if possible). A true calibration usually contains both “as found” and “as left” data.
A validation is a detailed process of confirming that the instrument is installed correctly, that it is operating effectively, and that it is performing without error. Because a validation must test all three of these operational parameters, it is broken into three different tests: the installation qualification (IQ), the operational qualification (OQ), and the performance qualification (PQ).