IMPORTANCE OF DESIGN, INSTALLATION AND OPRATIONAL QUALIFICATION OF LYOPHILLIZER ON ITS PERFORMANCE

Abstract

Lyophilization is a very critical and cost-effective process in pharmaceutical industry. So, the instrumentation of the instruments should be specified so that the required achievement for production is available to work on, i.e., the equipment should be qualified. The main goal in qualifying equipment is to ensure the validity of data. The current equipment qualification programs and procedures used within the pharmaceutical industry are based on regulatory requirements, voluntary standards, vendor practices, and industry practices. The result is a considerable variation in the way pharmaceutical companies approach the qualification of laboratory equipment and the way they interpret the often vague requirements.

Headnote

ABSTRACT

Lyophilization is a very critical and cost-effective process in pharmaceutical industry. So, the instrumentation of the instruments should be as specified so that the required achievement for production is available to work on i.e. the equipment should be qualified. The main goal in qualifying equipment is to ensure the validity of data. The current equipment qualification programs and procedures used within the pharmaceutical industry are based on regulatory requirements, voluntary standards, vendor practices, and industry practices. The result is considerable variation in the way pharmaceutical companies approach the qualification of laboratory equipment and the way they interpret the often vague requirements.

Keywords: Lyophilization; Instrumentation; Equipment validation; Design Qualification; Installation Qualification; Operational Qualification.

INTRODUCTION

Lyophilization or freeze drying is a process of three steps of removing almost total moisture content from the object subjected to the process of freeze drying. The steps are separate, but interdependent. First, the object is frozen. Next, the moisture in the object is removed via sublimation, or the transitioning of a solid directly to a gas. Approximately 90% of the object's moisture is removed in this step. Finally, the target goes through a secondary drying stage.

Biotechnology and pharmaceutical industries use lyophilization as frequently used method to both stabilize and increase the shelf-life of numerous vaccines, drugs, antibodies, and other biological materials.

Survey has concluded that lyophilizers appear to be most often purchased by CROs, companies that perform outsourced drug research and development for biotech and pharmaceutical companies. This is because it is often not cost-effective for these companies to make the capital investment in lyophilizers themselves. This appears to indicate that price is the most important aspect of lyophilizers.1

LYOPHILIZATION EQUIPMENT

Principle

Wet samples can be frozen in vacuum. With the escape of energetic molecules, sample temperature falls by evaporative cooling. Eventually it freezes.

The simplest form of lyophilizer would consist of a vacuum chamber where wet sample material is loaded, together for evaporation of moisture and sample freezing by evaporative cooling and freezing and maintenance of water-vapor pressure below the triple-point pressure. The temperature of the sample would then continue to fall below the freezing point and sublimation would slow down until the rate of heat gain in the sample by conduction, convection, and radiation was equal to the rate of heat loss as the more energetic molecules sublimed away were removed.

An alternative is to freeze the material before it is placed under vacuum. This is commonly done in laboratory lyophilizers. The product chamber is then attached to a manifold connected to the ice condenser.

For larger-scale equipment it is usual to place the material on product-support shelves inside the drying chamber, which can be cooled so that the material is frozen at atmospheric pressure before the vacuum is created. Without a controlled heat input to the sample its temperature would fall until drying was virtually at a standstill. For this reason it is usual to arrange a heat supply to the product-support shelves so that, after their initial use for freezing the product, they can be used to provide heat to replace the energy lost with the subliming water vapor and maintain the product at a constant low temperature.

Instrumentation

The most important are listed below:

* Separated drying chamber and ice condenser to reduce cross-contamination

* Provision of an isolation valve between chamber and ice condenser to allow for end-point determination and simultaneous loading and defrosting

* Construction of the chamber and ice condenser as pressure valves to allow for steam sterilization at 121 C or higher

* Cooling and heating of the product -support shelves by a circulating intermediate heat-exchange fluid to give even and accurate temperature

* Additional instruments to control, monitor, and record process variables

* Movable product-support shelves to close the slotted bungs used in vials and to facilitate cleaning and loading

* Automatic control system with safety interlocks and alarms, duplicated vacuum pumps, refrigeration systems, and other moving parts to enable drying to proceed without endangering the product in the event of mechanical breakdown.2

Process

The fundamental steps in the process of lyophilization are:

1. Freezing: As a necessary condition for low temperature drying, the product is frozen.

2. Vacuum: Subsequent to freezing, the product is placed under vacuum. This enables the frozen solvent in the product to vaporize devoid of passing through the liquid phase, a process known as sublimation.

3. Heat: Heat is applied to the frozen product to speed up sublimation.

4. Condensation: Low-temperature condenser plates remove the vaporized solvent from the vacuum chamber by converting it back to a solid. This completes the separation process.

The first step in the lyophilization process is to freeze a product to solidify all of its moisture. Once frozen, the product is placed in a vacuum and gradually heated without melting the product. This process, called sublimation, transforms the ice directly into water vapor, bypassing the liquid state. The water vapor given offby the product in the sublimation phase condenses as ice on a chamber, known as a condenser.2

Application

Highly heat-sensitive solids, such as some certain biotechnological materials, pharmaceuticals and foods with high flavor content, are freeze-dried at accost obviously higher than spray drying which itself is a cost-effective treatment. Here, liquid is dried by sublimation below triple point to its vapor state which gets removed from the chamber by mechanical vacuum pump or steam jet ejector. Generally, freeze drying yields the highest quality product of any dehydration techniques. Since the process is reasonable cost effective, freeze drying is not used in the chemical industry.

Most freeze dryers are batch-type with rather low capacities although some continuous freeze drying units are in operation. Industrial freeze dryers can be of several types such as most common simple tray freeze dryers.3

The pharmaceutical freeze dryer have very important applications that many aspects. These aspects are as follows:4

* Dosage form stabilization

* Accurate dosage of vial filling

* Rapid dissolution of the freeze-dried product

* Sterility of the manufacturing process

* Preservation of temperature sensitive products, particularly those of biological origin, such as enzymes, blood plasma, vaccines, etc.

* To achieve a chemical balance, such as for biological reagents.

* To provide a practical solution for certain delivery problems, for example, the packaging of constituents that cannot be mixed in the liquid state, but which are solidified in successive stages and then freeze dried.

* To implement an important stage of a product (such as concentration)

* To improve storage life and improved marketing of the pharmaceutical product6

The designing of a freeze dryer or a lyophilizer should be such that allows the following principle agenda:-

* Good accessibility for cleaning and maintenance

* Increased rate for heat transfer

* Energy efficiency

* reliability in operation & maintenance

* Made of components of high quality and latest technology

* Sufficient room for product loading and unloading

These all parameters or criteria are to be are per current Good Manufacturing Practice (cGMP) guidelines to improve the process and ensure compliance. These guidelines involve effective cleaning, for which the product chamber should be round cornered, sloped bottom to drain and mirror surface for smoothness. It should have certified sanitary fittings, diaphragm valves and orbital welded process pipes made of such material to comply with cGMP standards.

Since, the lyophilizer is a critical machine, manual operation can create overload to the parts as the values will be set as per experience and a new person operating may lead the product to degrade or to collapse. Eventually, for safety in operation, these numerous processes are customized or preprogrammed through Programmed Logic Circuit (PLC). This PLC is connected to Supervisory Control and Data Acquisition (SCADA) system which is a part of current Good Automated Manufacturing Practices (cGAMP) to result in a precise, stable control system that is higher than required precise control and validation requirements.5

EQUIPMENT VALIDATION

The drug products that are produced should be fit for intended use. The reason why, a thorough of the said process ant its performance is critical. Judgment only through in-process quality assurance and tests on finished products cannot sufficiently conclude its genuineness. To develop a secure and quality process, various factors such as quality material selection, component, product and process design, control of process, in-process control and finished product testing, should be taken into consideration. Equipment validation is based on its sophistication and complex nature depending on the quality of the final product. The parts of the equipment validation are as follows:

Design Qualification (DQ)

Design qualification (DQ) for instruments or machines is required for cGMP. It is the summary of documents of activities that define the functional and operational specifications of the respective instrument and criteria for selection of the vendor, depending on the intended use of the machine required. I is not only performed by the developer or producer but also tested by the buyer. The manufacturer is generally responsible for the robust deign and maintaining information regarding how the analytical instrument is manufactured (all type of specifications highlighted) and tested before shipment to user.

Moreover, the user should ensure that commercial off-the- shelf (COTS) instruments are suitable for their intended use that the manufacturer has adopted a quality system that provides for high standard equipment. The customer or the buyer or the user should also be sure of the capability of the manufacturer for support installation, service and training.7

The subjective parts of a DQ are as follows:8

* Objectives

* Reference Material

* Roles & Responsibilities

* Product Functional Requirements for Truscan Raman Handheld Spectrophotometer

- Introduction

- System Description Overview

- Basic Theory

- Instrument Overview

* GMP

* Technical Requirements

- Instrument/Basic Operational Design

- It Infra Structure (Computer Hardware, Operating System)

- Application Software

- Methods and Parameters

- Data Collection / Data Entry

- Report

- User Properties and Access

- User Account and Password Management

- Data Integrity / Audit Trail

- Data Backup and Restore

- Data Transfer (Export/Import)

- Safety

- Supplier's Quality System

- Documentation Requirements

- Service and Support

- Training

- Delivery and Installation

- Qualification Services

* Definitions

* Modifications / Change Control

* Approvals

Installation qualification (IQ)

Examination of equipment design, determination of calibration, maintenance and adjustment requirements are done in this stage of validation. Reference number is given to the equipment and its accessories after proper identification. The allotted reference number help the user or the vendor to identify equipment validation and other related issues. All instruments should be checked against highlighted supplier and purchase specifications.

Company should document preventive maintenance requirements for installed equipment and preventive maintenance schedule should be incorporated into the maintenance schedule.7

Generally, the intention of an IQ is the verification of an installation. The following sections will be reviewed in detail as the inspection forwards.

Approval pages: There are two approvals for each protocol: initial approval and execution approval. Approvers vary from facility to facility but the general sequence is as follows:

* Quality Assurance Manager

* Production Manager

* Engineering Manager

* Regulatory Affairs Manager

* Validation Manager

A letter of authorization from the manager should be placed in the validation files for the equipment or process represented by the protocol if this is a temporary assignment and not part of the normal facility organizational structure.

Initial approval: This generally forms the cover page of the document and approvals represent a review and acceptance of the content of the protocol; it signifies review of the protocol by appropriate individuals and details about the equipment and installation. There will also be a signature line for the individual preparing the protocol.

First Rule: No protocol may be executed without all required approvals.

Second Rule: Field execution of the protocol is done on a COPY of the approved protocol. Generally stamped COPY on each page.

Execution approval: Generally, this approval page is the last page in the protocol consisting of a review of the executed document for consistency and completeness. It constitutes all test verifications as per protocol requirements and respective personnel signatures as acceptance of that execution.

Table of contents: Generally self-explanatory and there are no differences in its usage in a validation protocol.

Protocol content and arrangement are not specified by the FDA or any other regulatory body. The use of validation is to note production consistency and operation controls to that extent that is mandatory to maintain product quality, purity and efficacy. Therefore to this end there are as many acceptable protocol arrangements as there are pharmaceutical companies.

The order of appearance of items within the protocol mimics the table of contents. They are generally covered in this order: General Information, Procedures, Tests, and Approval.

Signature page: It is a page showing the signature and position of each person approving, executing or reviewing the protocol. All persons who will or have written in the executed protocol, including Approval pages, must complete this signature page. Identification of individuals is provided in three formats

* Printed or typed

* Signature

* Initials

General: This section overviews how the overall validation effort will be accomplished, how this protocol fits into the Master Validation Plan and what the schedule for completion of the total validation effort will be. Unless the company requires this section it is generally not used.

Purpose/Scope of protocol: Here the reasons for the protocol are detailed. It is intended to prove that the equipment has been properly installed and at the conclusion of this IQ will be ready for testing under the OQ.

As a general rule all components of a process must be included in the protocols so even if the output we came from another source if it logically fits into the protocol for the other that is where it should be.

System description: Although this may contain some of the information from the Scope of Work section it goes into much more detail. As a guide this section contains paragraphs covering the following: Equipment Location: Generally the name and address of the facility along with the location of the equipment within the facility.

Equipment Function: A descriptive paragraph giving the basic purpose and capacity of the equipment.

Utility Requirements: Here we want a brief description of what utilities are required for proper operation.

Responsibilities: Here the critical area in the validation activity are detailed and their responsibility in validation effort. All applicable departments are listed. Not all of the "departments" listed will be part of the facility since a large percentage of validation is provided by outside companies.

Contractors: Prepare and execute validation protocols under the direction of the Validation Department of XYZ Pharmaceuticals.

Validation Department: Supervise preparation of protocols, approve protocols for execution and review executed protocols for approval.

Engineering Department: Ensure all equipment is properly installed and operational for protocol execution. Provide technical support to validation engineers as required. Approve protocols for execution and approve executed protocols.

Regulatory Affairs Department: Provide training in plant SOP's as required for operating personnel and validation engineers. Approve protocols for execution and approve executed documents.

Quality Assurance Department: Provide testing of samples as required during protocol execution through the QC labs. Approve protocols for execution and approve executed documents.

Production Department Provide trained operating personnel, necessary supplies and process materials as needed for the validation effort. Approve protocols for execution and approve executed documents.

Depending on the structure of the company and the departments available this list can grow but would most likely not shrink. Additions and deletions for specific protocols occur. It is not unusual to see Maintenance included with equipment such as Pure Steam Generators and Water for Injection systems. The IT department is usually added if the system is controlled by computers, DCS or PLC's.

Maintenance Department: Ensure all equipment has been serviced and that all critical instruments have been calibrated. Support Contractor's validation engineers.

IT Department: Ensure all computer control systems are functional and that backup software is available. Support Contractor validation engineers as needed.

Third Rule: Protocol approval must include those responsible for systems operation.

Executive procedure: This section details how the protocol is to be executed. There are some peculiarities with each company but the following are generally accepted guidelines. A short paragraph covering each item is the accepted format.

* Training of the validation engineer in SOP's for specific equipment although not always required is generally a sound plan. The FDA inspectors tend to think it is best if the person doing the execution understands the purpose of the equipment and in protocols requiring equipment operations this makes sense.

* Recording of data in the protocol is always in ink, always in a copy of the approved protocols and always by the person(s) doing the execution. Some companies will require only blue ink (from the days when copiers couldn't copy blue) and some will require black ink. Ink smears, wrinkles and stains are an indication to the FDA that the execution occurred in the field and not at the desk.

* Correction of data entry errors always seems like a big deal and something to be avoided. However, an executed protocol without some data entry error is suspect. In this paragraph detail how data entries are to be corrected.

* Frequently you will find (or create) spaces for COMMENTS and other data entry where nothing is written during execution. These blank spaces are unacceptable to most companies and the FDA. The concern is that after execution someone may write in additional information for whatever reason. That is an unacceptable possibility and so there needs to be instruction to eliminate these possibilities.

* On occasion you will need to add a page; the page may be a copy of a protocol page to record additional data or a data sheet from a recording instrument. Again the protocol must provide instruction to the executioner.

Documentation: This is the first section, which actually receives execution. The Documentation Section varies some from facility to facility but usually contains the following sections:

* Purchase Specification

* Manuals

* P&ID's

* Materials of Construction Certifications

* Welding Certifications

* Standard Operating Procedures

Test documents: There is generally a limited amount of test equipment used in an IQ. The following covers most of what might be used:

Voltmeter: Used to verify that the electrical utility(s) connected to the equipment meet requirements.

Pressure Gage: Used to verify proper pressure for air, nitrogen, water or other fluids essential to proper equipment operation.

Temperature Probe: Verification of temperature of water, heating or cooling fluids or air supplied to the equipment.

Rules, Micrometers and other dimension taking devices: Verification of equipment mounting position, position relative to other equipment, internal adjustment dimensions, etc.

Level: Used to verify equipment is installed in a level manner as required by the vendor's documentation and P&ID's.

Visual inspection: This is our first view of the equipment as installed. The intent is to verify that the correct machine is installed, that installation matches design, that installation matches equipment manufacturer's recommendation and that the installation is complete. Details vary widely depending on the equipment, Attachment E provides some guidelines.

Equipment components: Finally we look at the machine. Significant variation exists between companies as to the content, intent and execution of this section.

The basic guideline here is that we want information to verify that the machine is complete. All motors are installed, all components affecting operation are installed and all utilities are connected.

Information recorded should be sufficient to identify the component without getting into too much detail.

Instrumentation: We come back to the Critical and Non-Critical components, the same definitions apply. This is an area complete in itself. There should be a company listing of Critical, Non- Critical and Reference Instruments. List all instruments on each machine, make the Critical determination and proceed for there.

Utility verification: Utilities also fall under Critical and Non-Critical. All utilities should be listed along with their qualities.

Exception reports: Failure in execution must be resolved. Failures recorded as an exception on an Exception Report Form; the form then passed to someone responsible (Maintenance or Engineering generally) for corrective action.

Execution continues after the failure is corrected. Failures in an Installation Qualification are rare but do happen. They will generally be misconnected utilities or the like. All Exceptions must be corrected prior to submittal of the protocol for final approval.9

Operational qualification (OQ)

In this stage of inspection after completing DQ and IQ, the process parameters are tested to its extent of limit to determine whether it will provide a product with all predetermined and expected parameters under all anticipated environment of manufacturing i.e. "worst case tests". At the time of regular production and process control, it is required to measure the process parameters and/or product characteristics to allow for adjustment of the manufacturing process at various action levels maintain a state of control. These actions are evaluated, confirmed and documented during process validation to determine the robustness of the process and ability to avoid approaching "worst case condition".10

The considerations are:-

* Process control limits

* Software parameters

* Raw material specifications

* Process operating procedures

* Material handling requirements

* Process change controls

* Training

* Short term stability and capability of process (latitude studies and control charts)

* Potential failure modes, action levels and worst-case conditions ( Failure modes and Effects analysis, Fault tree analysis)

The use of statistically valid techniques such as screening experiments to optimize the process can be used during the phase. Refer Table 1 for list of critical steps and specifications and acceptance criteria.

CONCLUSION

The state of equipment qualification practices in the pharmaceutical industry is evolving and is subject to much variation. Although more extensive guidance exists for computerized systems than for non-computerized components of equipment, the additional validation requirements of the computerized systems present many new challenges. Some commercially available software may not completely meet current requirements. A need exists for greater consistency in the qualification and maintenance practices for common analytical instruments used within the pharmaceutical industry. In today's environment, there is a tendency to harmonize practices by simply incorporating new procedures into existing programs. In an atmosphere of growing regulatory expectations, this approach is common but not recommended as a means of upgrading qualification programs. The overall program should be evaluated periodically to ensure that current requirements are met and that excessive or inefficient practices are eliminated or changed. Although variations in equipment qualification practices never can be eliminated within the industry, it is recommended that the industry be consistent in meeting core requirements. This article outlines the core requirements that now are widely accepted. It also offers the rationale for making decisions about topics that are not widely accepted and that will continue to evolve in the industry.

References

REFERENCES

1. T2+2TM Market overview. Freeze-drying for biotechnology and pharmaceuticals. Foresight science and Technology. 24 Sep 2009. url: http://www.foresightst.com/pdf/Freeze_Drying _for_ Biotechnology_and_Pharmaceuticals.pdf

2. Dr. Thanaset Senawong, Lyophilization: Biochemistry, Science KKU; 2008.

3. Andrieu J, Vessot S, Chouvenc P, Hottot A; Study and optimization of pharmaceutical products freeze drying process. Lagep. url: http:// www.emse.fr /fr/ transfert/ spin /trs/pdf/ nucleation/andrieu.pdf

4. Majumdar A S; Classification and selection of industrial dryers. Chapter 2, 23-77.

5. GMP production freeze-dryers. Freeze-drying equipment. LyomegaEN. Ima Telstar. url: http:// www.telstar-lifesciences.com /en/ technologies/ freeze+ drying+ systems/ gmp+ production+ freeze+dryers.htm

6. Standard operating procedures for instruments. College of clinical pharmacy. King Faizal University. Ministry of Higher Education. Kingdom of Saudi Arabia. 2012.

7. Equipment qualification plan (EQP). Agilent Enterprise Edition Compliance Services. 1-28.

8. Design qualification of TruScan Raman Handheld Spectrophotometer. Ahura Scientific. 1-25.

9. Weaver W N; Creating a pharmaceutical installation qualification. PDH Online Course K111 (4PDH). PDH Online. PDH Center. 2012.

10. IQ/OQ protocol installation qualification/operational qualification. FreeZone® Freeze dryer Systems. Labconco No: 1059500 Rev. A - ECO D903.