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Laboratory Equipment Qualification

Article of Kenneth W. Sigvardson,* Joseph A. Manalo,Robert W. Roller, Fatieh Saless, and David Wasserman

The main goal in qualifying laboratory 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.The authors summarize the conclusions of the PhRMA Workshop on Acceptable Analytical Practices for the topic “Qualification of Laboratory Equipment.”They describe the areas of  agreement and offer options for areas in which there is variation on what is appropriate

The concept of Acceptable Analytical Practices (AAPs) was developed by the Analytical Research and Development Steering Committee of the Pharmaceutical Research and Manufacturers of America to share information about how the pharmaceutical industry has implemented the CMC and Quality Guidances of the International Conference on Harmonization and worldwide regulatory authorities.AAPs were designed

to provide a process by which one could learn from the experience of experts in pharmaceutical research and development and enhance the understanding of analytical practices that reflect good science

and sound regulatory compliance. The process of discussing and publishing AAPs also is intended to identify and address critical issues in which guidance is lacking, ambiguous, or contradictory.

Initially, the process adopted for the development of the first four AAPs involved a two-and-a-half-day workshop held 19–21 September 2000. The four topics discussed were Laboratory Equipment and Instrument Qualification; Out-of-Specification Results: How to Conduct Laboratory Investigations; Forced Degradation Studies: Issues and Controversies; and Analytical Methods Transfer. This article presents the

first of these presentations. The three remaining topics will be covered in future issues of this magazine. Regulations regarding the qualification of laboratory equipment often are vague and subject to interpretation. The good manufacturing practice requirements state that “the calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met” (1). The good laboratory practice regulations impose similar requirements, stating that “equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated, and/or standardized” (2).

Terminology and definitions

In this industry, considerable variation ex-ists in the terminology used in the qualification of equipment. The “Equipment qualification definitions” commonly used terms with their definitions. Throughout this document the term equipment is used to represent both instruments and equipment as they are defined

in the “Equipment qualification definitions”.

General requirements

The equipment qualification program must be defined and documented. The program must contain provisions for the qualification, maintenance, and documentation of failures of all equipment used to collect data for regulatory submissions.This is usually accomplished by using a standard operating procedure (SOP) that describes the overall program. Individual procedures, specific to the equipment used, also must be documented. Specific procedures for equipment qualification can be documented in one of two ways: First, separate SOPs can be written that contain the procedures used for qualifying and maintaining each type of equipment. Alternatively, master SOPs can be used to describe the compliance

requirements for a variety ofequipment, and specific equipment procedures can be created as separate documents similar to test methods. This second approach minimizes the repetition of the compliance requirements in many SOPs, and it provides additional flexibility in documentation practices. In addition to the documentation of the program and its associated procedures, all equipment used to generate reportable

data must be tagged or labeled and have records maintained. The labeling serves as a way to identify equipment that is unqualified or does not meet performance requirements. It prevents the use of such equipment while it is in its normal operating location. Records usually are maintained through some form of log book that documents all critical activities such as failures, maintenance, qualification testing, location, custodian, and so forth.

Qualification life cycle

It is not necessary to formally document any equipment prepurchase activities. These activities normally are referred to as design qualification, or DQ, and they lead to the selection of equipment. Once the equipment arrives, the installation phase begins. The first part of the qualification cycle requiring formal documentation occurs with the installation qualification (IQ). In addition to specific installation activities, a key part of IQ is to enter the equipment into inventory maintained as part of the program by labeling it and creating the equipment log. In some cases, vendors may require that they perform the installation themselves, resulting in shared documentation of IQ activities. The qualification life cycle also includes components commonly referred to as operational qualification (OQ) and performance qualification (PQ). Although no requirement exists to separate qualification components into IQ,OQ, and PQ, these terms often facilitate the qualification activities when complex equipment is involved. The OQ testing ensures that the equipment is capable of meeting performance criteria within the ranges used for all of the testing. The selection of OQ tests is based on good science and the intended use of the equipment. The purpose of such tests is to ensure the validity of the data. Suggestions of specific OQ tests for various equipment types are listed in the sidebar “Examples of operational qualification tests for common analytical equipment.”Depending on the specific use of each type of equipment, the appropriate tests and frequency of testing should be incorporated into the qualification program. Performance qualification involves the testing of the equipment using the specific method or assay to ensure that the method is producing valid data. PQ may consist of method validation testing, system suitability testing, and analysis and trending of control samples. PQ supplements the OQ by adding checks of the specific method used.Again, like OQ, PQ

testing procedures should be based on good science and will depend on the specific method being used. In summary, the procedures used throughout the entire qualification life cycle must be documented, be based on good science, and ensure the integrity of the data generated by the equipment. The procedures and the functions or components qualified also should be based on the intended use of the equipment. Some qualification should be performed on a periodic basis, and this practice should be defined in the written qualification procedures. The regulations and the supporting science offer no distinction between a manufacturing quality control laboratory and an R&D laboratory. The same quality standard applies in each situation.

Equipment maintenance

Some OQ testing should be performed following equipment maintenance. The testing should be limited to the operational functions that are affected by the specific maintenance procedure. This usually involves repeating the OQ tests that evaluate the component that has been repaired or replaced. Components that are subject to wear and require routine replacement are best handled with a preventive maintenance program. The preventive maintenance intervals should be defined, be documented, and be an integral part of the qualification life cycle. Intervals can be defined or adjusted on the basis of the actual equipment qualification or maintenance history. Preventive maintenance is performed mainly for business reasons because it represents the most cost-effective method of maintaining equipment that requires frequent service.

Computers and software used to control laboratory equipment

Current regulations require the validation of computers and software that are used to control laboratory equipment or process data. Systems that acquireprocess, or store data also have additional requirements defined by 21 CFR 11. Although qualification is considered a subset of validation, validation requires additional documentation and change control procedures. Guidance for validation of computers and software for general computer-related systems and data acquisition systems have been described in Parenteral Drug Association technical reports (3,4). These guidance documents offer procedures for the documentation, qualification, and change control aspects of validation. When multiple laboratory computers are maintained with the same configuration of hardware and software, complete validation on a single representative unit can be performed. All other identical configurations would require only the IQ portion of the qualification. All such computers must be maintained in the same system of change control, which requires the appropriate revalidation when any change in configuration is made.

Summary and 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 laboratory equipment, the additional validation requirement 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

1. “Laboratory Controls, General Requirements,”

Code of Federal Regulations, Part

211.160, Title 21, Rev. April 2000.

2. “Maintenance and Calibration of Equipment,”

Code of Federal Regulations, Part 58.63,

Title 21, Rev. April 2000.

3. PDA, Validation of Computer-Related Systems,

Technical Report No. 18, PDA J. Sci.

Technol. 49 (1), S1–S17 (1995).

4. PDA, Validation and Qualification of Computerized

Laboratory Data Acquisition Systems,

Technical Report No. 31, PDA J. Sci.

Technol. 53 (4), 1–12 (1999).

5. National Conference of Standards Laboratories,

Establishment and Adjustment of Calibration

Intervals, NCSL RP-1 (1996).

6. J.Agalloco, “Master Planning of Validation,”

PDA Training and Research Institute, April

1998.

7. M. Dorfman and R. Thayer, Standards,

Guidelines, and Examples on Software Requirements

Engineering (IEEE Computer Society

Press,Washington, DC, 1990).

8. P. Bedson, “The Development and Application

of Guidance on Equipment Qualification

of Analytical Instruments,”Accred. Qual.

Assur. 1 (6), 265–274 (1996).

9. P.A. Cloud, “Validating a Laboratory Incubator,”

BioPharm 10 (11), 30–42 (1997).

10. The Rules Governing Medicinal Products in

the European Community,Volume IV (Office

for Official Publications for the European

Communities, Luxembourg, 1992).

11. FDA, “Guidelines on General Principles of

Process Validation,”Rockville,MD,May 1987.

12. Department of Defense,“Definition of Terms

for Testing,Measurement, and Diagnostics,”

MIL-STD-1309D, PAR 3.1.326 (1983).

13. J.K. Taylor, “Standard Reference Materials:

Handbook for SRM Users,” National Technical

Information Services Publication

260–100 (1993).

14. National Conference of Standards Laboratories,

“General Requirements for the Competence

of Testing and Calibration Laboratories,”

ANSI/ISO/IEC 17025 (2000). PT

Definition of Pharmaceutical Terms

Design Qualification (DQ) :

The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

Installation Qualification (IQ) :

The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

Operational Qualification (OQ) :

The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

Performance Qualification (PQ) :

The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

Ref: Qualification and validation, Annex 15 to the EU Guide to Good Manufacturing Practice

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 5

Equipment/Line/Area Cleaning, Preparation, and Clearance

• Do written procedures detail how equipment is to be checked immediately prior to use for cleanliness, removal of any labels and labeling from prior print operations? Check here YES / NO
• Do written procedures detail any disconnection and reassembly required to verify readiness for use?

Operational Process Validation and Production Change Order Control,

• Have production procedures been validated? (Review selected procedures for validation documentation. Adequate?) Check here YES / NO
• Does the process control address all issues to ensure identity, strength, quality and purity of product? Check here YES / NO
• Does the procedure include formulation that is written to yield not less than 100% of established amount of active ingredients? Check here YES / NO
• Are all weighing and measuring preformed by one qualified person and observed by a second person? Check here YES / NO
• Have records indicated preceding policy been followed by presence of two signatures? Check here YES / NO
• Are actual yields calculated at the conclusion of appropriate phases of the operation and at the end of the process? Check here YES / NO
• Are calculations performed by one person? Is there independent verification by a second person? Check here YES / NO

In-Process Inspection, Sampling, and Laboratory Control

• Are written procedures established to monitor output and validate the performance of manufacturing procedures that may cause variability in characteristics of in-process materials and finished drug products? Check here YES / NO
• Are in-process materials tested at appropriate phases for identity, strength, quality, purity and are they approved or rejected by Quality Control? Check here YES / NO
• Are there laboratory controls including sampling and testing procedures to assure conformance of components, containers, closures, in-process materials, and finished product specifications? Check here YES / NO
• Reprocessing/Disposition of Materials Check here YES / NO
• Do written procedures identify steps for reprocessing batches? Check here YES / NO
• Are quality control review and approval required for any and all reprocessing of material? Check here YES / NO
• Does testing confirm that reprocessed batches conform to established specification? Check here YES / NO
• Does a written procedure outline steps required to reprocess returned drug products (if it can be determined that such products have not been subjected to improper storage conditions?) Check here YES / NO
• Does Quality Control review such reprocessed returned goods and test such material for conformance to specifications before releasing such material for resale?
  Check here YES / NO

Finished Product Control

• Finished Product Verification, Storage, and Handling Check here YES / NO
• Do written procedures indicate how and who verifies that correct containers and packages are used for finished product during the finishing operation? Check here YES / NO
• In addition, do written procedures require that representative sample of units be visually examined upon completion of packaging to verify correct labeling? Check here YES / NO
• Are expiration dates stamped or imprinted on labels? Check here YES / NO
• Are expiration dates related to any storage conditions stated on the label? Check here YES / NO
• Are all finished products held in quarantine until QC has completed its testing and releases product on a batch to batch basis for sale? Check here YES / NO
• Is finished product stored under appropriate conditions of temperature, humidity, light, etc. Check here YES / NO

Finished Product Inspection, Sampling, Testing, and Release for Distribution

• Has the formulation for each product been tested for stability based on a written protocol? (Containers must duplicate those used in final product packaging.) Check here YES / NO
• Are written sampling and testing procedures and acceptance criteria available for each product to ensure conformance to finished product specifications? Check here YES / NO
• Is a quantity of samples equal to at least twice the quantity needed for finished product release testing maintained as a reserve sample? Check here YES / NO
• Are sterility and pyrogen testing performed as required? Check here YES / NO
• Are specific tests for foreign particles or abrasives included for any ophthalmic ointments? Check here YES / NO
• Do controlled release or sustained release products include tests to determine conformance to release time specification? Check here YES / NO

Distribution Controls

• Does a written procedure manage stocks to ensure that oldest approved product is sold first? Check here YES / NO
• Are deviations to the policy above documented? Check here YES / NO
• Does a written procedure identify the steps required if a product recall is necessary? Check here YES / NO
• Is the recall policy current and adequate? Check here YES / NO
  
  

Marketing Controls

• The current regulation does not address marketing controls per se except that all finished products must meet their specifications. Check here YES / NO

Complaint Handling and Customer Satisfaction Program

• Are complaints, whether received in oral or written form, documented in writing and retained in a designated file? Check here YES / NO
• Are complaints reviewed on a timely basis by the Quality Control Unit? Check here YES / NO
• Is the action taken in response to each complaint documented? Check here YES / NO
• Are decisions not to investigate a complaint also documented and the name of the responsible person documented? Check here YES / NO
• Are complaint investigations documented and do they include investigation steps, findings, and follow-up steps, if required? Are dates included for each entry? Check here YES / NO
   

Reference : WHO guideline for GMP/Internet

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 4

Material Component Storage and Handling with respect to

• Are incoming material and components quarantined until approved for use? Check here YES / NO
• Are all materials handled in such a way to prevent contamination? Check here YES / NO
• Are all materials stored off the floor? Check here YES / NO
• Are materials spaced to allow for cleaning and inspection? Check here YES / NO
• Are labels for different products, strengths, dosage forms, etc., stored separately with suitable identification? Check here YES / NO
• Is label storage area limited to authorized personnel? Check here YES / NO
• Are rejected components, material, and containers quarantined and clearly marked to prevent their use? Check here YES / NO
  
  

Inventory Control Program for GMP

• Are inventory control procedures written? Check here YES / NO
• Does the program identify destruction dates for obsolete or out-dated materials, components, and packaging materials? Check here YES / NO
• Is stock rotated to ensure that the oldest approved product or material is used first? Check here YES / NO
• Is destruction of materials documented in a way that clearly identifies the material destroyed and the date on which destruction took place? Check here YES / NO

Vendor (Supplier) Control Program

• Are vendors periodically inspected according to a written procedure? Check here YES / NO
• Is the procedure for confirming vendor test results written and followed? Check here YES / NO

Operational Control

• Material/Component/Label Verification, Storage, and Handling Check here YES / NO
• Do written procedures identify storage time beyond which components, containers, and closures must be reexamined before use? Check here YES / NO
• Is release of retested material clearly identified for use? Check here YES / NO
• Are retesting information supplements originally obtained? Check here YES / NO
• Do written procedures identify steps in the dispensing of material for production? Check here YES / NO
• Do these procedures include (1) release by QC, (2)Documentation of correct weight or measure, and (3) Proper identification of containers? Check here YES / NO
• Does a second person observe weighing/measuring/dispensing and verify accuracy with a second signature? Check here YES / NO
• Is the addition of each component documented by the person adding the material during manufacturing? Check here YES / NO
• Does a second person observe each addition of material and document verification with a second signature? Check here YES / NO
• Does a written procedure specify who is authorized to issue labels? Check here YES / NO
• Does a written procedure specify how labels are issued, used, reconciled with production, returned when unused, and the specific steps for evaluation of any discrepancies? Check here YES / NO
• Do written procedures call for destruction of excess labeling on which lot or control numbers have been stamped or imprinted? Check here YES / NO

Reference : WHO guideline for GMP/Internet

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 3

Equipment Identification with respect to GMP

• Are all pieces of equipment clearly identified with easily visible markings? Check here YES / NO
• Are all pieces of equipment also marked with an identification number that corresponds with an entry in an equipment log? Check here YES / NO
• Does each piece of equipment have written instructions for maintenance that includes a schedule for maintenance? Check here YES / NO
• Is the maintenance log for each piece of equipment kept on or near the equipment? Check here YES / NO

Equipment Maintenance & Cleaning with respect to GMP

• Are written procedures established for the cleaning and maintenance of equipment and utensils? Check here YES / NO
• Are these procedures followed? Check here YES / NO
• Does a written procedure assign responsibility for the cleaning and maintenance of equipment? Check here YES / NO
• Has a written schedule been established and is it followed for the maintenance and cleaning of equipment? Check here YES / NO
• Has the cleaning procedure been properly validated? with respect to who GMP guide for quality assurance .Check here YES / NO
• If appropriate, is the equipment sanitized using a procedure written for this task? Check here YES / NO
• Has a sufficiently detailed cleaning and maintenance procedure been written for each different piece of equipment to identify any necessary disassembly and reassembly required to provide cleaning and maintenance? Check here YES / NO
• Does the procedure specify the removal or obliteration of production batch information from each piece of equipment during its cleaning?
• Is equipment cleaned promptly after use? IS GMP FOLLOWED Check here YES / NO
• Is clean equipment clearly identified as "clean" with a cleaning date shown on the equipment? Check here YES / NO
• Is clean equipment adequately protected against contamination prior to use? Check here YES / NO
• Is equipment inspected immediately prior to use? Check here YES / NO
• Are written records maintained on equipment cleaning, sanitizing and maintenance on or near each piece of equipment? Check here YES / NO

Measurement Equipment Calibration Program for GMP

• Does the facility have approved written procedures for checking and calibration of each piece of measurement equipment? (Verify procedure and log for each piece of equipment and note exceptions in notebook with cross reference.) Check here YES / NO
• Are records of calibration checks and inspections maintained in a readily retrievable manner? Check here YES / NO

Equipment Qualification Program for GMP

• Verify that all pieces of equipment used in production, packaging, and quality assurance are capable of producing valid results. Check here YES / NO
• When computers are used to automate production or quality testing, have the computer and software been validated? Check here YES / NO
• Have on-site tests of successive production runs or tests been used to qualify equipment? Check here YES / NO
• Were tests repeated a sufficient number of times to ensure reliable results? Check here YES / NO
• Is each piece of equipment identified to its minimum and maximum capacities and minimum and maximum operating speeds for valid results? Check here YES / NO
• Have performance characteristics been identified for each piece of equipment? (May be provided by the manufacturer, but must be verified under typical operations conditions.) Check here YES / NO
• Have operating limits and tolerances for performance been established from performance characteristics? Check here YES / NO

Material/Component Specification and Purchasing Control

• Although purchasing is not specifically addressed in the current GMP regulation, incumbent upon user of components and materials to ensure quality of product, material or component. Check here YES / NO
• Has each supplier/vendor of material or component been inspected/audited for proper manufacturing controls? (Review suppliers and audits and enter names, material supplied, and date last audited in notebook.) Check here YES / NO
• Material/Component Receipt, Inspection, Sampling, and Laboratory Testing Check here YES / NO
• Does the facility have current written procedures for acceptance/rejections of drug products, containers, closures, labeling and packaging materials? (List selected materials and components in notebook and verify procedures.) Check here YES / NO
• Is each lot within each shipment of material or components assigned a distinctive code so material or component can be traced through manufacturing and distribution? Check here YES / NO
• Does inspection start with visual examination of each shipping container for appropriate labeling, signs of damage, or contamination? Check here YES / NO
• Is the number of representative samples taken from a container or lot based on statistical criteria and experience with each type of material or component?
• Is the sampling technique written and followed for each type of sample collected? Check here YES / NO
• Is the quantity of sample collected sufficient for analysis and reserve in case retesting or verification is required? Check here YES / NO
• Verify that the following steps are included in written procedures unless more specific procedures are followed:Containers are cleaned before samples are removed. Check here YES / NO
• Stratified samples are not composited for analysis. Check here YES / NO
• Containers from which samples have been taken are so marked indicating date and approximate amount taken. Check here YES / NO
• Each sample container is clearly identified by material or component name, lot number, date sample taken, name of person taking sample, and original container identification. Check here YES / NO
• At least one test is conducted to confirm the identity of a raw material (bulk chemical or pharmaceutical) when a Certificate of Analysis is provided by supplier and accepted by QA. Check here YES / NO

• If a Certificate of Analysis is not accepted for a lot of material, then additional testing is conducted by a written protocol to determine suitability for purpose. 
• Microbiological testing is conducted where appropriate. Check here YES / NO
  Reference : WHO guideline for GMP/Internet

Audit checklist for who GMP guideline compliance in pharmaceuticals_Part 2

Design Control with respect to who gmp,not directly related to the Drug Regulation

• Facility Control Check here YES / NO
• Facility Design and Layout Check here YES / NO
• Are all parts of the facility constructed in a way that makes them suitable for the manufacture, testing, and holding of drug products? Check here YES / NO
• Is there sufficient space in the facility for the type of work and typical volume of production? Check here YES / NO
• Does the layout and organization of the facility prevent contamination? Check here YES / NO

Environmental Control Program for GMP compliance

• The facility is NOT situated in a location that potentially subjects workers or product to particulate matter, fumes, or infestations? Check here YES / NO
• Are grounds free of standing water? Check here YES / NO
• Is lighting adequate in all areas? Check here YES / NO
• Is adequate ventilation provided? Check here YES / NO
• Is control of air pressure, dust, humidity and temperature adequate for the manufacture, processing, storage or testing of drug products? Check here YES / NO
• If air filters are used, is there a written procedure specifying the frequency of inspection and replacement? Check here YES / NO
• Are drains and routine cleaning procedures sufficient to prevent standing water inside the facility? Check here YES / NO
• Does the facility have separate air handling systems, if required, to prevent contamination? (MANDATORY IF PENICILLIN IS PRESENT!) Check here YES / NO

Facility Maintenance and Good Housekeeping Program for GMP

• Is this facility free from infestation by rodents, birds, insects and vermin? Check here YES / NO
• Does this facility have written procedures for the safe use of suitable, (e.g. those that are properly registered) rodenticides, insecticides, fungicides, and fumigating agents? Check here YES / NO
• Is this facility maintained in a clean and sanitary condition? Check here YES / NO
• Does this facility have written procedures that describe in sufficient detail the cleaning schedule, methods, equipment and material? with respect to who gmp guide for quality assuarance
• Does this facility have written procedures for the safe and correct use of cleaning and sanitizing agents? with respect to who gmp guide for quality assuarance, Check here YES / NO
• Are all parts of the facility maintained in a good state of repair ?
• Is sewage, trash and other refuse disposed of in a safe and sanitary manner (and with sufficient frequency?) Check here YES / NO

Outside Contractor Control Program

• Are contractors and temporary employees required to perform their work under sanitary conditions? with respect to who gmp guide for quality assuarance. Check here YES / NO
• Are contractors qualified by experience or training to perform tasks that may influence the production, packaging, or holding of drug products? Check here YES / NO

 Equipment Control with respect to who gmp

• Equipment Design and Placement Check here YES / NO
• Is all equipment used to manufacture, process or hold a drug product of appropriate design and size for its intended use? Check here YES / NO
• Are the following pieces of equipment suitable for their purpose? Blender(s), Conveyor(s), Tablet, Presses, Capsule Fillers, Bottle Fillers, Other (specify). Check here YES / NO
• Are the following pieces of equipment suitable in their size/capacity? Blender(s), Conveyor(s), Tablet, Presses, Capsule Fillers, Bottle Fillers, Other (specify). Check here YES / NO
• Are the following pieces of equipment suitable in their design? Blender(s), Conveyor(s), Tablet, Presses, Capsule Fillers, Bottle Fillers, Other (specify). Check here YES / NO
• Are the locations in the facility of the following pieces of equipment acceptable? Blender(s), Conveyor(s), Tablet, Presses, Capsule Fillers, Bottle Fillers, Other (specify). Check here YES / NO
• Are the following pieces of equipment properly installed? Blender(s), Conveyor(s), Tablet, Presses, Capsule Fillers, Bottle Fillers, Other (specify). Check here YES / NO
• Is there adequate space for the following pieces of equipment? Blender(s), Conveyor(s), Tablet, Presses, Capsule Fillers, Bottle Fillers, Other (specify),for GMP Check here YES / NO
• Are machine surfaces that contact materials or finished goods non-reactive, non-absorptive, and non-additive so as not to affect the product? Check here YES / NO
• Are design and operating precautions taken to ensure that lubricants or coolants or other operating substances do NOT come into contact with drug components or finished product? Check here YES / NO
• Fiber-releasing filters are NOT used in the production of injectable products? Check here YES / NO
• Asbestos filters are NOT used in the production of products, with respect to who gmp guide for quality assuarance? YES / NO
• Is each idle piece of equipment clearly marked "needs cleaning" or "cleaned; ready for service"? Check here YES / NO
• Is equipment cleaned promptly after use? YES / NO Check here YES / NO
• Is idle equipment stored in a designated area? Check here YES / NO
• Are written procedures available for each piece of equipment used in the manufacturing, processing or holding of components, in-process material or finished product? Check here YES / NO
• Do cleaning instructions include disassembly and drainage procedure, if required, to ensure that no cleaning solution or rinse remains in the equipment? Check here YES / NO
• Does the cleaning procedure or startup procedure ensure that the equipment is systematically and thoroughly cleaned? Check here YES / NO

Reference : WHO guideline for GMP/Internet

Audit checklist for who gmp guideline compliance in pharmaceuticals_Part 1

Dear all, here I provide a list of possible questions which an auditors are most likely going to ask and cheek for who gmp guideline compliance in pharmaceuticals inspection.

Before any inspection, hand over the copy of this to respective departments and make them ready for compliance of these questions.

Check pervious audit report , costumers feedback's , complaints etc and use this to verify the compliance for the particular point.

Following is the step by step guideline

With respect to requirements of who gmp guide for quality assuarance

• Does the pharmaceutical manufacturing firm ,organizational units ,operate in a state of control as defined by the GMP regulations? who gmp guidelines are followed? Check here YES / NO
• Organizational & Management Responsibilities for gmp. Check here YES / NO
• Does this facility/business unit operate under a facility or corporate quality policy? Check here YES / NO
• Does a Quality Assurance unit (department) exist as a separate organizational entity to ensuer all aspects of who gmp guide ? Check here YES / NO
• Does the Quality Assurance unit alone have both the authority and responsibility to approve or reject all components, drug product containers and closures, in-process materials, packaging materials, labeling and drug products? Check here YES / NO
• Does the QA department or unit routinely review production records to ensure that procedures were followed and properly documented with respect to GMP who gmp guide for quality assurance? Check here YES / NO
• Are adequate laboratory space, equipment, and qualified personnel available for required testing ? with respect to who gmp guide for quality assurance Check here YES / NO
• If any portion of testing is performed by a contractor, has the Quality Assurance unit inspected the contractor’s site and verified that the laboratory space, equipment, qualified personnel and procedures are adequate? Check here YES / NO
• Date of last inspection:____________________
• Are all QA procedures in writing? with respect to who gmp guidelines,who gmp guide for quality assuarance Check here YES / NO
• Are all QA responsibilities in writing? with respect to who gmp guide for quality assuarance Check here YES / NO
• Are all written QA procedures current and approved? (Review log of procedures) Check here YES / NO
• Are the procedures followed? (Examine records to ensure consistent record-keeping that adequately documents testing.)Check here YES / NO
• Are QA supervisory personnel qualified by way of training and experience with respect to who gmp guide for quality assuarance? Check here YES / NO
• Are other QA personnel, e.g., chemists, analysts, laboratory technicians) qualified by way of training and experience with respect to who gmp guide for quality assuarance? Check here YES / NO

Document Control Program

• Does the QA unit have a person or department specifically charged with the responsibility of designing, revising, and obtaining approval for production and testing procedures, forms, and records ,with respect to who gmp guide for quality assurance? Check here YES / NO
• Does a written SOP, which identifies how the form is to be completed and who signs and countersigns, exist for each record or form ,with respect to who gmp guide for quality assurance? Check here YES / NO
• Is the production batch record and release test results reviewed for accuracy and completeness before a batch/lot of finished product is released? Check here YES / NO

Employee Orientation, Quality Awareness, and Job Training with respect to gmp

• Circle the types of orientation provided to each new employee: (1) Company brochure (2) Literature describing GMP regulations and stressing importance of following instructions. (3) On-the-job training for each function to be performed (before the employee is allowed to perform such tasks). (4) Other: enter in notebook. Check here YES / NO
• Does each employee receive retraining on an SOP (procedures) if critical changes have been made in the procedure? Check here YES / NO
• Indicate how on-going, periodic GMP training is accomplished. Check here YES / NO
• Is all training documented in writing that indicates the date of the training, the type of training, and the signature of both the employee and the trainer? Check here YES / NO
• Are training records readily retrievable in a manner that enables one to determine what training an employee has received, which employees have been trained on a particular procedure, or have attended a particular training program? Check here YES / NO
• Are GMP trainers qualified through experience and training Check here YES / NO
• Are supervisory personnel instructed to prohibit any employee who, because of any physical condition (as determined by medical examination or supervisory observation) that may adversely affect the safety or quality of drug products, from coming into direct contact with any drug component or immediate containers for finished product? Check here YES / NO
• Are employees required to report to supervisory personnel any health or physical condition that may have an adverse effect on drug product safety and purity? Check here YES / NO
• Are temporary employees given the same orientation as permanent employees?
• Are consultants, who are hired to advise on any aspect of manufacture, processing, packing or holding, of approval for release of drug products, asked to provide evidence of their education, training, and experience? Check here YES / NO
• Are written records maintained stating the name, address, qualifications, and date of service for any consultants and the type of service they provide? Check here YES / NO

Plant Safety and Security

• Does this facility have a facility or corporate safety program? Check here YES / NO
• Are safety procedures written? Check here YES / NO
• Are safety procedures current? Check here YES / NO
• Do employees receive safety orientation before working in the plant area? Check here YES / NO
• Is safety training documented in a readily retrievable manner that states the name Check here YES / NO
• of the employee, the type of training, the date of the training, and the name of the trainer and the signature of the trainer and the participant? Check here YES / NO
• Does this facility have a formal, written security policy? Check here YES / NO
• Is access to the facility restricted? Check here YES / NO
• Describe how entry is monitored/restricted: Check here YES / NO
• Is a security person available 24 hours per day? Check here YES / NO
  
  

Internal Quality/who gmp Audit Program

• Does this business unit/facility have a written quality policy? Check here YES / NO
• Is a copy of this quality policy furnished to all employees? Check here YES / NO
• If "yes" to above, when provided? __________________
• Is training provided in quality improvement? Check here YES / NO
• Does a formal auditing function exist in the Quality Assurance department? Check here YES / NO
• Does a written SOP specify who shall conduct audits and qualifications (education, training, and experience) for those who conduct audits? Check here YES / NO
• Does a written SOP specify the scope and frequency of audits and how such audits are to be documented? Check here YES / NO
• Does a written SOP specify the distribution of the audit report? Check here YES / NO

Quality Cost Program for gmp cgmp

• Does this facility have a periodic and formal review of the cost of quality? Check here YES / NO
• Does this facility have the ability, through personnel, software, and accounting Check here YES / NO
• Records, to identify and capture quality costs? Check here YES / NO
• Does this facility make a conscious effort to reduce quality costs? Check here YES / NO

Reference: WHO guideline for GMP/Internet

Guideline handling of loose containers of raw materials

1.0 After dispensing of material,container & inner polybag of the loose material to be closed properly.
1.1 Weigh the loose container and record the Gross weight on the label.
1.2 Based on the original tare weight calculate the net weight of the loose material and record the net weight on the label as per annexure attached.
1.3 Sign the label and affix the loose container label on the container over the earlier loose container label after verifying the details.
1.4 Before affixing the loose container label strike off the earlier loose container label.
1.5 Send back the loose container to warehouse through the material exit box after dedusting and cleaning
1.6 The same loose container to be taken first for next dispensing

Guideline for sterility test procedure of eye drops

Preparation of media: (Thioglycollate & Sabouraud Dextrose)

Prepare as directed in the label of the manufacturer. Transfer 15-20 ml to each 50 ml flat bottom flask (about 10 flask taken) and introduce a cotton plug to each, wrapping with paper and fasten the neck with thread. Sterilize in an autoclave at 121⁰c/15 lb pressure for 20 minutes. After autoclaving place them in front of LAFB. After achieving the room temperature, incubate for 24-48 hours and then store for use if no evidence of contamination is found.

Filtration Method (Pore Size 0.2 µm): Prepare each membrane filter as follows. Transfer a small quantity (sufficient to moisten the membrane filter) of sterile diluent of 0.1% w/v neutral solution of meat peptone. Sample taken 2 ml in 100 ml sterile 0.1% w/v neutral solution and filter through the membrane filter and further pass through the membrane filter about 150 ml sterile diluent in such a manner that the effect of the antibiotic is neutralized in a greater magnitude. The filtration apparatus and membrane are sterilized by appropriate means. The preparation being tested is transferred through a membrane filter paper. The membrane is washed at least three times by filtering through it each time with the sterile dilute isopropyl myristate.

The membrane is cut aseptically into two equal parts and transfer one half to each of the media i.e. Thioglycollate  broth & Sabouraud dextrose broth. (also perform a control test without the sample). Incubate at 30-35⁰c for bacteria (or 20-25⁰c for fungi) for 7 days. Observe the culture media several times during the incubation period. At intervals during the incubation period and its conclusion, examine the media for microscopic evidence of microbial growth.

When the material being tested render the media turbid so that the presence or absence of microbial growth can not be determined readily by visual examination 7 days after the incubation started, transfer suitable portions of the cultured media to fresh vessel of the same medium. Continue incubation of the original and transferred vessel for a total 14+7 = 21 days from the original incubation. If no evidence of microbial growth is found, the product being examined complies with the test for sterility.  If evidence of microbial growth is found  (turbid solution), the product being examined does not comply with the test for sterility.

PRECAUTION:

               I.      Before entering the working room wash the hands and mouth and dry in fresh air.

             II.      Swab the hands with sterile 70% isopropyl alcohol and put on mask & sterile hand gloves.

            III.      During working infront of LAFB, the UV light must be off.