Good Manufacturing Practice (cGMP) is the term used to define the latest best practice for the manufacture of pharmaceutical and allied products in various countries around the world. In New Zealand, this requirement is set out in the New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Goods published by the Ministry of Health In practice, these provisions mean compliance with the requisite domestic and/or international legislation and regulations.
Good Manufacturing Practice (cGMP) is the term used to define the latest best practice for the manufacture of pharmaceutical and allied products in various countries around the world. In New Zealand, this requirement is set out in the New Zealand Code of Good Manufacturing Practice for Manufacture and Distribution of Therapeutic Goods published by the Ministry of Health In practice, these provisions mean compliance with the requisite domestic and/or international legislation and regulations.
PRINCIPLE OF “CGMP” :
The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practices that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs.
Good Manufacturing Practices (GMPs) is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorization or product specification. GMP is concerned with both production and quality control. 1
Worldwide, there are different official regulatory statements and guidelines, national and international, on Good Manufacturing Practices for pharmaceutical (or “drug” or “medicinal”) products. They may be regulations (as in the US, Japan or Korea), directives (as in the EU), guides (as in the UK), codes (as in Australia), or WHO code (as in many Southeast Asia Countries). Out of them, following stands out as being the most influential and most frequently referenced:
-The US Current Good Manufacturing Practices for Finished Pharmaceuticals regulations (the “US cGMPs”) 2
-The Guide to Good Manufacturing Practice for Medicinal Products of the European Union (the “EC GMP Guide”) 3
-ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients4.
WHO good manufacturing practices5.
The other guidelines and regulation referred by the pharmaceutical manufacturers are as under
-Schedule M “Good Manufacturing Practices and Requirements of Premises, Plant and Equipment for Pharmaceutical Products” The Drugs And Cosmetics Act And Rules, India 6.
-PIC/S Guide to Good Manufacturing Practice for Medicinal Products 7.
-Centre for Drug Evaluation and Research (CDER); Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients 8.
2. FINISHED PHARMACEUTICAL : GENERAL PROVISION: (SUBPART A)
(a) The regulations in this part contain the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals.
(b) The current good manufacturing practice regulations in this chapter, as they pertain to drug products, and in Parts 600 through 680 of this chapter, as they pertain to biological products for human use, shall be considered to supplement, not supersede, the regulations in this part unless the regulations explicitly provide otherwise. In the event, it is possible to comply with applicable regulation both in this part and in the other parts of this chapter or in parts 600 through 680 of this chapter, the regulation specifically applicable to drug product in question cell supersede the regulation in this part.
(c) Pending consideration of a proposed exemption published in the federal register of September 29, 1978, the requirements in this part shall not be enforced for OTC drug products if the products and all their ingredients are ordinarily marketed are consumed as human foods, and which products may also fall within the legal definition of drug by virtue of their intended use. Therefore, until further notice, regulation under part 110 of this chapter, and where applicable , parts 113 to 129 of this chapter, shall be applied in determining whether this OTC drug products that are also foods are manufactured, processed, packed, or held under current good manufacturing practice.
This section states that the company’s adherence to the requirements of the entry set of regulation determined whether its output will be judged as adulterated or violative. Adherence to the requirements initially necessitates an analysis of all current operations within the company that if a fact the quality of the finished products. Such an analysis surveys as a framework for structuring decision and information follows between managers, operators, scientists, technicians, and other personnel who regulate product quality. An analysis of current conditions also divides the flow of materials into discrete, sequential operations from the receipt and sampling of raw materials to final accountability computations during the market distribution, in order that critical procedures can be specified and more closely examined.
The first step is to evaluate the chances of establishing and maintaining a god quality control program. The first list, therefore, is a description of the organization.
Product Information: In order to initiate quality control procedures, the dimensions of operations should be estimated. This requires the following information for the entire product line of the firm
Type and Quality Quantity Packaged
Product name Manufactured Own label Other label
Tablets, enteric coated
Tablets, repeat dosage
Tablets, sustained release
Capsules, sustained release
Liquids, oral, sustained release
Parenteral, sterile fill
Aerosols, metered dose
How are the products promoted? (Obtain samples and package inserts.) _____ Professional journal ______ Lay journal _____ Internet _____ Newspaper ______ Other.
The same procedures should be followed in assessing the operations of all outside contractors who contribute to the production of the finished pharmaceutical.
Attention should be focused on the critical concepts of a quality control system. The production cycle for each drug must be controlled so that optimum quality levels can be attained for each manufacturing sequence. The efforts of all personnel making product integrity decisions during processing must be coordinated and standardized to attain these desired levels.
SUPPLEMENTARY INFORMATION AS TO CGMPS FOR MEDICAL DEVICES AS PROVIDED BY FOOD AND DRUG ADMINISTRATION :
Manufactures establish and follow quality systems to help ensure that their products consistently meet applicable requirements and specifications. The quality systems for FDA regulated products (food, drugs, biologics. And devices) are known as CGMPs. CGMP requirements for devices (part 820 (21 CFR part 820)) were first authorized by section t520(f) of the Federal Food, drug and Cosmetic Act (the Act) (21 U.S.C. 360j(f)), which was among the authorities added to the Act by the Medical Device Amendments of 1976 (Pub L. 94-295). The Safe Medical Devices Act (the SMDA) of 1990 (Pub. L.101-629), enacted on November 28, 1990, amended section 210(f) of the Act, providing FDA with the explicit authority to add preproduction design validation controls to the CFMP regulation. The SMDA also added a new section 803 to the Act (21 U.S.C. 393) which, among other things, encourages FDA to work foreign countries toward mutual recognition of CGMP requirements.
Requirements for Expiration Dating and Stability Testing
Current Good Manufacturing Practices for Finished Pharmaceuticals (CGMP) introduced requirements concerning expiration dating and stability testing which became effective September 29, 1979. The purpose of this guide is to delineate those situations in which the Center is prepared to consider regulatory action.
1. Lack of assurance that a product labeled as sterile has been tested to ascertain that the container and closure can maintain a sterile state throughout the labeled shelf life.
2. Lack of a written stability program for bulk drug substances or an indication that it is either inadequate or not being followed.
3. Lack of an expiration date on finished dosage forms or a written stability program.
4. Lack of a labeled date indicating stability after reconstitution or lack of studies to support the appropriateness of that date.
5. Lack of an ongoing testing program to verify product stability after the shelf life has been determined appropriate.
6. Lack of assurance that meaningful, specific, or reliable test methods and storage conditions are employed.
7. Lack of assurance that the currently marketed container or closure will provide adequate protection of the drug product.
8. Lack of follow-up studies at the labeled storage condition or, if there are no storage conditions specified, at room temperature, for drug products for which the shelf life was determined by accelerate studies.
9. Lack of assurance of the effectiveness of any preservations used throughout the labeled shelf life.
10. Lack of an adequate number of batches (i.e. less than three) employed as the basis for either confirming a tentative expiration date or establishing the long-term stability of the product.
11. Distribution of product past the labeled expiration date.
3. ORGANIZATION AND PERSONNEL (SUBPART B)
Responsibilities of quality control unit
(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, and the authority to review production records to assure that no errors have occurred, or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufacture, processed, packed, or held under contract by another company.
(b) Adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, in-process materials, and drug products shall be available to the quality control unit.
(c) The quality control unit shall have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the drug product.
(d) The responsibilities and procedures applicable to the quality control unit shall be in writing: such written procedures shall be followed.
The CGMP’s focus all responsibility for quality onto the QC unit. There are no defined responsibilities for production management – unlike the European and World Health Organization (WHO) guidelines, which define both separate and joint responsibilities for these functions. This latter approach more clearly emphasizes that the consistent achievement of quality standards requires a team effort.
Within the production operation all quality-impacting procedures and systems are to be approved by QC. Typically, these include such procedures as standard operating procedures (SOPs), process validation protocols, supplier certification protocols, complaint handling, process control procedures, and even design of buildings. Since some of these systems are “owned” by other functions, it is essential that QC have effective procedures to ensure that such systems are reviews in a timely manner and that changes cannot be introduced without approval. During 1985 and 1986 several companies had serious problems associated with changes in formulations and manufacturing processes, which then failed to comply with requirements of NDA and ANDA documentation. These discrepancies resulted in halting of distribution and recalls, with significant loss of revenue to the companies involved. Some of these situations occurred because economies and expedition overwhelmed inadequate approval systems.
QC is also responsible for approving or rejecting labeling. This responsibility lies in two areas. First, new or modified labeling should be reviews to ensure that it complies with the ANA, NA, OTC monograph, or other official requirements that are applicable. This checking may be delegated to other functions, but QC must assure that the checkers are qualified to perform their function and that they have done so. Second, incoming labeling supplies are to be evaluated to assure they are correct. These responsibilities to no apply to promotional literature.
The approval/rejection responsibility also applies to operation contracted out to other companies. This does not necessarily require any additional or duplicate testing. Provided the contractor has adequate procedures and is in full compliance with CGMPs, it should only be necessary to compare the test data with specification and with data from previous batches to identify trends.
No guidance is provided about the actual organization of the QC department, and a wide range of viable alternatives are in effect. One of the simplest, but very effective, is the subdivision into quality control-all inspection and testing and quality assurance-all systems and procedures including batch review and audit. With the increased reliance on non-QC personnel for quality-related activities, such as in-process control ad customer complaint coordination, the role of the quality assurance (QA) unit has become critical. The regulations essentially expect the QC/QA function to provide an independent policy-type role, to monitor the entire production process from purchasing of materials to distribution and use of the product. The function should also be proactive by evaluating data on processes, materials, and suppliers and recommending changes that will improve efficiency and consistency. QC should be a resource that plays a positive role in improving profitability. More will be said about this in future chapters.
Plant manager Group QA or Tech. dir
Safety Materials management Production Employee relations Finance Engineering Quality assurance
Some companies have taken the team approach a stage further by the introduction of self-managed work teams. The various functions or disciplines are incorporated into the team, which can be responsible for all its operational requirements. This can include, in extreme cases, hiring of new team members, discipline, allocation of wage increases or bonuses, work scheduling, product testing, and release/rejection decisions. In these instances there still needs to be an independent QC evaluation for final release/rejection to satisfy the regulations.
(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee's functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.
(b) Each person responsible for supervising the manufacture, processing, packing, or holding of drug product shall have the education, training, and experience, or any combination thereof to perform assigned functions in such a manner as to provide assurance that the drug product has the safety, identity, strength, quality, and purity that it purports or is represented to possess.
(c) There shall be an adequate number of qualified personnel to perform and supervise the manufacture, processing, packing, or holding of each drug product.
The development and training of employees, at all levels, should be seen as a continuous process (figure ) in which performance appraisal plays a key role.
Position requirements defined
Evaluation and appraisal
Additional training or retraining
Figure : Training and development cycle
The GMP regulations do not attempt to define the education, knowledge, skills, or experience required for the different types of job within a pharmaceutical company. This is significantly different from the European and WHO guidelines, which do specify the knowledge and experience requirements for those individuals designated as responsible for production and quality. The consistent achievement of quality standards requires understanding of, and compliance with, established procedures. Consequently, initial screening should select only those individuals who have such basic skills as reading, writing, and numeracy. An employee who cannot understand written instructions will find it difficult to follow procedures, an inability to write coherently will inhibit the recording of a typical situations, while a lack of numeracy could make it impossible to perform certain in-process testing such as statistical process controls. For certain positions color vision may also be important, and some 10% of the population have some degree of color vision problem.
Education and training records must be maintained and kept current : FDA inspectors may ask for confirmation of adequate training.
The responsibility for training of employees should reside with departmental management. However, the QC department should monitor or audit to ensure that the appropriate training has been given. This could include review of training module content and also of training records. Additionally, QC staff themselves are likely to be involved in providing some of the training.
Training, although essential, is more effective in a supportive environment. If management, by example, demonstrate that compliance with procedures is important and encourage participation in improvements, then training will be put into practice. The acknowledgement of ahievement by public recognition or remuneration, often termed positive reinforcement, has a significant impact. The demonstration by example is further illustrated in a later section.
(a) Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.
(b) Personnel shall practice good sanitation and health habits.
(c) Only personnel authorized by supervisory personnel shall enter those areas of the buildings and facilities designated as limited-access areas.
(d) Any person shown at any time (either by medical examination or by supervisory observation) to have an apparent illness or open lesions that may adversely affect the safety or quality of drug products shall be excluded from direct contact with components, drug product containers, closures, in-process materials, and drug products until the condition is corrected or determined by competent medical personnel not to jeopardize the safety or quality of drug products. All personnel shall be instructed to report to supervisory personnel any health conditions that may have an adverse effect on drug products.
The wearing of uniforms for manufacturing and control operations is not mandated. Only that clothing shall be cleaned and appropriate for the duties being performed. In defining what clothing is appropriate it is necessary to consider the end purpose. For example, it would be inappropriate to require hair covering to protect the product from the inadvertent ingress of hair and then to allow employees to wear clothing that incompletely covered the hair, did not cover beards or moustaches, or left the arms uncovered. Yet such situations do exist.
The use of plant uniforms is generally a more satisfactory way of maintaining adequate standards of dress and the following guidelines may be applied :
1. A sufficient amount of clean uniforms is provided so that changes can be made at an adequate denied frequency or whenever they became soiled.
2. Washing and sanitation procedures should be checked to confirm their effectiveness.
3. Employees in special clean areas should wear only lint-free garments to prevent scheduling.
4. Garments should be designed and use material that maximizes personal comfort.
5. The range of clothing available would normally include:
a. Hats or hair cover
b. Beard and moustache covers
c. Coveralls – preferably with no pockets, or pockets suitably designed to prevent articles falling out
d. Disposable gloves
e. Foot covers or shoes
g. Safety glasses or goggles
h. Appropriate clean-room for sterile areas
6. Employees should be shown how and when to wear the appropriate clothing.
7. Work clothing should not be worn outside of the appropriate plant area, and changing rooms should be available.
Separating an ill worker or one with open lesions from the product by use of gloves, masks, or special clothing is not recommended. The discomfort involved in their use tempts the worker to discard them when not being observed. The requirement of this section to report adverse health conditions will not be effective unless a set of specific conditions to be reported is provided. Again, be guided by current legal advice as to the substance and receipt of such information.
The primary objective of this section of the regulations is to protect eh product from potential contamination from personnel – particulate matter including hair, fibers, and outside "dirt" cross-contamination carried on clothing from other processes, microorganisms shed from skin and from the mouth and nose. However, an employer also has a responsibility to protect the employee from unacceptable exposure to the materials being handled, many of which have physiological properties. Where potential exposure is to very potent materials, testing of blood or urine samples may be warranted. Wherever possible, barrier or containment facilities or equipment should be used to protect personnel from extremely hazardous materials. The use of masks or breathing equipment should only be used as the sole precaution in rare circumstances of for less hazardous materials.
4. BUILDINGS AND FACILITIES (SUBPART C)
DESIGN AND CONSTRUCTION FEATURES:
(a) Any building or buildings used in the manufacture, processing, packing or holding of drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.
Regarding buildings and facilities, there are two major areas of concern: the external environment and the internal environment. The external environment must be amenable to the location of well-designed and constructed buildings. It is insufficient that the building in which the production operations are to occur are clean and orderly and of suitable size and construction. If the land, air, or water resources that surround the plant offer the potential for water damage, infestation, or contamination of any type, the facilities are in jeopardy of being judged unsuitable.
Pertinent consideration prior to purchase, construction, or alteration of existing facilities includes the following:
1. Adequate space for future expansion.
2. Zoning laws to allow anticipated development while restricting undesirable developments in the vicinity.
3. Availability of water (quality and quantity), power, fuel, sewage and waste-stream removal.
4. Accessibility for employees (availability of public transportation), materials, and visitors (customers, suppliers).
5. Environmental issues such as site history; soil, water, and air quality; and geological and topological issues (potential for flooding, earthquakes, foundation instability).
6. Proximity of undesirable activities likely to pollute or act as a source of vermin, insects, odor, or microorganisms-such as other industries, disposal sites, or open mining.
7. Availability of a suitable labor force (people, skills, wage expectation, labor relations and attitudes, access to further education sources).
8. Ability to provide adequate security arrangements.
9. Proximity or accessibility to interrelated operations of the company – R&D, marketing, internally produced intermediates or components.
10. Political situation – government stability, trade policies and taxation (for foreign-based operations), financial incentives.
Having identified a suitable location for the facility, the site development plan is prepared and will include:
1. Compliance with appropriate laws and regulations and any additional company standards.
2. Site resources and infrastructure such as amenities, green spaces, parking (employees, delivery and distribution vehicles, visitors), road and rail access, recreation areas, site utilities, tank farms and other external storage, and protection of wetlands and other restricted environments.
3. Storm water and waste management.
4. Site security and access – fences, guard posts, cameras.
5. Buildings – siting, layout, usage, function interrelations for efficiency, possible expansion, surface finishes.
6. Utilities – design, layout, backup (especially for critical utilities as electricity and nitrogen for some chemical operations).
7. Equipment – design, layout, spares, capacity.
8. Traffic flow – pedestrian and vehicular (internal and external).
9. Safety – for personnel and equipment, containment for hazardous materials, sprinkler system, emergency egress, and emergency services access.
10. External architecture to take into account local environmental conditions (wind, snow, humidity) and aesthetic appearance blending local atmosphere, comparative image, and functionality.
11. Ease of maintenance accessibility to services (service ducts), ease of cleaning, access for equipment.
12. Selection and use of experience contractors.
13. Identification of project management responsibility.
14. Validation plans and an effective change control procedure. Provision of design and "as-built" drawings.
15. Construction materials.
a. Walls. Walls in manufacturing areas, corridors, and packaging areas should be of plaster finish on high-quality concrete blocks or gypsum board. The finish should be smooth, usually with enamel or epoxy paint.
b. Floors. Floor covering should be selected for durability as well as clean ability and resistance to the chemicals with which it is likely to come into contact.
i. Terrazzo provides a hard-wearing finish; both tiles and poured-in-place finishes are available. The latter is preferable for manufacturing areas, and if tiles are used, care must be taken to ensure effective sealing between the tiles, which otherwise could become a harboring area of dirt and microorganisms.
ii. Ceramic and vinyl tiles usually are not recommended for production areas. However, if used, the between-tile sealing should be flush and complete.
iii. Welded vinyl sheeting provides an even easy to clean surface. This is not practical for heavy traffic areas, but can be of value in production areas, especially for injectables. Here the lack of joints improves the ease of cleaning and sanitation.
c. Ceilings, Suspended ceilings may be provided inn office areas, laboratories, toilets, and cafeterias. They usually consist of lay-in acoustical panels of nonbrittle, nonfriable, nonasbestos, and non-combustible material.
Manufacturing areas require a smooth finish, often of seamless plaster or gypsum board. All ceiling fixtures such as light fittings, air outlets and returns, PA system and sprinkler heads should be designed to assure ease of cleaning and to minimize the potential for accumulation of dust.
d. Services. In the building design, provisions must be made for drains, water, stream, electricity, and other services to allow for ease of maintenance. Access should, ideally, be possible without disruption of activity within the actual rooms provided with the services.
(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination. The flow of components, drug product containers, closures, labeling, in-process materials and drug products through the building or buildings shall be designed to prevent contamination.
(c) Operations shall be performed within specifically denied areas of adequate size. There shall be separate or defined areas or other such control systems for the firm's operations as are necessary to prevent contamination or mix-ups during the course of the following procedures:
(1) Receipt, identification, storage, and withholding from use of components, drug product containers, closures, and labeling, pending the appropriate sampling, testing, or examination by the quality control unit before release for manufacturing or packaging;
(2) Holding rejected components, drug product container, closures, and labeling before disposition;
(3) Storage of released components, drug product containers, closures, and labeling;
(4) Storage of in-process materials;
(5) Manufacturing and processing operations;
(6) Packaging and labeling operations;
(7) Quarantine storage before release of drug products;
(8) Storage of drug products after release;
(9) Control and laboratory operations.
Adequate lighting shall be provided in all areas.
In order to meet lighting requirement, it is necessary for the manufacturer to define the term "adequate". This may be done by defining the amount of light (lux or foot-candles) reaching the working surface for each area involved in the production of pharmaceuticals. Public standards exist for some types for work. Normally, a range of 30-50 foot-candles ensures worker comfort and ability to perform efficiently and effectively; however, 100 foot-candles may be needed in some areas, as well as special lighting for some operations, such as inspection of filled vials. Once the light levels have been defined, it is necessary that they may be measured periodically and the results recorded. The specifications should call either for replacement of light sources when some level above the established minimum has been reached or alternatively, routine replacements of light sources on some schedule that has been shown adequate to ensure that light levels do not drop below the established minimum.
VENTILATION, AIR FILTRATION, AIR HEATING AND COOLING:
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air pressure, microorganisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.
(c) Air-handling systems for the manufacture, processing and packing of penicillin shall be completely separate from those for other drug products for human use.
Air-handling systems should consider the following factors:
1. Placement of air inlet and outlet ports. These should be sited to minimize the entry of airborne particulates or odors from the surrounding areas. Outlets should not be sited near inlets.
2. Where recirculation of air is acceptable, adequate precautions must be taken to ensure that particulates from a processing areas are removed. This will usually require an alarm system or an automatic cutoff in the event that a filter develops ahole. Dust extraction systems should be provided where appropriate, to further minimize this potential problem.
3. The degree of filtration and the air volumes should be matched to the operations involved.
4. Temperature and humidity conditions should provide personnel comfort-which will enhance employee performance.
5. Where differential pressures are required between adjacent areas, suitable monitoring equipment must be provided. For example, solids manufacturing areas are usually maintained at a negative pressure in relation to adjacent rooms and corridors in order to minimize the possibility of dust migration to these other areas.
6. The siting of final air filters close to each room being services eliminates concerns regarding the possibility of small leaks in the air duct system. Air usually enters rooms near the ceiling and leaves from the opposite side near the floor.
(a) Potable water shall be supplied under continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. Potable water shall meet the standards prescribed in the Environmental Protection Agency's Primary Drinking Water Regulations set forth in 40 CFR Part 141. Water not meeting such standards shall not be permitted in the potable water system.
(b) Drains shall be of adequate size and, where connected directly to a sewer, shall be provided with an air break or other mechanical deice to prevent back-siphonage.
SEWAGE AND REFUSE:
Sewage, trash, and other refuse in and from the building and immediate premises shall be disposed of in a safe and sanitary manner.
A pharmaceutical plant may consider disposal in several different ways:
1. Product disposal. Any product requiring disposal should initially be separated from its packaging if approved landfill site should not be left in impermeable glass, plastic, or other containers which would significantly delay destruction. Tipping of product to bulk or crushing would be viable pretreatments. There are risks associated with the destruction of products-potential for the product to get diverted, legitimately or otherwise, during the disposal sequence and contamination of groundwater. Disposal procedures should involve agents with a proven record of dealing with such sensitive materials or the use of company personnel to accompany the material from plant to disposal. Ideally, incineration procedures have preference over landfill. Where incineration is used, product in plastic of other flammable packaging may not need to be returned to bulk.
2. Printed packaging disposal. The disposal of printed packaging components including labels, inserts, and cartons poses no health risk. However, ineffective disposal, such as into public landfill, can give rise to public concern that product may be associated with the packaging. Such materials should preferable be incinerated.
3. General trash and sewage. Normal local services will usually be adequate for trash and sewage. However, internal procedures should be sufficiently rigorous and monitored, to ensure that product and packaging waste does not get intermixed. Containers used within the plant to accumulate waste materials should be clearly marked to denote their designated use.
WASHING AND TOILET FACILITIES
Adequate washing facilities shall be provided, including hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas.
In addition to GMP regulations, Occupational Safety & Health Administration (OSHA) regulations impact on washing and toilet facilities. These require toilet rooms to be separate for each sex except where individual locked toilet rooms are available and also define the minimum number of water closets based on the number of users. The legal requirements of Good Manufacturing Practices specify minimum facilities for personnel. Management concern with employee morale, and extra measures to ensure minimum probability of contamination, suggest additional emphasis and activities.
1. Eating facilities:
a. Eating and drinking are permitted only in separate eatiung facilities well segregated from all production areas . Smoking is permitted only where an adequate disposal device is provided and apart from production areas.
b. Prominent signs indicating these rules are posted at entrances to production areas.
c. Enforcement procedures against violators are taken by management.
d. Permanent facilities for breaks and people bringing lunches are required. Cafeterias serving hot meals are ideal to reduce the amount of food, a potential contamination source, being brought into the plant.
2. For production and materials processing areas:
a. Drinking, eating, smoking, tobacco chewing, and expectorations are prohibited.
b. Tissues and closed disposal containers are readily available.
3. Lavatories and lockers:
a. Adequate in number for the number of personnel employed.
b. Conveniently located to all areas.
c. Hot shower facilities are provided
d. Disinfectant soaps are utilized.
e. Adequate ash and waste receptacles are provided.
f. Periodic cleaning of the area during each shift with logging of times and conditions is mandatory.
g. Complete cleaning with cleaning and disinfectant agents daily. Follow-up inspection by supervisory personnel is logged.
h. Specific rest areas for female employees are provided.
i. Eating and drinking are not permitted. Foods and beverages for meals and breaks may be stored only in lockers and then removed to a separate eating area.
j. Areas separated from all aseptic spaces by an air lock.
(a) Any building used in the manufacture, processing, packing, or holding of a drug product shall be maintained in a clean and sanitary condition. Any such building shall be free of infestation by rodents, birds, insects and other vermin (other than laboratory animals). Trash and organic waste matter shall be held and disposed of in a timely and sanitary manner.
(b) There shall be written procedures assigning responsibility for sanitation and describing in sufficient detail the cleaning schedules, methods, equipment, and materials to be used in cleaning the buildings and facilities; such written procedures shall be followed.
(c) There shall be written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents and cleaning and sanitizing agents. Such written procedures shall be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, lableling materials, or drug products and shall be followed. Rodenticides, insecticides and fungicide shall not be used unless registered and used in accordance with the Federal Insecticide Fungicide, and Rodenticide Act
(d) Sanitation procedures shall apply to work performed by contractors or temporary employees as well as work performed by full-time employees during the ordinary course of operations.
5. EQUIPMENT (SUBPART D)
EQUIPMENT DESIGN, SIZE, AND LOCATION:
Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance.
The effectiveness of equipment, like the quality of a product, starts at the design stage. Most pharmaceutical companies are not directly involved with the designs and construction of equipment but hey can contribute indirectly. They can, and don, provide information on requirements and feedback on existing equipment.
When evaluating alternate types of makes of equipment, several parameters need to be considered:
1. Operating criteria are adequate for the process-size, speed, effectiveness (of, say, a mixer).
2. Availability of spares and servicing. This can result in using different makes of equipment in different parts of the world.
3. Maintenance. The frequency and ease of maintenance will significantly impact on productivity and even quality. Equipment breakdown during processing could adversely affect quality. Included in the maintenance evaluation should be the cleanability of the equipment. This will involve accessibility to the parts needing to be cleaned and the relative ease of disassembly and reassembly.
4. Environmental issues. Does the equipment disseminate dust, with the potential for contaminating other products or making it necessary for operators to wear additional protective clothing and facilities to be cleaned more frequently? The possible impact of noise and energy use and dissipation should be considered.
5. Construction materials, and design.
6. Availability of process controls such as automatic weight adjustment on tablet presses and temperature recorders on ovens. Although initially more expensive they could prove to be very economic overall by providing more consistent product quality and better records.
7. Cost. A comprehensive cost should, if possible, be compiled which will include the base price plus any additional costs associated with points 2-4 above.
8. Availability of design and maintenance manuals from the supplier that are important for validation/qualification and maintenance programs.
(a) Equipment shall be constructed so that surfaces that contact components, in-process materials, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
(b) Any substances required for operations, such as lubricants or coolants, shall not come into contact with components, drug product containers, closures, in-process materials, or drug products so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.
This requirement affects the design, construction, and placement of manufacturing equipment. Motors, drive belts, gears, and other potential sources of lubricant contamination should be located away from vessel or package openings that could result in product contamination. For equipment where this is not possible, such as some mixers and tablet and encapsulating machines, lubrication needs to be controlled and monitored; buildup of lubricant and powdered product should be regularly removed and lubricants should be of food grade.
Gaskets and other connecting surfaces should be monitored to ensure they don't break down, thereby allowing environmental contamination or gasket particles into the product.
EQUIPMENT CLEANING AND MAINTENANCE
(a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength quality, or purity of the drug product beyond the official or other established requirements.
(b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product. These procedures shall include, but are not necessarily limited to the following:
(1) Assignment of responsibility for cleaning and maintaining equipment;
(2) Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;
(3) A description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance;
(4) Removal or obliteration of previous batch identification;
(5) Protection of clean equipment from contamination prior to use;
(6) Inspection of equipment for cleanliness immediately before use.
(c) Records shall be kept of maintenance, cleaning, sanitizing, and inspection as specified .
The importance of cleaning was further emphasized by the publication of FDA "Guide to Inspections of Validation of Cleaning Procedures" in July 1993. This guide suggests that FDA investigators evaluate key areas including:
1. Availability of approved validation protocols.
2. Approved validation reports.
3. Equipment design and cleanability.
4. Defined, reproducible cleaning procedures that address difficult to clean areas. Different cleaning procedures are acceptable products. For manual cleaning operations, it is essential that sufficient detail is provided to give a high level of assurance that the procedure will be performed essentially the same way by different operators. For example, "wash with water" would be totally unacceptable. Repeat cleaning until test results are acceptable is considered indicative of a nonvalidated process.
5. Time scales between use and cleaning and between cleaning and reuse.
6. Operator training.
7. Specificity and sensitivity of analytical methods – which must be validated, along with recovery levels. Although specific analytical methods are most frequently used, another alternative is a general method such as total organic carbon, which will evaluate all carbon-containing materials.
8. Sampling methods.
AUTOMATIC, MECHANICAL, AND ELECTRONIC EQUIPMENT:
(a) Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.
(b) Appropriate controls shall be exercised over computer or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. Input to and output from the computer or related system of formulas or other records or data shall be checked for accuracy. The degree and frequency of input/output verification shall be based on the complexity and reliability of the computer or related system. A backup file of date entered into the computer or related system shall be maintained except where certain data such as calculations performed in connection with laboratory analysis, are eliminated by computerization or other automated processes. In such instances a written record of the program shall be maintained along with appropriate validation data. Hard copy or alternative systems, such as duplicates, tapes, or microfilm, designed to assure that backup data are exact and complete and that it is secure from alteration, inadvertent erasures, or loss shall be maintained.
Filters for liquid filtration used in the manufacture, processing, or packing of injectable of drug products intended for human use shall not release fibers into such products. Fiber-releasing filters may not be used in the manufacture, processing, or packing of these injectable drug products without the use of such filters. If use of a fiber-releasing filter is necessary, an additional non-fiber-releasing filter of 0.22 micron maximum mean porosity (0.45 micron if the manufacturing conditions so dictate) shall subsequently use of a specific non-fiber-releasing filter, is permissible only upon submission of proof to the appropriate bureau of the Food and Drug administration that use of a non-fiber-releasing filter will, or is likely to compromise the safety or effectiveness of the injectable drug product.
6. CONTROL OF COMPONENTS AND DRUG PRODUCT CONTAINERS AND CLOSURES (SUBPART E)
(a) There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing and approval or rejection of components and drug product containers and closures; such written procedures shall be followed.
(b) Components and drug product containers and closures shall at all times be handled and stored in a manner to prevent contamination.
(c) Bagged or boxed components of drug product containers, or closures shall be stored off the floor and suitably spaced to permit cleaning and inspection.
(d) Each container or grouping of containers for components or drug product containers, or closures shall be identified with a distinctive code for each lot in each shipment received. This code shall be used in recording the disposition of each lot. Each lot shall be appropriately identified as to its status.
RECEIPT AND STORAGE OF UNTESTED COMPONENTS,
DRUG PRODUCT CONTAINERS, AND CLOSURES:
(a) Upon receipt and before acceptance, each container or grouping of containers of components, drug product containers, and closures shall be examined visually for appropriate labeling as to contents, container damage or broken seals, and contamination.
(b) Components, drug product containers, and closures shall be stored under quarantine until they have been tested or examined, as appropriate, and released. Storage within the area shall conform to the requirement.
TESTING AND APPROVAL OR REJECTION OF
COMPONENTS, DRUG PRODUCT CONTAINERS, AND
(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.
(b) Representative samples of each shipment of each lot shall be collected for testing or examination. The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon appropriate criteria such as statistical criteria for component variability, confidence levels and degree of precision desired, the past quality history of the supplier, and the quantity needed for analysis and reserve where required by 211.70
(c) Samples shall be collected in accordance with the following procedures:
(1) The containers of components selected shall be cleaned where necessary, by appropriate means.
(2) The containers shall be opened, sampled, and selected and resealed in a manner designed to prevent contamination of their contents and contamination of other components, drug product containers, or closures.
(3) Sterile equipment and aseptic sampling techniques shall be used when necessary.
(4) If it is necessary to sample a component from the top, middle and bottom of its container, such sample subdivisions shall not be composted for testing.
(5) Sample containers shall be identified so that the following information can be determined: name of the material sampled, the lot number, the container from which the sample was taken, the date on which the sample was taken, and the name of the person who collected the sample.
(6) Containers from which samples have been taken shall be marked to show that samples have been removed from them.
(d) Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.
(2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals.
(3) Containers and closures shall be tested for conformance with all appropriate written procedures. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/ closures by the manufacturer and provided that the manufacturer validation of the supplier's test results at appropriate intervals.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.
(6) Each lot of a component, drug product container, or closure that is liable to microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.
Vendor verification is a system that assures that a supplier's produced under controlled conditions, resulting in consistent quality conformance. Being based on the principle of defect prevention, rather than defect detection and inspection, it significantly reduces the need for customer inspection.
Vendor certification is a supplier-customer partnership and can only be successful with the full involvement and agreement of both partners.
The team will include representatives from manufacturing, package engineering, purchasing and quality assurance with support, as appropriate, from other disciplines such as finance and research and development. The initial task of the team will be to define the objectives and potential benefits and to write a process that can be used as a basis for discussion with suppliers.
The initial selection of potential partners should take into account the supplier's history in terms of quality, delivery, and support service as well as the importance of the specific material to the business. Vendor certification has a higher chance of success with a supplier who already has a high commitment to quality and customer service.
Initial Supplier Contacts
The proposed process will be discussed with the supplier.
a. Supplier process. Some or all the customer vendor certification team should visit the supplier's plant to gain an understanding of the production process and the key elements which impact on the achievement of quality standards. Where a material may be supplied from more than on plant of the supplier, each plant must be treated as a separate entity for certification purposes.
b. Specifications. A detailed review should be made of product specifications with particular reference to legal requirements and fitness for use.
c. Process evaluation. The supplier must have suitable equipment to monitor the process. This equipment must be routinely calibrated and test methods validated. Statistical process control techniques will usually be applied to demonstrate that the process remained under control, within acceptable operating ranges, throughout each production run. Process control data for several batches, chosen at random, should be reviewed to confirm supplier compliance. Vendors are being requested to demonstrate that their production processes are validated, especially for the manufacture of bulk pharmaceutical chemicals.
Process and Specification Changes:
Vendor certification process is the procedure for handling any changes to the process or the specification. Any proposed changes must be clearly documented, with reasons and supporting data, and be reviewed and accepted by the customer prior to introduction.
A similar procedure should be in place in the event the customer intends to change the specification. Any proposed changes to the customer's process which could impact on the usability or performance of the supplier's material also require prior review and agreement with the supplier.
After it has been confirmed that a supplier has a control process, there usually will be a period when both parties evaluate material quality and compare data. Vendor certification provides a strong basis for the application of reduced testing by the customer. The customer should perform audits of the supplier's process at appropriate intervals. This can be a useful opportunity to review the entire vendor certification process and to evaluate success.
Vendor certification is a partnership, it is important that both supplier and customer are kept informed of each other's difficulties. The supplier should also provide certificates of compliance or certificates of analysis for every batch-formatted in a manner which is acceptable to the customer. The customer should also provide feedback to the supplier with respect to compliance with specification, performance in use, and delivery service.
Certification results in a high level of reliance on the supplier: reduced incoming inspection, reduced inventories, higher output. Any failure by the supplier can therefore have serious consequences and may require decertification of that supplier for that material.
a. The tighter specification ranges usually result in higher yields and reduced equipment downtimes for the supplier, thereby providing an opportunity to reduce prices or minimize price increases. A similar situation can occur with the customer and should also result in more consistent product quality.
b. More consistently compliant batches can result in lower inventories for both supplier and customer. This reduces the cost of carrying inventory.
c. Reduced testing by the customer eliminates some testing costs but more importantly can make materials available to production more quickly. This allows further inventory reductions and is also of benefit when materials are urgently required for unexpected production.
USE OF APPROVED COMPONENTS, DRUG PRODUCT
CONTAINERS, AND CLOSURES
Components, drug product containers, and closures approved for use shall be rotated so that the oldest approved stock is used first. Deviation from this requirement is permitted if such deviation is temporary and appropriate.
Materials management systems now include a need to reevaluate material after a predetermined time and prior to use. This will further minimize the chance that materials in an unsuitable condition will be use.
RETESTING OF APPROVED COMPONENTS, DRUG
PRODUCT CONTAINERS, AND CLOSURES
Components, drug product containers, and closures shall be retested or reexamined, as appropriate, for identity, strength, quality, and purity and approved or rejected by the quality control unit in accordance with 211.84 as necessary, e.g., after storage for long periods or after exposure to air, heat or other conditions that might adversely affect the components, drug product container, or closure.
REJECTED COMPONENTS, DRUG PRODUCT
CONTAINER, AND CLOSURES
Rejected components, drug product containers, and closures shall be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.
FDA investigators frequently use a visit to the reject area as a potential source of deficiencies. If rejections occur it is possible to assume that the vendor process is not adequately under control, and an evaluation of the cause should have been performed and documented.
7. PRODUCTION AND PROCESS CONTROLS
WRITTEN PROCEDURES; DEVIATIONS
(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.
(b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.
The procedures for production and process control are to be reviewed and approved by quality control. It will be essential to that:
a. The various requirements referenced in the CGMP regulations (especially the other subsections of Subpart F) have been adequately addressed.
b. The documents are in compliance with the relevant sections of any NDA and ANDA.
The FDA is currently reevaluating approval requirements with respect to production changes. The objectives are to reduce the work load at the FDA, harmonize via ICH, and allow quicker implementation of changes. The status is somewhat confused by the ICH approach, which primarily focuses on stability requirements while the FDA also addresses levels of approval (Annual Report, Change being Effected, Prior Approval). Due to lack of consensus between the ICH parties, the ICH project is currently on hold. The situation further compounded by the issuance by the FDA of two similar but not identical proposals in November and December 1994 (see Suggested Readings 16 and 19). The November guideline developed by the Scale-Up and Post Approval Change (SUPAC) Expert Working Group of the Chemistry Manufacturing Controls coordinating Committee of the Center for Drug Evaluation and Research was limited to immediate release solid dosage forms. Guidelines on other dosage form will be issued.
Change control should include changes to raw materials, packaging, components, labeling, expiration dating, formulation, production process, production equipment (including major maintenance), critical plant systems, facilities, computerized systems, specifications, and test methods.
The procedure will involve multiple disciplines including sales and marketing, medical, legal, regulatory affairs, R&D, technical services, and maintenance, as well as QC/QA. No all functions will need to be involved with all changes. The evaluation of the change, which must be documented, will include:
• Clear definition of the proposed change with the reason for the change.
• Identification of potential impact and the evaluations to be performed, such as accelerated stability, revalidation, retraining.
• Regulatory impact (all countries involved) approvals required.
• Schedule for implementation.
• Definition of who needs to approve the change and a record of their concurrence.
• Post introduction review to confirm that the change did not have any adverse impact.
Evaluation of change control should be part of the QA plant audit.
CHARGE-IN OF COMPONENTS
(a) The batch shall be formulated with the intent to provide not less that 100 percent of the labeled or established amount of active ingredient.
(b) Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information:
(1) Component name or item code
(2) Receiving or control number
(3) Weight or measure in new container
(4) Batch for which component was dispensed, including its product name, strength, and lot number.
(c) Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be examined by a second person to assure that:
(1) The component was released by the quality control unit.
(2) The weight or measure is correct as stated in the batch production records.
(3) The containers are properly identified.
(d) Each component shall be added to the batch by one person and verified by a second person.
(a) All compounding and storage containers, processing lines and major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.
(b) Major equipment shall be identified by a distinctive identification number or code that shall be recorded in the batch production record to show the specific equipment used in the manufacture of each batch of a drug product. In cases where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used in lieu of a distinctive identification number or code.
SAMPLING AND TESTING OF IN-PROCESS MATERIALS AND
(a) To assure batch uniformity and integrity of drug products, written procedures shall be established to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited, to the following, where appropriate:
(1) Tablet or capsule weight variation
(2) Disintegration time
(3) Adequacy of mixing to assure uniformity and homogeneity
(4) Dissolution time and rate
(5) Clarity, completeness, or pH of solutions
(b) Valid in-process specifications for such characteristics shall be consistent with drug product final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing samples shall assure that the drug product and in-process material conforms to specifications.
(c) In-process materials shall be tested for identity, strength, quality and purity as appropriate, and approved or rejected by the quality control unit, during the production process, e.g., at commencement or completion of significant phases or after storage for long periods.
The FDA in "Guidelines on General Principles of Process Validation "defines process validation as "establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics." The designing of quality into a product and its production processes, coupled with supporting validation data, increase the potential for consistently achieving quality standards and reduces dependence on both in-process and end-product testing.
IQ OQ PQ
Process/ Product Design
Equipment installation Equipment operation
Equipment use in processing
Evaluation and appraisal
Additional training or retraining
Figure : Validation Stages
8. PACKAGING AND LABELING CONTROL (SUBPART G)
MATERIALS EXAMINATION AND USAGE CRITERIA
(a) There shall be written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials; such written procedures shall be followed. Labeling and packaging materials shall be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a drug product.
(b) Any labeling packaging materials appropriate written specifications may be approved an release for use. Any labeling or packaging materials that do not meet such specifications shall be rejected to prevent their use in operations for which they are unsuitable.
(c) Records shall be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected.
The terms labeling and packaging in the context of this section specifically exclude containers and closures, which are covered in Subpart E; advertising and promotional material are not subject to GMP regulation. However, unlabeled packaging such a corrugated shippers and dividers are to be included, although the evaluation and control may not need to be so extensive.
Labels and labeling errors have been the most frequent reason for product recall in recent years. The effective control of printed labeling (labels, inserts, cartons, foil) commences well before materials are ordered; it starts at the design and approval stage. For new or changed labeling there must be in place a procedure that clearly defines:
1. Who is to review and approve the copy. This will usually include marketing, medical, legal, regulatory affairs, production, materials management, quality assurance, and editorial.
2. What each function is to check and approve. With so many people involved, individuals may be tempted to assume that someone else has checked the various points. A typical system might include the following detailed responsibilities:
a. Materials management – evaluate inventory situation, identify an implementation date that will comply with regulatory or company requirements while minimizing stock write-offs or production interruptions. Identify which countries take this product so that Regulatory Affairs can evaluate any regulatory requirements and potential impacts, including potential delays in implementation.
b. Production – confirmation that equipment is available, or will be to introduce the change; adequate space for batch coding and expiry dating.
c. Marketing (or other function) – identify whether the specific change will require modification to other materials, e.g., changes to a label may require changes to inserts and cartons – identify whether other pack sizes may need to incorporate the same or equivalent change.
d. Medical – confirmation that any medical claims, warnings, dosage are correct.
e. Legal & Regulatory Affairs – confirmation that the changes meet all legal and regulatory requirements in all countries that sell the product.
f. Technical Service & Quality Control – identify any stability issues (primary pack changes).
g. Editorial – to confirm grammatical correctness and absence of typographic and print errors or omissions.
h. System Manager – to confirm that all appropriate approvals have been given and in the event of queries to recirculate through the system if necessary.
3. Whether the change is mandatory or voluntary and the date of introduction. For voluntary changes this is likely to relate to depletion of inventories of existing labeling.
4. Whether the labeling in question is interrelated with any other labeling and to note any impact. For example, a change to the dosage requirements on a label will almost certainly require amendment to inserts and cartons.
5. The reviewers and approvers (item 1) should preferably be defined by name. Since the approval process is so important, it is essential that approvers have undergone adequate training in the system. Additional individuals should not be allowed to authorize new labeling or changes without having undergone this training.
6. The feedback loop that confirms that the change has actually been introduced.
7. A unique numbering system that clearly distinguished between labeling for different products and strengths and also between different versions of the same labeling.
8. Ownership of the procedure. As with any system or procedure but especially one that involves so many people, there should be designated responsibility for operation and monitoring of the system itself. This individual should routinely identify any potential weaknesses in the operation of the system and have them corrected.
Gang printing consists of printing different labeling on the same sheet and then cutting and separating the different labeling. This technique has high potential for mix-up during the cutting and separating stages, and most pharmaceutical companies now avoid this approach.
(a) Strict control shall be exercised over labeling issued for use in drug product labeling operations.
(b) Labeling conformity to the labeling specified in the master or batch production records.
(c) Procedures shall be written describing in sufficient detail the control procedures employed for the issuance of labeling; such written procedures shall be followed.
(d) procedures shall be utilized to reconcile the quantities of labeling issued, used, and returned, and shall require evaluation of discrepancies found between the quantity of drug product finished and the quantity of labeling issued when such discrepancies are outside narrow preset limits based on historical operating data. such discrepancies shall be investigated. Labeling reconciliation is waived for cut or roll labeling if a 100% examination for correct labeling is performed
(e) All excess labeling bearing lot or control numbers shall be destroyed.
(f) Returned labeling shall be maintained and stored in a manner to prevent mix-ups and provide proper identification.
PACKAGING AND LABELING OPERATIONS
There shall be written procedures designed to assure that correct labels, labeling and packaging materials are used for drug products; such written procedures shall be followed. These procedures shall incorporate the following features:
(a) Prevention of mix-ups and cross-contamination by physical or spatial separation from operations on other drug products.
(b) Identification and handling of filled drug product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lots. Identification need not be applied to each individual container but shall be sufficient to determine name, strength, quantity of contents, and lot or control number of each container.
(c) Identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch.
(d) Examination of packaging and labeling materials for suitability and correctness before packaging operations, and documentation of such examination in the batch production record.
(e) Inspection of the packaging and labeling facilities immediately before use to assure that all drug products have been removed from previous operations. Inspection shall also be made to assure that packaging and labeling materials not suitable for subsequent operations have been removed. Results of inspection shall be documented in the batch production records.
9. HOLDING AND DISTRIBUTION (SUBPART H)
(a) Quarantine of drug products before release by the quality control unit.
(b) Storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected.
Traditionally, there have been two types of warehouse storage conditions:
1. Ambient conditions. For many products an adequate shelf-life can be determined that encompasses the relatively wide range of conditions that constitute "ambient". Local and national weather records are available which provide data on temperature ranges. Maintenance of actual temperature data in a warehouse provides the assurance that the assumptions made in determining shelf-life continue to be met.
Humidity and light are rarely controlled, or even monitored, since, product packaging is usually designed to take these two conditions into account.
2. Refrigerator and freeze. Certain products that are relatively unstable at ambient conditions require storage at lower temperature. Appropriate equipment or areas must be provided and the conditions monitored to confirm compliance with the prescribed storage requirements.
Written procedures shall be established, and followed, describing the distribution of drug products. They shall include:
(a) A procedure whereby the oldest approved stock of a drug product is distributed first. Deviation fro this requirement is permitted if such deviation is temporary and appropriate.
(b) A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary.
Distribution records must be constructed and procedures established to facilitate recall of defective product. A requisite of the system is approval and specific release of each lot of drug by the quality control function before distribution can occur. This control of finished goods for shipment allows only those drugs into commerce that have been shown by testing to conform to appropriate requirements.
The manufacturer must maintain records of all distribution transactions involving in-process or finished goods. All records should be indexed by either the manufacturing batch-lot number of the packaging control number as a means of accountability until the shipment passes from the direct control of the manufacturer. This type of indexing permit an efficient determination of the receiver of a lot to be recalled since only one shipment record need be examined. Depending on the marketing procedures of the individual company, distribution records may list shipments to consignees for packaging or labeling, or to an independent distributor, a wholesaler, a retail pharmacist, a physician, or possibly the ultimate consumer.
A variety of distribution recording systems may be utilized. Two of the more commonly used approaches are to record the lot or control number on the retained copies of the shipping invoices or to record the dates on which each lot commenced distribution. This latter approach has disadvantages in that it does not readily accommodate the redistribution of small amounts of returned good or the occasional need to distribute part lots out of sequence.
10. LABORATORY CONTROLS (SUBPART I)
(a) The establishment of any specifications, standards, sampling plans, test procedures or other laboratory control mechanisms required by this subpart, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms, shall be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit. The requirements in this subpart shall be followed and shall be documented at the time of performance. Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms shall be recorded and justified.
(b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling and drug products conform to appropriate standards of identity, strength, quality and purity. Laboratory control shall include.
(1) Determination of conformance to appropriate written specifications for the acceptance of each lot within each shipment of components, drug product, containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.
(2) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials. Such samples shall be representative and properly identified.
(3) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for drug products. Such samples shall be representative and properly identified.
(4) 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. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.
The subject of analytical validation has been covered in numerous publications over the years. However, this section will primarily focus on the approach resulting from the ICH review that was published in the Federal Register, March 1,1995.
Four different analytical applications were reviewed- identification tests, quantification of impurities, limit tests for impurities, and assay of actives or other key components of drug products. It was acknowledged that there are other important analytical procedures, including dissolution testing for drug products and particle size characterization of materials, but they were not addressed at this time.
Identification tests normally compare the sample under evaluation with a known reference sample standard.
Impurity tests may be either quantitative or limit tests, and different validation requirements apply. For limit tests, specificity and detection limits only may be required. For quantification the requirements are similar to those for assay methods (including those used for dissolution and content uniformity) except that for assay methods, detection and quantification limits do not need to be established since the methods are operating well in excess of these limits.
Table : ICH Validation Guideline
Type of analytical procedure, characteristics Identification Impurities purity test Assay;
content/potency dissolution; measurement only
Accuracy – + – +
Precision – + – +
Repeatability – +c – +c
Intermediate precision – –a – –a
Specificity + + + +b
Detection limit – + + –
Quantitation limit – + – –
Linearity – + – +
Range – + – +
Note :- Signifies that this parameter is not normally evaluated; + signifies that this parameter is normally evaluated.
a May be needed in some cases.
b May not be needed in some cases.
c Incases where reproducibility has been performed, intermediate precision is not needed.
Accuracy – defines the agreement between the true value and the value found in the testing.
Precision – defines the degree of variability in a series of measurements ally expressed as a standard deviation or coefficient of variation. Three levels of evaluation of precision are defined.
(a) Repeatability – relating to testing performed ever a short time interval.
(b) Intermediate precision – evaluations performed on different days with different analysts and possibly different equipment.
(c) Reproducibility – relates to collaborative studies between laboratories. This evaluation is a measure of the robustness of the method since many variables are involved- different facilities, different equipment, different analysts, different reagents. This is a key element in analytical verification and confirmation that a new laboratory (e.g., QC laboratory) obtained equivalent results to the originator laboratory (e.g., R&D).
Specificity – confirms the ability of the method to evaluate the desired analyte in the presence of known other components: degradants, impurities, potential contaminants, and excipients. Frequently this is assessed by comparing results from "normal" material with those from stressed samples (heat, light, moisture, acid and/or base).
Detection limit – particularly important for limit tests.
Quantitation limit – relates to the lowest level that can be determined quantitatively with adequate accuracy and precision.
Linearity – applies only to methods involving quantification and involves the demonstration of a linear response over the range being evaluated. For example, an assay method may be evaluated only over the range of 85-115% of the specification since any results outside of these values would be out of specification.
Range – defines the upper and lower levels that have suitable levels of precision and accuracy. This is sometimes omitted since the linearity provides equivalent information.
Reggedness – while not a specific requirement in the ICH approach, it is an additional measure of the reliability of the method when normal variabilities in the product or method are experienced. Product variables can include excipient levels, pH ranges for liquids, hardness of tablets (potential impact on dissolution). Analytical method variables could include extraction process, sample preparation, HPLC flow rate, wavelength, mobile phase composition. The potential impact of these variables may be examined using a matrix design approach.
The validation and verification (technology transfer) protocols should include acceptance criteria and be approved. Any discrepancies from the agreed acceptance criteria need to be evaluated and explained.
Validation and verification data must be reviewed and approved by responsible persons. In the case of new methods it is advisable to have sign off by both the method development unit (R&D) and the method receiving unit (QC). This acknowledges that the method has been transferred effectively.
(f) Drug products failing to meet established standards or specifications and any other relevant quality control criteria shall be rejected. Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria.
The analytical failure should be reported to the section supervisor or manager. The critical steps in the analytical procedure should be reviewed with the analyst and appropriate evaluation initiated. A typical decision path for such an evaluation is outlined below (and in figure) immediately following.
1. Investigate laboratory and production records for an assignable cause.
2. If an assignable laboratory cause is identified and there is sufficient sample preparation remaining, the initial analyst ("A") should repeat the analysis in duplicate.
(a) If both results pass, consider release.
(b) If one or both of the duplicate results fail, go to step 4 (assumes the possibility of analyst bias)
3. If there is no assignable laboratory cause but there is a relevant production deviation, reject the batch (it may be acceptable for rework).
4. If there is no assignable laboratory cause and no relevant product deviation or there is an assignable laboratory cause but no remaining sample preparation, retest in duplicate using two analysts ("A" and "B").
(a) If all results pass, consider release.
(b) If one or both results from "A" fail but both results from "B" pass, go to step 5.
(c) If one or both results from "B" fail, reject.
5. Retest in duplicate by another analyst ("C").
(a) If both results pass, consider release.
(b) If one or both results fail, reject.
6. Additional samples and testing maybe necessary in order to resolve any problems that may be associated with analytical techniques, non-representative sampling, or inhomogeneous material. Retesting of reference samples or previously released batches may be of value.
7. Where analyst bias or error is involved, retraining may be required.
8. If at any point in the decision path process it can be demonstrated that the result was invalid because of a specific identifiable error, that result can be ignored and a repeat analysis performed. The failing result must be reported with the supporting explanation. In rare cases an individual result may be excluded from the decision path if it deviates significantly from the average of the remaining values. The use of the statistical outlier approach requires adequate scientific justification for FDA acceptance.
9. Duplicate analysis results must agree with the limits of precision defied during validation.
10. The final decision should not be a mechanistic application of the decision path. QC management must be involved and must apply its experience and knowledge of product history. Persistent or frequent failures are indicative of inadequate analytical method validation or verification, inadequate training, or inadequate process validation.
11. RECORDS AND REPORTS (SUBPART J)
(a) Any production, control, or distribution record that is required to be maintained in compliance with this part and is specifically associated with a batch of drug product shall be retained for at least 1 year after the expiration date of the batch or, in the case of certain OTC drug products, lacking expiration dating because they meet the criteria for exemption under 211.137, 3 years after distribution of the batch
(b) Records shall be maintained for all components, drug product containers, closures, and labeling for at least 1 year after expiration date or, in the case of certain OTC drug products lacking the expiration dating because they meet the criteria for exemption under 211.137, 3 years after distribution of the last lot of drug product incorporating the component or using the container, closure, or labeling.
(c) All records required under this part, or copies of such records, shall be readily available for authorized inspection during the retention period at the establishment where the activities described in such records occurred. These records or copies thereof shall be subject to photocopying or other means of reproduction as part of such inspection. Records that can be immediately retrieved from another location by computer or other electronic means shall be considered as meeting the requirements of this paragraph.
(d) Records required under this part may be retained either as original records or as true copies such as photocopies, microfilm, microfiche, or other accurate reproductions, of the original records. Where reduction techniques, such as microfilming, are used, suitable reader and photocopying equipment shall be readily available.
(e) Written records required by this part shall be maintained so that data therein can be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. Written procedures shall be established and followed for such evaluations and shall include provisions for:
EQUIPMENT CLEANING AND USE LOG
A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. If equipment is dedicated to manufacture of one product, then individual equipment logs are not required, provided that lots or batches of such product follow in numerical order and are manufactured in numerical sequence. In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be chronological order.
COMPONENT, DRUG PRODUCT CONTAINER,
CLOSURE, AND LABELING RECODS
(a) The identity and quantity of each shipment of each lot of components, drug product containers, closures, and labeling; the name of the supplier; the supplier's lot number(s) if known; The name and location of the prime manufacturer, if different from the supplier, shall be listed if known.
(b) The results of any test or examination performed and the conclusions derived there from.
(c) An individual inventory record of each component, drug product container and closure and, for each component, a reconciliation of the use of each lot of such component. The inventory record shall contain sufficient information to allow determination of any batch or lot of drug product associated with the use of each component, drug product container and closure.
(d) Documentation of the examination and review of labels and labeling for conformity with established specifications in accord
(3) The disposition of rejected components, drug product containers, closure, and labeling.
MASTER PRODUCTION AND CONTROL RECORDS.
(a) To assure uniformity from batch to batch, master production and control records for each drug product, including each batch size thereof, shall be prepared, dated and signed (full signature, handwritten) by one person and independently checked, dated and signed by a second person. The preparation of master production and control records shall be described in a written procedure and such written procedure shall be followed.
(b) Master production and control records shall include:
(1) The name and strength of the product and a description of the dosage form;
The product name is usually the manufacturer's trade or proprietary name and where possible should be used consistently in all documentation. Dosage form refers to tablet, capsule, injection, etc. Since many pharmaceutical products are manufactured with more than one strength this should be clearly obvious in the master documentation.
(2) The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product, and a statement of the total weight or measure of any dosage unti;
Master records usually record weights and measures of both active and inactive compounds per dosage unit for solid dosage forms such as tablets and capsules, while for liquid dosage forms percentage is more common.
(3) A complete list of components designed by names or codes sufficiently specific to indicate any special quality characteristic;
Components are usually specified by name and by an internally generated alphanumerical code. This double identification, although frequently used primarily for accounting purposes, helps to reduce the potential for usage of incorrect components-particularly if the chemical name is complex or similar to other materials. This is particularly relevant with regard to different varieties of the same component such as hydrated/anhydrous (e.g., critic acid) or crystalline/powder).
BATCH PRODUCTION AND CONTROL RECORDS
Batch production and control records shall be prepared for each batch of drug product produced and shall include complete information relating to the production and control of each batch.
Production and control operations occur at different locations within the plan. The batch records that accompany material through processing provide information for operators and also serve as a means for documenting which ingredients were added, which control measures were exercised in process and final assay of drug product, and the huge amount of information produced during the manufacturing cycle. Because this flow of information accompanies the product through all operations, the medium of transmission must be durable and provide protection for the forms which it encloses. Since it is advisable to keep the manufacturing and packaging portions of the batch records together during these operations, many manufacturers keep batch records for a single production cycle consolidated in a polyethylene bag. In order to minimize handling and possibility of loss, laboratory records for the batch may be added just prior to release review by the control section. In addition to the information that is attached to the batch production record, the departments contributing to the manufacturing cycle must retain accurate records and comments about operations within the department.
(a) An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed.
(b) Documentation that each significant step in the manufacture, processing, packing or holding of the batch was accomplished, including;
(3) Specific identification of each batch of component or in-process material used;
(4) Weights and measures of components used in the course of processing;
(5) In-process and laboratory control results;
(6) Inspection of the packaging and labeling area before and after use;
(7) A statement of the actual yield and statement of the percentage of theoretical yield at appropriate phases of processing;
(8) Complete labeling control records, including specimens or copies of all labeling used;
(9) Description of drug product containers and closures;
(10) Any sampling performed;
(11) Identification of the persons performing and directly supervising or checking each
significant step in the operation;
PRODUCTION RECORD REVIEW
All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and follow up.
(a) Laboratory records shall include complete data derived from all tests necessary to assure compliance with established specifications and standards, including examinations and assays, as follows:
(1) A description of the sample received for testing with identification of source (that is, location from where sample was obtained), quantity, lot number or other distinctive code, date sample was taken, and date sample was received for testing.
Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product. For compressed medical gas products, distribution records are not required to contain lot or control numbers.
(a) Written procedures describing the handling of all written and oral complaints regarding a drug product shall be established and followed. Such procedures shall include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 211.192. Such procedures shall include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience which is required to be reported to the Food and Drug Administration in accordance with 310.305 of this chapter.
(b) A written record of each complaint shall be maintained in a file designated for drug product complaints. The file regarding such drug product complaints shall be maintained at the establishment where the drug product involved was manufactured, processed, or packed, r such file may be maintained at another facility if the written records in such files are readily available for inspection at that other facility. Written records involving a drug product shall be maintained until at lest 1 year after the expiration date of the drug product, or 1 year after the date that the complaint was received, whichever is longer. In the case of certain OTC drug products lacking expiration dating because they meet the criteria for exemption such written records shall be maintained for 3 years after distribution of the drug product.
(1) The written record shall include the following information, where known: the name and strength of the drug product, lot number, name of complaint, and reply to complainant.
(2)The written record shall include the findings of the investigation and follow up. The record or copy of the record of the investigation shall be maintained at the establishment where the investigation occurred
(3)The written record shall include the reason that an investigation was found not to be necessary and the name of responsible person making such a determination.
12. RETURNED AND SALVAGED DRUG PRODUCTS (SUBPART K)
RETURNED DRUG PRODUCTS
Returned drug products shall be identified as such and held. If the conditions under which returned drug products have been held, stored, or shipped before or during their return, or if the condition of the drug product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product, the returned drug product shall be destroyed unless examination, testing, or other investigations prove the drug product meets appropriate standards of safety, identity strength, quality, or purity. A drug product may be reprocessed provided the subsequent drug product meets appropriate standards, specifications and characteristic. Records of returned drug products shall be maintained and shall include the name and label potency of the drug product dosage form, lot number (or control number or batch number), reason for return, quantity returned, date of disposition, and ultimate disposition of the returned drug product. If the reason for a drug product being returned implicates associated batches, an appropriate investigation shall be conducted. Procedures for holding, testing, and reprocessing of returned drug products shall be in writing and shall be followed.
The intent of this section is:
1. To provoke an examination of the reasons for return in order to decide whether further action is required on the lot, on related lots, or to the storage and distribution chain.
If the goods are known to have been handled within the normal range of conditions in the distribution chain, it may be adequate to redistribute after visual examination.
Where the distribution or storage conditions are unknown or have been extreme, then return to stock, as is or after reprocessing, can only be considered after appropriate evaluation which confirms no unacceptable deterioration.
2. To maintain full and comprehensive records to allow identification of returned goods distribution and accountability in the event of a recall. This places a considerable burden of work on those responsible for distribution since returns from the trade can be considerable-incorrect deliveries, ordered in excess, damaged in transit, nearing the end of shelf-life. The regulations require recording of the product details and disposition of returns and also the reason for the return.
3. To remove from commerce portions of a lot this may have been adversely affected by a typical distribution conditions.
DRUG PRODUCT SALVAGING
Drug products that have been subjected improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age or radiation due to natural disasters, fires, accident, or equipment failures shall not be salvaged and returned to the marketplace. Whenever there is a question whether drug products have been subjected to such conditions, salvaging operations may be conducted only if there is (a) evidence from laboratory tests and assay (including animal feeding studies where applicable) that the drug products meet all applicable standards of identity, strength, quality and purity and (b) evidence from inspection of the premises that the drug products and their associated packaging were not subjected to improper storage conditions as a result of the disaster or accident. Organoleptic examinations shall be acceptable only as supplemental evidence that the drug products, meet appropriate standards of identity, strength, quality, and purity. Records including name, lot number, and disposition shall be maintained for drug products subject to this section.
1.Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems,Eighth Edition, Loyd V.Allen,jr. Nicholas G.Popovich Howard C.Ansel.
2.Good manufacturing Practices for Pharmaceuticals by Sydney H. Willing.
3.The Theory and Practice of Industrial Pharmacy,Leon Lachman.Herbert a.Lieberman.THIRD EDITION.