CGMP
Manufacturing Operation & Control
By: Supriya Sharma, Shamita Kohli
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
Good manufacturing practices, should be followed at some point in carrying out all manufacturing operations and their control. Mainly Four key words should forever be kept in mind, they are identity, strength, safety, and purity.
The manufacturing areas where all the production & other related activities are carried out have to be maintained in the state of cleanliness & necessitate sanitary environment. All areas must be cleaned using appropriate detergents & methods of cleaning at pre-decided time intervals by the people who are assigned for this job.
SOP on housekeeping covering cleaning & disinfection of the various areas. Reports of cleaning & disinfection activities that have been actually carried out are required.
In pharmaceutical manufacturing, mix-ups & cross contamination is a immense danger & hence crucial precaution & measure should be in use to stay away from the same. Mix-ups can be defined as presence of unwanted materials into most wanted materials, which can normally be manifestly seen e.g. cartons of one product into another. Tablets of one product with another product which have different size, shapes or color etc. contamination is also existence of some materials where it is not required. However this may not always be evidently seen, e.g. fine dust of one product into another product, fine black particles of dust into processing materials etc.
The main source of mix-up & contamination are materials, men, machines, operations and areas, Improper managing of material, people working in the processing area, unmanageable activities, infectious nature of skin or other body parts. Machines, equipments and equipment related actions. Definite procedures should be used to manage contamination and mix-ups. Exhaust system with appropriate air filtration and dust collection, separate air handling units for apiece work-station and also keep differential pressure, segregation of packing lines and maintaing. People should be trained in their jobs and also in the philosophy of cGMP Cross contamination should be avoided by proper technical or managerial measures like, providing suitable airlocks, pressure differentiation and air extraction, wearing defensive clothing, making use of “closed system” for material handling and production.
Starting from the reception of raw materials till these materials are converted into bulk goods complete for packaging into their primary and then finished packs, Definite points are reserved in mind so that the identity, strength, safety and purity of the product is maintained. Previous to starting any processing, the materials received from the stores should be checked for the identity and quantity. Processing area and equipment must be dirt free and no traces of earlier product should be there. Environmental conditions must meet the processing necessities e.g. temperature, relative humidity etc. Yield of materials at all critical stages of operations should be checked. Checks should be conceded out to make sure that pipeline and other parts of equipment used for the shipping of products from one area to another are associated in a correct manner. All measuring, weighing, recording and controlling equipment and instruments should be calibrated habitually.
Some of the serious points should be remembered during packaging operations. Cross contamination of the material. Every packaging equipment and lines must be cleaned before starting a fresh packaging action. Filling & sealing should be followed as rapidly as possible by doing labeling & final packaging of the product. Over printing on labels, cartons, coated tablet etc. should be cautiously planned & actions are clearly segregated to avoid mix-ups. On line confirmation of all labels by automated electronic beam or by other technique can be helpful in preventing the mix-ups.
Standard operating procedures should be on hand & followed for in-process quality control activity during manufacturing as well as in the packaging actions. Critical steps should be recognized in every formulation procedure & specifications are defined for the parameters to be tested at such critical stages. Records for I.P.Q.C. test are necessary.
Releasing of finishing product is the last activity in the manufacturing & packaging operations at the factory this is extremely imperative activity & should be passed out with extra care. Finished goods must be placed in quarantine. Samples must be retained for examination by the quality control laboratory & for withholding purpose. Documentation should be reconciled completed/& sent for a complete documentation audit by quality assurance department. When all mandatory parameters are fulfilled, Q.C. may recommend discharging of the product from its quarantine. The finished product should be free for sale by the authorized person from Q.A. department.
Process deviation can be defined as discrepancy, in the production or any other procedure, from the predefined actions. Such deviation may unfavorably affect the preferred quality of the pharmaceutical manufactured goods & hence such deviations should be normally avoided & if exceptionally required, then such deviations must be defensible & appropriately authorized & recorded. If a meticulous type of deviation is happening regularly then such deviation must be entirely investigated & if necessary this may be permanently changed through a change control procedure. SOP/R on process deviation & control are required.
A pharmaceutical manufacturing operation should be completed in a particular period of time. Normally, starting & finishing of a pharmaceutical process should be noted & it should be as minimum as possible.
Drug product inspection propose that the samples should be collected randomly by the I.P.Q.C./I.P.Q.A. department from the finished products, which have been already received in the finished goods warehouse & awaiting to free for send out from the factory. SOP/R of visual Drug Product Inspection of finished products.
The accountability of the pharmaceutical producer is that the drug product should have the confirmed potency & therapeutic efficiency till the ending of the shelf life of the manufactured goods. This shelf life should be based on the stability studies statistics of the product concerned. For this reason a comprehensive SOP on carrying out drug stability studies is necessary. The statistics so obtained should be used to set up of the shelf life of every manufactured goods; previous to it goes into the marketplace.
List of manufactured goods names along with the shelf life of the manufactured goods are necessary.
The real yield & % of hypothetical yield shall be determined at the end of each suitable segment of manufacturing, processing, packaging or holding of the drug manufactured goods. Such calculations shall be performed by one person & in competition confirmed by a second person.
All drugs product production & control records, including those for packaging & labeling shall be reviewed & permitted by the quality control unit to decide compliance with all established, accepted written procedures previous to a batch released or dispersed. Any mysterious inconsistency or the failure of a batch is thoroughly investigated, whether or not the batch has already been distributed. The examination of these type of batches shall extend to other batches of the same drug product & other drug products that may have been associated with the specific failure or inconsistency. A written record of such investigation shall be made & shall include the conclusion & follow up.
Read Full Post | Make a Comment ( 7 so far )Pharmaceutical Validation
By: Shamita Kohli, Supriya Sharma
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
Validation is a documented evidence, which provides a high degree of assurance that a specific process will consistently produce, a product meeting its pre-determined specifications and quality attributes. Pharmaceutical validation is a vast area of work. We can point out some areas for pharmaceutical validation. e.g. Analytical test methods, Instrument calibration, Process utility services, Raw material, Packaging materials, Equipments, Facilities, Manufacturing operations, Product design, Cleaning, Operators etc.
Every activity in any business unit is done to get some benefit from that, and naturally pharmaceutical validation is no exception. Four major advantages of validation namely;
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Reduction of Quality cost
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Process optimization
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Assurance of quality and
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Safety
We must remember that ‘perfection’ is a state of mind and not reality. Perfection also means a stoppage of improvement and hence nothing can be perfect permanently. If we clearly understand the concept of change, perfection, environmental adaptation and transition, we will also understand the limitation of validation. Validation also has a practical limit and related cost. Hence, while deciding the limits of validation, we need to balance between the process cost and the benefits derived from such a limit.
Validation activity is not the responsibility of any one single department in an organization. The team members may be taken from R and D, Quality, Production and Engineering. Any one person who has a basic understanding of Validation and Capability and maturity of a manager should head this team.
The building and facilities should have following five documents regarding validation e.g. User requirement specification, Design Qualification, Installation Qualification, Operational Qualification, Performance Qualification.
Equipment is one of the basic components of the basic components of the pharma processing and hence, a critical validation issue also. The equipment validation process generally covers following steps:
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Customer Requirements or User Requirement Specifications.
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Preparation of Design Qualification and its Certification.
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Installation Qualification
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Operational Qualification
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Performance Qualification.
Process validation starts only after the complete qualification programme (D.Q, I.Q, O.Q, P.Q.) of facilities and equipment is over. Validation should be considered in the different situations such as totally new process, new equipment, processes and equipment, which have been altered to suit changing properties and processes where the end product test if poor and unreliable indicator of product quality. process validation can be categorized in Prospective validation, Concurrent validation, Revalidation and Retrospective validation.
Cleaning validation may be defined as “ a process of attaining and documenting sufficient evidence to give reasonable assurance, given the current state of Science and Technology, that the cleaning process under consideration does, and/or will do, what it purports to do”. Cleaning is directly related to the safety and purity of the pharmaceutical products. Cleaning continuum can be defined as “an organizational model which helps to draft the operational details of a specific cleaning validation programme”. The cleaning validation is highly complex process and if refers to the following aspects of cleaning activities viz. establishing critical parameters, developing grouping philosophies, establishing the scientific rationale for a cleaning programme, determining the processes, equipments and products that represent the greatest concern and establishing the criticality of cleaning limits and methods. When similar products, similar equipment, similar cleaning methods and similar cleaning agents, etc. are grouped together and a worst case is selected to demonstrate the validity of a specific cleaning programme is called as grouping philosophy in cleaning. The prime objective of the cleaning validation is removal of the various materials processed earlier in the equipment or area. To avoid the contamination of the next processed materials. This includes residues of previous processed materials, cleaning agents used and any other materials. The cleaning method should consider material of construction, compatibility with cleaning agents, complexity of the equipment, cleaning equipment parts which come in contact with the processing materials, cleaning of the parts of equipment which do not come in contact with the processing materials, mechanical side of the equipment, electric panels etc. Facility refer to building and surroundings. Building incorporate areas like corridors, offices, stores and ware houses, change rooms, processing areas, packaging areas and utilities area etc. surrounding incorporate roads, plinth protection, lawn etc.
Designing of a cleaning method starts with addressing such as what is being cleaned? What are the contaminants? What is the level of cleanliness expected etc. The cleaning agents must be compatible with the area/equipment. Sampling of area is required to evaluate the effectiveness of cleaning method using swabs, rinses, solvent wash placebo, etc. There are different testing methods like visual inspection, pH, analytical and instrumental method, chromatographic method etc.
Use of computer systems in pharmaceutical production, quality control, quality assurance and R and D is increasing every day. This has naturally raised certain typical issues of its performance and security of information systems being handles by the computer systems. With this increased use of computers, it has become mandatory to confirm the performance of such systems with respect to its consistency, repeatability and accuracy of the results and reports.
Read Full Post | Make a Comment ( 2 so far )Sterile Pharmaceutical Products
By: Supriya Sharma, Shamita Kohli
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
The manufacturing of sterile products should be carried out in dirt-free areas, access to which should be through airlocks for personnel and/or for equipment and materials. Dirt-free areas should be maintained to an appropriate standard of hygiene and air has to be passed through filters of the required efficiency. The variety of operations of component of product preparation, filling and sterilization should be carried out in separate & clean areas. These areas are classified into four grades.
Generally manufacturing operations are divided into two categories. These categories are: first, those where the product is terminally sterilized, and seconds, those which are conducted aseptically at some or all stages.
Only the minimum number of personnel are required to be present in clean areas; this is particularly imperative throughout the aseptic processes. Inspections and controls should be monitored & controlled from the outside in such areas as far as possible.
All personnel (including those concerned with cleaning and maintenance) employed in such areas should have initial and regular training in disciplines relevant to the correct and good manufacture of sterile products, including hygiene and the basic elements of microbiology. While coming of out side staff (e.g. building or maintenance contractors) when need to be brought in, the in such a case extra care should be taken over their instruction and supervision.
Staff who have responsibility in the processing of animal-tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless thorough and clearly defined decontamination actions have been followed.
High standards of personal hygiene and cleanliness are very much essential in the sterile production, and personnel involved in the make of sterile preparations should be instructed to account any situation that may cause the shedding of uncharacteristic numbers or types of contaminants; routinely health checks for such situation are enviable. The action to be taken in respect of personnel who might be introducing undue microbiological hazards should be determined by a elected capable person.
Outdoor clothing should not be allow into clean areas, and personnel entering changing rooms should be dressed in standard factory shielding garments. For changing and washing written procedure has to be followed, designed to minimize the contamination of clean area clothing or the carry-through of contaminants to dirt-free areas.
All types of jewellery and wrist-watches should not be worn in clean areas and aseptic area, no cosmetics that can shed particles are to be used.
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Documentation & Records
By: Shamita Kohli, Supriya Sharma
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
“Pharmaceutical Manufacturing Documentation” (PMD) is a really complex subject. It may be very difficult to make a consolidated list of documents, which will meet the requirements of all the companies. For this you have to evaluate the needs of each company. Hence, one cannot think of a readymade solution for PMD for every one all alike, but it has to be tailor made.
Total PMD programme consists of some steps. The first step is to identify at least two fairly knowledgeable persons, one each from production & QC/QA who are familiar with organization product profiles & QC/QA requirements. Second step is to list out the manufacturing formulation departments, existing or planned. This step is followed by listing out the QC/QA activities, section wise, listing out countries to, which the products are likely to be sold /distributed & collect the specific PMD requirements if any, of each of the countries, categorizing the sets of documents needed to meet the requirements, designing the document considering contents, formatting, size and paper quality etc., explaining the document to concerned people and training them, trial running of documents, modifying if necessary and implementing the document, and finally reviewing the documents at regular interval.
Guidelines for designing & implementing P.M.D. programme includes definition of document, objective of documentation, importance of documentation, preparation, issue & use of documents, product traceability, storage & retention of documents & records, storage & retrieval of document and disposal of documents.
Specifications may be defined as a set of parameters expected to be met by a particular material, peace of equipment or any such object. In case of pharmaceutical products, we need specification for active & inactive starting materials, primary, printed & other packaging materials, intermediate & bulk products and finished pharmaceutical products.
One of the major documents involved in manufacturing is Master production & control records (M.P.C.R.). The purpose of this document is to assure uniformity from batch to batch. This document should be prepared for each product, including each batch size thereof. It should be dated & signed by the one person & independently checked, dated & signed by a second person. There should be a detailed S.O.P. for preparation of M.P.C.R. This document contains the name & strength of the product & description of the dosage form, the name & weight of each active ingredient per dosage unit, complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristics like particle size, bulk density, color etc., a statement concerning any calculated excess of components should be there in MPCR, statement of theoretical weight at appropriate phase of processing, statement of theoretical yield, including the maximum & minimum % of theoretical yield beyond the investigation, description of drug product containers, closures & packaging materials
Batch production & control records (B.P.C.R.) is a recurring document which gives the detail history of batch produced or in other sense B.P.C.R. is a replica of M.P.C.R. but it gives the actual information about the process which is carried out. All the contents mentioned in the M.PC.R. are include in the B.P.C.R.
Change control is a system of procedures from which changes are reviewed, justified, approved, documented & implemented in conformances according to requirements. While considering the management of change control, there is actual deviation & should be considered as deviation control.
Site master file is a document which gives the complete information regarding the site of pharmaceutical manufacturing plant. Generally it includes general information about Pharmaceutical manufacturing plant, Personnel details, Information about premises & equipments, Documentation system, Production description, Quality control system, Description about contract manufacturing & analysis & other services, Information post operational activities, Self inspection system and finally , Export of drugs.
Read Full Post | Make a Comment ( None so far )Material Management
By: Supriya Sharma, Shamita Kohli
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
The quality of finished products solely depends upon the quality inputs & hence material management becomes very important activity in pharmaceutical manufacturing operations. The total material management activity starts right from selection of vendors for raw material, packaging material to dispatch of finished product to its destination. All materials & products should be stored under appropriate conditions in orderly fashion to permit batch segregation & stock rotations by first in first out & first expiry first out.All materials should be purchased against an approved & adequate specification which defines not only the grade & quality required but also the nature of packaging containers to be used. The quality material should clearly specify important pharmacoepial specifications & characters. Materials should be purchased only from approved supplier or manufacturer. Raw material & packaging material should be purchased by trained buyers by preferably material managers who has sufficient exposure of raw material & packaging material.All the raw materials should be checked after receiving for the name of manufacturer, batch no., date of manufacture, date of expiry etc.Records for receipt of material e.g. bills, customs etc. should be available. There should be special sampling booths & identified Quality control person for sampling of receiving materials. Material in the storage area should be appropriately labeled. Containers from which samples have been taken out should be identified. Only materials released by quality control department & with in there shelf life should be used. There should be SOP/R on sampling, storage & dispensing of material.There should be a classified list of approved vendors along with name of the packaging material. e.g. primary, secondary, printed packaging material. Printed packaging material should be stored securely in lock & key system. SOP/R should be available for dispensing of packaging material. There should be registers for sampling & dispensing of packaging material in chronological order. Out dated or obsolete packaging material should be destroyed by suitable approved method under the supervision of quality assurance person. Access to the storage area should be limited to the authorized person only. A list of material is based on storage material to be available.The storage of intermediate & bulk product is the responsibilities of production department. These products should be stored under appropriate storage conditions & the bulk products which are purchased as such should be handled on receipt as though they were raw materials.These products should be held in quarantine until their final release. Each batch of finished product should be tested as per laid down testing procedures & then only released for distribution. Products failing to meet established specifications should be rejected. If feasible reprocessing is performed. SOP/R for release & reprocessing should be available.Rejected & recovered material can be reprocessed & retested to see whether it meets our specific requirements or can be destroyed or has to be sent to the supplier. Such material should be clearly marked & stored in restricted areas which are normally painted red in color.
Reprocessing should be permitted only if the resulting batch is going to meet the specifications. The addition of recovered product should be authorized before hand & after the addition of recovered or reprocessed product to the batch. Additional testing of finished product should be done. SOP/R on handling & disposal of rejected & recovered material should be available.
Products which are already distributed or sold may be required at times to be recalled for various reasons e.g. substandard quality, damage of goods during transit etc. such recalled product should be clearly identified & stored separately until a decision is taken on there fate. SOP/R on handling of recall product should be there.Pharmaceutical products can be returned from market for various reasons e.g. quality problems, accidental damage of goods etc. such product should be physically examined & evaluated for quality. if possible reprocessing & releasing is done otherwise the product is destroyed. SOP/R on handling of returned goods should be available.A register of reagent & culture media should be maintained. Reagents should be prepared according to SOP’s both positive & negative control should be applied to verify the suitability of culture media.Pharmaceutical manufacturing operations generate a lot of waste materials. Provisions should be made for proper & safe storage of disposal of waste materials. SOP/R of handling of waste material should be available.Reference standards should be prepared by using a defined procedures & to be tested, released & then stored in the same way as official standard under the responsibility of designated person in secured area. SOP/R on handling of reference & working standard should be available.
Read Full Post | Make a Comment ( None so far )Personnel
By: Shamita Kohli, Supriya Sharma
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
The main resource in manufacturing & distributing quality medicines is the people behind all the activities that are carried out in a pharmaceutical factory. All the regulatory requirements through out the world talk about handling the pharmaceutical process by trained people. Establishment and maintenance of satisfactory system of QA and manufacturing of products and actives rely on people. People must be sufficient qualified personnel to carry out tasks. Individual responsibilities must be clearly understood by individuals concerned. All personnel should be aware of the principles of GMP that affect them. Adequate number of qualified people should be there with practical experience.An individual’s responsibilities should not be so extensive as to present a risk to quality. The useful reference documents for inspectors in this context are Organisation Charts and Job responsibilities. Each personnel should be provided with clearly defined job responsibilities. There should be no gaps or unexplained overlaps in job responsibilities. Adequate authority should be provided to personnels to carry out their responsibilities.People in an organization is the main resource and has more value & importance than other resources like facilities, equipment & materials; provided these people are trained & trained appropriately to carry out their assigned task.Training may be defined as the acquisition of technology which permits employees to perform their present jobs to standards.Development is training people to acquire new horizon, technologies or viewpoints. Unlike training & education, which can be completely evaluated, development cannot always be fully evaluated.Education is training people to do a different job. There are many methods of training employees during employment. One of the latest methods to train people in employment is by “Instructional System Design”. Output is trained person.The organization should have training manual for each level of personnel. There should be written programme for training of all the personnels working in production areas and control laboratories and for all the other personnels whose activities affect the quality of product. Individuals must receive initial and continuing training in theory and practice in GMP including training for maintaining personal hygiene standards, approved by either the head of Production or QC as appropriate. All the personnels must be motivated to support the establishment and maintain high-quality standards. Training records should be kept. Training should be provided before undertaking any new task. Staff in special areas such as clean areas; or working with highly active, toxic, infectious, sensitizing materials should be given specific training. The concept of QA and its understanding and implementation should be fully discussed during training.All personnel should be trained in the practices of personal hygiene and clothing. Organization should develop and implement detailed hygiene programmes for their employees. This should include training employees regarding high standards of cleanliness. Pre and post employment medical check-up, annual eye examinations, penicillin sensitivity tests should be carried out. There should be SOP on handling of illness of employees. A detailed Dress Code should be implemented. There should be an organization policy on smoking, eating, chewing and drinking.Visitors or Untrained Personnel preferably should not to be taken in. If this is unavoidable, for example GMP inspectors they must be given information in advance; particularly about personal hygiene; and protective clothing requirements. They must be accompanied and closely supervised at all times. Key personnel normally should be full-time. These positions include Head of Production, Head of Quality Control, Head of Sales and Distribution. Heads of Production and Quality Control should be independent of each other. Key personnel should posses the qualifications of Scientific education for example chemistry, biochemistry, chemical engineering, microbiology, pharmaceutical sciences and technology, pharmacology and toxicology, physiology; or other related science subjects relevant to the responsibilities to be undertaken. They should also posses qualifications of Practical experience under professional guidance. They should be able to take difficult decisions in a professional and scientific way and to resolve the problems encountered in manufacturing and QC.Heads of Production and Quality Control may share some responsibilities depending on national regulations. For example, authorization of written procedures (SOPs) and other documents, including amendments, environmental monitoring and control, and plant hygiene, process validation and calibration, training, including application and principles of QA, approval and monitoring suppliers, designation and monitoring of storage conditions, retention of records, monitoring compliance with GMP, inspection, investigation, and taking of samples to monitor factors which may affect quality. The responsibilities of Head of Production are Product production and storage according to appropriate documentation, Approval and implementation of production instructions, in-process QC and ensure strict implementation, Evaluate production records; signed by designated person before passing to QC, Maintenance of production department, premises and equipment, Process validation and calibration performed, recorded and reports made available, Training of production personnel; initial and continuing etc.The responsibilities of Head of Quality Control are Approval or rejection of materials, packing materials, intermediates, bulk and finished products, Evaluation of batch records, Carrying out of necessary testing, Approval of quality control procedures like sampling instructions, specifications, test methods, and other QC procedures, Approval and monitoring of all contract analysis, Maintenance of quality department, premises and equipment, Validation, including analytical procedure validation, and calibration of control equipment, Initial and continuous training of QC personnel etc.Consultant is a person who provides expert advice professionally. Regulatory authorities allow, pharmaceutical manufacturer to seek such advice from consultants if they need. U.S.F.D.A. has identified certain areas for advice e.g. manufacture, processing, packaging and holding of products. As per U.S.F.D.A., such consultants must have sufficient education, training and experience or any combination of them to advice on the subjects for which they are retained. Manufacturer should maintain records of such consultants giving details of their name, address, qualifications and type of service provided. As per M.C.C., only in exceptional circumstances should persons be engaged part time or in a consultative capacity be appointed to key positions.From the above review of GMP requirement for personnels, we can conclude that the key personnel issues that may arise during an inspection are limited number of staff, inadequate qualifications, inadequate experience, owner interferes in quality decisions, lack of means to develop training materials, company procedures take precedence over local legislation, unclear organisation diagram, staff movement, inadequate training records,and illness.
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Current Good Manufacturing Practices 