CGMP
Quality management system: Review on “Outsourcing”.
QUALITY MANAGEMENT SYSTEMS
Review on “Outsourcing”
Sunny Modi, Prof Manohar A Potdar
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, India
Keywords: Outsourcing, Contract, Contract giver, Contract acceptor, Responsibility.
Outsourcing is rapidly growing in the pharmaceutical industry. Most of the pharmaceutical industry outsource (contract) at least some activities or operations due to inadequate personnel, equipments, Analytical laboratories or due to any other reasons. In such cases regulatory authorities allow outsourcing or contracting services with the external party/supplier. Therefore outsourcing activity is more important and is carried out based on legal agreement between two parties i.e. organization (contract giver) and supplier (contract acceptor) and contains detailed and precise contractual specifications regarding data privacy and protection etc.
Outsourcing is the process of subcontracting to a supplier external to the organization an activity that is currently conducted in house.
Or
Outsourcing is the contracting of services or tasks to an external company.
Outsourcing fits well with the” just-in-time (JIT)” concept of minimizing waste in a company’s operations. Outsourcing is the company’s activities which should allow it to minimize the effects of fluctuating revenues in what has become a more dynamic business environment. Outsourcing therefore allows the company to maintain a basic level of operations in core departments but expand or contract out in areas in which additional resources are required. This can be done on a project by project basis. Outsourcing reduces internal costs, reduces cycle time or improves quality because the companies have adequate technology and knowledge to perform certain tasks more efficiently than some companies can internally. Outsource companies possess better developed skills in the particular area and a reduced cost structure in comparison to the client companies.
There are three primary considerations that need to be addressed when identifying the “right” supplier for the organization:
(1) Does the supplier have the proper training to assist with the validation programme?
(2) Does the supplier have adequate time to devote to the validation effort and are they willing to guarantee this contract?
(3) Has the supplier actually participated in this type of work previously? Have they actually done this specific work, and if so, are they willing to provide references?
Assuming these three primary considerations are met, a fourth and extremely critical factor to consider is whether the supplier has the type of personality that will allow for effective integration into the project team. The supplier must be integrated into the overall cooperative partnership that is necessary for successful validation. The organization must certain that the supplier has the necessary interpersonal skills to build and maintain the proper relationship for a long time.
The contract giver must work closely with the supplier to ensure all the regulatory “bases” are covered.
Reasons for Outsourcing
Organizations that outsource are seeking to realize benefits or address the following issues:
· Cost Savings. The lowering of the overall cost of the service to the business. This will involve reducing the scope, defining quality levels, re-pricing, re-negotiation, cost re-structuring. Access to lower cost economies through off shoring called “labor arbitrage” generated by the wage gap between industrialized and developing nations.
· Cost Restructuring. Operating leverage is a measure that compares fixed costs to variable costs outsourcing changes the balance of this ratio by offering a move from variable to fixed cost and also by making variable costs more predictable.
· Improve Quality. Achieve a step change in quality through contracting out the service with a new Service Level Agreement.
· Knowledge. Access to intellectual property and wider experience and knowledge.
· Contract. Services will be provided to a legally binding contract with financial penalties and legal redress. This is not the case with internal services.
· Operational Expertise. Access to operational best practice that would be to difficult or time consuming to develop in-house.
· Staffing Issues. Access to a larger talent pool and a sustainable source of skills.
· Capacity Management. An improved method of capacity management of services and technology where the risk in providing the excess capacity is borne by the supplier.
· Catalyst for Change. An organization can use an outsourcing agreement as a catalyst for major step change that can not be achieved alone. The outsourcer becomes a Change Agent in the process.
· Reduce Time to Market. The acceleration of the development or production of a product through the additional capability brought by the supplier.
· Co modification. The trend of standardizing business processes, IT Services and application services enabling businesses to intelligently buy at the right price. Allows a wide range of businesses access to services previously only available to large corporations.
· Risk Management. An approach to risk management for some types of risks is to partner with an outsourcer who is better able to provide the mitigation.
· Time Zone. A sequential task can be done during normal day shift in different time zones – to make it seamlessly available 24×7. Same/similar can be done on a longer term between earth’s hemispheres of summer/winter.
Activities Mainly Outsourced:
The list below shows the types of activities currently outsourced by many organizations are,
· Manufacturing/Packaging of finished products
· Validation services
· Calibration activities
· Analytical testing/Analytical method development etc.
· Auditing services
· Other services i.e. security, pest control etc.
General guidelines for outsourcing: Based on USFDA guidelines outsourcing operations can be divided into three parts in terms of individual responsibilities.
(1) Contract Giver:
· The contract giver is responsible for assessing the competence of the contract acceptor in successfully carrying out the work or tests required and for ensuring by means of the contract that the principles of GMP are followed.
· A contract giver should assure him self that the contract acceptor has adequate premises, equipment, and staff with sufficient knowledge and experience, to carry out satisfactorily the work given to him. For this purpose the contract giver should carry out technical audit of the contract acceptor. This audit is required to be carried out before the activities are stared and at regular intervals thereafter. Audit reports should be issued and kept on record.
· A contract giver may only use the contract manufacturer, packer or analytical services as approved in the registration dossier.
· A contract giver shall not authorise a contract acceptor to commence manufacturing, packing, testing of a medicine, until he has assured himself, and authorised by him, that all necessary master documents and/or specifications, generated by contract acceptor for use in his own facility, are in accordance with the particulars contained in contract giver, master documentations and registration dossier.
· The contract giver should provide the contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorisation and any other legal requirement.
· The contract giver should ensure that the contract acceptor has fully aware of any problems associated with the product, work, or tests that might pose a hazard to premises, equipment, personnel, other materials or other product.
· The contract giver should ensure that all provided products and materials delivered by contract acceptor comply with their specifications or that the product has been released by the authorised person(s).
(2) Contract Acceptor:
· The contract acceptor must have adequate premises, equipments, knowledge and experience and competence personnel to carry out satisfactorily the work ordered by the contract giver. Contract manufacturer can only be undertaken by manufacturer who holds a manufacturing authorisation.
· The contract acceptor should not pass to third party any of the work entrusted to him under the contract without the contract acceptor givers prior evaluation and approval of the arrangements. Arrangements made between the contract acceptor and any third party should ensure that the manufacturing and analytical information is made available in the same way as between the original contract giver and contract acceptor.
· The contract acceptor should refrain from any activity that may adversely affect the quality of the product manufactured and/or analysed by contract giver.
· The contract acceptor should ensure that all products or materials delivered to him are suitable to their intended use.
· If a contract acceptor supplies materials, the contract giver should specify the quality required in the specifications/master document.
(3) Contract:
· The contract should be drawn up between the contract giver and the contract acceptor specifies their respective responsibilities relating to the manufacture and control of the product. Technical aspects of the contract should be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis and GMP. All arrangements for production and analysis must be in accordance with the marketing authorisation and agreed by both parties.
· The contract should specify the way in which authorised person releasing the batch for sale ensures that each batch has been manufactured in, and checked for compliance with the requirements of the marketing authorisation.
· The contract should describe clearly who is responsible for purchasing, testing and releasing materials and for undertaking production and quality control, including in process controls and who has responsibility for sampling and analysis. In case of contract analysis the contract should state whether or not the contract acceptor should take samples at the premises of the manufacturer.
· Manufacturing, analytical or any other records and reference samples should be kept or be available to, contract giver. Any records relevant to assessing the quality of a product in the event of complaints or suspected defect must be accessible and specified in the defect/recall procedure of the contract giver.
· The contract should describe the handling of the starting materials, intermediates, bulk products or finished products, if they are rejected. It should also describe the processing of information if the contract analysis shows that the tested product must be rejected.
Contract finalization
At the heart of every outsourcing deal is a contractual agreement that defines how the sponsor and the supplier will work together. This is a legally binding document and is core to the governance of the relationship. There are three significant dates that each party signs up to the contract signature date, the effective date when the contract terms become active and a service commencement date when the supplier will take over the services.
Conclusions:
This article gives the idea of the outsourcing operations and benefits of the outsourcing services based on FDA audit questionnaire or any other regulatory requirements and selection of the supplier. Outsourcing is the new pathways for the organization to carry out his business by means of more efficient, effective, and cost-competitiveness based on rising customer expectations, dwindling pipeline for the new blockbusters, ever-increasing regulatory burden, reducing the cycle times, and minimizing the time to market. So, the need for contracting with an outside supplier has become necessary business strategy for the pharmaceutical industry. After the initial evaluation of the supplier, the successful contract validation will enable both parties to achieve the economic benefits desired.
References:
(1) Draft Guidance for industry, “Quality system approach to pharmaceutical current good manufacturing practice regulation”, September 2004, pharmaceutical CGMPs.
(2) U.S.Food and Drug Administration Centre for Drug Evaluation and Research, “21 Code of Federal Regulations Parts 210 and 211”.
(3) Validation of Pharmaceutical Processes, Third Edition, by James Agalloco and rederick J. Carleton.
(4) Validation in Contract Manufacturing by Dilip M. Parikh, Maryland, U.S.A.
(5) Anu Linna, Mirka Korhonen, et. al., “Developing a tool for the preparation of GMP audit of pharmaceutical contract manufacturer”.
(6) D. Smith, The effect of outsourcing on the pharmaceutical – fine chemical industry relationship, Pharm. Technol. 24 (Suppl. 8) (2000) 52–56.
(7) Juan’s Quality Planning & Analysis for Enterprise Quality, Fifth Edition by Joseph M.Juran, Tata McGraw Hill.
(8) A.D. Bardhan and C. Kroll, The New Wave of Outsourcing (2003).
(9) Mark Kobayashi-Hillary. 2004. (2nd ed 2005) Outsourcing to India. ISBN 3-540-23943-X.
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Design and Develop Product and Processes
Quality Management System
Design and Develop Product and Processes
Prof. Manohar A. Potdar
Head of Quality Assurance Department, Poona College of Pharmacy, Pune, India
Mr. Prafulla P. Apshingekar
Quality Assurance Department, Poona College of Pharmacy, Pune, India
Product development is the process of creating a new product to be sold by a business or enterprise to its customers. In the document title, Design refers to those activities involved in creating the styling, look and feel of the product, deciding on the product’s mechanical architecture, selecting materials and processes, and engineering the various components necessary to make the product work. Development refers collectively to the entire process of identifying a market opportunity, creating a product to appeal to the identified market, and finally, testing, modifying and refining the product until it is ready for production.
The task of developing outstanding new products is difficult, time-consuming, and costly. People who have never been involved in a development effort are astounded by the amount of time and money that goes into a new product. Great products are not simply designed, but instead they evolve over time through countless hours of research, analysis, design studies, engineering and prototyping efforts, and finally, testing, modifying, and re-testing until the design has been perfected.
As a general rule, the cost of a development effort is a factor of the number of people involved and the time required to nurture the initial concept into a fully-refined product.
(a)“ In modern quality systems manufacturing environment, the significant characteristics of the product being manufactured should be defined, from design to delivery and control should be exercised over all changes.”
A pharmaceutical Product should be designed in such a way that it should meet five basic characteristics namely, identity, strength, safety, purity & efficacy. By keeping this in mind, specifications for required product are finalised.
Change control is another well-known CGMP concept that focuses on managing change to prevent unintended consequences. The CGMP regulations provide for change control primarily through the assigned responsibilities of the quality control unit. Certain major manufacturing changes (e.g., changes that alter specifications, a critical product attribute or bioavailability) require regulatory filings and prior regulatory approval.
Effective change control activities (e.g., quality planning and control of revisions to specifications, process parameters, procedures) are key components of any quality system. In this guidance, change is discussed in terms of creating a regulatory environment that encourages change towards continual improvement. This means a manufacturer is empowered to make changes subject to the regulations based on the variability of materials used in manufacturing and process improvements resulting from knowledge gained during a product’s lifecycle.
(b) “Quality and manufacturing processes and procedures and changes made to them should be defined, approved, and controlled. Responsibility of person in this regard should be established.”
It is important to establish responsibility for designing or changing product. Documenting associated processes will ensure that critical variables are identified.
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. 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.
Both (a) and (b) should be documented, this documentation must include -:
Þ Resources and facilities needed
Þ Procedures to carryout the process
Þ Identification of the process owner who will and update the process
Þ as needed
Þ Identification and control of critical variables
Þ Quality control measures, necessary data collection, monitoring, and
Þ appropriate controls for the product and process
Þ Any validation activities, including operating ranges and acceptance
Þ criteria
Þ Effects on related process, functions, personnel
(c) “Management should see that product specifications and process parameters are determined by technical experts. e.g. engineers, microbiologist, chemist, pharmacist, etc..”
Few products are developed by a single individual working alone. It is unlikely that one individual will have the necessary skills in marketing, industrial design, mechanical and electronic engineering, manufacturing processes and materials, tool-making, packaging design, graphic art, and project management, just to name the primary areas of expertise. Development is normally done by a project team, and the team leader draws on talent in a variety of disciplines, often from both outside and inside the company.
In the pharmaceutical environment, experts must have an understanding of pharmaceutical science , risk factors, and manufacturing process as well as how variations in materials and process can ultimately affect the finished product.
The process of developing new products varies between companies, and even between products within the same company. Regardless of organizational differences, a good new product is the result a methodical development effort with well defined product specifications and project goals.
REFERENCES
1. Guidance for Industry -Quality Systems Approach to Pharmaceutical CGMP Regulation(http://www.fda.gov/CDER/guidance/7260fnl.htm)
2. 21 code of Federal Regulation (21 CFR 314.70, 514.8, and 601.12).
3. Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals–21 CFR Parts 21 CFR part 21.100(a)
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Inspection
Inspection
Prof. Manohar A. Potdar
Head of Quality Assurance Department, Poona College of Pharmacy, Pune, India
Supriya Sharma, Shamita Kohli
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, India
Inspection means the control and enforces compliance with general Good Manufacturing Practices or we can say to authorize the manufacture of specific pharmaceutical products normally in response to a licensing application.
In pharmaceutical field the inspection of manufacturing & Quality Control facilities are to be done prior to marketing authorization for the product to be granted.
Inspector may be the independent person or a group of person who review the quality system of a company in compliance with the standards issued by the International Organization for Standardization (ISO 9000-9004) or British Standards Institution (BS 5750) with other equivalent National Standards.
Basic requirements for the Inspector:
Inspector should have previous training and practical experience in the manufacture and Quality Control of pharmaceutical product. Inspector should be graduate Pharmacist, Chemist or Scientist with an industrial background in pharmaceutical product. In-post training should include an element of apprenticeship gained by accompanying experienced inspectors on site visits as well as participation in courses and seminars on relevant subjects including modern pharmaceutical technology, microbiology, and the statistical aspects of quality control.
The inspector should have the following attributes:
· good knowledge of pharmacy, drugs, and poisons
· good knowledge of the laws and regulations to be enforced
· good command of technical terms and excellent communication skills
· awareness of the probable methods of using forged or false documents for transactions in pharmaceutical preparations and skill in determining the genuineness of documents presented for examination
· maturity, honesty and integrity
· responsible conduct which commands respect
· willingness to accept challenges
· ability to organize their own work with minimum supervision
· ability to assess facts quickly and take rational and sound decisions without delay
· ability to assess character and honesty of persons being interviewed
· good public relations image with key personnel/pharmacists in charge of premises while remaining firm, fair and resolute
· ability to hold discussions with company management at the completion of inspection
· ability to motivate others
· commitment to hard work and long hours
· ethical approach to any potential conflict of interest.
Inspector’s requirements
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Good Inspector |
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Experience concerning usage and quality problems |
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Good communication with staff of all levels |
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Experience of the components manufacturing process |
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Full understanding of G.M.P. & legal requirements |
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Familiar with general manufacturing standards operated in industry concerned |
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Prepare in advance of visit |
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Realistic prepared to listen |
Responsibilities of an Inspector:
An inspector should present a detailed factual report on standards of manufacture and control applied to specific products. However, inspection should not be limited to compilation of an inventory of faults, irregularities, and discrepancies. Provided it is in keeping with national policy and does not breach understandings regarding confidentiality of information having commercial value, advice may be offered on how production and control procedures can be usefully upgraded. An inspector should always be expected, to offer advice on how to improve an in-process test procedure or to offer other assistance which, in his or her opinion. An inspection should be regarded as an opportunity to assist and motivate a manufacturer to comply with GMP and to correct any specific deficiencies.
Types of inspections:
Routine inspection
This is a full inspection of all relevant components of GMP and licensing requirements. It may be indicated when the manufacturer is newly established or requests the renewal of a license or he has introduced a new product, or has made a significant modifications to the manufacturing methods or has made some changes in key personnel, premises, equipment, etc.;
Concise inspection
Manufacturers with reliable records of compliance with GMP in the course of previous routine inspections are appropriate for concise inspection. The heart of a concise inspection is on a partial number of GMP requirements chosen as indicators of overall GMP recital, with respect to the identification of any noteworthy changes that could have been introduced since the last inspection. Cooperatively, the information obtained will indicate the overall attitude of the firm towards GMP. Evidence of unsatisfactory GMP recital observed throughout a concise inspection should set off a more comprehensive inspection.
Special inspection
Special inspection are generally carried by visits which may be essential to carry out spot checks for following complaints or recalls associated to supposed quality defects in products. Reports of adverse drug reactions may also point out that all is not well. Such inspections may be focused on one product, a group of related products, or specific operations such as mixing, sterilization, or labelling. Special visits may also be made to set up how a specific product is manufactured as a precondition for marketing approval or issuance of an export certificate. A supplementary reason for special visits is to congregate specific information on or to investigate specific operations and to advise the manufacturer of regulatory requirements.
Inspection procedures
The GMP inspectorate should have the necessary resources such as financial, human, facilities and documented procedures to allow the inspection of manufacturing operations to be carried out in accordance with the general requirements of the WHO guidelines on GMP and/or the national GMP guidelines. The GMP inspectorate should require the manufacturer to have documented procedures in accordance with a quality management system, and complying with the WHO guidelines on GMP and/or the national GMP guidelines. The GMP inspectorate should perform regular inspections of the manufacturing premises, procedures and quality systems of authorization holders at least once every 2 years in accordance with a written inspection programme. Written inspection reports should be prepared and sent to the national regulatory authority to keep it informed of the outcome of such inspections. The arrangement of inspections of manufacturers and the evaluation of compliance with the planning concerning the performance of the different types of inspections should be documented. The types of inspections should include as a minimum routine inspections, specific inspections, follow-up inspections and concise inspections.
INSPECTION
The activities relating to post-marketing surveillance and product testing should be described. The description should also cover the process of handling non-conforming products (e.g. substandard or counterfeit products). The procedure for operations in support of a surveillance sampling programme should be documented. The GMP inspectorate should have the documented procedures and resources to enable the inspection of manufacturing and wholesale distribution operations to be carried out in accordance with the official guidelines and national legislation. A formal inspection plan should be followed. All instructions, standards or written procedures, worksheets, checklists and reference data relevant to the work of the GMP inspectorate should be kept up to date and be readily available to staff. A chief inspector should be appointed to coordinate inspection activities if more than one inspector is involved in an inspection. The lead inspector, who should be selected by all the participating inspectors, should normally prepare the inspection report. Observations and/or data obtained in the course of inspections should be recorded in a timely manner to prevent loss of relevant information. Completed inspections should be reviewed to ensure that the requirements have been met.
Carrying out the inspection
Emphasis should be positioned on the assessment of the manufacturing procedure, together with the data verification and the measurement of compliance with GMP. The production and control procedures described in the application must be compared with those of used for the make of pre-approval batches. If warranted by records of past label mix-ups, packaging and labelling control procedures should be evaluated. A programme of ongoing stability testing needs to be addressed.
The inspection team will determine whether the application provides the scientific data justifying full-scale production procedures and controls. The validation of pertinent manufacturing procedures, including equipment qualification, will also be evaluated. However, inspectors should not suggest withholding endorsement of applications based on be short of of complete full-scale, multiple-batch validation of sterile and non-sterile processes, except the data submitted in the application are found to be of doubtful validity or entirety. It should be understood that full-scale validation may be done after endorsement of the application, but previous to consignment of the first profitable batches. Yet, convinced data must be built-in the application to reveal that the sterilization or aseptic fill procedure has been qualified. The inspection team is anticipated to audit the data to resolve their genuineness, accuracy and entirety. Tentative products are frequently produced in facilities other than those used for full-scale production. These facilities and the related manufacturing and control procedures are not habitually inspected except validation of the transfer of the methods from the “investigational” facilities to the full-scale facilities is deficient or doubtful. The facilities may be periodically inspected when this is required by national legislation/regulation.
Generally inspection is carried out for Quality Management System, Production, Quality Assurance and Quality Control, Premises and Equipment, Utilities, Safety, Complaints and Product Recall etc. Basic principles of GMP like Training, documentation, authorized release, etc should be the main criteria for the inspection.
What the inspector expect and keep in his mind during his inspection according to W.H.O. and how we can prepare for the same?
There are following things in the mind of inspector. These are classified section wise as follows:
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Site and Plant Security
By: Shamita Kohli, Supriya Sharma
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
Site is a geographic location where one or more pharmaceutical plants are situated and operated. Plant is a physical block or building on a site, engaged in the manufacturing of pharmaceuticals. M.C.C. South Africa provides guidelines on security personnel, entry to site, entry to buildings and internal security. Security personnels include security manager and security staff. A security manager should be capable of handling plant, site and internal security. He should be trained in area of security techniques, legal requirements and sufficient leadership qualities. There should be sufficient security staff, who is trained enough to perform their specified duties. Plant should be guarded on 24 X 7 basis.
Site should restrict, entry of unauthorised persons. Sufficient security measures should be taken. e.g. a perimeter fence of good quality of sufficient height and strength, adequate security lighting, limited and restricted access to the production and storage areas should be provided, sufficient but limited number of gates with vigilant security staff.
Entry to the plant buildings is restricted according to the contents of building. Entry can be controlled by good quality locks, inaccessible windows, installation of burglar alarm. Entry should be controlled to vital areas of a building like sterile product area.
There should be a detailed procedure for managing internal security of site and plant. Such procedure may include locking of areas and storage of keys, making access controlled vital areas, control over movement of visitors, control of movement of stock to prevent pilferage, checking of waste, checking batch yield, screening of staff before leaving and screening of delivery services and vehicles. Theft is one of the major issues in plant and site security management. Extra care should be taken during construction stage.
Read Full Post | Make a Comment ( None so far )Safety and Environmental Protection
By: Shamita Kohli, Supriya Sharma
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
Employees of an organization are one of the most important resource and their safety is of prime importance. All the employees must be trained in industrial safety requirements. Safety audits must be carried out at least once a year by internal experts or outside agencies. The deficiencies observed should be actively corrected.
Some areas must be kept in mind while formulating safety policy and procedures. Buildings, machinery, vehicles, equipment should be kept in good state of repair. Fire preventive measures should be in place. Depending on the nature of work, safety devices like helmets, safety glasses, masks, gloves etc. should be worn. First aid kit should be available and accessible for treatment. Qualified physician shall be present. Special attention should be given to handling of hazardous materials.
Environmental protection should be looked in carefully by pharmaceutical industries. Procedures and controls should be present to minimize the discharge of hazardous substances to the environment. Methods should be adopted to render the waste materials harmless to the environment. Procedures should be there to control the generation, transportation, storage, treatment or disposal of hazardous waste. It is advisable to re-use, recycle or inactivate the hazardous waste materials. Emergency procedures to minimise hazards associated with discharges to the environment should be developed. The capabilities of vendor suppliers and contract acceptors should also be evaluated from an environmental point of view. Monitoring programmes should be developed to determine that compliance with legal and in house specifications are maintained. Procedures should be developed for the operation and maintenance of pollution control and monitoring equipment and should include preventive maintenance and training programmes. Records should be retained in accordance with legal requirements of the country and in-house requirement. The integrity of the underground storage tanks and associated piping and equipment should be routinely verified. The preferred strategy for all waste management is reduction of waste at source.
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Outsourcing
By: Supriya Sharma, Shamita Kohli
Poona College of Pharmacy, Bharati vidyapeeth University, Pune
Outsourcing or we can say contract manufacturer. Some times pharmaceutical manufacturer depend upon other manufacturer for manufacturing of his product because if manufacturer not have sufficient capacity to produce the required volume & if he may not have capacity in terms of facility, equipment etc. so, regulatory authorities allow them for contract manufacturing.
Regulatory guidelines on manufacturing & analytical services states that contract production & analysis must be clearly stated to avoid misunderstanding because that will lead to unsatisfactory quality. Contract must be in written format between the contract giver & contract acceptor. Contact must clearly show the way in which authorized person releasing batch for sale & issuing analysis certificate. Also the contract should clearly show the specifications of the product which relevant legal requirements & that should be maintained during storage, transport & distribution. There is a permission in the contract for the contract giver to audit the facilities of the contract acceptor. The final approval for release of product must be given by authorized person in case of contract analysis.
For manufacturing & packaging outsourcing three items must be clearly understood by the parties that are, contract giver, contract acceptor and contract.
Contact giver is responsible for assessing the competence of contract acceptor is successfully carrying out work. There should be assurance to contract giver that contract acceptor has adequate premises, equipment staff with sufficient knowledge & experience to carryout the work for this audit is carried out & records for this is maintained. Contact giver shall not authorize the contract acceptor to commence manufacturing, packaging, testing of medicine until he has assured himself & authorized by him that all necessary master documents are in accordance with particulars contained in contract giver, master documents & registration dossier. Also the master document must be comply with the regulation of importing country or domestic. Contract giver should ensure that the contact acceptor is fully aware of any problem associated with product, work test that might cause any hazard to premises, equipment, personnel etc.
Contract acceptor must have adequate facility, knowledgeable & experienced staff. Also contact acceptor should not pass to third party any of his work. For doing this he must take permission from the contact giver. Contact acceptor should reframe from any activity that adversely affects the product quality. Contact acceptor should ensure that all product delivered to him are suitable to their intended use. If contact acceptor supplies material, then the contract giver should specify the quantity required in master document.
Contract should be drawn between contract giver & contract acceptor that shows their responsibilities related to the manufacturing of product. In contract clearly describe that who is going to responsible for purchasing, testing & release of materials for production & quality control & who is responsible for sampling & analysis. In contract analysis contract should state that whether or not the contract acceptor should take samples at the premises of manufacturers. Manufacturing, analytical & distribution records & reference sample should kept to contract giver. Also contract should define the handling of starting material, intermediate, bulk & finished product. If they are rejected. It also describes the processing of information’s if contract analysis shows that the tested product must be rejected.
In analytical outsourcing although analysis & testing may be undertaken be contract analyst, the responsibilities of quality control cannot be delegated to him. Contact analyst should be supplied with full specifications/ master documents of material to be tested & details of test methods. Audit should be carried out on work performed by contract laboratory & maintain the records.
Some times other services such as maintenance, calibration, validation etc. are also outsourced. For maintenance work the contract giver should assure himself that contact acceptor has sufficient equipment, staff etc. there should be written contact which shows that what work is to be carried out & detail of report is also required. SOP/R on contract manufacturing/packaging model contract agreement should exist. It should specify the acceptable limits between services or maintenance of equipment, system etc.
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Surrounding, Building & Facilities
By: Shamita Kohli, Supriya Sharma
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
A pharmaceutical manufacturing facility should be located in such an environment which protects the manufacturing process and presents minimum risk of causing any contamination to materials or products. It should have good surrounding environment with sufficient protection from drains, sewage or other nearby factories. The manufacturer should have profile of industries surrounding the pharmaceutical facility in the area of about 15km radius. Other factors like natural air flow, rainfall, temperature and relative humidity should also be considered. Guidelines provided by regulatory authorities state that building used for factory shall be situated & shall have such measures as to avoid risk of contamination from external environment, open sewage, drains, public lavatories, fumes, dust, smoke etc.
There are some general requirements of buildings and facilities. Pharmaceutical premises should provide well sanitation system. Premises should be carefully maintained and repair & maintenance operations should not present any hazard to quality of product. There should be SOPs for cleaning, sanitation and disinfection of premises. Electric supply, lighting, temperature, humidity & ventilation should be appropriate & premises should be designed & equipped so as to allow maximum protection against entry of insects, birds, rodents etc.
Pharmaceutical manufacturing facilities are divided into different areas based on type of formulations and their quantities manufactured. These areas are namely Ancillary areas, Warehousing areas, Production areas and Quality control areas.
Ancillary areas include rest & refreshment rooms, toilets, engineering workshops etc.
Ware house areas include raw material, packaging material, intermediate material, bulk product & finished product etc.
Production area should include separate manufacturing facilities with adequate space for general category products, highly potent sensitive or live micro-organisms, product like technical poisons herbicides etc. to avoid cross contamination. Premises should be designed to have logical flow of materials well organized layout plant & machinery & ease of cleaning, both equipment & facility. All areas should be hard, smooth, impervious & without open joints for easy cleaning & sanitization. Drains should be adequate in size, sufficient in number & suitably located & equipped to prevent backflow product areas should have an effective HVAC system. Packaging area should meet the environmental conditions required by the products. Production area should be well lit.
Quality control area should be separated from production areas. Q.C lab should provide facility for wet chemical analysis instrumental analysis biological microbiological analysis. Storage for control samples, glass wares, chemicals etc. there should be separate HVAC system for Q.C. area. A separate area should be provided for highly sensitive instrument.
Documents like site master plan, area statement, plant capacity etc should be maintained for premises.
Potable water shall be supplied under continuous pressure in a plumbing system that could prevent contamination. Portable water shall meet the standards in environmental protection agency. Drains can be adequately sized & provided with an air break or other mechanical devices to prevent backflow.
Documents like plan of drainage system of plant & SOP/R of cleaning & sanitization of drain are required.
C.F.R 2.11.44 states that “adequate lighting shall be provided in all areas.”
Sewage, Trash & other refuse in & from the building & immediate premises shall be disposed of in a safe & sanitary manner. SOP/R on handling of scrap material should be there.
C.F.R. 2.11.52 states that adequate washing facilities shall be provided including hot & cold water, soap or detergents, air dryers or single service towels & clean toilet facilities easily accessible to working areas. The number of washrooms and toilets should be based on number of people working in the facility.
SOP/R on cleaning & sanitation of washing & toilet facilities are required.
C.F.R. 2.11.56 gives guidelines on sanitation which gives statements about cleanliness & sanitary conditions of pharmaceutical building. All building should be free of insects, rodents, birds etc. there should be SOP’s for sanitation, use of rodenticides, insecticides, sanitizing agent etc.
Document like SOP/R on control of pests, rodents, birds, insects etc. & job description of sanitary supervisor are required.
C.F.R. 2.11.58 states that any building used in the manufacturing, processing, packaging or handling of drug product shall be in a good state of repair. Facility maintenance include maintenance of spoilage of plasters, peeling off of paints, leakage from ceilings and pipes, plumbing, loose or broken tiles, improper closing of doors and windows, electrical wiring etc. There should be SOP/R for break down maintenance. Preventive maintenance should be planed at regular interval.
Read Full Post | Make a Comment ( 1 so far )Quality Management
By: Supriya Sharma, Shamita Kohli
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
Quality should be built into the product & testing alone cannot be relied on to insure product quality. Objectives of quality management are to provide high quality drug product, to prevent the recalls, returned or salvaged products & effective products, harmonize the cGMP to handle many types of changes to help in quality by design, to achieve success in business. Quality management system involves the concepts of quality, quality by design & product development, risk management & risk assessment, corrective & preventive action, quality control & quality assurance. The quality management system is divided into four parts that are management responsibilities, resources, manufacturing operations, evaluation activities.
Quality is effective at every stage of industrial cycle. Quality knows no functional boundaries, quality is everybody’s job & require carefully plan organization wide integration.
The basic concepts of quality assurance, GMP & quality control are interrelated.
Quality Assurance deals with all matter related quality of the product. Quality of a medicine must meet the requirements of the intended used or as required by the customer. It is the sum total of organized arrangement made for producing a quality product.
A pharmaceutical product which meets the five characteristics namely, identity, strength, safety, purity & efficacy can be accepted on a quality product. A system of Q.A appropriate to manufacture of pharmaceutical products should ensure that pharmaceutical products are designed & developed according to GMP, GLP, GVP, GCP etc., production & control operation are clearly specified in a written form & GMP requirements are adopted, managerial responsibilities are clearly specified in job descriptions, arrangements are made for manufacture supply & use of correct starting & packaging materials, all necessary control on starting material, intermediate products & bulk products & other in process controls, calibrations & validation are carried out, the finished product is correctly processed & checked, according to defined procedures, pharmaceutical products are not sold before the authorized persons have certified that each production batch has been produced & controlled in accordance with the requirements of the marketing authorization, satisfactory arrangements exist to ensure, as on far as on possible, that the pharmaceutical products are stored by the manufacturer, distributed and subsequently handled so that quality is maintained throughout their shelf life, there is a procedure of self inspection &/or quality audit that regularly appraise the effectiveness of the Q.A. system, production environment and service to production operations are monitored, and deviation should be adequately recorded, investigated & responded. The company should have documents for Quality Policy.
Good Manufacturing Practices is a part of Q.A. whose main function is to produce quality product consistently. Main function of GMP is to diminish the risks of mix-ups & contaminations. The activities of GMP involves clear defining of all manufacturing processes, validation of critical steps of manufacturing processes and any significant changes made to them, arrangement of all necessary facilities, production department should manage to arrange adequate personnel, laboratories & equipment in IPQC, writing all the instructions and procedures in clear and unambiguous language, training of operators to carry out procedures correctly.
Q.C. is a part of GMP. It deals with sampling, specifications & testing, documentation & release procedures. Q.C ensures that the necessary & relevant test are actually carried out & that materials are not released for use, nor products released for sale or supply, unless their quality is satisfactory. Q.C. should be independent of production department.
Q.C. department should have adequate facilities, trained personnel & approved procedures must be available for sampling, inspecting & testing of starting materials, packaging materials & intermediate bulk & finished products & where appropriate for monitoring environmental conditions for GMP purpose. There should be written SOP for sampling for RM/PM/Int. & finished products. The method for sampling, testing and other activities must be validated. Records must be made for sampling and testing activities.
Sampling activities get lot of attention of all the regulatory authorities. Sampling should be representative of the batches of materials from which they are taken.. Care should be taken during sampling to guard against contamination or mix-ups of or by the material being sampled. Sampling equipment should be cleaned. Documents like SOP for sampling are required. Sampling & dispensing of sterile materials shall be conducted under aseptic conditions confirming to Grade-A.
Reference sample means a representative sample of a substance used in the manufacture of a product. Major guiding principles states that retention samples from each batch of finished product should be kept for at least one year after the expiry date in their final packaging & stored under the recommended conditions.
SOP should be prepared for sampling of IPQC the materials & their testing. Parameters to be considered which are responsible for causing variability in the characteristics of the in-process materials & the drug product are selected. What specifications should be met at each critical stage of manufacturing should be identified & limits should be defined.
Testing of materials involves testing of active & inactive pharmaceutical ingredients, primary, secondary & other packaging material, in-process materials, finished bulk product, finished packed product.
Reference standards, any secondary standards prepared from them & purchased reagent should be dated where necessary & be stored, handled & used following written SOP procedures.
After the batch of a finished pharmaceutical is packed, certain quality of samples is kept aside for future & should be kept for at least one year after the expiry date of the finished product.
A written record of the investigation should be made & should include the conclusion & follow-up action.
Stability studies of a finished pharmaceuticals is an important activity under quality system. Documents showing that the stability studies are carried out for each products being manufactured, are required by regulatory authorities. Documents like SOP/R on stability studies are required.
Self-inspection is carried out to evaluate the manufacturers compliance with G.M.P. in all aspects of production & quality control. The self inspection SOP should cover items for self inspection, self inspection team, frequency o self inspection, self inspection report and follow-up action.
Quality audit may be defined as an examination & assessment of all parts of a quality system with a specific purpose of improving it. A quality audit is usually conducted by outside or independent specialists or a team designated by the management for this purpose. Such audits may also be extended to suppliers & contractors.
Documents like SOP/R on self inspection, quality audit & supplier audit are required.
Read Full Post | Make a Comment ( 2 so far )Post Operational Activities
By: Shamita Kohli, Supriya Sharma
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune
Pharmaceutical manufacturing & distribution starts with getting feed back as to what a customer wants. This will leads to developing & manufacturing & distributing of desired product to the customer. When customer receives & uses the product he may give good feed back or he may give adverse feed back. Manufacturers must use this feed back to improve products & eliminate deficiencies.
If the product has shown same defects the manufacturer recalls the product, handles the returned product appropriately & either salvage or destroy it.
Post operational activities includes distribution of finished products, recalled products, returned products, complaints & adverse effect & drug product salvaging.
Product is distributed either for sale or samples to doctors. A detailed record of its distribution should be maintained up to the wholesales. Finished products should be held in quarantine until final release & after that, should be stored as usable stock. Records of evaluation should be available with manufacturers.
Recalled products: Distributed product may get recalled for various reasons e.g. if the product is substandard quality. Stability related problems, accidental damage during transportation. A detailed SOP/R should be there for product recall. A person should be designated for execution of recall supported by staff. Recalled product should be stored in separate secure area. A final report should be prepared on reconciliation between distributed & recovered products.
Returned: Distributed products can be returned for substandard quality, damaged packaging, stability issues etc. Such products should be stored securely & should be destroyed unless modified to a satisfactory quality state. Such products should be assessed by quality control & then considered for resale & relabelling. A detailed SOP should be available for handling of returned products. Records of returned product should include name & label potency of product, reason of return, quality returned, date of disposition etc.
Complaints & adverse effects: A product complaints should be used for improving the product quality. there should be detailed SOP/R for complaint handling. A person should be designated for complaint handling with sufficient staff. All decisions & actions taken should be recorded & a file should be maintained for such products & shall be maintained for one year after expiry date of the product. The record should mention name & strength of product, batch no., name of complainant, nature of complaint, investigation made, if not made, reason for it is not investigated.
Adverse events: There should be a system for dealing with adverse events. A detailed SOP/r should be available indicating the responsible person with appropriate knowledge & experience. He will investigate the events & will take necessary actions.
Salvaging: Sometimes batches of finished product which are either stored in company’s ware house or in market place are required to be salvaged. SOP/R for salvaging should exist. Finished products which have been subjected to improper storage conditions shall not be salvaged. Salvaging must be done if lab tests & assays indicate that drug product meets all applicable standards of identity, strength, quality & purity. Records must be maintained for salvaging.
Read Full Post | Make a Comment ( 1 so far )
Equipment
By: Supriya Sharma, Shamita Kohli
Poona College of Pharmacy, Bharati Vidyapeeth University, Pune.
Equipment is important because all the pharmaceutical manufacturing or control activities depends upon good performance of equipment. While selecting a piece of equipment we should consider about design, size, location and construction of the equipment.
The design of equipment should meet our requirements. For this purpose we should prepare our User Requirement Specification & send it to the supplier for preparation of Design Qualification. This will help to incorporate all design parameter into the equipment which we need for ease of operation, cleaning & maintenance.
Size of the equipment is decided on the basis of volumes of materials which we are going to handle. In case of size of equipment the things that should be considered are physical dimension of machinery, size of room in which machine is going to be installed, holding & output capacity is directly related to size, what is the minimum & maximum volume of material we are going to handle.
Location of the equipment in plant depends upon logical process movement & also chances of contamination & mix-ups should be taken into account. Factors which influence the location of equipment are utility services required, material handling & movement, movement for processing & cleaning, men movement for repair & maintenance.
There are four main factors which are considered regarding construction of equipment. These are ease of cleaning the equipment & surroundings area, ease of operation of equipment, ease of maintenance of equipment, the material of construction.
Documents like machine/equipment manuals, machine/equipment layout certificate of material of construction & equipment validation reports should be maintained.
Four major parameters of GMP are identity, strength, safety and purity. So, it is important to have a unique identity or identification number for each equipment. C.F.R. 2.11.105 states that all compounding & storage container, processing lines, major equipment used during the production of a batch of a product shall be properly identified at all the times to indicate there contents & when necessary, the phase of processing of batch. It also states that major equipment shall be identified by distinctive identification or code number that shall be recorded in Batch Processing Records to show the specific equipment used in manufacture of each batch of product.
Documents like SOP on numbering of plant equipment & list of major equipment with there identification number are required in this context.
Pharmaceutical manufacturer must maintain a log of various operations carried out on various equipment including cleaning & maintenance.
For achieving the four parameters of GMP, the equipments should be cleaned, maintained and sanitized. There should be SOPs giving full details of cleaning & maintenance of equipment. Level of cleaning required may be defined & categorized. All equipments should be cleaned immediately after use & must be checked for cleanliness before use.
Equipment should be installed in such a way as to prevent any risk of error or of contamination. Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard. Balances and measuring equipment of an appropriate range and precision should be available for production and control operations. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained. Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective.
Automatic, mechanical, or electronic equipment include computers, or related systems that will perform a function satisfactorily. These equipment 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 and inspected according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained. 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. A backup file of data entered into the computer or related system shall be maintained. All automatic mechanical & electronic equipment like computer should be validated.
Filters for liquid filtration used in the manufacture, processing, or packing of injectable drug products intended for human use shall not release fibers into such products. Fiber-releasing filters may not be used. unless it is not possible to manufacture such drug products without the use of such filters
There should be an SOP/R of planned preventive maintenance programme which would help in maintaining the equipment in a good state of repair and maintenance at all the time.
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