Despite the fact India has become a global leader in manufacturing high quality affordable pharmaceutical and bio pharmaceutical medicinal products, many players are still following the traditional processing methods, which needs constant upgradation aver industry experts.
As the pharma and bio pharmaceuticals industry is knowledge intensive and needs to abide highest standards to ensure quality and efficiency, it is high time that drug manufacturing companies adopted advanced manufacturing standards and keep abreast with the western world, they point out.
The pharma and biotechnology manufacturing process in India needs to be continuously upgraded in tune with the developments in the world, so as to compete and sustain its growth both domestically and globally, opined S.V. Krishna Prasad, M.D and CEO of Cito Healthcare in Hyderabad.
For instance, in Andhra Pradesh which is the leading producer of active pharmaceutical ingredients (APIs) and bulk drugs, majority players are still following traditional manufacturing processes adopted one or two decades ago. Even the companies in the northern India and elsewhere are slow in adopting new manufacturing technology for pharma and biopharmaceuticals. Many companies which are SMEs are seeking government support for installation of modern manufacturing and other processing technology needed for the industry.
“The upgradation of manufacturing process and installation of advance technology in India is taking place at a slower pace. China is far ahead of us in adopting modern manufacturing technology. Major concern for lack of adoption of advance technology in India is cost. As majority players in pharma are SMEs, it is difficult for them to cope up with technology upgradation costs,” opined Krishna Prasad.
According to Krishna Prasad, the Indian pharma and biotechnology industry follows many types of manufacturing processes depending up on the kind of product that is being produced. For instance a few pharma companies are involved in manufacture of bulk drugs or APIs. This involves the mixing up of different chemicals and their reagents to form the bases for manufacturing various kinds of medicinal products.
After this APIs undergo another process of formulation, where they are made into different shapes and sizes of tablets and other useful medicines which are safely packed for human consumption later on.
In fact, APIs are chemicals used in everyday prescription and over-the counter medications. These are biologically engineered proteins and recombinant molecules created for biotech drugs falling under different definitions and regulatory schemes.
According to the U.S. Food and Drug Administration, APIs are defined as any substance or mixture of substances intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient in the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body.
For maintaining high quality standards, the pharma industry needs to implement the advanced technology continuously with the changing trends. Past experiences and innovations in technology will not only help the industry to rectify the faults, but also help upgrade the quality of products.
GMP practices and process requirements for APIs
The Q7A of Good Manufacturing Practice provides guidance for the manufacturing of APIs under an appropriate system for managing quality. The GMP procedures ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess.
Every industry involving in manufacture of bulk drugs should include all operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage and distribution of APIs and the related controls.
Industry in its manufacturing process should identify recommendations that, when followed, will ensure compliance with CGMPs. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes.
According to manufacturing process, the APIs for use in human drugs must first follow the sterilization and aseptic processes. The APIs that are manufactured by chemical synthesis, extraction, cell culture/fermentation, recovery from natural sources, or any combination of these processes should follow certain standard guidelines for their safety and efficacy.
API starting materials normally have defined chemical properties and structure. The manufacturing company should designate and document the rational for the point at which production of the API begins. For synthetic processes, this is known as the point at which API starting materials are entered into the process. For other processes (e.g. fermentation, extraction, purification), this rationale should be established on a case-by-case basis.
From the point at which the API starting material is normally introduced into process, the pharma companies should follow appropriate GMP regulations applied to those intermediates. This would include the validation of critical process steps determined to impact the quality of the API.
The stringency of GMP in API manufacturing should increase as the process proceeds from early API steps to final steps, purification and packaging. Physical processing of APIs, such as granulation, coating or physical manipulation of particle size e.g. milling, micronizing should be conducted.
Quality management
For every manufacturer, quality should be the responsibility of all persons involved in manufacturing. Each manufacturer should establish, document and implement an effective system for managing quality that involves the active participation of management and appropriate manufacturing personnel.
The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities to ensure confidence that the API will meet its intended specifications for quality and purity. All quality related activities should be defined and documented. There should be a quality unit that is independent of production and that fulfils both quality assurance (QA) and quality control (QC) responsibilities. The quality unit can be in the form of separate QA and QC units or a single individual or group, depending up on the size and structure of the organization.
For product quality, companies should regularly perform quality reviews of APIs. They should consistently verify the processes. Such reviews should normally be conducted and documented annually and should include review of critical in-process control and critical API test results, review of all batches that failed to meet established specifications, review of all critical deviations or non-conformances and related investigations, review of changes carried out to the processes or analytical methods and review of results of the stability monitoring programmes.
More importantly the personnel hygiene is vital in manufacturing units. Personnel should practice good sanitation and health habits. They should wear clean clothing suitable for the manufacturing activity. Additional protective apparels, such as head, face, hand and arm coverings should be worn as per required to protect intermediates and APIs from contamination.
Personnel should avoid direct contact with intermediates or APIs. Smoking, eating, drinking, chewing and the storage of food should be restricted to certain designated areas separate from the manufacturing areas. Personnel suffering from any infectious diseases or having open lesions on the exposed surface of the body should be excluded from activities since the health of the personnel could adversely affect the quality of the APIs.
Buildings and facilities used in manufacture of intermediates and APIs should be located, designed, and constructed to facilitate cleaning, maintenance and operations as appropriate to the type and stage of manufacture. Facilities should also be designed to minimise potential contamination. Where microbiological specifications have been established for the intermediate or API, facilities should also be designed to limit exposure to objectionable microbiological contaminants as appropriate.
Laboratory area and operations should normally be separated from production areas. Some laboratory areas, in particular those used for in-process controls, can be located in production areas, provided the operations of the production process do not adversely affect the accuracy of the laboratory measurements and the laboratory and its operations do not adversely affect the production process intermediate or API.
All utilities that could affect product quality example steam, gas, compressed air, heating, ventilation and air conditioning should be qualified and appropriately monitored and action should be taken when limits are exceeded. Adequate ventilation, air filtration and exhaust systems should be provided wherever appropriate. These systems should be designed and constructed to minimise risk of contamination and cross-contamination as should include equipment for control of air pressure, micro-organisms, dust, humidity and temperature as appropriate to the stage of manufacture.
Water used in the manufacture of APIs should be suitable. Processed water should meet world health organization guidelines for drinking water quality. To contain the pollution of environment, pharma companies need to install advanced zero liquid discharge plants and recycle the water for the manufacturing processes.
Avoiding contamination
Dedicated production areas which can include facilities, air handling equipment and process equipment should be employed in the production of highly sensitizing materials such as penicillin’s or cephalosporin’s. The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved for example certain steroids or cytotoxic anti-cancer agents unless validated inactivation and cleaning procedures are established and maintained.
Any production activities including weighing, milling or packing of highly toxic non-pharmaceutical materials, such as herbicides and pesticides should not be conducted using the buildings and equipment being used for the production of APIs. Handling and storage of these highly toxic non-pharmaceutical materials should be separated from APIs.
Equipment maintenance and cleaning
For preventive maintenance of equipment, the pharma companies should maintain schedules and procedures like assignment of responsibility. Written procedures should be established for cleaning equipment and its subsequent release for use in the manufacture of intermediates and APIs.
Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner.
Finally in the manufacturing procedure the packing and labelling operations are regarded as most important. All manufacturers should document procedures and ensure that packaging materials and labels are used. Labelling operations should be designed to prevent mix-ups. There should be physical or spatial separation from operations involving other intermediates or APIs. Label used on containers of intermediates or APIs should indicate the name or identifying code, batch number and storage conditions when such information is critical to ensure the quality of intermediate or API.
Process Validation
Process Validation (PV) is the documented evidence that the process is being operated within established parameters can perform effectively and reproducibly to produce an intermediate or API meeting its predetermined specifications and quality attributes.
There are three approaches to validation. Prospective validation is the preferred approach, but there are situations where the other approaches can be used. Prospective validation should normally be performed for all API processes.
Prospective validation of an API process should be completed before the commercial distribution of the final drug product manufactured from that API. Concurrent validation can be conducted when data from replicate production runs are unavailable because only a limited number of API batches have been produced, API batches are produced infrequently or API batches are produced by a validated process that has been modified.
Prior to the completion of concurrent validation, batches can be released and used in final drug product for commercial distribution based on thorough monitoring and testing of the API batches.
Maintenance of diaphragm valves vital
In the biotechnology and pharmaceutical processing industries, maintaining diaphragm valves is considered the primary bottleneck of the maintenance process. A typical diaphragm change-out can easily take a full week of plant downtime, resulting in significant hours of lost production time.
Properly changing valve diaphragms is a tedious process and typically takes a team of maintenance technicians to get the job done on time. Time studies have shown that it takes on average 23 minutes to complete the installation and fastener torque process for a single valve. As large bio-pharma plants typically have thousands of hygienic diaphragm valves installed, the number of hours to change out the entire system can be significant (over 300 man hours for a plant with 1000 valves.)
Implementing a preventative maintenance programme and incorporating evolving enhancements in valve designs into a plant system can have significant financial implications on the bottom line.
From installation, to monitoring and control, the process of maintaining a diaphragm valve through its total lifespan can cost hundreds of thousands of dollars. Thankfully, new advances in the bio-processing industry have created highly engineered technologies to impede these costly challenges, and create a more streamlined, easy-to-use diaphragm valve with virtually no leakage.
Most bio-pharma plant environments utilize bioreactors as the primary production method for products. The cell culture manufacturing process typically requires an organism that was chosen to produce the drug and is maintained in solution under exacting temperature and pH conditions best suited for the organism to produce the desired output. These processes can take roughly 7 – 31 days to finish a batch and it is critical to keep the process sterile so that the product is not contaminated.
This requires a lot of steam sterilization and leak free valves and piping joints. The hygienic valves in this environment usually require regular maintenance including diaphragm change out where a torquing procedure and thermal cycling loosens and compresses the seal.