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Pilot plant scale-up techniques involve reproducible manufacture of an experimental formulation on high-speed production equipment, in a cost-effective manner. It is a part of the pharmaceutical industry, where the same processes used during Research and Development (R & D) of dosage forms are applied to different output volumes; usually greater than that obtained during R & D.
In every emerging pharmaceutical industry or an already existing one, there is always a need to have an intermediate batch scale representing procedures and simulating that used for commercial manufacturing. It is achieved by determining the ability of the formula to withstand batch scale and process modification.
There is equally a need for equipment evaluation and validation to ensure that the aim of your company which is the mass production of the drug in question is not defeated. For a pilot scale-up to be successful, a product must be capable of being processed on a large scale often with equipment that only remotely resembles that used in the development laboratory. The idea is that you understand what makes these processes are similar, identify and eliminate many scale-up problems before investing a large sum of money in a production unit.
Maintain the chemical attributes of the product, its quality, and efficacy even though the production processes are modified as a result of sample size increase and equipment changes.
Pilot Plant Scale-up must include:
1. A close examination of the formula to determine its ability to withstand large-scale and process modification.
2. A review of a range of relevant processing equipment to determine which would be most compatible with the formulation as well as the most economical, simple, and reliable in producing the product.
During pilot plant scale-up ensure the:
1. Determination of the availability of raw materials that consistently meet the specifications required to produce the product.
2. Determination of the physical space required and the layout of related functions to provide short-term and long-term efficiency.
3. Evaluation, validation, and finalizing of production and process controls.
4. Issuing of adequate records and reports to support Good Manufacturing Practices (GMPs) and provision of the historical development of the product formulation process, equipment train, and specifications.
5. Development and validation of meaningful product reprocessing procedures.
6. Identification of all critical, features of a scale-up process, so that it can be adequately monitored to assure that the process is under control and that the process at each level of the scale-up maintains the specified attributes originally intended.
7. Production rate and future market requirements.
GENERAL CONSIDERATIONS DURING PILOT PLANT SCALE-UP
Pilot plant scale-up is of practical interest to formulation scientist/ production managers and should be considered from the inception of a development project. This is because a process using the same type of equipment can perform quite differently when the size of the equipment and the amount of material involved is significantly increased. The chemical attributes of the product, its quality, and efficacy should be maintained even though the production processes are modified as a result of sample size increase and equipment changes. You should also bear in mind that pilot plant scale-up, in itself, does not guarantee a smooth transition. A well-defined process may fail quality assurance tests in full manufacturing scale even after generating a perfect product in both the laboratory and the pilot plant.
Plant: It is a place where the 5M’s like Money, Material, Man, Method, and Machine are brought together for the manufacturing of the products.
Pilot Plant: It is the part of the Pharmaceutical Industry where a lab-scale fortune is transferred into a viable product by the development of the liable and practical procedure of manufacture.
Scale-up: It is the art designing of a prototype using the data obtained from the pilot plant model.
Objectives of Scale-up:
1. To try the process on a model of the proposed plant before committing a large sum of money on the product unit.
2. To examine the formula for determination of the ability to withstand batch scale.
3. Evaluation and validation for process and equipment.
4. To identify the critical features of the process.
5. To provide guidelines for production and process controls.
6. To provide master manufacturing formula with instruction for manufacturing produces.
7. To avoid scale-up problems.
Steps in Scale-up:
Define product economics based on projected market size and competitive selling and guide allowable manufacturing costs.
Conduct Laboratory studies and scale-up planning at the same time.
Define key ratter controlling steps in the proposed process.
Conduct Preliminary larger-than laboratory studies with equipment to be used in rate-controlling steps to aid in plant design.
Design and contract a pilot plant including provisions for process and environment controls, cleaning and sanitizing systems, packaging and waste handling systems, and meeting regulatory agency requirements.
Evaluate pilot plant’s result (Product and process) including process economics to make any corrections and a decision on whether to process or not with full-scale plant development.
NEED OF PILOT PLANT STUDIES
1. A pilot plant allows investigation of a product and process on an intermediate scale before a large amount of money is committed to full-scale production.
2. It is usually not possible to predict the effects of a many-fold increase in scale.
3. It is not possible to design a large-scale processing plant from laboratory data alone with any degree of success.
A pilot plant can be used for:
1. Evaluating the results of laboratory studies and making a product of the process.
2. Monitoring of quality of Drugs and Cosmetics, manufactured by respective state units and those marketed in the state.
3. Investigation and prosecution in respect of a contravention of large provisions.
4. Administrative actions.
5. Pre and post-licensing inspection. 6. Recall of sub-standard drugs states drug control organization.
STATE DRUG CONTROL ORGANIZATION CDSCO
joined with state drug control board organization to regulate the import/export of drugs and medical devices.
The State Drug Control Organization is responsible for:
- Providing license to drug testing laboratories.
- Approving drug formulation for manufacture.
- Carrying out pre and post-licensing.
- Observing the drug manufacturing process by respective state units and those marketed in the state.
Functions of State Licensing Authorities:
1. Licensing of manufacturing site for drugs including API and finished formulation.
2. Licensing of establishment for sale or distribution of drugs.
3. Approval of drug testing laboratories.
4. Monitoring of quality of drugs and cosmetics marketed in the country.
5. Investigation and prosecution of contravention of a legal provision.
6. Recall of sub-standard drugs.
USES OF PILOT PLANT
1. To evaluate the results of laboratory studies.
2. To make process corrections and improvements.
3. To produce small quantities of product for sensory, chemical, microbiological evaluations, limited market testing or furnishing samples to potential customers, shelf-live, and storage stability studies.
4. To provide data that can be used in deciding on whether or not to proceed to a full-scale production process; and in the case of a positive decision, designing and constructing a full-size plant or modifying an existing plant.
GENERAL REQUIREMENTS FOR PILOT SCALE AND SCALE-UP
1. Reporting Responsibilities:
(i) R and D group with separate staffing.
(ii) The formulator who developed the product can take into the production and provide support even after the transition into production has been completed.
2. Personal Requirements:
(i) Scientists with experience in pilot plant operations as well as in actual production areas are the most preferable, as they have to understand the intent of the formulator as well as understand the perspective of the production personnel.
(ii) The group should have some personnel with engineering knowledge as well as scale-up also involves engineering principles.
3. Space Requirements:
(i) Administration and information process: Adequate office and desk space should be provided for both scientists and technicians. space should be adjacent to the working area.
(ii) Physical testing area: This area should provide permanent benchtop space for routinely used physical testing equipment.
(iii) Standard pilot-plant equipment floor space: Discrete pilot plant space, where the equipment is needed for manufacturing all types of dosage forms, is located.
(a) Intermediate-sized and full-scale production equipment are essential in evaluating the effects of scale-up of research formulations and processes.
(b) Equipment used should be made portable. So that after use it can be stored in the small storeroom.
(c) Space for cleaning of the equipment should also be provided.
(iv) Storage area:
(a) It should have two areas divided as approved and unapproved areas for active ingredients as well as excipients.
(b) Different areas should be provided for the storage of the in-process materials, finished bulk products from the pilot plant, and materials from the experimental scale-up batches made in the production. Storage area for the packing material should also be provided.
4. Review of the Formula:
(i) A thorough review of each aspect of the formulation is important.
(ii) The purpose of each ingredient and its contribution to the final product manufactured on the small-scale laboratory and equipment should be understood.
(iii) Then the effect of scale-up using equipment that may subject the product to stresses of different types and degrees can more readily be predicted or recognized.
5. Raw Materials:
(i) One purpose/responsibility of the pilot plant is the approval and validation of the active ingredients and excipient’s raw materials.
(ii) Raw materials used in small-scale production cannot necessarily be representative of large-scale production.
(i) The most economical and the simplest and efficient equipment, which are capable of producing products within the proposed specifications, are used.
(ii) The size of the equipment should be such that the experimental trial’s run should be relevant to the production-sized batches.
(iii) If equipment is too small, the process developed will not scale up; whereas if the equipment is too big, then there is wastage of the expensive active ingredients.
7. Production Rates:
The immediate, as well as the future market trends/requirements, are considered while determining the production rates.
8. Process Evaluation Parameters:
(i) Order of mixing of components.
(ii) Mixing speed.
(iii) Mixing time.
(iv) Rate of addition of granulating agents, solvents, solutions of the drug, etc.
(v) Heating and cooling rates.
(vi) Filters size (liquids).
(vii) Screen size (solids).
(viii) Drying temperature and drying time.
The knowledge of the effects of various process parameters as mentioned above forms the basis for process optimization and validation.
9. Master Manufacturing Procedures:
(i) The weight sheet should identify the chemicals required in a batch. To prevent confusion the names and identifying numbers for the ingredients should be used on batch records.
(ii) The process directions should be precise and explicit.
(iii) A manufacturing procedure should be written by the actual operator.
Various specifications like addition rates, mixing time, mixing speed, heating, and cooling rates, temperature, storing of the finished product samples, etc. should be mentioned in the batch record directions.
10. Product Stability and Uniformity:
(i) The primary objective of the pilot plant is the physical as well as chemical stability of the products.
(ii) Hence each pilot batch representing the final formulation and manufacturing procedure should be studied for stability.
(iii) Stability studies should be carried out in finished packages as well as raw material.
1. Equipment qualification.
2. Process validation.
3. Regularly schedule preventative maintenance.
4. Regularly process review and revalidation.
5. Relevant written standard operating procedures.
6. The use of competent technically qualified personnel.
7. Adequate provision for training of personnel.
8. A well-defined technology transfer system.
9. Validated cleaning procedures.
10. An orderly arrangement of equipment to ease material flow and prevent cross-contamination.
1. Members of the production and quality control divisions can readily observe scale-up runs.
2. Supplies of excipients and drugs, cleared by the quality control division, can be drawn from the more spacious areas provided to the production division.
3. Access to engineering department personnel is provided for equipment installation, maintenance, and repair.
1. The frequency of direct interaction of the formulator with the production personnel in the manufacturing area will be reduced.
2. Any problem in manufacturing will be directed towards its pilot-plant personnel.
It is the art designing of a prototype using the data obtained from the pilot plant model.
1. Formulation related: Identification and control of critical components and another variable.
2. Equipment related: Identification and control of critical parameters and operating range.
3. Production and process-related: Evaluation, validation, and finalization of controls.
4. Product-related: Development and validation of reprocessing procedures.
5. Documentation: Records and reports according to C-GMP.
Need of Scale-Up:
1. A well-defined process.
2. A perfect product in laboratory and pilot plant.
3. But may fail in QA tests.
4. Because processes are scale-dependent.
5. Processes have different on a small scale and a large scale.
6. Scale-up is necessary to determine the effect of scale on product quality.
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