The development of product prior to the preparation of the first pilot-production batch. The development activities are listed as follows:
1. Formulation design, selection, and optimization
2. Preparation of the first pilot-laboratory batch
3. Conduct initial accelerated stability testing
4. If the formulation is deemed stable, preparation of additional pilot laboratory batches of the drug product for expanded nonclinical and/or clinical use.
The pilot program is defined as the scale-up operations conducted subsequent to the product and its process leaving the development laboratory and prior to its acceptance by the full scale manufacturing unit. For the pilot program to be successful, elements of process validation must be included and completed during the developmental or pilot laboratory phase of the work.
Thus, product and process scale-up should proceed in graduated steps with elements of process validation (such as qualifications) incorporated at each stage of the piloting program
A. Laboratory Batch
The first step in the scale-up process is the selection of a suitable preliminary formula for more critical study and testing based on initial design criteria, requirements, and/or specifications. The work is performed in the development laboratory. The formula selected is designated as the (1 × ) laboratory batch.
The size of the (1 × ) laboratory batch is usually
- 3–10 kg of a solid or semisolid,
- 3–10 liters of a liquid, or
- 3000 to 10,000 units of a tablet or capsule..
B. Laboratory Pilot Batch
After the (1 × ) laboratory batch is determined to be both physically and chemically stable based on accelerated, elevated temperature testing (e.g., 1 month at 45°C or 3 months at 40°C or 40°C/80% RH), the next step in the scale-up process is the preparation of the (10 × ) laboratory pilot batch.
The (10 × ) laboratory pilot batch represents the first replicated scale-up of the designated formula. The size of the laboratory pilot batch is usually 30–100 kg, 30–100 liters, or 30,000 to 100,000 units.
It is usually prepared in small pilot equipment within a designated CGMP approved area of the development laboratory. The number and actual size of the laboratory pilot batches may vary in response to one or more of the following factors:
1. Equipment availability
2. Active pharmaceutical ingredient (API)
3. Cost of raw materials
4. Inventory requirements for clinical and nonclinical studies
Process demonstration or process capability studies are usually started in this important second stage of the pilot program. Such capability studies consist of process ranging, process characterization, and process optimization as a prerequisite to the more formal validation program that follows later in the piloting sequence.
C. Pilot Production
The pilot-production phase may be carried out either as a shared responsibility between the development laboratories and its appropriate manufacturing counterpart or as a process demonstration by a separate, designated pilot-plant or process-development function. The two organization piloting options are presented separately in Figure 1. The creation of a separate pilot-plant or process development
unit has been favored in recent years because it is ideally suited to carry out process scale-up and/or validation assignments in a timely manner. On the other hand, the joint pilot-operation option provides direct communication between the development laboratory and pharmaceutical production.
The object of the pilot-production batch is to scale the product and process by another order of magnitude (100 × ) to,
For example, 300–1,000 kg, 300– 1,000 liters, or 300,000–1,000,000 dosage form units (tablets or capsules) in size.
For most drug products this represents a full production batch in standard
production equipment. If required, pharmaceutical production is capable of scaling
the product/process to even larger batch sizes should the product require
expanded production output. If the batch size changes significantly, additional
validation studies would be required.
Usually large production batch scale-up is undertaken only after product introduction. Again, the actual size of the pilot-production (100 × ) batch may vary due to equipment and raw material availability.
The need for additional pilot-production batches ultimately depends on the successful completion of a first pilot batch and its process validation program. Usually three successfully completed pilot-production batches are required for validation purposes.
In summary, process capability studies start in the development laboratories and/or during product and process development, and continue in well defined stages until the process is validated in the pilot plant and/or pharmaceutical production.
An approximate time table for new product development and its pilot scale-up program is suggested in Below Table -1 .
Table 1: Approximate Timetable for New Product Development and Pilot Scale-Up Trials
|Formula selection and development||2–4 Months|
|Assay methods development and formula optimization||2–4 Months|
|Stability in standard packaging 3-month readout (1 × size)||3–4 Months|
|Pilot-laboratory batches (10 × size) 1–3||1–3 Months|
|Preparation and release of clinical supplies (10 × size) and establishment of process demonstration||1–4 Months|
|Additional stability testing in approved packaging
6–8-month readout (1 × size)
3-month readout (10 × size)
|Validation protocols and pilot batch request||1–3 Months|
|Pilot-production batches (100 × size)||1–3 Months|
|Additional stability testing in approved packaging
9–12-month readout (1 × size)
6–8-month readout (10 × size)
3-month readout (100 × size)
|Interim approved technical product development report with approximately 12 months stability (1 × size)||1–3 Months|
Source & Reference-Drug and Pharmaceuticals sciences (Volume 129)
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