Pilot Plant Scale-Up for Solid Dosage Forms

Posted on Dec 24, 2024 in Other subjects

Pilot Plant Scale-Up Considerations for Solids

Steps Involved in Scale-Up:

Scale-up is the process of designing a prototype using the data acquired from the pilot plant model.

For Solids:
It includes tablets and capsules and is mostly used for tablets.

The main aim of a pilot plant is to ensure that newly formulated tablets will be efficient, economical, and regularly reproducible on a production scale.

Steps Involved

  1. Material Handling System: Systems used to handle materials such as ingredients and raw materials.
    These systems are used for transferring, delivering, and mixing materials.

  2. Dry Blending: Also known as mixing. Powders should be well blended to ensure good drug distribution.
    Improper blending can cause flow problems, non-reproducible compressions, and non-uniformity of content.
    Equipment used: V-blender, double cone blender, ribbon blender, etc.

    Scale-Up Considerations:

    • Blending time
    • Blender loading
    • Blender size

  3. Granulation:
    It is the process in which primary powder particles are adhered to form larger ones called granules.

    It facilitates uniform drug distribution, increases material density, improves flow rates and uniformity, reduces dust production, and improves general appearance.

    Methods:

    1. Wet granulation
    2. Tray fluid bed dryer
    3. Spray dryer
    4. Vacuum/microwave
    5. Dry granulation
    6. Direct compression
    7. Slugging mill

  4. Drying:
    In this, dry the granules to prevent moisture. The most common conventional method of drying a granulation is to circulate granules in a hot air oven.

  5. Reduction of Particle Size: Particle size should be small and uniform for product quality and performance, and also for better flow properties. Improper particle size leads to weight variations, flowability problems, etc.

  6. Blending: This blending is used for achieving blend uniformity and for distributing the lubricant.

  7. Dry Compression: In this, materials are compressed by applying pressure (up to 10 tons per linear inch) on the powder passing between two rollers. Materials of very low density require this to achieve a bulk density sufficient to allow compression.

  8. Slugging: A dry powder blend that cannot be directly compressed because of poor flow or compression properties.

  9. Compression: The ultimate test of tablet formulation and the granulation process is whether the granulation can be compressed on a high-speed tablet press.

    During Compression:
    Filling of empty die cavity
    Pre-compression
    Compression of granules

    In this, granules are formed into tablets. Considerable points: feed rate, speed, loading capacity.

  10. Direct Compression: This process involves direct compression of a powder mixture of API and other excipients into tablets.

    Equipment: Manual punching machines, high-speed rotary machines, multi-rotary machines, double rotary machines, single rotary machines, etc.

  11. Tablet Coating: It involves the process of coating tablets to mask the taste and improve the appearance.
    Equipment: Sugar coating is carried out in a conventional coating pan.

SUPAC Guidelines

SUPAC: Scale-Up and Post-Approval Changes.

SUPAC involves the scale-up processes and the changes made after approval in the composition, manufacturing equipment, and the change of site.

Purpose of Guidance:

SUPAC guidelines provide instructions to sponsors of NDAs (New Drug Applications) and abbreviated antibiotic applications (AADAs) who want to change the following after post-approval:

SUPAC Guidelines:

Level of Changes:

  • Minor changes
  • Moderate changes
  • Major changes

Tests:

  1. Application/compendial tests
  2. In vitro dissolution/release
  3. In vivo

Key Terms and Definitions

Corrective Action (CA): Any action to be taken when the results of monitoring at a critical control point indicate a loss of control.

Critical Control Point (CCP): A step at which control can be applied and is essential to prevent a pharmaceutical quality hazard.

Good Manufacturing Practices (GMP): That part of quality assurance which ensures that products are produced and controlled to the quality standards appropriate to their intended use.

In-Process Control (IPC): Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the product conforms to its specification.

Installation Qualification (IQ): The performance of tests to ensure that the installations used in a manufacturing process are appropriately selected.

Operational Qualification (OQ): Documented qualification verification that the system performs as intended over all anticipated operating ranges.

Performance Qualification (PQ): Documented verification that the equipment operates consistently and gives reproducibility within defined specifications and parameters for a prolonged time.

Quality Assurance (QA): Quality assurance is a wide-ranging concept concerning all matters that individually or collectively influence the quality of a product.
Quality Control (QC): Quality control covers all specifications and sampling, testing, and analytical procedures to ensure that the ingredients and materials used in pharmaceutical products conform with established standards for identity, purity, and other characteristics.
Quality Risk Management (QRM): Quality risk management is a systematic process for the assessment, control, communication, and review of risks to the quality of the pharmaceutical product across the product life cycle.
Receiving Unit (RU): The involved disciplines at an organization where a designated product, process, or method is expected to be transferred.
Sending Unit (SU): The involved disciplines at an organization where a designated product, process, or method is expected to be transferred from.

Additional Technologies

Inhalation Technology: It includes metered-dose inhalers, dry powder inhalers, etc.

Sprinklers: Primarily used for pediatric patients, they are sprinkled over a child’s food for making the drug palatable.

Frequently Asked Questions

  1. What do you mean by Pilot Plant Scale-Up?

  2. What is TOT?

    Technology Transfer (TOT) refers to the process of transferring knowledge, expertise, and technology from one organization or individual to another with the goal of improving pharmaceutical development, manufacturing, and quality control.

Change Control (CC) is a systematic process used to manage changes to products, processes, or systems in a controlled and predictable manner, ensuring that changes are thoroughly evaluated, approved, implemented, and verified to minimize risks and ensure compliance with regulatory requirements.

Ultimately, a few presentations are made to the investigators and IRB.

Its purpose is to provide the investigators and others involved in the trial with information to facilitate their understanding of the rationale for and their compliance with many key features of the protocol, such as DOE and DDE frequency.

The IRB also provides insight to support the clinical management of the study subjects during the course of the clinical trials. The information should be presented in a simple, objective, and nonpartisan form that enables a clinician investigator to understand it and make his or her own unbiased risk-benefit assessment of the appropriateness of the proposed trials.

What are MOUs?

  • Memorandum of Understanding refers to a formal agreement between two or more parties outlining the terms and scope of their partnership.

Define ISO 9000?

  • ISO 9000 is a set of standards that provides a framework for organizations to ensure the quality of their product.

API Granularity and Premises of TT Process

  • Granularity of API & Manufacture
    • Flowchart of synthetic pathway/critical steps, process controls/solubility profile
    • The SU should provide the Drug Master File (DMF) and any relevant additional information on the API to the RV to be checked against the specifications of the API.

Following information should be provided:

  • Manufacture
  • Flowchart of synthetic pathway, outlining the process
  • Solubility profile, etc.

Premises of TT Process

The SU should provide information on relevant health and inherent risks of the manufacturing process. The SU should provide information to the RV on the layout (services/heating, ventilation, and air conditioning (HVAC), temperature) impacting the product/process, method of transferring.

Health and Safety Requirements to Minimize Operator Exposure.

  1. Discuss in detail about IB (Investigator’s Brochure)
  2. The IB is an important document, not only required as a part of the IND but also prepared for presentations to potential clinical investigators.
  1. Transfer from R&D to Production:
    The SV should provide any information on the history of process development which may be required to enable the RV to perform further development and process optimization after successful transfer.
    Such information may include the following:
    • Information on clinical development.
    • Information on scale-up activities.
    • Information on full-scale development activities.
  1. What are BE Studies and Regulatory Requirements for Drugs?
  2. BE (Bioequivalence) studies are a critical component of the regulatory requirements for drugs, ensuring that generic drugs are equivalent to the reference listed drug in terms of their pharmacokinetic properties.
  3. Write the key aspects of QbD?
    • Target product profile
    • Critical Quality Attributes
    • Risk assessment
    • Design space
    • Control strategy
    • Life cycle management
  4. Define ISO 14000.
  5. Write the full form of CDSCO and OOS?
    • CDSCO: Central Drugs Standard Control Organization
    • OOS: Out of Specification

Post-Approval Phase

  • Compliance
  • Submission of variations
  • Renewals
  • Pharmacovigilance

Responsibilities of Regulatory Affairs Professionals

  • Keep up to date with a company product range.
  • Monitor the progress of all registration submissions.
  • Keep up to date and in touch with international legislation, guidelines, and customer practices.
  • Respond to queries and ensure that approvals are granted without delay.
  • Manage and review audit reports and compliance, regulatory, and customer inspections.

Good Laboratory Practices (GLP)

GLP is a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, archived, and reported.

Purpose of GLPs:

  • GLP is to certify that every step of the analysis is valid or not.
  • Assure the quality and integrity of data submitted to the FDA in support of the safety of regulated products.
  • GLPs have a heavy emphasis on data recording.
  • Good Laboratory Practices Principles:
    • Test facility organization and personnel
    • Quality assurance program
    • Facilities
    • Apparatus
    • Test systems
    • SOP

Benefits of Good Laboratory Practices:

  • It will give a better image of the company as a quality procedure in the global market.

  • Provide guidelines for doing testing and measurements in detail.

  • Provide guidelines and better control for the maintenance of instruments, environment control, and preservation of test records.

  • Write in detail about the Six Sigma concept. Write about OOS. (10)

Six Sigma Concept

  • Six Sigma works to improve the quality of process outputs by identifying and removing the causes of defects.

Packaging:
Information on packaging to be transferred from the SV to the RU includes specifications for a suitable container system, as well as any additional information on design requirements needed for the qualification of packaging components.

The quality control testing of packaging components specification should be provided for ensuring artwork and materials.

Cleaning:
The SV should provide information on cleaning procedures in use at the SU to minimize cross-contamination due to residues from previous manufacturing steps, operator, and including solubility interactions of active ingredients, excipients, and vehicles.

  • Discuss the Role and Responsibilities of RA?

A) In the Development Phase:

  • Ensuring that the legislative requirements are met.
  • Advice on development studies to demonstrate safety, quality, and efficacy parameters.
  • Ensure application to guidelines for clinical trials.

B) In the Approval Phase:

  • Check the progress of evaluation and anticipate questions.
  • Plan and manage agency meetings.
  • Negotiate approval and product information with agencies.

The reason for OOS can be classified as:

  1. Assignable
  2. Non-assignable

GLP

  • GLP is a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, archived, and reported.
  • Purpose of GLP:
    • GLP is to certify that every step of the analysis is valid or not.
    • Assure the quality of data submitted to the FDA in support of the safety of regulated products.
    • GLP has a heavy emphasis on data recording.

Principles:

  • Test facility organization and personnel
  • Quality assurance program
  • Facilities
  • Apparatus, material, test systems

Benefits of GLP:

  1. It will give a better image of the company as a quality producer in the global market.
  2. Provide guidelines for doing testing and measurement in detail.
  3. Provide guidelines and better control for the maintenance of instruments and environment control.

The Six Sigma approach is a collection of management and statistical deficiencies to the product. The concept of variation states “no items will be perfectly identical.” In a process that has achieved Six Sigma capability, the variation is small compared to the range of specification limits. So a process that has achieved 6 Six Sigma process is one in which 99.999996% of the products manufactured are statistically expected to be free of defects. Most manufacturing methods of Six Sigma are used in batch production and mass production.

Objectives of Six Sigma:

  • Overall business improvement
  • Remedy defects
  • Reduce costs
  • Improve cycle time
  • Increase customer satisfaction

Out of Specification (OOS)

The term OOS is defined as the result of in-process or finished product testing which falls out of specified limits, drug master files, or drug application. The OOS may arise due to deviations in the product manufacturing process, errors in testing procedures, or due to analytical equipment.

Modules for Drug Approval

Module 1: Administrative Information

This module should contain documents specific to each region.
For example: application forms or the proposed label for use in the region.

Module 2: Summaries

Module 2 should begin with a general introduction to the pharmaceutical, mode of action, and proposed clinical use.

Module 3: Quality Information

Information on quality should be presented in the structured format described in the guidance M4Q. It contains all the quality documents for the chemistry, manufacture, and controls of the drug substance & the drug product.

Module 4: Non-clinical Information

The purpose of this section is to present a critical analysis of the non-clinical data pertinent to the safety of the medicinal product in the intended population. It gives the final copy of all of the final copy of detailed clinical study reports.

  1. Preparation of the quality information for drug submission for new drug approval
  1. Drug Substance
  2. Characterization
    • Physicochemical characterization
    • Biological characterization
  3. Drug Product
  4. Control of Drug Product
  1. Briefly discuss about different phases of clinical trials of NDA – Write the concept of CDP?
  • Different Phases of Clinical Trials:
    • Pre-clinical study – Mice, rat, rabbit
    • Phase 1 – Human pharmacology trial – estimation of safety and tolerability
    • Phase 2 – Exploratory trial – estimation of effectiveness and short-term side effects
    • Phase 3 – Confirmatory trial – confirmation of therapeutic benefits
    • Phase 4 – Post-marketing trial – studies done after drug approval
  1. Stages of Approval:
    1. Submission of clinical trial Applications for evaluating safety and efficacy.
    2. Phase-I and Phase-II Clinical Trials:
      1. General information
      2. Chemistry manufacturing control
      3. Non-clinical data
      4. Proposed Phase I & II studies
    3. Phase-III Clinical Trials:
      • General information
      • Chemistry manufacturing control
      • Non-clinical data
      • Proposed Phase-III studies
  2. Requirements for permission of new drugs approval.