Food and Drugs Administration, (FDA) Haryana, India. |
Email ID: dahiya19@yahoo.com
- Key Notes on Revised Schedule M: Investigational Pharmaceutical Products - February 6, 2025
- Key Notes on Revised Schedule M: Phytopharmaceuticals - January 25, 2025
- Key Notes on Revised Schedule M: Radiopharmaceutical Products - January 20, 2025
Last Updated on February 6, 2025 by The Health Master
Investigational Pharmaceutical Products
Key considerations for Investigational Pharmaceutical products for compliance under revised Schedule M are outlined below.
Continued from: Key Notes on Revised Schedule M: Phytopharmaceuticals
Good Manufacturing Practices for Investigational Pharmaceutical products
Investigational Pharmaceutical Products Manufacturing: A Guide for Pharma Manufacturers
We have described the specific requirements for manufacturing investigational pharmaceutical products for the purpose of clinical trials, as per the revised Schedule M.
All the pharma manufacturers must comply these requirements to follow the revised schedule M.
It also covers the general principles of GMP (Part I) and the guidelines of Good Clinical Practices (GCP) for clinical trials in India.
It is very crucial for all the manufacturers to adhere to these guidelines to ensure the efficacy and safety of investigational pharmaceutical products and the reliability of clinical trial data.
Key Requirements for manufacturing of Investigational Pharmaceutical Products:
GMP Compliance:
All the manufacturers have to adhere to all the GMP principles mentioned in Part I and also fullfilling the specific requirements for investigational pharmaceutical products.
This requirements ensures consistency of the batches, efficacy and saftey of the commercial batches.
It also protects trial subjects from substandard drugs.
Dosage Form Considerations:
The dosage form of investigational pharmaceutical products used in the Phase III trials should closely resemble the projected commercial drug presentation.
The differences require data showing bioequivalence and stability to the final product.
Final manufacturing methods of these drugs must be revalidated after changes in processes or site transfer etc.
Quality Assurance System:
It is very important to implement a robust Quality Assurance system which cover all aspects of manufacturing process, storage of drugs, shipping, and even additional labeling.
This system should be documented properly and should address the interface between manufacturing and the trial site.
Validation:
It is possible that full validation may not be done for all processes in early development but there should be no reduction for sterile product manufacturing in validation standards, especially for sterilization equipment.
Aseptic processing with small batch sizes requires heightened environmental monitoring.
Complaint Investigation:
Complaints must be investigated collaborativly both by the manufacturer and sponsor (if different), or by the manufacturing and clinical trial personnel.
There should be a goal to assess the impact on the clinical trial and the development of the products and determine the root cause, and correc tive action must be done.
Product Recall Procedures:
product recall procedures, as described the GMP guidelines must be understand and implemented by the all parties involved (sponsor, investigator, monitor, and manufacturing personnel.
Personnel:
Well qualified and designated personnel are required for the manufacturing and and quality control process.
GMP training must be done for all the personnel involved in development, production, and quality control process.
Premises and Equipment:
To prevent the contamination, cross contamination and mix-ups of the products, thorough cleaning and line clearance is must.
It is very essention to adopt the validated cleaning procedures.
Campaign working might be acceptable, but cleaning process is crucial, considering the solubility of products and excipients.
Materials:
Starting Materials:
Quality of the starting materials is paramount.
It should be defined in the documenst and controlled regarding the physical, chemical, and microbiological properties.
Consideration of compendial standards must be in the mind.
Specifications for active ingredients should be comprehensive and the same should be reassessed periodically.
Reference Standards:
Preference of reputable sources must be there for the procurement of the reference standards.
If unavailable, a list be prepared for the the product manufacturer or active ingredient producer, test, and release reference materials.
Reference Products:
Integrity and quality of reference products must be ensured.
Data mustb be prepared demonstrating that quality isn’t compromised.
Documentation:
Specifications, Master Formulae, and Instructions:
Frequent changes are expected, but each version must reference the previous one with a documented rationale.
Batch Records:
Batch records must be retained for at least two years post-trial or product approval.
Sponsor Requests:
Sponsor requets must be written, precise, authorized, and refer to the approved product specification file.
Product Specification File:
Procut specification file must contains comprehensive information for processing, packaging, testing, release, storage, and shipping, including the authorized release personnel.
Specifications:
Focus must be there on efficacy and safety characteristics (dose accuracy, homogeneity, content uniformity, release of active ingredients, and stability).
Changes in specifications require written procedures and documentation.
Master Formulae and Processing:
Changes in master formulae require proper documentation and assessment of impact on stability and bioequivalence of the products.
It is mandatory to maintain records of all written instructions for every operation.
Packaging Instructions:
Packaging instruction must be there regarding the number of units is specified pre-packaging, considering quality control and sample retention needs.
Reconciliation must be performed post-packaging.
Labeling Instructions:
Specific information is required on the labels of the products e.g. batch number, patient ID, storage conditions, expirat date, sponsor name, “for clinical research use only,” trial reference number.
Copies of all the labels must be retained.
Processing and Packaging Batch Records:
Detailed records of processing and packaging are essential for traceability and process improvement.
Coding Systems:
It is mandatory to maintain a procedures for code generation, distribution, handling, and retention.
Blinding requires a system for product identification and emergency unblinding.
Production:
Types of Facility:
Manufacturing must be done in a licensed facility (pilot plant, small-scale facility, larger-scale production line, or normal production line).
The guidelines apply to pilot plants and small-scale facilities.
Contract manufacturing is permissible but close collaboration is required.
Manufacturing Operations:
Provisional parameters and controls can be derived from analogous product experience.
Sterility assurance for sterile products must be equivalent to licensed products.
Cleaning procedures must be validated and designed considering incomplete toxicity knowledge.
There may be a need of an additional quality control testing.
Packaging and Labeling:
Intensified supervisory procedures and independent checks and required for the complex and error-prone packing and labelling.
Packaging must be proper for the protection the product during transport and storage. Tampering must be readily discernible. (Keywords: pharmaceutical packaging and labeling)
Blinding Operations:
In-process control must verify the similarity of blinded products.
Quality Control:
End-Product Testing:
End-product testing is very important due to non-standardized or incompletely validated processes.
Testing must comply with Schedule L1.
Product Release:
Two-stage process:
- Bulk product assessment (production conditions, in-process testing, documentation review).
- Finished product assessment (includes packaging conditions).
Blinded Product Verification:
Quality control verifies the similarity of blinded products.
Sample Retention:
Samples must be retained for at least two years post-trial and should be stored in the primary container or a suitable bulk container.
It is necessaru to maintain stability data if not stored in the study pack.
Shipping, Returns, and Destruction:
Procedures:
The manufcaturer must follow written procedures in the protocol.
Unused products should be returned or destroyed as mentioned in the instructions.
Shipping:
Follows sponsor orders regarding the shipping of the products.
Requires a two-step release:
- Quality control release (“technical green light”).
- Sponsor authorization (“regulatory green light”).
Shipment receipt must be acknowledged.
It is mandatory to maintain a detailed inventory.
Returns:
Returns goods must follow the agreed conditions mentioned by the sponsor.
Returned products are identified, stored in a dedicated area, and inventory must be prepared.
Destruction:
Sponsor is responsible for the destruction of goods.
Manufacturer must destroy the products only with sponsor authorization.
Destruction process must follow environmental safety requirements and and the process must be documented.
Certificates of such destruction must be provided to the sponsor.
Pharma Manufacturers’ Responsibilities:
A comprehensive quality system must be established and maintained by the pharma manufacturer that includes all aspects of investigational pharmaceutical product manufacturing, starting from material procurement to product destruction.
This includes:
Developing the product and adhering to the procedures as per GMP guidelines.
Validation of processes and equipment.
Maintaining the proper documentation.
Implementation of proper measures for quality control.
Effective Collaboration between sponsors and investigators.
Ensuring the efficacy and safety of investigational pharmaceutical products.
Pharma manufacturers contribute significantly to the success of clinical trials and the development of safe and effective medicines by implementing these resposibilities.
Please note: This information is for general guidance only and may not be exhaustive. Refer to the official regulations and any applicable guidance documents for specific requirements and interpretations.
Compiled by:
Rakesh Dahiya, SDCO cum Licensing Authority, FDA Haryana
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