Qualification, validation and Analytical Method Transfer

Qualification and validation

The qualification and validation protocol should be determined based on Quality Risk Management (QRM) principles and must be provided by the Supplier (SU) to the Recipient (RU) in a well-documented manner.

All equipment must undergo the following stages of validation:

1. Design Qualification (DQ)
2. Installation Qualification (IQ)
3. Operational Qualification (OQ)
4. Performance Qualification (PQ)

1. Design Qualification (DQ): Design Qualification is the initial phase of equipment or system validation. It involves documenting and verifying that the design of the equipment or system is suitable for its intended purpose and meets all relevant regulatory and quality standards. DQ ensures that the design specifications, requirements, and functionality are well-defined and correctly understood before any physical equipment or system is built or installed.

2. Installation Qualification (IQ): Installation Qualification is the second phase of validation and focuses on ensuring that the equipment or system is properly installed in accordance with the manufacturer's specifications and installation requirements. IQ involves documenting and verifying that the equipment is correctly placed, connected, and configured. It ensures that all components and accessories are in place and functioning as intended.

3. Operational Qualification (OQ): Operational Qualification is the stage where the equipment or system is tested to ensure that it operates consistently and reliably within its specified operating range. OQ involves a series of tests and procedures to verify that the equipment functions correctly under different operational conditions. This phase aims to establish that the equipment or system can consistently produce results that meet predetermined specifications and quality standards.

4. Performance Qualification (PQ): Performance Qualification is the final stage of equipment or system validation. It focuses on demonstrating that the equipment or system can consistently produce results that meet the predetermined acceptance criteria under real operating conditions. PQ involves testing the equipment or system using production materials and processes. It ensures that the equipment or system performs reliably and consistently in its intended environment and that it meets all regulatory and quality requirements.

All processes should undergo validation through the following approaches:

1. Prospective Validation
2. Concurrent Validation
3. Retrospective Validation

1. Prospective Validation: Prospective Validation is a validation approach where the validation process is carried out before a new product, process, or system is put into routine use. It involves establishing documented evidence demonstrating that a process or system consistently produces results that meet predetermined specifications and quality attributes. Prospective validation is typically conducted for new processes or systems or when significant changes are made to existing ones. The validation protocol and criteria are defined in advance, and data is collected during actual production or operation to confirm compliance with established standards.

2. Concurrent Validation: Concurrent Validation is a validation approach that occurs during routine production or operation of a process or system. In this method, the validation activities are conducted in real-time as part of the ongoing manufacturing or operation process. It involves continuously monitoring and collecting data to ensure that the process or system consistently meets predefined quality standards. Concurrent validation is often used for well-established processes or systems where there is a high degree of confidence in their performance. It helps ensure that quality is maintained throughout regular production.

3. Retrospective Validation: Retrospective Validation is a validation approach used for processes or systems that have been in use for some time without formal validation documentation. In this method, historical data and records of the process or system's performance are reviewed and analyzed to determine whether it has consistently met the required quality standards. If the historical data demonstrates that the process or system has consistently produced acceptable results, retrospective validation can be used to establish formal validation documentation after the fact. However, if discrepancies or issues are identified during the retrospective analysis, corrective actions may be required.

Analytical Method Transfer

Analytical Method Transfer is essential for ensuring the accurate analysis of raw materials, finished products, packaging materials, and cleaning samples. This transfer process should include comprehensive information regarding analytical testing. The Supplier (SU) is responsible for providing the following information for analytical method transfer:

• Methods for analyzing and testing raw materials and finished products.
• Equipment details used for testing.
• Training programs for analysts and staff.
• Testing parameters.
• Experimental principles, design, and methodologies.
• Quality control test results.
• Validation reports.

Once the Supplier (SU) provides this information, the Recipient (RU) also has responsibilities for a successful analytical transfer, including:

• Agreement on acceptance criteria.
• Review of analytical methods.
• Training of competent staff.
• Availability of necessary equipment.

Additionally, both the Supplier (SU) and Recipient (RU) must fulfill the following responsibilities and jointly prepare the transfer protocol report:

• Documenting analytical results.
• Executing the transfer protocol.
• Ensuring proper validation to implement the process.

Various analytical parameters must be considered during the transfer, including:

• Precision
• Accuracy
• Limit of detection
• Limit of quantification
• Specificity
• Linearity
• Range

Moreover, access to relevant Pharmacopoeias is essential for comprehensive analytical testing.

The World Health Organization (WHO) has outlined possible experimental designs for analytical testing, encompassing tests for:

• Assay or percentage purity of components.
• Identification tests.
• Content uniformity.
• Solubility.
• Dissolution parameters.
• Qualitative and quantitative microbiological assays.
• Limit tests for impurities.
• Residue recovery.

To ensure the successful execution of the transfer protocol, both the Supplier (SU) and Recipient (RU) must collaborate and jointly prepare the necessary reports.

Introduction & Terminologies of Technology Transfer

 Technology Development & Transfer :

Introduction :

Pharmaceutical technology transfer, as per the World Health Organization (WHO) guidelines, refers to the process of transferring pharmaceutical product and process knowledge from one site or organization to another. This transfer ensures that the receiving site can reliably produce the same quality pharmaceutical products as the original site. The WHO guidelines emphasize the importance of maintaining product quality, safety, and efficacy throughout the transfer process.

The technology transfer process typically involves the transfer of various elements, including product formulation, manufacturing processes, analytical methods, quality control procedures, and regulatory documentation. It aims to ensure that the receiving site can replicate the production process with consistent quality and meet the required standards set by regulatory authorities.

Key principles of pharmaceutical technology transfer, in line with WHO guidelines, include:

•  Documentation and Knowledge Sharing: Comprehensive and well-documented information about the product, process, and quality requirements should be shared between the transferring and receiving sites. This includes process parameters, critical quality attributes, analytical methods, and any relevant regulatory documentation.

•       Risk Assessment: Both sites should conduct a thorough risk assessment to identify potential challenges, deviations, and critical points in the technology transfer process that could impact product quality, safety, or efficacy.

•   Quality Management: Quality management systems should be established at both the transferring and receiving sites to ensure that quality standards are maintained throughout the transfer process and during ongoing production.

•  Validation and Qualification: The receiving site should validate the manufacturing process and analytical methods to ensure that they consistently produce products meeting the required specifications. This may involve process validation, equipment qualification, and analytical method validation.

•  Training and Personnel Competence: Personnel at the receiving site should be adequately trained to understand and implement the transferred technology accurately. This includes training in manufacturing processes, quality control procedures, and other relevant aspects.

•   Regulatory Compliance: The technology transfer should adhere to regulatory requirements of the receiving site's jurisdiction. Any changes or modifications in the transferred technology that impact the product's quality, safety, or efficacy should be communicated to regulatory authorities and appropriately documented.

•   Continuous Improvement: The technology transfer process should be subject to continuous improvement, with regular monitoring and evaluation of product performance, process robustness, and quality metrics.

Pharmaceutical technology transfer is a complex and critical process that involves collaboration between different departments within organizations and often spans multiple geographic locations. Adhering to the principles outlined in the WHO guidelines helps ensure the successful transfer of pharmaceutical technology while maintaining the highest standards of product quality and patient safety.

Different Terminologies of Technology Transfer :

1. Active Pharmaceutical Ingredients (API): The chemical substances or compounds responsible for the pharmacological effects in a pharmaceutical product. APIs are the key therapeutic agents in medications.
2. Change Control (CC): A systematic process for evaluating, implementing, and documenting changes to processes, procedures, or equipment in a controlled manner to prevent unintended consequences on product quality.
3. Critical Control Point (CCP): A specific point in the manufacturing process where control measures are applied to prevent, eliminate, or reduce risks that could impact the quality, safety, or efficacy of the final product.
4. Corrective Actions (CA): Actions taken to address and rectify identified problems, issues, or non-conformities, with the goal of preventing their recurrence.
5. Preventive Action (PA): Proactive measures taken to identify and eliminate potential causes of problems or non-conformities in order to prevent their occurrence.
6. Quality Assurance (QA): The set of activities and processes that ensure products meet the required quality standards and regulatory requirements throughout their lifecycle.
7. Quality Control (QC): The process of evaluating, testing, and monitoring products to ensure they meet defined quality standards and comply with specifications.
8. Design Qualification (DQ): The documented process of demonstrating that the design of equipment or systems is suitable for their intended purpose.
9.  Installation Qualification (IQ): The documented process of verifying that equipment, systems, or facilities are correctly installed and meet specified requirements.
10. Operational Qualification (OQ): The documented process of verifying that equipment or systems operate according to their intended functions under various conditions.
11.  Performance Qualification (PQ): The documented process of demonstrating that equipment, systems, or processes consistently perform as intended within specified operating ranges.
12. Drug Master File (DMF): A confidential document submitted by a manufacturer to regulatory authorities containing detailed information about the manufacturing, composition, quality, and testing of an API or drug product.
13. Finished Pharmaceutical Product (FPP): The final form of a pharmaceutical product that is ready for distribution and use, containing all the necessary active and inactive ingredients.
14. Technology Transfer: Inter-Company Transfer: The transfer of technology, knowledge, and processes between different pharmaceutical companies or organizations.
15. Technology Transfer: Intra-Company Transfer: The transfer of technology, knowledge, and processes within the same pharmaceutical company or organization, often between different sites or facilities.
16. Standard Operating Procedure (SOP): Detailed written instructions and procedures that guide employees on how to perform specific tasks consistently and in accordance with established standards.
17. Technology Transfer Protocol (TTP): A document that outlines the procedures, responsibilities, and steps involved in transferring technology from one unit to another.
18. Technology Transfer Report (TTR): A comprehensive report that documents the entire technology transfer process, including the results, findings, challenges, and actions taken.
19. Sending Unit (SU) and Receiving Unit (RU): The sending unit refers to the site or organization transferring technology, while the receiving unit is the site or organization receiving and implementing the transferred technology.
20. Validation Protocol (VP): A document that outlines the planned approach, procedures, and acceptance criteria for validating a process, method, or system.
21. Validation Report (VR): A comprehensive document that summarizes the results of the validation process, including data, findings, and conclusions.

Please note that the explanations provided here are simplified for clarity. In practical applications, these terms may involve more detailed and specific processes and considerations.

Technology transfer from research and development (R&D) to production 

Technology transfer from research and development (R&D) to production in the pharmaceutical industry, specifically focusing on starting materials like Active Pharmaceutical Ingredients (APIs) and excipients:

• Capacity and Process Development:
• The receiving unit (RU) needs to have the necessary infrastructure, equipment, and resources to accommodate the production capacity required for the transferred process.
• Process development involves fine-tuning the manufacturing process based on the R&D findings to ensure scalability and reproducibility.
• Expert Personnel and Facility:
• Skilled personnel at the RU are essential for successfully executing the transferred process. They should understand the nuances of the process and possess the expertise to troubleshoot issues.
• The production facility at the RU should have the required equipment, utilities, and operating conditions to replicate the process developed in R&D.
• Joint Development of Protocol:
• The sending unit (SU) and RU collaborate to create a comprehensive protocol for the technology transfer. This protocol acts as a roadmap, detailing each step of the transfer process.
• Responsibilities of both the SU and RU are clearly defined in the protocol, along with timelines and quality control checkpoints.
• Starting Materials:
• The specifications and characteristics of starting materials, including APIs and excipients, must remain consistent between the SU and RU locations to ensure product quality and efficacy.
• 1 Active Pharmaceutical Ingredients (API):
• The SU provides the RU with a complete API master file, including essential information for the manufacturing process.
• Information about the API manufacturer and supplier is crucial, including contact details and quality assurance practices.
• Details of the synthesis scheme, process outline, and raw materials used in API production are shared.
• Information about intermediate products, which are stages of API synthesis, is communicated to aid the RU's understanding.
• Comprehensive information about the API's physicochemical parameters is included:
  • Solubility and the method of determination.
  • Particle size distribution.
  • Bulk and tap density, along with the method of evaluation.
  • Disintegration profile.
  • Water content and loss on drying.
  • Limits of impurities to ensure product purity.
• Microbiological and environmental factors affecting API quality are provided.
• Pharmacopoeial standards, along with the methods of determination, guide the RU in quality testing.
• Stability studies demonstrate the API's performance under different conditions.
• Storage and handling guidance, as mentioned in Pharmacopoeias, ensure API integrity.
• 2 Excipients:
• Excipients, supporting ingredients in pharmaceutical formulations, play a significant role in product quality and characteristics.
• The SU should provide detailed information about the excipients to the RU.
• This includes manufacturer and supplier details, excipient category, available dosage forms, descriptions, solubility, specific properties for different dosage forms (transdermal, solid, semi-solid, liquid, parenteral, aerosol/inhaled), such as lipophilicity, particle size distribution, compaction properties, viscosity, specific gravity, water content, osmotic pressure, and more.

For different dosage forms:

• Transdermal Dosage Form:
  • Lipophilicity and partition coefficient.
  • Particle size and distribution.
  • Specific gravity.
  • Water content and loss of drying.
  • Dissolution rate, including the detailed process.
• Solid Dosage Form:
  • Bulk and tap density profile with the method of evaluation.
  • Compaction properties.
  • Particle size and distribution.
  • Water content and loss of drying.
  • Nature of hygroscopicity.
• Semi-Solid Dosage Form:
  • Melting point.
  • Range of pH.
  • Specific gravity.
• Liquid Dosage Form:
  • Range of pH.
  • Specific gravity.
  • Water content.
• Parenteral Formulation:
  • Range of pH.
  • Specific gravity.
  • Water content.
  • Osmotic pressure.
  • Ionic strength.
• Aerosol/Inhaled Dosage Form:
  • Bulk and tap density.
  • Particle size and distribution.
  • Surface area.
  • Water content.

This comprehensive information sharing ensures that the RU can reproduce the intended product characteristics, maintain product quality, and comply with regulatory standards during the technology transfer from R&D to production in the pharmaceutical industry.

Packaging :

• Packaging Procedures in Transfer The procedures for packaging should adhere to the established procedural protocols similar to those followed during production transfers. This seamless transition ensures consistency and reliability throughout the packaging process.
• Transferring Packaging Information from SU to RU During the transition of packaging responsibilities from the Source Unit (SU) to the Receiving Unit (RU), a comprehensive set of information needs to be conveyed. This includes the following key elements:
• Container and Closure System Specifications: Precise specifications for an appropriate container or closure system are essential. These specifications outline the physical attributes and characteristics required to ensure the integrity and suitability of the packaging.
• Design, Packing, Processing, and Labeling Requirements: Detailed information about the design aspects, packing procedures, processing techniques, and labeling requirements should be communicated. This information ensures that the packaging is aligned with the intended product and meets all regulatory and quality standards.
• Tamper-Evident and Anti-Counterfeiting Measures: To maintain product security and authenticity, strategies for implementing tamper-evident features and anti-counterfeiting measures must be transferred. These measures safeguard the product from unauthorized access and protect against counterfeit activities.
• Qualification of Packaging Components: The information necessary for the qualification of packaging components at the Receiving Unit (RU) is crucial. This involves providing the RU with all the relevant data required to assess and validate the packaging components according to established standards.
• Specifications for Drawings, Artwork, and Material: Precise specifications for drawings, artwork, and the material used in packaging creation should be communicated. These specifications guide the RU in ensuring accurate replication of packaging designs and maintaining consistency in material quality.
• Ensuring Uncompromised Quality and Integrity By effectively transferring packaging-related information, the continuity of quality and integrity in packaging operations is upheld. This comprehensive information exchange empowers the Receiving Unit to seamlessly integrate packaging responsibilities while adhering to established standards and guidelines. This approach not only guarantees a smooth transition but also facilitates the maintenance of product safety, regulatory compliance, and overall consumer confidence.The primary goal of cleaning procedures is to effectively mitigate the risk of cross contamination, ensuring the utmost product quality and safety. In order to achieve this objective, several critical aspects must be addressed and thoroughly considered throughout the process.

Cleaning: 

Understanding Solubility and Environmental Impact A comprehensive comprehension of the solubility characteristics of active ingredients, excipients, and vehicles is pivotal. This knowledge aids in determining appropriate cleaning agents and procedures that effectively eliminate residues without compromising the environment. The environmental impact of cleaning procedures is a significant concern, underscoring the importance of selecting methods that minimize ecological repercussions.

• Balancing Therapeutic Doses and Toxicological Assessment The cleaning process should take into account the minimum therapeutic doses of active ingredients, as well as a thorough therapeutic category and toxicological assessment. This evaluation ensures that residues are eradicated without undermining the therapeutic efficacy of subsequent batches and guarantees consumer safety.
• Integrating Existing Cleaning Protocols Existing cleaning procedures from the Source Unit (SU) should be integrated seamlessly into the Receiving Unit's (RU) operations. This ensures a smooth transfer and maintains the established quality standards. Furthermore, additional relevant information, such as cleaning validation reports encompassing both chemical and microbiological aspects, can contribute to a robust cleaning strategy.
• Validating Cleaning Agents and Sampling Methodology Information pertaining to the efficacy of cleaning agents used, along with evidence that these agents do not interfere with analytical testing for active pharmaceutical ingredient (API) residues, is essential. Moreover, recovery studies that validate the sampling methodology reinforce the accuracy of residue detection methods.
• Establishing Limits and Rationale Before the transfer of responsibilities, the SU should communicate residue limits and the rationale behind their selection. This information serves as a foundation for designing appropriate cleaning procedures at the RU, considering aspects such as potency, toxicity, solubility, corrosiveness, and temperature sensitivity of starting materials. The configuration of manufacturing equipment and the characteristics of cleaning agents also factor into this design.
• Transitioning to Formal Validation As part of quality assurance, trial batch production, often referred to as "demonstration batches," is conducted to assess process capability. This phase aids in confirming that critical processing parameters and finished product specifications align with predetermined criteria. Once process capability is established at the RU, the groundwork is laid for conducting process validation and cleaning validation. These validation processes ensure that the product, method, or process at the RU aligns with predefined and justified specifications, guaranteeing consistent quality and regulatory compliance.
• By integrating all these elements into the cleaning procedures, the RU can confidently assure the integrity of the products, enhance consumer safety, and uphold industry standards.

 Questions on Technology development and Transfer

 

10 Marks Questions:

1. Explain the key components of the WHO guidelines for Technology Transfer (TT) and how they contribute to ensuring the quality and safety of pharmaceutical products. Provide examples where relevant.
2. Discuss the process of transferring technology from Research and Development (R&D) to production, particularly focusing on the challenges and risk management strategies involved. Use specific examples from the pharmaceutical industry.

5 Marks Questions:

1. Define and elaborate on the concept of "Granularity of TT Process" as it relates to pharmaceuticals. How does it impact the technology transfer of finished products?
2. What role do premises and equipment play in ensuring successful technology transfer in the pharmaceutical industry? What is importance of qualification and validation in this context?
3. Describe the quality control measures that need to be in place during the technology transfer process. How does analytical method transfer contribute to quality assurance?
4. Explain the significance of approved regulatory bodies and agencies in the context of technology transfer for pharmaceutical products. Provide examples of such regulatory bodies and their roles.
5. Using case studies or real-world examples, discuss the practical aspects and common problems associated with the commercialization of pharmaceutical technologies. Highlight the role of technology transfer in this process.
6. Briefly introduce the technology transfer agencies in India, including APCTD, NRDC, TIFAC, BCIL, and TBSE/SIDBI. Describe their primary functions and contributions to technology transfer in the country.

2 Marks Questions:

1. What is the purpose of a confidentiality agreement in technology transfer, and why is it important in the pharmaceutical industry?
2. Differentiate between licensing and Memorandums of Understanding (MoUs) in the context of technology transfer. When might each be more appropriate?
3. What is the significance of quality risk management in technology transfer within the pharmaceutical industry?
4. How does documentation play a crucial role in ensuring the success of technology transfer processes in pharmaceutical manufacturing?
5. Explain the importance of legal issues in technology transfer, particularly in the context of pharmaceutical products.
6. What is the role of packaging materials in technology transfer, and why is it essential to consider them in the process?
7. Describe the primary objectives of technology transfer protocols and their role in ensuring consistency in pharmaceutical manufacturing.