How to ensure quality and compliance in clinical supply chain management

Kazi
Last modified: August 17, 2024

Clinical supply chain management of investigational medicinal products ensures the overall success of introducing new drug molecules in the market. Stringent regulations govern clinical supply chain management for medicinal products, biologics, and medical devices during clinical trials.

To maintain the integrity and safety of these investigational products, you must adhere to Good Manufacturing Practice (GMP), FDA Clinical Trail Guidance Documents, and relevant ISO or EN standards. Compliance with EN 46001 and 21 CFR 820 is essential for medical devices.

A robust quality assurance (QA) system produces the framework for managing clinical supplies. To ensure compliant and robust clinical supply chain management, you should establish approved protocols, process validation, rigorous audits, etc.

Other aspects, including fit-for-purpose organizational structure, personnel competence, validation of facilities, qualification of equipment, meticulous documentation, etc., ensure traceability and compliance.

This article explores the essential components of the clinical supply chain for investigational pharmaceutical products and medical devices and provides a comprehensive guide to maintaining the highest standards in clinical trials.

Key Takeaways

Quality management: A robust quality assurance system based on GMP principles is essential for investigational products. This includes self-inspections and quality audits.

Organization and personnel: Ensuring those responsible for releasing clinical supplies are organizationally separate from those producing them, with clear responsibilities and adequate training.

Facilities and equipment: Maintaining facilities and equipment according to written instructions to prevent contamination and ensure cleanliness, particularly for sterile products.

Documentation: Keeping detailed records of orders, specifications, manufacturing processes, packaging, and labeling to ensure traceability and compliance.

Production: Managing starting materials, manufacturing operations, and ensuring proper reconciliation and sterilization processes.

Distribution and return: Following proper shipping, return, and destruction procedures for investigational products.

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Designing quality assurance for clinical supply chain management

While designing and establishing the quality assurance system, describe everything in writing. Considering the GMP principles applicable to investigational products. In the case of medical devices, apply the principles of EN46001 and 21 CFR 820.

Some production processes for investigational clinical products that do not require marketing authorization may not be required to be validated to the extent necessary for routine production operations.

Product specifications and manufacturing instructions may vary during development.

Packaging and labeling operations for investigational products are often complex and must meet specific requirements to ensure the integrity of clinical trials.

Self-inspections or independent quality audits are integral to the clinical quality assurance system.

Organization and personnel requirements

According to best clinical practice, the people responsible for releasing clinical supplies should be organizationally separate from those responsible for producing those supplies.

All production operations should be controlled by authorized people nominated by production management. If necessary, according to local law, the responsible people should be known to and approved by the relevant national authority.

When defining the QA unit with batch release responsibility, a distinction should be drawn between processing, packaging, and distribution activities.

The QA unit at the development site responsible for formulation and specification development is responsible for the quality assurance release of the dosage form, regardless of where processing occurs.

A separate QA unit may delegate responsibility for developmental batch release functions.

Packaging and distribution are independent of the dosage form characteristics (except storage conditions and shelf life). Therefore, the quality assurance unit at the site where packaging and distribution occur is responsible for releasing packaged lots.

All personnel involved in manufacturing products for clinical trials should have competence and training within their area of responsibility and knowledge of GMP and EN46001 (for devices) as applicable.

Written job responsibility descriptions, curricula vitae for key personnel, and up-to-date and approved organizational charts, training programs, and individual training records for all personnel involved in GMP-regulated activities are required.

When work is shared between intra-company sites or contracted to a third party, the appropriate quality assurance unit should prepare and review a written agreement capturing essential information.

Facilities and equipment in the clinical supply chain

Facilities should be maintained according to written instructions and suitable for the operations in them.

Different products may be handled in the same area simultaneously during the manufacture of investigational products. Appropriate procedures must minimize contamination risks, including cross-contamination and accidental mix-ups.

Investigational materials are typically not manufactured or packaged in registered product-dedicated facilities.

Because the material’s toxicity may not be fully known, evidence of effective cleaning must be obtained, and facilities and equipment must not be reused until effective cleaning has been verified. Additional precautions may be necessary for highly toxic materials.

Critical equipment, systems, and facilities used in manufacturing should be maintained according to written instructions.

To demonstrate their performance, facilities, and utilities should be validated according to written protocols.

Always document the use of equipment and schedule maintenance and performance checks. Critical process measuring equipment should be regularly calibrated using traceable and certified standards.

In the case of sterile clinical products, the validation of sterilizing equipment should meet the same standards as marketed products.

While hand filling and sealing are feasible for small-scale batches, they present significant challenges to sterility assurance and require enhanced quality assurance attention.

How to manage documentation in clinical supply chain management

Effective documentation in the clinical supply chain is crucial for ensuring the integrity, quality, and traceability of investigational products throughout their lifecycle.

It serves as the foundation for regulatory compliance, enabling transparent communication between all stakeholders, including manufacturers, regulators, and clinical sites.

Proper documentation ensures that each step in the production, packaging, and distribution process is meticulously recorded, reducing the risk of errors, maintaining consistency across batches, and facilitating the tracking of products from manufacture to patient administration.

In clinical trials, where the accuracy and reliability of data are paramount, robust documentation practices are essential for safeguarding patient safety, supporting regulatory approvals, and ultimately contributing to the success of the clinical study.

1. Order (request)

The order may request the processing, packaging, or shipment of a certain number of units. Orders may only be submitted by authorized company personnel to an authorized provider of investigational products.

Appropriate order forms should be in writing, formally authorized, and precise enough to avoid ambiguity.

2. Specifications

A responsible person should establish and approve specifications for starting materials, primary packaging materials, and intermediate and bulk products before the lot is used in clinical studies.

Specifications should be based on scientific data, technology, and regulatory and pharmacopeia requirements.

3. Manufacturing formula and processing instructions

Manufacturing formula and processing instructions may be allowed, but consideration must be given to any possible repercussions on stability and bioequivalence between batches of finished products.

4. Master documents

A master processing and packaging document may not be required, but for each manufacturing operation, there must be clear and adequate instructions and written records.

Systems or procedures should be in place to ensure that the correct formula version is supplied.

5. Processing and packaging batch records

Processing and packaging batch records should be kept in sufficient detail so that the sequence of operations, the equipment used, and the personnel who performed the operations can be accurately traced back.

Original batch documents and relevant validation documents supporting the processing or packaging of clinical supplies are archived at the site of processing or packaging.

6. Packaging instructions

Packaging and labeling of investigational products are likely more complex and more liable to errors (also harder to detect) than licensed products when “blinded” labels are used.

Procedures such as label reconciliation line clearance, etc., and the independent checks by personnel performing quality control tasks should be intensified accordingly.

Packaging instructions are based on the order and medical protocol. Batches of investigational products may be subdivided into different packaging batches and packaged in several operations over a period of time.

The number of units to package should be specified before the start of the packaging operations, considering also the number of units necessary for carrying out quality controls and the number of samples to be kept.

Reconciliation should occur at least at the end of the packaging and labeling processes.

7. Labelling instructions

Labels on the IMMEDIATE container should include the following:

i. Name and address of the company producing or distributing the packaged supplies. Suppose the company name and address cannot appear on the label (i.e. some trials for consumer products). In that case, traceability must be documented between the distributor name/address on the label and the company site.

ii. Batch (lot) and code number to identify the contents and packaging operation

iii. Storage conditions and precautions if space permits. For small containers, this information may be displayed in the outer container.

iv. Appropriate caution statement(s) as required by applicable regulations.

The following items should also be present unless it is determined that their inclusion would unblind the clinical trial.

i. Product identifier and strength

ii. Pharmaceutical dosage form and quantity of dosage form

Labels on the OUTER container should include the items mentioned above and additional necessary or applicable information. For example:

i. Directions for use or reference to an enclosed leaflet or requirement to take as directed by the physician.

ii. The trial subject identification number.

iii. Protocol title and protocol number.

iv. Expiry or re-test date of the supplies (unless an appropriate system tracks this).

When mandatory for a country, information related to the center (such as the investigator’s name and center number) should be printed on labels affixed to the outer container.

An appropriate system should track the location to which the specific supplies are shipped.

An additional label may be affixed to the investigational product if the expiry or re-test date is extended.

This additional label should include the new expiry or re-test date and repeat the batch number. It may be superposed on the old expiry or re-test date but not on the original batch number.

i. A copy of each type of study-specific label should be kept in the batch packaging record.

ii. Approvals, representing compliance with protocol and regulatory requirements, should be documented.

8. Product specification file

A product specification file should reference all the information necessary to draft detailed written instructions on processing, packaging, quality control testing, batch release, storage, and shipping conditions.

This file should be continually updated, ensuring appropriate traceability to the previous versions (The information in the files supporting the US IND is essentially equivalent to the information in the Product Specification File).

9. Device master record

A device master record containing all necessary information to document the performance and configuration characteristics defined for a medical device should be established.

This device master record should be continually updated to ensure appropriate traceability to the previous versions.

10. Document change control

Specifications (for starting materials, primary packaging materials, intermediate and bulk products, and finished products), manufacturing formula and processing, packaging, and labeling instructions may be changed frequently due to new experience.

A responsible person should approve each new version, take into account the latest data, and refer to the previous version so that traceability is ensured. Reasons for changes should be recorded.

11. Document retention

Batch records should be retained following the retention schedule or according to national requirements, whichever is longer. Order forms are considered part of the batch documentation.

Control of production processes in clinical supply

Effective control of production processes is critical to the success of clinical trials, as it ensures the quality and safety of investigational products.

Adhering to stringent guidelines, including material reconciliation, sterility assurance, and proper handling of comparator drugs and radioactive materials, can maintain the integrity of the clinical trial.

To preserve the reliability of trial outcomes, it is essential to manage blinding operations, secure storage conditions, and carefully manage randomization codes.

The points below summarise the key procedures and controls necessary for managing the production of clinical trial material.

1. Starting Materials

The quality of the starting materials influences the consistency of production. Therefore, their physical, chemical, and, where relevant, microbiological properties should be defined, documented in their specifications, and controlled.

Specifications for the active pharmaceutical ingredient (API) should reflect the current state of knowledge.

Specifications for both the active and non-active pharmaceutical substances must be reviewed in case of a process change or change in supplier.

Detailed information on the quality of the components should be available to recognize and assess the impact of any variation on production.

2. Manufacturing operations

Validated procedures may not always be available during the development phase.

Provisional production parameters and in-process controls should be set based on the knowledge and experience of key personnel.

Where some steps in the process, such as mixing, have not been validated, additional in-process information (observations and monitoring results) should be recorded in batch documents.

Additional quality control testing of investigational products may also be necessary.

Investigational products must be appropriately identified at all stages during manufacturing.

Reconciliation is an essential part of controlling the manufacturing operation. It compares the mass of material used in a process step to the mass of material accounted for at the end of a process step (the sum of product, waste, samples, measured loss, etc.).

Material reconciliation should be calculated after significant process steps, and any abnormal discrepancy should be investigated.

Sterility assurance for sterile investigational products should be no less than for marketed products.

Sterilization in the final product container is the preferred process where the formulation’s nature permits or as required by regulations.

Aseptic processing, if necessary, must be validated by media fills. The media fills must accurately represent the production process to be used in the manufacture of clinical supplies.

The integrity of any container closure system used for sterile investigational products should be suitably validated.

3. Principles applicable to comparator drug

In studies where an investigational product is compared with a marketed product, attention should be paid to ensuring the comparator product’s integrity and quality (final dosage form, packaging materials, storage conditions, etc.).

Suppose significant changes will be made to the product or primary packaging material. In that case, documentation should be available to ensure that these changes do not influence the product’s original quality characteristics.

The expiry or review date stated on the original package has been determined for the dosage form in that particular package. It may not apply to the product where it has been repackaged in a different container.

The sponsor is responsible for determining a suitable expiry or review date, considering the product’s nature, the container’s characteristics, and the storage conditions to which the article may be subjected.

Such a date must be no later than the expiry date of the original package.

4. Radioactive investigational products

Investigative products containing radio-labeled material should be produced in suitable facilities, according to GMP guidelines and applicable radiological safety requirements.

Where routine quality assurance release procedures cannot be followed, a written protocol should be approved, which details all production and quality control data to be considered before the investigational product is released.

The QA unit will approve this protocol before the investigational product is manufactured.

5. Randomization code

Procedures should describe the generation, distribution, handling, and retention of any randomization code used for packaging investigational products.

The clinical supply logistic unit is responsible for generating the randomization code unless local regulations dictate otherwise (for example, in Japan).

6. Blinding operations

Implement a proper system to allow for the identification of the ‘blinded’ products.

This system, together with the randomization code and randomization list, should allow proper identification of the product, including any necessary traceability to any codes and batch numbers of the product before the blinding operation.

Particular attention must be paid to the appearance of clinical supplies manufactured at different development sites or at the same development site at different times if the supplies are intended to be used in the same blinded clinical study.

This is to ensure that the clinical supplies are sufficiently identical to prevent the clinical study from being blinded.

7. Storage conditions

Investigational products must be stored securely under labeled storage conditions to assure product stability and avoid mix-ups with other products.

The development site is responsible for providing information on storage/shipping conditions for the dosage form and packaged clinical supply.

8. Retained and archived samples

Store the retained and archived samples of clinical supplies at the site of processing and/or packaging.

Additional retained samples of each test batch (sufficient to perform the release tests required in the NDA at least three times) are required for bioavailability and bioequivalence (BA/BE) clinical study supplies.

These are to be retained at the clinic site or an appropriate third-party facility.

9. Testing

Laboratory testing of processed lots will usually be conducted at the development site responsible for drug candidate development, no matter where the supplies are manufactured.

Laboratory testing of packaged lots will usually be conducted at the site responsible for packaging.

Appropriate tests may be conducted at the site of processing or packaging with the approval of the responsible QA unit (for example, cleaning validation/verification tests, final packaged identification tests, etc.).

How to release investigational products to clinic sites

Delivery of investigational products requires multiple approvals. The first approval is based on the approval of the batch record and the conformance of the results of the quality control tests carried out with established specifications.

The QA unit conforms to this release. Subsequent approvals ensure that the legal and regulatory commitments for the shipment of the investigational product have been met.

1. Quality Assurance for release of investigational products

Appropriately validated analytical methods should be used to test drug substances and investigational products.

Primary data was obtained from testing each bulk and packaged investigational product, and each component of the lot should follow the retention schedule or according to national requirements, whichever is longer.

Before the Phase III trial, drug substances, excipients, drug product containers, and closures used in the preparation of investigational products should be evaluated and released by the QA unit prior to the release of the investigational product for use in clinical studies.

For Phase III and after, the QA unit must evaluate and release drug substances, excipients, drug product containers, and closures used in the preparation of investigational products prior to use in manufacturing.

As processes may not be standardized or fully validated, in-process and end-product testing becomes more important to ensure that each batch meets its specifications.

The QA unit should especially pay attention to compliance with specifications, which bear on the safety and efficacy of medicinal products, namely:

i. Accuracy of the therapeutic or unitary dose (e.g., homogeneity, content uniformity)

ii. Release of active ingredients (e.g., dissolution time)

iii. Estimation of stability, if necessary, in accelerated conditions, determination of the product’s preliminary storage conditions and shelf life.

The similarity of “blinded” medicinal products (including packaging) should be checked using appropriate methods.

Samples of each batch of product (or drug substance) should be retained under the responsibility of the manufacturer or importer, which released the batch for use.

They should be kept in the primary container used for study or a suitable bulk container under the recommended storage conditions for the product (or drug substance).

Samples are kept for 15 years from the time of processing or packaging (as appropriate) unless the stability of the investigational material justifies a shorter time.

If the investigational product is not stored in the package used for the study, stability data should be available to justify the shelf life in the pack used.

2. Investigational product release

Product release is often carried out by QA in two stages, before and after final packaging:

i. Bulk product assessment: it should cover all relevant factors, including production conditions, in-process testing results, a review of manufacturing documentation, and compliance with the product specification file or device master record (or IND) and the order.

ii. Finished product assessment: It should cover all relevant factors besides the bulk product assessment, including packaging conditions, results of in-process testing, a review of packaging documentation, compliance with the product specification file, device master record (or IND), and the order.

Quality controls should be carried out on investigational products released, including batch documentation.

Independent quality assurance staff appropriately trained in quality systems, GMP, and specific clinical and regulatory requirements should carry out quality controls.

In the EU, a Qualified Person, as referred to in Article 17 of Directive 75/319/EEC, should carry out this task.

3. Free movement of investigational products between sites

Since investigational products are released by appropriately qualified company staff at one site, subsequent analysis after shipping to other sites is not required for final labeled and packaged clinical goods if documented evidence is available that appropriate analysis and release procedures have been conducted. Appropriate shipment and storage controls are in place.

When bulk investigational products are shipped to another qualified company site, an identification test is typically performed prior to QA releasing the final packaged supplies to the clinic.

Distribution and return in the clinical supply chain

Shipping, returning, and destroying unused investigational products should be carried out according to written procedures. The distribution of clinical supplies to clinics is governed by GMP and GCP requirements.

1. Shipping of investigational products

Shipping of investigational products is conducted according to orders given by the Sponsor or their designee in the shipping order.

The packaging should ensure that the medicinal product remains in good condition during transport and storage at intermediate destinations. Any opening of, or tampering with, the outer package during transport should be readily discernible.

Systems should be in place to ensure that shipments are delivered to the correct addressee, and investigators should document the receipt of shipments.

Those making the shipment should maintain a detailed inventory of the shipments made to the market or the clinical investigation site. This inventory should particularly mention the addressees’ identification.

The transfer of investigational products from one trial site to another should remain the exception and be carried out following applicable regulatory requirements.

2. Returns of investigational products

Investigational products may be returned to control and re-released for distribution under specified regulatory conditions for clinical supplies. The returned clinical supplies must be managed using written instructions approved by the responsible quality assurance unit.

The returned investigational products must be identified and stored in a dedicated area. Inventory records of returned products should be kept.

3. Destruction of investigational products

The sponsor is responsible for destroying unused investigational products. The destruction can be done at the investigation site, hospital pharmacy, or by the manufacturer, but the sponsor should always authorize it.

Destruction operations should be recorded in such a manner that all operations must be accounted for. The sponsor should keep the records.

If the manufacturer is other than the sponsor and is requested to destroy the products, they should deliver a certificate of destruction or a receipt for destruction to the sponsor.

These documents should clearly identify the batches involved and the actual quantities destroyed.

Contract manufacture in clinical supply chain management

If clinical supplies are manufactured or tested by a third party outside the company, there must be a written agreement that clearly establishes the responsibilities of each party.

The written agreement must clearly state, among other provisions, that the investigational products or devices are being used in clinical trials. The contracting parties should cooperate very closely.

Authorized personnel should check that the GMP and EN 46001 levels are in accordance with company methods, specifications, and legal requirements. This should normally be done through site audits.

Quality audits in clinical supply chain

All units involved in the production of investigational products should have operational programs of self-inspection or quality audits. Designated competent persons should perform the inspections and audits independently and in detail.

Conclusion

Effective management of the clinical supply chain is essential for ensuring compliance with GMP and ISO standards, maintaining product integrity, and supporting the success of clinical trials.

Organizations can confidently navigate the complexities of clinical supply management by implementing robust quality assurance systems, maintaining detailed documentation, employing competent personnel, using validated facilities, and adhering to stringent production and distribution protocols.

Author: Kazi Hasan

Kazi is a seasoned pharmaceutical industry professional with over 20 years of experience specializing in production operations, quality management, and process validation.

Kazi has worked with several global pharmaceutical companies to streamline production processes, ensure product quality, and validate operations complying with international regulatory standards and best practices.

Kazi holds several pharmaceutical industry certifications including post-graduate degrees in Engineering Management and Business Administration.