Manufacturing drug products for clinical studies present many unique challenges that contrast to the manufacturing of commercial drug products. This article will explore the uniqueness of manufacturing IMPs (investigational medicinal products). Additionally, careful consideration will be paid to the planning phase and the challenges associated with manufacturing and packaging.

Uniqueness of Clinical Supplies

All aspects of manufacturing, including the process, batch size, analytical methods, in process and finished product specifications, are well established for a commercial product. The stability of the finished drug product in the final package has been thoroughly studied during development and process validation. Based on stability studies, a suitable expiry date is established and printed on the label. On most occasions, clinical supplies are manufactured prior to approval.

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The manufacturing process and analytical methods are still under development and not fully validated at the time of manufacture. Sometimes multiple formulations are evaluated in clinical studies. Hence the formula, batch size, process parameters, and analytical methods are not well defined and are constantly evolving. Due to these changes, one cannot rely on the expertise of regular manufacturing operators or QC analysts for the manufacture and release of clinical supplies. For the most part, development scientists and analysts are required to conduct manufacturing operations and analysis.

Many times, stability studies are conducted in concurrence with clinical trials. Thus, a confirmed expiry date cannot be printed on the label and mostly the retest date or use-by date are preferred. Once a clinical study starts, the expiry/retest/use-by date should be updated on the remaining clinical supplies based on additional stability data. The expiry update on IMP labels present unique challenges and require quality assurance oversight. This presents additional challenges in managing the existing inventory at clinical sites and depots.

Sometimes, clinical supplies require matching placebo and comparator blinding. The blinding presents unique challenges. All of these requirements should be considered during the planning stage.

A comparison between chemistry, manufacturing and controls (CMC) requirements for manufacturing and release of IMPs, and commercial drug products is presented in Table 1.

Table 1: Comparison of CMC Requirements for Manufacturing and Releasing IMP/Clinical Supplies and Commercial Drug Products

CMC Requirements

Commercial Product

IMP/Clinical Supplies
  • Formula, batch size, manufacturing process and package
  • Predefined
  • Evolutionary and customized
  • Analytical Methods
  • Fixed and validated
  • Evolving and qualified for early clinical studies
  • Specifications
  • Well-established
  • Evolving
  • Manufacturing Operators
  • Line operators dedicated to specific operations or products
  • Development scientists usually highly educated and perform numerous operations
  • Batch Size
  • Usually large batches made repetitively with a fixed and validated process
  • Usually smaller batches made with a process still under development
  • Strengths
  • May include multiple strengths
  • May include placebos, multiple dose strengths or comparators with matching placebos
  • May require blinding techniques
  • Stability
  • Well-established
  • Limited stability data. Stability may be conducted concurrently with clinical study
  • Expiry Date
  • Defined and printed on label
  • Expiry date is projected using stability data available from development and validation batches
  • Emphasis on end-user to discontinue use post expiry date
  • Retest or use-by dates are preferred
  • May or may not appear on label
  • Emphasis on the sponsor to ensure the product is used within use-by date

Due to the challenges described above, a lot of planning is required before manufacturing and packaging clinical supplies. Some of the important considerations include:

  • The clinical development phase
  • The location of clinical sites
  • Trial design
  • Drug substance cost
  • Availability and stability
  • Packaging requirements
  • Time to start a clinical study

Important Considerations for Manufacturing and Releasing of IMPs

Clinical Development Phase

The batch size is generally defined based on the size of clinical studies which in turn depends on the clinical development phase. Phase I studies are generally conducted at a small scale and hence require only smaller quantities of clinical supplies. On the other hand, phase II and III clinical studies are conducted at a large scale and hence require large quantities of clinical supplies. Depending on the stage of the manufacturing process, these supplies can be made either at the laboratory scale, pilot scale or sometimes at the commercial scale.

For phase III studies, it is desirable to have a formulation similar to the intended commercial product. If not, additional bioequivalence studies are required to provide the equivalence of phase III and commercial products. A smaller batch size generally leads to the production of multiple batches, and that adds to the complexity of inventory management for phase III trials.

The clinical supplies are manufactured under cGMP. The cGMP requirements increase as drug development progresses under an IND. The amount of information provided in a regulatory submission for a clinical trial depends on the study phase. A CMC submission for phase I trials should contain sufficient information to evaluate the safety of subjects.

Generally, full analytical method validation is not required for phase I/II studies. A phase-appropriate analytical method validation and limited stability data are sufficient to start a clinical study. Crucially, CMC regulatory requirements increase with the advanced stages of development. Therefore, clinical supplies for these phases should be manufactured as per the requirements shown in Figure 1.

Figure 1: CMC Regulatory Requirements in United States

Location of Clinical Sites

The geographical location of clinical sites should be known before manufacturing IMPs. What’s essential is that the clinical supplies are manufactured based on the regulatory requirements of the region. For example, if a clinical program is focused only in U.S., the raw materials that are compendial only in the United States Pharmacopeia (USP) can be used. On the other hand, for global studies, raw materials that are compendial both in the USP and in the European Pharmacopeia (Ph. Eur.) are generally recommended.

Additionally, for clinical trials in Europe, supplies should be released by a Qualified Person (QP) as per Annex 16. Since QP release requires a manufacturing site to be audited by a QP, it is recommended to work with a CMO or a site that has already been audited by a QP to save time during QP release. This is an important factor that must be considered during the planning phase.

Package Selection

The IMP package must be defined based on the target patient population, study design (dosing requirements) and available stability data. For clinical studies where an IMP is used in a household setting, child resistant packages are generally recommended. For example, for long-term, open label studies with solid oral drug products, HDPE bottles with child resistant closures are generally preferred.

On the other hand, for smaller studies or for studies with complex dosing instructions, blister cards or wallets are generally preferred since a lot of study and product specific information can be included in the wallet card. The stability of drug product is another important factor to be considered before designing a package for IMP to be used in a clinical study. Most of the times, during early development stages, stability studies are performed on the packaged IMP concurrently with the clinical study.

Labeling of IMP

The design considerations for an IMP label include the package design and regulatory requirements. The label size is governed mainly by the package size whereas the content depends on the regulatory requirements and the languages pertinent to the region where the trial is being conducted. Additionally, various types of labels (single panel, double panel and booklets) are used for different studies.

Representative Timeline

A representative timeline for manufacturing and packaging of clinical supplies is presented in Figure 3. On average, it takes about six to eight months to manufacture, package, label and release an IMP for clinical use. This timeline can vary depending on the complexity of study design and the size of the study.

The clinical trial management function requires the feedback and cooperation of multiple departments. Therefore, an effective communication between various groups is the key to success in delivering the IMP for a clinical study in a time effective manner.

Figure 2: Representative Timeline for Clinical Supplies Manufacturing and Packaging

Summary

Due to the uniqueness of IMPs and its associated challenges, it is important to consider all the factors described in this article before starting the manufacturing and packaging of IMP. Effective planning and execution is important to deliver the IMP to clinical sites in a timely fashion.

 

Kavita Vermani

Senior Manager, Pharmaceutical Development and Clinical Supplies

Adamas Pharmaceuticals, Inc.

 

Disclaimer

The views and information presented in this article are my own, non-confidential, and do not necessarily represent the views of my employer Adamas Pharmaceuticals, Inc.

 

References:

  1. FDA Guidance for Industry for cGMP for Phase 1 Investigational Drugs (July 2008)
  2. FDA Guidance for Industry for INDs for Phase 2 & 3 Studies – Chemistry, Manufacturing and Controls Information (May 2003)
  3. The Code of Federal Regulations 21 CFR 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals Part 210 and Part 211
  4. FDA Guidance for Industry for Container Closure Systems for Packaging Human Drugs and Biologics – Chemistry, Manufacturing, And Controls Documentation (May 1999).
  5. EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use. Annex 16: Certification by a Qualified Person and Batch Release (Oct 2015)