Essential Insights Into Pharmaceutical Product Release, Part 1 of 2

This two-part series will explore the critical process of product release in pharmaceutical manufacturing. Part one will cover fundamental concepts, including the definition of product release, its importance in ensuring drug safety and efficacy, and the specific regulatory requirements in the pharmaceutical industry. We'll examine the various types of data and records essential for a successful product release, emphasizing that it's a comprehensive review process beyond simply signing off on executed batch records or standard operating procedures (SOPs).

Introduction

When bringing a commercial drug product to market the focus tends to be R&D, clinical trials, scale-up, tech transfer, and validating the commercial manufacturing process. Unfortunately, pharmaceutical product release is usually an afterthought. This is where companies face difficulty in complying with U.S. Food and Drug Administration Good Manufacturing Practice (FDA GMP) requirements as they try to manage multiple data streams to create an effective pharma product release program. Some companies will utilize contract manufacturing organizations (CMOs) or contract development manufacturing organizations (CDMOs), thinking that the pharma contract manufacturing organization will be responsible for all of the product release activities, but this is not accurate. The responsibility of pharma product release rests in the hands of the manufacturer/license holder.

What Is Product Release?

Pharmaceutical product release (sometimes called batch release, lot release, or pharma product release) is the process of reviewing all of the elements of the acquisition, manufacturing, testing, and inspection activities for a particular batch of pharmaceutical product. The primary focus of pharma product release is to ensure that only “good” products that conform to specifications and FDA regulations are released for use. Generally, a pharmaceutical product is approved for distribution and use after it has been manufactured, tested, and verified to meet all required quality, safety, and efficacy standards.

As part of pharma product release it is important to define the product type and quantity being reviewed. Companies often release pharmaceutical products by batch. A “batch” is defined as a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture. (Ref: FDA 21 CFR § 210.3 Definitions.)

In this article we refer to drug products (pharma products) as the finished dosage form that contains an active drug substance in association with inactive ingredients. We will refer to components as any material intended for use in the manufacture of the drug product, including those that may not appear in the final finished drug product. (See FDA 21 CFR Sect. 210.3 for definitions.)

The Importance of Pharma Product Release

The pharma product release process is the “gatekeeper” for the quality, safety, and efficacy of each batch. The pharma product release program should systematically evaluate the manufacturing and quality control processes for each batch of drug product and should review all of the elements impacting drug safety and efficacy for that specific batch.

Robust specifications help to ensure drug safety and efficacy. During pharma product release, the quality representative verifies that the drug product meets predefined quality specifications (e.g., potency, purity, dissolution, and stability). Using the same recipe or master production and control records helps to ensure consistency across batches so that patients receive the same therapeutic effect from every dose. (See § 211.186 Master production and control records and § 211.188 Batch production and control records.)

Pharma product release is vital because it ensures:

• Alignment with GMP requirements (not optional).
• Product integrity and efficacy.
• Patient safety.
• Regulatory compliance.
• Release of conforming (unadulterated) products.
• Manufacturing consistency and process improvement.
• Reduced company liability and regulatory risk.
  

Regulatory Requirements

When discussing pharma product release and finished drug products that are intended for sale, marketing, or distribution in the United States we first need to look at the Code of Federal Regulations (CFR or eCFR.) In the U.S., drug products are required to follow current Good Manufacturing Practices (cGMPs). GMPs are not optional. Products that do not comply with the cGMPS are considered “adulterated” and are subject to regulatory actions and other consequences.

Two important sets of regulations include:

• FDA Title 21, Part 210 CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PROCESSING, PACKING, OR HOLDING OF DRUGS; GENERAL.
• FDA Title 21, Part 211 CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS.

The regulations in 21 CFR Part 211 contain the minimum current good manufacturing practice for preparation of drug products (excluding positron emission tomography drugs) for administration to humans or animals, while 21 CFR Part 210 covers drug substances. These cGMP regulations apply to drugs that are also biological products for human use, and they are applicable to drugs that are also human cells, tissues, and cellular and tissue-based products (HCT/Ps).

The FDA Code of Federal Regulations defines specific requirements for the manufacture, testing, holding, and release of drugs and drug products. For example:

• Product Testing: Sec. 211.165 Testing and release for distribution.
• Packing and Label Inspection: Sec. 211.134 Drug product inspection.
• Quality Review: Sec. 211.22 Responsibilities of quality control unit.
• Batch Records: Sec. 211.188 Batch production and control records. (See also § 211.186 Master production and control records.)
• Production Record Review: Sec. 211.192 Production record review.
• In-Process Testing Required: Sec. 211.110 Sampling and testing of in-process materials and drug products.

Data Supporting Pharma Product Release

Gathering data to establish the product release processes begins early in development. The data and quality records that are needed to support final pharma product release come from across the organization. The pharma product release process will impact almost every department with a GMP function. This will include facilities, maintenance, receiving, purchasing, testing laboratories, warehouse and storage, cleaning and sterility, gowning, training, component acceptance, drug substance information, manufacturing, quality investigations, in-process testing, and final release testing and inspection. Some mistakenly think that the quality department is responsible for product release, but quality is actually relying on good GMP data from multiple departments across the company. Quality will work with the organization to establish the specifications against which product release occurs as well as review the final data and records at the completion of a given batch.

Summary: Comprehensive Batch Review Is Needed

Pharma product release is a comprehensive review process beyond simply signing off on executed batch records or SOPs. Pharma product release reviews all of the manufacturing and quality records in context to determine if there are nonconformances or potential for unintended product impact. Pharma product release evaluates component quality, in-process testing, manufacturing processes, product sampling, equipment, software, instrumentation used, personnel, storage and holding, packaging, labeling, and release testing of a drug product. It is important to consider the product release process during development of a drug product to ensure appropriate specifications are set for the release. Beyond the quality records, specifications, and documentation, companies need to remember to focus on drug safety and efficacy. The culmination of quality records and executed production batch records tells the story of a particular batch of product. It is up to the pharma product release process to determine if the batch is acceptable for release and to ensure adherence to company and FDA requirements.

The second part of this two-part series will cover optimizing the product release process in pharma manufacturing.