A production process is only as good as its development. Although this statement may seem cliché, it is particularly significant for the manufacture of pharmaceuticals, especially sterile injectables.

At the beginning of the product development, the application area of the new drug or combination product, and the resulting requirements for the medication, are defined. This quality target product profile includes such aspects as dosage form, concentration or required dose, physical properties or requirements for the closure system, and stability.

Once these aspects are clarified, the necessary quality attributes for the new product need to be derived. Known as critical quality attributes (CQA), these include all physical, chemical, or (micro-)biological properties that ensure the desired product quality. Specifications of these parameters must be strictly adhered to, which is achieved through appropriate manufacturing processes.

This is where process development comes into play, with the task of determining which process parameters are necessary to maintain the desired CQAs within their specified range. The process must be robustly developed, meaning that small variations during production in raw materials, packaging materials, or other parameters still lead to the desired outcome. These parameters are also known as critical process parameters (CPPs), which directly influence the CQAs of the product.

One might argue that after process development, only process validation remains, when it is demonstrated, for example through three batches, that the process leads to the desired outcome. If the process validation with the established parameters is successfully completed, the process is approved for commercial production, and the produced batches are controlled through appropriate release parameters. But this is only one-half of the truth.

Both United States and European regulations require that process validation consist of three phases: the mentioned phases of process development and process validation (process performance qualification) and the third phase of continued process verification (CPV, US) or ongoing process verification (OPV, European Union).

The FDA Guidance for Industry from 2011 describes this as follows (1): “The goal of the third validation stage is continual assurance that the process remains in a state of control, also known as the validated state, during commercial manufacture.

“Continued process verification must allow detection of undesired process variability to enable manufacturers to spot any potential problems with the aim to correct or improve the production process. In an effort to maintain quality standards and keep the process in a state of control, CPV must effectively collect and analyze product and process data. This data should be analyzed statistically by relevant personnel and outcomes must point to an appropriate control strategy.”

Formulations in Annex 15 of the EU good manufacturing practice (GMP) guideline (2) read similarly and outline that manufacturers are responsible for monitoring product quality to support a continued state of control over the course of the product’s full lifecycle. Similarly, the process verification itself must be reviewed and modified as needed based on its performance. Above all, OPV must operate based on a pre-approved protocol with adequate documentation to enable a full understanding of its effectiveness and consistency.

Behind these terms lies the expectation that processes are regularly monitored and evaluated throughout their lifecycle. How this should be done is clearly specified. Whenever possible and sensible, statistical methods should be used to evaluate the process parameters relevant for the product’s manufacturing process. This evaluation aims to detect negative process developments or trends early, before severe deviations occur in the manufacturing or filling and CQAs are no longer met. Which parameters need to be monitored again results from process development—namely the CPPs, as they determine or influence the later product quality. To evaluate the data, several prerequisites are necessary:

an appropriate control strategy for these CPPs and corresponding data collection

an appropriate statistical method for detecting and evaluating trends

Philip Hoersch is Director, Quality Assurance, Process Performance & System Compliance, Vetter.

BioPharm International®/Pharmaceutical Technology®/Pharmaceutical Technology® Europe

When referring to this article, please cite it as Hoersch, P. Continued Process Verification Is Critical in Pharmaceutical Manufacturing. 

BioPharm International®/Pharmaceutical Technology®/Pharmaceutical Technology® Europe 

Articles

Effective pharmaceutical manufacturing, particularly for sterile injectables, hinges on robust process development and validation. Initial product development defines the quality target product profile, including dosage and stability. Critical quality attributes (CQAs) are derived, necessitating strict adherence to specifications through manufacturing processes. Process development identifies critical process parameters (CPPs) to maintain CQAs. Regulatory guidelines from the US and EU mandate a three-phase process validation: development, performance qualification, and continued process verification (CPV/OPV). CPV/OPV ensures ongoing control, requiring statistical analysis to detect and address process variability.

Continued process verification ensures pharmaceutical manufacturing stays in control through data analysis, trend detection, and lifecycle monitoring.

Continued Process Verification Is Critical in Pharmaceutical Manufacturing

A specification as previously defined is a list of tests, references to analytical procedures, and appropriate acceptance criteria (1). The specification establishes the methodology to be applied and the corresponding acceptance criteria to which a drug substance or drug product must conform to be considered acceptable for its intended use. Conformance to specifications means that the drug substance and/or drug product meets the specified acceptance criteria when tested following the test procedure contained within the specification. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by regulatory authorities as conditions of market authorization. Specifications are foundational to a robust control strategy for all components of a finished dosage form. In this article, the authors consider both the method and acceptance criteria components of the specification.

Methods included in the specification must be validated and/or verified as described in current regulatory and compendial guidance documents. Methods are either used for release testing purposes or to detect changes in quality attributes over time (i.e., for stability testing). Also, as noted in the previous paper (1), if compendial methods for compendial articles are not used, the in-house method is defined as an alternate method to the official method per the regulations.

Various regulations are applicable when establishing method equivalency, including those from health authorities, compendial standards, and the International Council for Harmonisation (ICH) standards. The ICH Q2 document (2) describes the specifics regarding analytical method validation requirements, and the complementary ICH Q14 (3) describes the scientific and risk-based approaches for analytical procedure development and maintenance. It is critical to develop and validate an analytical method that is fit for purpose, which makes it vital to understand the intended use of the method prior to initiating any work. The intended use of a method is typically described in an analytical target profile (ATP). The ATP provides the basis for the required method development and subsequent method validation parameters per ICH Q2.

An option during method development is to define the method operable design regions (MODRs), which is a type of quality by design (QbD) for methods. Defining a MODR provides flexibility in an individual method, such that the operating ranges provided in the method are larger than the standard single points. Methods compared with a MODR cannot be theoretically compared unless there is overlap in their MODR design space. If there is no overlap in design space, an experimental equivalence study must be performed.

Methods may be developed internally or obtained from external sources, such as compendial monographs or other vendors/suppliers. During the lifecycle of a material, there will be method changes for any number of reasons, such as manufacturing changes, discontinuation of technology, automation introduction, and method modernization. The significance of the changes to the method and a review of the approved marketing authorization filing by the relevant health authorities must be considered. A change that impacts the method in the approved marketing dossier must be submitted to the health authorities for some level of approval prior to implementation.

Any changes to internal documents, whether or not they impact the filed dossier, must be managed under a change control process, required of each company as part of good manufacturing practices (GMPs). The change control process must include a step for the company’s regulatory department to review the changes and determine the impact, if any, to the filed dossier(s). If there is an impact to the filed dossier(s), the company’s regulatory department must submit the method to the relevant health authorities, and there must be a hold on implementation of the new method until the required filings are completed and approvals granted. During this process, the change(s) to the method will be reviewed and approved by the relevant health authorities. As part of this review, the reviewers may evaluate how the equivalency or superiority of the new method was established relative to the originally approved method.

Equivalency studies are performed to demonstrate that results generated using either the original analytical method or the proposed modified method, alternative method, or fully new method, yield insignificant differences in accuracy and precision, meaning that equivalent results are produced using either analytical procedure, and the same accept or reject decision is reached. 

) <1010> (4) presents numerous methods and statistical tools to design, execute, and evaluate equivalency protocols and data generated in these protocols. While the chapter is a valuable educational tool, it requires a proficient understanding of statistics to apply it well and, in many cases, may be more than is required in typical pharmaceutical analytical laboratories. With a deep knowledge of the methods being evaluated and the material or product being tested, basic statistical tools (e.g., mean, standard deviation, pooled standard deviation, evaluation of data generated against historical data, and comparison of data against approved specifications) may be sufficient to determine method equivalency or lack thereof. Equivalence of more complicated methods, such as methods that require the use of modeling will most likely require more sophisticated evaluation. Ultimately, the value in determining specification equivalence is the ability for a bio/pharmaceutical company to reduce analytical testing by choosing to perform one method to ensure compliance with other equivalent methods. If the methods under consideration are compendial, the outcome may be considered an internal or in-house harmonization of the various pharmacopoeial test methods.

Gail Reed is senior scientist with Johnson & Johnson; Joseph A. Albanese is the managing director and consultant with Albanese Consulting, LLC; Yelena Ionova is senior manager, Data Strategy and Analytics with Redica Systems; and J. Mark Wiggins is owner and compendial consultant with Global Pharmacopoeia Solutions, LLC.

When referring to this article, please cite it as Reed, G.; Albanese, J.A.; Ionova, Y.; and Wiggins, J. M. Specification Equivalence: A Practical Approach to Method and Acceptance Criteria Equivalence. 

Pharmaceutical Technology Quality and Regulations

Specifications are critical quality standards for drug substances and products, ensuring they meet acceptance criteria for intended use. Methods within specifications must be validated and fit for purpose, with flexibility provided by defining method operable design regions (MODRs). Changes to methods require regulatory approval and adherence to change control processes. Equivalency studies ensure modified methods yield equivalent results to original methods, facilitating internal harmonization and reducing analytical testing. Understanding statistical tools is essential for evaluating method equivalency, particularly for complex methods requiring sophisticated evaluation.

The authors propose a streamlined, efficient approach to determining specification equivalence that starts with a paper-based assessment of the methods and progresses to a data assessment for the methods under evaluation.

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Continued Process Verification Is Critical in Pharmaceutical Manufacturing

Specification Equivalence: A Practical Approach to Method and Acceptance Criteria Equivalence