Process Validation: Working Toward Harmonization Of Terms Used To Identify Validation Lots

By Humberto Vega, Ph.D., former global head MS&T at JnJ and BMS; Robert Dream, Nivagen Pharmaceuticals, Inc.; and Igor Gorsky, Valsource

Process validation spans three stages during its continuum – process design (Stage 1), qualification (Stage 2), and continued verification (Stage 3) – to ensure consistent product quality throughout its life cycle. This paper reviews the lexicon the industry currently uses when referring to those lots or batches manufactured as part of process validation activities.

The terms “confirmatory and conformance batches” seem to be inconsistently used in the industry and may require definition, recommendations on their use, or a recommendation to remove them from the pharmaceutical process validation lexicon to prevent confusion. Keep in mind that process validation is a continuous, data-driven process — not a one-time event — essential for maintaining compliance, detecting variability, and ensuring patient safety. Therefore, harmonization of the terms to avoid confusion is strongly recommended.

Regulatory And Industry Guidance

The general concept of process validation (PV) is similar across health authorities and the pharmaceutical industry. Nevertheless, some specific terms may vary, but the concepts underlying the definitions are similar.

U.S. FDA Process Validation Guidance: “Conformance to specification”

In 1987, process validation was defined as “establishing documented evidence which provides a high degree of a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.”

The definition of process performance qualification was “establishing confidence that the process is effective and reproducible.”

Product performance qualification was defined as “establishing confidence through appropriate testing that the finished product produced by a specified process(es) meets all release requirements for functionality and safety”.

The FDA clarified its definition of PV in its 2011 revision of PV guidance¹ as “the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products.” Also according to this FDA guidance, during the process performance qualification (PPQ) stage, as well as the continued process verification stage “studies… must conform to cGMPs and must be approved by the quality unit in accordance with the regulations studies.” Thus, the batches may be called conformance batches or PPQ batches by some, and “a successful PPQ will confirm the process design and demonstrate that the commercial manufacturing process performs as expected.”

USP: “Conformance to specifications”

In the context of the United States Pharmacopeia (USP), "conformance to specification" means that a drug substance or product meets all the requirements outlined in its USP monograph and General Notices. These specifications, which include tests, analytical procedures, and acceptance criteria, are designed to ensure the drug's identity, strength, purity, and overall quality.

Process transfer: Transfer of technology is defined as “a logical procedure that controls the transfer of any process together with its documentation and professional expertise between development and manufacture or between manufacture sites.”² Typically, “confirmatory batches” confirm that the process, as defined in the master batch record, can be successfully executed in the new site.

EU GMP Annex 15³ defines PV as “documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medical product meeting its predetermined specifications and quality attributes.”

Health Canada’s Pharmaceutical Validation Guide mirrors this concept: In Phase 2 (PPQ), batches must be manufactured at commercial scale “to confirm that the commercial-scale manufacturing process… consistently produces product meeting its critical quality attributes.”

EMA Annex 15 Qualification and Validation uses the word “confirm” 16 times, mainly to confirm specifications, requirements, settings, and, finally, reproducibility of the process.

FDA Process Validation 2011 uses the word “confirm” seven times in a similar but more frugal way, mainly as demonstrated in the following statement prior to Stage 2 – Qualification:

“The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next stage for confirmation.”

Health Canada⁴ uses the word “confirm” even less: four times in the same capacity as EMA and FDA.

How Is Industry Using The Terms?

PV is a set of activities required for a comprehensive consolidation of data supporting the design of a product and manufacturing process, qualification of the manufacturing process, and continued monitoring of the manufacturing activities during the life of the product. In the past, PV was mainly used to highlight the execution of a validation protocol while qualifying the process. Later, the definition and scope of the term PV progressed to capture now three key stages that are adopted across regulatory organizations and the industry as the scientific- and risk-based approach.  

It should be noted that confusion in nomenclature may occur before we are ready to run PPQ batches. Typically, manufacturers will run several batches to gain extra knowledge about the equipment and the process/product and generate data that can be useful to integrate the main PPQ approach. This is important to provide additional confidence in the process before commercialization, which occurs at PPQ batches.

The following are examples of these pre-PPQ batches and their names that authors comprising the Industry Leading Volunteer Organization Process Validation Interest Group gathered from different industry sources:

• Water runs
• Placebo runs
• Integrated performance qualification runs
• Scale-up runs
• Engineering batches
• Clinical trial batches
• Registration stability batches
• Demo batches

There could be many more; we don’t claim this list of terms is complete. Different companies may be using different ones. Those batches/lots/runs could have variable approaches in terms of batch size, duration, extent, application of quality systems, etc., and be performed for different purposes.

However, it is important not to confuse those terms with the “real PPQ/PV batches,” which ultimately have to meet the acceptance criteria stated in the PPQ/PV protocol.

Sometimes the term “confirmatory” could be used for some of those types of batches, and our caution is that practitioners should assure that “confirmatory” batches are NOT mixed up with the “real PPQ batches.”

The goal of the PV runs is to assess process variability. It is not just the goal of satisfying the regulatory expectation of validation runs supporting a filing or process changes. It is the data collection for documented evidence that the process variability associated with raw material attributes, equipment performance, and personnel techniques, and environmental conditions are narrow enough to result in consistent product quality that meets preset specifications. Therefore, understanding process variability is essential for the robust knowledge of how a process performs under real-world commercial conditions. The goal of PV is to understand, quantify, and control the variability rather than eliminating it. This links to the terms “conformance” and “confirmatory” when results are compared vs. the acceptance criteria and specifications during the process performance qualification (Stage 2). Variability is addressed through appropriately designed sampling plans and the execution of multiple validation runs under normal operating conditions and statistical comparison to the historical data.

Defining the number of lots and sampling plans for PV is a risk-based decision guided by scientific rationale, regulatory expectations, and product complexity. The industry’s historical standard that is typically accepted by regulatory bodies (e.g., FDA, EMA, WHO, etc.) is a minimum of three consecutive commercial-scale PPQ batches produced under normal operating conditions to demonstrate process consistency and control. Nevertheless, the practice is not a regulatory requirement. In cases where robust platform knowledge exists, a smaller number of lots may be used given that strong supporting data is available. However, be prepared to justify your decision first to yourselves and then to regulators. Remember, it is you who will have to justify your decisions to provide the best quality product to the patients. The number of PPQ runs and the extent of sampling must be scientifically justified, documented in the validation protocol, and agreed upon by all cross-functional stakeholders (e.g., QA, MS&T, and RA).

Analysis And Recommendations From The Process Validation Interest Group

The topics discussed in this article were further discussed at a recent Process Validation Interest Group meeting and some of the key points are listed below. These points and the group’s opinions may reflect on industry’s current principles and practices. Some of these practices the authors agree with and the others they wish to discuss further in light of what already was shared.

1. All participants agreed that the industry should refrain from using the term “confirmatory batch.” We feel this is a good practice that will promote consistency and avoid confusion.

2. One of the participants suggested the site process validation master plans should include a glossary of terminology to define the firm’s terms for qualification and validation tasks to assure formal definition and their consistent use. The authors recommend going a bit further to develop a firm-wide living document that would house the glossary of all terms and abbreviations used in manufacturing, packaging, testing, storage, and distribution of the products. This will be a useful document that would help practitioners to use terms based on regulatory and industry accepted definitions, as well as include terms specifically utilized in the given firm, as it is a typical practice.

3. The participants also discussed current use of the term “confirmatory batch.” Two examples were brought up:

a. It is either the first batch during a technology transfer project or

b. a single lot PPQ batch due to a change in the life cycle that may be sufficient to confirm continued state of control in which an extensive PPQ study with additional batches may not be needed.

4. One of the participants, a former FDA reviewer, shared an opinion that whatever the firm calls these kinds of batches, the regulatory reviewer or inspector needs to understand what the term means. This reinforces the point that a firm-wide glossary document/procedure would be a useful tool for everyone.

5. Finally, one of the participants stated that “the biggest mistake is to validate the change in the product life cycle with only one PPQ batch followed by some confirmatory batches.” Furthermore, the participant felt that the firms should be doing multiple lot PPQ exercises. This opinion seems to be based on a fear that the firm did not do enough to prove or confirm consistency of the process that yields safe, pure, and effective products.

As we have discussed in this article, the decision to make one batch or more batches should lay in the preponderance of knowledge attained in pharmaceutical development, technology transfer, and qualification of the process as intended by FDA’s GMP for the 21^st Century initiative launched about 20 years ago. The initiative was intended to shift from traditional compliance to quality systems, incorporating elements like training, facility design, equipment, processes, and controls throughout the manufacturing process using science, process knowledge, and risk-based approaches. We should continue educating the practitioners across the industry on this, as doing more does not mean better compliance.

Conclusion

The industry uses all kinds of terms and expects people to know what they mean, when the industry has no clear definition of what they are and, moreover, has contradictory meanings for those terms. These authors feel it is important to discuss terms and what those terms mean to different people. For instance, when practitioners are talking about “conformance or confirmatory batches,” do they have different meanings as to what those batches could be? Therefore, should we continue using these “internal” terms or call activities what they are, such as scale-up, technology transfer, engineering, demonstration, stability (although a separate stability batch that is different from a validation batch may indicate a deficiency in planning), process performance qualification, and continued process verification?

The authors recommend eliminating the use of terms that could mean different activities and name activities for what they are to prevent confusion, especially if this confusion arises from regulatory inspections.

Process validation is no longer a one-time compliance task — it is a continuous, data-driven commitment to quality. As the industry and the regulatory environment evolve, driven by novel modalities and therapies, PV must also harmonize terms to avoid confusion while keeping pace with industry.

Peer reviewed by Harold S. Baseman, Valsource.

References

1. U.S. Food and Drug Administration (FDA), Guidance for Industry Process Validation: General Principles and Practices, Office of Communications, Silver Spring, MD, January 2011, available from: https://www.fda.gov.
2. World Health Organization (WHO) Technical Report Series, No. 961, Annex 7 WHO guidelines on transfer of technology in pharmaceutical manufacturing, 2011.
3. European Medicines Agency Quality, Safety and Efficacy EudraLex Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Annex 15: Qualification and Validation, Brussels, 30 March 2015
4. Health Canada Guide to validation – drugs and supporting activities (GUI-0029)

About The Authors:

Most of the authors of this article are the principal leaders of the currently in review Technical Report on Process Validation Lifecycle Approach revision. The combined experience of the authors includes traditional pharmaceuticals and novel therapies (e.g., sterile and non-sterile drug products, biologics, cell therapies, and medical devices) with over 100 years in the industry while leading manufacturing operations, quality, and science & technology functions, among others.

Humberto Vega-Mercado’s 37 years of experience span traditional pharmaceuticals (vaccines: solid and sterile dosage forms), food processes, and next-generation platforms (gene and cell therapies) to support introduction of new methods and optimize existing products. As global head of MS&T at Johnson & Johnson, he facilitated the technology transfers, validations, and commercial launches of three cell therapies (Abecma, Breyanzi, and Carvykti) as well as associated vector manufacturing processes in the USA and EU. In previous roles, he facilitated the validation and commercial launches of vaccines (Gardasil, Rotavirus, Varivax) as well as generics drugs (Enoxaparin, Metformin, and more). He holds B.S. and M.S. degrees in chemical engineering from the University of Puerto Rico and a Ph.D. in engineering science from Washington State University. He is a member of PDA, ISPE, and AIChE.

Robert Dream has over 30 years of experience in the life sciences sector, including executive leadership roles. He has successfully led projects, optimized processes, and scaled products by leveraging operational excellence and deep technological expertise. Business-minded and strategically focused, he has functional knowledge across manufacturing, supply chain, and regulatory domains. His background includes senior executive experience in therapeutic biotechnology and biological product manufacturing. He has authored numerous guidances. Dream is a licensed Professional Engineer and an active member of ISPE and PDA. He also serves on the Editorial Advisory Boards of Pharmaceutical Processing, Pharmaceutical Engineering, Pharmaceutical Technology, Pharmaceutical Manufacturing, and the INTERPHEX Advisory Council.

Igor Gorsky is a principal consultant at Valsource and has been a pharmaceutical industry professional for over 40 years. His prior positions were in quality, manufacturing and validation management at Alpharma, Wyeth, and Shire. He is an author and a co-author of over 40 articles and two books on various topics in pharmaceutical technology, validation, quality, and compliance. He is a member of ASTM E55 Executive Committee and a PDA Pharmaceutical Interest Group Leader. Gorsky was also a leader of the current revision of ASTM E2500-25 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment Science and Risk Based Approach, as well as co-author of multiple ASTM, ISO, and PDA standards and technical reports.