Patricia Santos-Serrao, RAC, is the market segment manager of global pharmaceutical, blood, and biologics at MasterControl, info@mastercontrol.com.

Patricia Santos-Serrao

Process validation is more than just running three consecutive batches under manufacturing protocol and assessing the results (1). As defined in FDA’s 

Guidance for Industry, Process Validation: General Principles and Practices 

(2), process validation is 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 product,” clearly constituting a much more comprehensive, ongoing effort than final batch testing alone.

	In pharmaceutical development and manufacturing, the lifecycle of a drug or product spans years and often involves enormous amounts of change in every aspect of development, including materials, equipment, facilities, methods, specifications, contractors/vendors, and personnel. Formal process validation typically becomes of concern only when a product is about to enter the commercial market, when it can be difficult to produce the necessary data and information from years of development, especially for companies that use a paper-based or piecemeal document management system.

	This article focuses on the collection and evaluation of data part of FDA’s definition of process validation. In particular, it discusses how documentation is crucial to process validation, and how a document management system that supports good documentation practices can help pharmaceutical manufacturers manage the vast amount of information generated as a drug or product moves from being just an idea to reaching the commercial market, ultimately expediting a product’s time to market.


	Process validation can be considered a collective term for critical disciplines like quality assurance, change management, and risk management/mitigation, which take place throughout the product lifecycle. As FDA’s guidance on process validation suggests, process validation is relevant and necessary throughout all stages of pharmaceutical development. It is the manufacturer’s responsibility to understand and demonstrate--through documented evidence--that its manufacturing process consistently produces a result or product meeting its intended quality attributes and predetermined specifications (3).

	Developing a process validation strategy early in the product lifecycle will help manufacturers focus their documentation, and thus their process validation efforts, by identifying the exact processes to be validated. These processes are typically those that are most crucial to the final manufactured product, determined by performing risk assessments, then closely monitoring them. While the strategy is not required to be contained in a validation master plan (VMP), a best practice is to document decisions made along the way and outline the plan for processes that will need to be validated.

	Process validation strategies will look different to each company, depending on size, type of products, outsourcing activities, and level of in-house knowledge and expertise in the area of process validation. All companies should consider a lifecycle approach to process validation, which entails strategy planning already during the early phases of process design followed by continuous reevaluation of the plan throughout the lifecycle of the product. Smaller entities that plan to eventually market a product or -compound--even if they do not perform all of the activities in the product lifecycle in-house--are still held responsible for process validation and must ensure that their plan is being executed.


	While the guidance document on process validation is not legally enforceable, its ultimate objective is shared by FDA regulations describing cGMP in 21 Code of Federal Regulations (CFR) Parts 210 and 211 (4). Among numerous other references throughout the rules, the basis for process validation is first established in §211.100(a), which states, “there shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.” Another important topic addressed in the rules is managing and documenting change, which is of great importance in process validation and a familiar challenge for pharmaceutical manufacturers.  

	In particular, production scale-up poses unique challenges for manufacturing companies of all sizes. When a drug or product is in the initial R&D phase, it is unknown whether it will become a commercial product. Through each phase of scale-up, the complexity of the project increases, as does the amount of data produced. Documentation requirements also become more formal and demanding. During process validation, it is often discovered that supporting documentation for a manufacturing process tends to be diffuse. Sometimes, documents such as batch records are saved in a different format, or in a different repository; document versioning can also be an issue. A major effort may be required to reconcile the documentation required to satisfy process validation requirements and regulatory submissions, assuming the documentation exists.

	The need for good documentation is obvious, but there are many methods of collecting and storing documentation. While many companies still use paper-based or hybrid systems, quality and regulatory experts--along with professionals in the field--will agree that electronic document management systems (EDMS) are much more reliable, configurable, and can provide the type of transparency and accessibility needed to inform business decisions made at the highest levels of management. A good EDMS should address the following challenges:

	Document control--An electronic system should automate routing, delivery, escalation, and approval of documents. It also should accommodate documents generated by any software system and feature a centralized repository for easy document retrieval during process validation and regulatory submission. An EDMS also should connect all quality subsystems like corrective action and preventive action (CAPA), change management, audit, and training.

	Document revision control--In a paper-based system or hybrid system, employees check out documents and other materials (e.g., engineering drawings, etc.) manually. Tracking down any document activity can be difficult. An electronic system should ensure that only the current version of a document is available at a given time.

	Complex document control lifecycle--Each company has a different product lifecycle, but not all document management systems can model complicated workflows and routing. A good electronic system should allow for multiple lifecycle statuses, timed lifecycle movement, and flexible approval rules.

	Reporting--An EDMS should offer advanced analytics and reporting to provide a real-time view of quality processes and allow proactive decision-making to improve quality systems and processes.


	Pharmaceutical industry guidelines that address process validation--from FDA and the European Medicines Agency (5) to the International Conference on Harmonization’s Q10 (6), and others--echo the sentiment that process validation is a science- and a risk-based approach to continuous improvement at each stage of the product lifecycle. It is up to each manufacturer to conduct process validation, initially to ensure a given process consistently delivers the level of quality that it was intended and designed to in preparation for scale-up, and ultimately to satisfy FDA’s cGMP requirements in regulatory submission for product commercialization. Good documentation practices are necessary to establish and maintain control over manufacturing processes, to facilitate regulatory submission writing, and to support pre-approval inspection. But while there are various methods of creating and maintaining documentation, an automated document management system can expedite process validation activities and help companies avoid costly inaccuracies and the need to repeat required and supporting activities from any stage of the product lifecycle. It can assist all stakeholders in the product lifecycle, from the chemist in the laboratory to senior management, in their ability to access information and interpret it, as opposed to sorting through disparate and diffuse information. A good system allows companies to focus their efforts on the end goal of accelerating time to market.

Guidance for Industry, Process Validation: General Principles and Practices

Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 

, Title 21 Food and Drugs Part 210 and 211.
	5. EMA, 

Guideline On Process Validation For Finished Products-Information And Data To Be Provided In Regulatory Submissions

:
	When referring to this article, please cite it as P. Santos-Serrao, "Reducing the Documentation Burden in Process Validation," 

Articles

The author discusses the collection and evaluation of data part of FDA’s definition of process validation.