A Change in the US Food and Drug Administration Opinion on Process Validation: What has Changed?

Printable Version

A Change in the US Food and Drug Administration Opinion on Process Validation: What has Changed?

Dates on Documents: 1987; 1990; and 2011

Title

First, the title has changed from ''Guideline on General Principles of Process Validation'' to ''Process Validation: General Principles and Practices''. From my experience with validation and Food and Drug Administration, the latter title implies a more through understanding of process validation.

 

I. Introduction versus Purpose, Scope and Introduction

Process Validation: General Principles and Practices emphasizes the alignment of validation activities with product lifecycle concept and existing US Food and Drug Administration documents. (1) As for lifecycle concept, it is a link of product and process development, qualification of commercial manufacturing processes, which refers to a manufacturing process resulting in commercial product (a drug that is marketed, distributed, and sold or intended to be sold and NOT clinical trial or treatment IND material), and maintenance of the process in a state of control during routine commercial production.

In contrast to the older document, Process Validation: General Principles and Practices excludes Medical Devices and it is more specific with respect to definition of drugs. (2) According to Drugs@FDA Glossary of Terms, a Drug is defined as: (4)

• A substance recognized by an official pharmacopeia or formulary; A substance intended for use in the diagnosis, cure mitigation, treatment, or prevention of disease; A substance (other than food) intended to affect the structure or any function of the body; A substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device; and Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process).

As the reader may notice, the FDA does not define pharmaceutical but does provide a definition for pharmaceutical equivalent at Drugs@FDA Glossary of Terms. (4) The older document used the term pharmaceuticals. The term of pharmaceutical is defined in a Memorandum of Understanding with Japan: (6)

• A pharmaceutical product means those products, including active ingredients, that are defined as "drugs for human use". As you can see, the latter terminology is used in Process Validation: General Principles and Practices.

Although the introduction of Process Validation: General Principles and Practices discusses human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), which is referred as drugs or products in the Process Validation: General Principles and Practices, it does NOT mention Medical Devices. In contrast, Guidelines on General Principles of Process Validation includes medical devices. Currently, Quality Management Systems-Process Validation, edition 2, which is available at http://www.ghtf.org/sg3/sg3-final.html, covers Medical Devices. Process Validation: General Principles and Practices specifically mentions that the document covers the following categories of drugs:

• Human drugs, Veterinary drugs, Biological and biotechnology products, Finished products and active pharmaceutical ingredients (API or drug substances), The drug constituent of a combination (drug and medical device) product, and validation of processes that include automated equipment in processing.

The guidance document Process Validation: General Principles and Practices, which was authored by the Division of Manufacturing and Product Quality, Center for Drug Evaluation and Research (CDER), CDER's Office of Pharmaceutical Sciences, Center for Biologics Evaluation and Research (CBER), Office of Regulatory Affairs (ORA), and the Center for Veterinary Medicine (CVM) at the Food and Drug Administration, does NOT cover:

• Type A medicated, Medical devices, Dietary supplements, Human tissues intended for transplantation regulated under section 361 of the Public Health Service act, and not specific information about validation of automated process control systems, which is referred as computer hardware and software interfaces.

II. Background

A. Process Validation and Drug Quality versus General Concepts

After a first reading, the newer document Process Validation: General Principles and Practices seems to emphasize more of a mathematical and modular way of thinking about the manufacturing process. One that concentrates on a dynamic lifecycle but utilizes a risk analysis approach based on statistical process control and design of experiments as a means to concentrate more thoroughly on certain sub-sections:

• Each step of a manufacturing process is controlled to assure that the finished product meets all quality attributes including specifications.

B. Approach to Process Validation versus General Concepts

In Process Validation: General Principles and Practices, the definition of process validation is more specific when considering collection and evaluation of data but more broad when considering the range of suggested data collection.

As a comparison, Process Validation: General Principles and Practices specifically mentions collection and evaluation of data from the process design stage, which is defined as the stage where past development and scale-up activities is used as a basis to define the commercial manufacturing process, through commercial production, which includes Process Qualification and Continued Process Verification. Although the older document discusses other periods, the stages are not as well defined. In addition, the US FDA also spends more time discussing evaluation prior to finished pharmaceuticals, and emphasizes that a successful validation program should:

• Understand the sources of variation; Detect the presence and degree of variation; Understand the impact of variation on the process and ultimately on product attributes; Control the variation in a manner commensurate with the risk it represents to the process and product.

The Process Validation: General Principles and Practices then states that a focus of qualification efforts does not ensure quality when one does not have an understanding of the manufacturing process.

III. Statutory and Regulatory Requirements for Process Validation versus GMP Regulation for Finished Pharmaceuticals

In this section, Process Validation: General Principles and Practices lists the importance of the Food and Drug Cosmetic Act, which is the basis for the regulations.

In fact, the FD&C Act definition for adulteration is given, and US Code of Federal Regulations, Chapter 21, Parts 210 and 211 are mentioned. The latter was also mentioned in the older document. The Process Validation: General Principles and Practices document and the older document quote Part 211.100(a), but designed to assure is emphasized in Process Validation: General Principles and Practices. I believe the reason for the emphasis is because the US FDA expects future consistent and rigorous statistical process control and design of experiments. In fact, Process Validation: General Principles and Practices emphasizes Part 211.110(a), Sampling and testing of in-process materials and drug products as well, which is quoted in the older document as well. In contrast, the older document does not specifically mention Parts 211.160(b)(3); 211.165(c) and (d), which provide greater emphasis on sampling plans and statistical confidence. Furthermore, Process Validation: General Principles and Practices discusses Parts 211.180(e), 211.24, 211.63, and 211.68, which are related to data analysis, equipment, facilities, and calibration/inspection of automated equipment, respectfully.

The older document refers to Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211 along with specific mentioning of Section 211.110 and 211.113, and discusses an understanding of research, but Process Validation: General Principles and Practices appears to provide guidance in a ordered format. More specifically, the older document discusses documentation of changes during development as a means to understand future problems, but Process Validation: General Principles and Practices, in my opinion, specifies the inclusion of development data during validation as a means to prove process consistency. According to Process Vailidation: General Principles and Practices, one needs to understand the manufacturing process and not just focus on validation as a means to reach quality product. The latter my be a hint that consultants and company experts need to "work" as a team during process validation. In addition, one may expect companies to become more dependent upon their own validation departments.

The section appears to concentrate on statistics and sampling, which implies the importance of appropriate statistical sampling and evaluation. When combined with the latter section, one can expect statistical analysis to cover a greater range of the product's lifecycle when considering process validation. In addition, the section provides more guidance on other Code of Federal Regulation parts, and seems to specifically concentrate on statistics, sampling and controls, and manufacturing environment. Once again, the latter, in my opinion, infers a future concentration on the development and manufacturing connection to process validation by FDA investigators during future inspections. A connection that will be codified by proper statistical sampling, data evaluation, and understanding of the manufacturing process.

IV. Recommendations versus Preliminary Considerations

A. General Considerations for Process Validation versus Preliminary Considerations

In many ways, a comparison of this area is difficult to accomplish because the organization of recommendations has changed, which, in my opinion, is the US FDA's means of conveying level of importance. I believe the main points of emphasis have changed from general discussions of possible critical areas, equipment and personnel, to the use of statistical control, Design of Experiments, and automated equipment as a means of reducing or eliminating negative impacts from critical components. In fact, Process Validation: General Principles and Practices emphasizes the following and I quote exactly:

• The term attribute(s) (e.g., quality, product, component) and parameter(s) (e.g., process, operating, and equipment) are not categorized with respect to criticality in this guidance. With a lifecycle approach to process validation that employs risk based decision making throughout that lifecycle, the perception of criticality as a continuum rather than a binary state is more useful. All attributes and parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the process and process output. In other words, a higher degree of control is appropriate for attributes or parameters that pose higher risk. The Agency recognizes that terminology usage can vary and expects that each manufacture will communicate the meaning and intent of its terminology and categorization to the Agency.

Although control is emphasized in both documents, Process Validation: General Principles and Practices seems to concentrate more on an omnipresent statistical control and organization. It is through such control that proper equipment will be purchased and implemented during scale-up operations within a proper environment. In comparison, it is similar to the ideology of measure twice and cut once within carpentry. As far as most statistical grouping requirements are concerned, one would expect a minimum of three measures but the rule is similar. In other words, it appears the FDA is emphasizing the importance of cross functional teams in the recording and verification throughout the lifecycle of the process, while utilizing statistical methods to eliminate and reduce variability.

B. Stage 1-Process Design versus Preliminary Considerations

Although the older document mentions research and development, Process Validation: General Principles and Practices has emphasized past data as important to a properly controlled and understood process.

As mentioned, early process design experiments do not need to be performed under CGMP conditions required for drugs that are manufactured during Stage 2 (process qualification) and Stage 3 (continued process verification), but it is recommended that they be conducted in accordance with sound scientific principles and good documentation practices, which is consistent with ICH Q10 Pharmaceutical Quality System. Process Validation: General Principles and Practices spends much time discussing how research and development data can and should be used to prepare for process validation. Like commissioning studies, the data can be, if organized and evaluated properly, used to reduce studies and process validation runs. In a nutshell, the US FDA is suggesting a ground-up plan and execution methodology.

The section of Establishing A Strategy for Process Control appears to be unique to Process Validation: General Principles and Practices. Although controls are discussed through-out the older document, a separate section was not used to highlight the importance of such methods. To be specific, Parts 211.110(c), 211.186(a) and 211.186(b)(9) were referenced. In addition, Process Validation: General Principles and Practices mentions process analytical technology, PAT, which I am partial to as a chemical engineer who suggested waveguides and artificial intelligence, process controls, as a process support engineer.

As a personal side note, I have a book on in-situ measurements, which is titled: Spectroscopy in Process Analysis Edited by John M. Chalmers. I also suggested the use of ionic solvents but that is another story! Waveguides are fiber optic material that can be engineered to react to environmental conditions of a process. In some cases, the diameter may expand with temperature, or the surface may be affected by a chemical derivative or pH. In the latter case, the imaginary portion of the refractive index may become important for measurement, which is a means I had suggested as a validation engineer working on test method characterization during a need to measure the thickness of bound protein on the surface of a polystyrene. At the time, they were using a generalized pan-cake method. In the latter case, a laser-diffraction particle sizer's ability to recognize a shift due to the imaginary portion of the Refractive Index could be used to create an effective index. I believe the latter are good examples of considering future process controls that will significantly reduce human bias, decrease cost, and increase efficacy of the product. I also believe the FDA suggests such technology when discussing Process Analytical Technology, PAT.

C. Stage 2-Process Qualification versus Elements of Process Validation

Most of the Process Validation: General Principles and Practices is similar to the older document, but Process Validation: General Principles and Practices appears to concentrate on risk analysis as a means of achieving suitable qualification. To be specific, the following were specified:

• The studies or tests to use; the criteria appropriate to access outcomes; the timing of qualifications activities; the responsibilities of relevant departments and the quality unit, and; the procedures for documenting and approving the qualification.

Strangely, Process Validation: General Principles and Practices does not mention the need to challenge the equipment beyond normal processing ranges. In other words, I did not read about worst-case scenarios, but the latter bullet may have inferred a need to state why one is not used. Although criticality has been replaced with risk analysis, a worse-case scenario may be apart of a risk analysis in some situations.

2. Process Performance Qualification versus Process: Performance Qualification

In these sections, Process Validation: General Principles and Practices concentrates on statistical process controls and development data once again, with an emphasis on broad manufacturing understanding of scale, and Process Validation: General Principles and Practices mentions that process design data, if obtained and evaluated appropriately, can be used to minimize scale and reduce the need to operate at the entire operating range of the commercial scale. In addition, Process Validation: General Principles and Practices strongly recommends that firms employ objective measures (e.g., statistical metrics) wherever feasible and meaningful to achieve adequate assurance. As with other sections, statistical process control and design of experiments are emphasized, and PAT is looked at positively.

3. and 4. PPQ Protocol versus c. Product: Performance Qualification

The older document only discusses PPQ's as they apply to medical devices. As such, Process Validation: General Principles and Practices will be quite different since it does not include guidance on medical devices. For this reason, I will review and see if the theme of statistical process controls and design of experiments are emphasized. As we know, the lifecycle principle with risk analysis was emphasized at the begining.

As expected, lifecycle understanding, Code of Federal Regulations, training, statistical process controls, design of experiments, and risk analysis were emphasized.

D. Stage 3 - Continued Process versus System to Assure Timely Revalidation

Once again, Process Validation: General Principles and Practices specifies a need to have statistical process control in place to ensure lack of deviation from a controlled process. If a deviation does occur, means of detecting such deviations are essential for deciding if re-validation is needed. In addition, Process Validation: General Principles and Practices emphasizes a need to properly train personnel to evaluate trends for elements such as incoming quality of materials and random but continuous process sampling and evaluation. 21 Code of Federal Regulations Part 211.180(e) is referenced as well.

In contrast, the older document is more specific when mentioning revalidation requirements. On the other hand, Process Validation: General Principles and Practices refers to similar in other sections. As an example, the older document specifically requires revalidation if packaging, formulation, equipment, etc.

V. Concurrenet Release of PPQ Batches

Process Validation: General Principles and Practices mentions the need for high degree of assurance in the process before transitioning to commercial distribution. Remember, there is a new emphasis on lifecycle and risk analysis so, if gathered and evaluated appropriately, all past data can be used to prove a high degree of assurance. This section also discusses when PPQ batches can be released.

VI. Documentation versus Documentation

Process Validation: General Principles and Practices provides more guidance on documentation, and emphasizes the lifecycle. Organization is emphasized as well with a need to connect different parts of the lifecycle to create a dynamically controlled risk-analyis project that provides continuous positive and negative feed-back loops. Specifically, Process Validation: General Principles and Practices mentions:

• Documentation is important so that knowledge gained about product and process is accessble and comprehensible to others involved in each stage of the lifecycle. Information transparency and accessibility are fundamental tenets of the scientific method. They are also essential to enabling organizational units responsible and accountable for the process to make informed, science-based decisions that ultimately support release of a product to commerce.

It appears that Process Validation: General Principles and Practices provides more guidance on the use of documentation to show a dynamically controlled lifecycle.

VII. Analytical Methodology

Once again, Process Validation: General Principles and Practices emphasizes the need for a means to gather and evaluate data through design of experiments or statistical process control. Although there is no need to have validated methods for research, development, or characterization data, sound scientific principles are emphasized when collection of data occurs.

As a final statement, Process Validation: General Principles and Practices provides a useful glossary at the end of the document.

A Personal Comment

When I worked as a validation engineer, I believed pharmaceutical validation was similar to Six Sigma from the electronics industry, and I was interested with the idea of incorporating more six-sigma principles. In fact, I discussed the implementation of waveguides as a Process Support Engineer, which allowed in-situ control and elimination of human bias. Personally, I believe the pharmaceutical industry is in a position to advance six-sigma's statistical methods when considering human bias.

It appears that the US FDA is looking towards more in-situ measurements as well. Currently, the means of obtaining such measurements involves much human bias. As such, an actual plan to implement six sigma within the pharmaceutical industry may actually improve the methodology of six sigma itself since it was born from an industry with much robotic control. In other words, I would expect more statistical methods that consider human bias.

In a nutshell, I believe the FDA is moving Process Validation towards a pseudo six-sigma evaluation. In such evaluations, one may expect a switch between customer and developer when considering the relationship between validation consultants and corporate experts. Instead of the consultants providing a questionnaire about targets that allow costumer satisfaction, the company experts may provide the questionnaire as a means to select consultants. In my opinion, consultants may want to develop individual niches within teams. A chemical engineer for processes that involve chemistry and process control, a mechanical engineer that better understands the stress and strain relationships of bottles on a fill line, an electrical engineer that understands PLC and specific element process controls, and a combination of people, cross functional team that contains scientist, operators and planners, that can analyze the non-newtonian biological fluid with reactivity and is being filled on a glass-vial fill line.

References:

1. United States Food and Drug Administration. Process Validation: General Principles and Practices, 2011. FDA[online]. 2011. Available from: Document.

2. United States Food and Drug Administration. Guideline on General Principles of Process Validation, 1990. Biologics Consulting Group[online]. 2011. Available from: Document. Has been replaced by (1).

3. United States Food and Drug Administration. Drugs. Compliance & Regulatory Information. Guidances (Drugs). FDA[online]. 2011. Available from: Guidances.

4. United States Food and Drug Administration. druginfo@fda.hhs.gov. FDA[online]. 2011. Available from: Glossary of Terms.

5. United States Food and Drug Administration. CFR-Code of Federal Regulations Title 21. FDA[online]. 2011. Available from: CFR.

6. United States Food and Drug Administration. Memorandum of Understanding: U.S., FDA-Japan, 2000. FDA[online]. 2011. Available from: Letter.