Compliance Risk Management Using a Top-Down Validation Approach

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Pharmaceutical Technology, Pharmaceutical Technology-07-02-2008, Volume 32, Issue 7

Patient safety must be the primary concern of any validation effort. The author explains how a risk-based approach to validation and compliance follows naturally from this premise.

Validation has been an established fact of life within the pharmaceutical and healthcare industries since the mid-1970s. It has evolved from a poorly understood concept into a major source of difficulty for manufacturers. Initially conceived in response to specific sterility problems in the large-volume parenteral industry, it has morphed into a broad-based regulatory expectation for a myriad of activities.

David Joel/getty images

In the healthcare industry, the difficulties associated with validation have much to do with its origins. Validation in the pharmaceutical industry was imposed on the pharmaceutical industry by regulators as an appropriate means to establish the sterility of large-volume parenterals where the earlier control methods had proved inadequate (1). Because it was first associated with the preparation of sterile materials, validation has always been pursued with a near-absolutist mentality in all aspects. It has never been considered a valuable activity, likely because of its regulatory origins, but one that is largely associated with maintaining compliance.

Where did we go wrong?

Nearly every early validation effort was focused on sterilization and depyrogenation processes, and this focus continued to predominate until the 1990s. Real consideration of the need to validate pharmaceutical products with respect to their critical quality attributes did not begin until the US Food and Drug Administration began its preapproval-inspection program (2). This initiative brought attention to what had largely been missing in validation efforts previously.

What are the true objectives of validation in the broadest sense? The answer is rather simple: patient safety considerations must be the focus of validation activities. The sterility concerns of the 1970s might represent the most direct evidence of that focus, but other relevant patient-protection items must be addressed. Validation efforts must be properly defined and focused to the extent that they support patient needs. The value of validation diminishes markedly when it fails to focus on factors that clearly affect the patient's well-being. Excessive levels of documentation of systems with little link to the patient are all too commonplace. Risk, as it relates to how the validation effort should be shaped, has not been fully considered until quite recently (3, 4). The result is that costs are excessive, timelines are extended unnecessarily, and an entire industry is developed around preparing massive documents qualifying and validating increasingly irrelevant components of the overall manufacturing process.

An excellent example of this trend might be the delayed introduction of isolation technology into the US healthcare industry. Early implementation of the technology was hampered by efforts to eliminate leaks in the system, evaluate the microbial resistance on every substrate, sterilize the interior to a 1 in a million probability of a nonsterile unit, and other matters of little import. These endeavors wasted resources and greatly delayed the implementation of what is widely acknowledged to be a superior aseptic processing technology. These tasks were considered important for ensuring the sterility of the materials produced using isolators.

Although a degree of caution is always necessary, these concerns were clearly off target. Cleanrooms, which have never been sterile, have always leaked, and there are a myriad of substrates treated in a much less effective manner. In pursuit of the perfect isolator, firms lost sight of the real point: the substantial improvement in patient safety that isolation technology afforded. Isolators are inherently safer than cleanrooms and preferable in every way as an aseptic production technology. The hours spent on resolving these allegedly important issues delayed isolator implementation by nearly a decade. The perceived "problems" with isolators persist to this day, and FDA's 2004 aseptic processing guidance contains several misconceptions regarding isolators (5). Lack of awareness about how isolators benefited patients served no one's purposes.

Regulatory perspective

Globally, regulators understand their mission to be one of safeguarding patient health by ensuring that drugs are safe to administer. In the US, a steady evolution of drug regulation shaped the current environment in which the industry operates. The landmark events that resulted in the current good manufacturing practices (CGMPs) industry follows include:

  • Nostrums in the late 19th century that led to FDA's creation in 1906

  • Diethylene glycol erroneously used in drug products in the 1930s

  • Thalidomide administration to pregnant women outside the US in the 1950s

  • Large-volume parenteral sterility failures in the 1970s

  • Tylenol poisoning in the 1980s.

These incidents resulted in deaths and serious injury to patients. Specific regulations in the US and elsewhere were instituted to force conformance to basic canons of pharmaceutical GMPs. Globally, firms must adhere to a defined set of CGMPs that ensure product safety. These practices can be summarized by seeking the following characteristics in all development and production activities:

  • Safety—a drug does no harm to the patient

  • Purity—a drug is free of contamination

  • Efficacy—a drug works as intended

  • Identity—a drug is what its supposed to be

  • Strength—a drug is sufficiently potent.

These qualities are briefly stated in FDA's CGMPs:

... this chapter contain[s] the minimum current good manufacturing practice for methods to be used in, and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as to safety, and has the identity and strength and meets the quality and purity characteristics that it purports or is represented to possess (6).

If we focus our intention on those elements of pharmaceutical operations that directly affect those concerns and pay reduced attention to activities whose effect is less apparent, the validation activities will have true meaning and purpose and be inherently risk-based.

Addressing process and product validation properly

The product is the result of the process. The process exists only to make the product. The two are unalterably linked. We cannot speak of validating a process without evaluating the product, nor could we somehow support the efficacy of a product without knowledge of its underlying process. They exist in combination and must be evaluated in the same fashion. A product results from the process through the procedures applied to materials in a piece of equipment. In its simplest form, the product might be a single material such as an active pharmaceutical ingredient (API) transformed by a process such as sterilization, which, when filled into a suitable container, results in a parenteral dosage form. More commonly, the product is composed of many materials and undergoes several transformational processes before it is considered a drug product. The drug product can be considered the consequence of three primary elements:

  • Materials and components—the API, excipients, and its final product container

  • Batch records, standard operating procedures, and test methods—the instructions and practices that define the process steps and are the means for evaluating the product

  • Equipment and facilities—the mechanical systems that effect the material transformation.

The production of the drug product takes place in a CGMP environment under quality systems that provide the necessary controls to ensure the required quality attributes are attained (see Figure 1). The validation effort provides documented evidence of the controls' effectiveness.

Figure 1

To properly validate any product or process, we must focus on the critical quality attributes of the specific drug product and the parts of the overall system that directly affect those attributes. To the extent that a material, piece of equipment, process utility, control system, or operating procedure affects one or more of those critical attributes, it requires greater attention in the overall validation exercise. Treated in this manner, the validation effort is inherently risk-based.

An example product applying the top-down approach

A sterile dry powder is filled into vials without excipients for later reconstitution with a sterile diluent (see Figure 2). The API is gamma-irradiated in bulk before the aseptic fill. The validation effort must support the methods and practices that ensure the product's critical quality attributes.

Figure 2

In this example (and most others), it should be immediately evident that the various quality concerns will overlap to some extent. The critical quality attributes for this product (excluding the need for a sterile diluent, which should undergo a separate assessment) are:

  • Safety—sterility, endotoxin control, foreign matter, container-closure integrity, residual solvent

  • Purity—impurities, foreign matter, lack of cross-contamination

  • Efficacy—particle size, crystal morphology, weight control, shipping studies

  • Identity—chemical structure, labeling

  • Strength—potency, stability.

Each of these primary considerations must be defined to identify the individual qualification or validation activities required to support the quality attribute in total.

Product safety requires many studies, including:

  • Aseptic filling capability

  • Sterilization of bulk powder

  • Sterilization or depyrogenation of glass containers and rubber closures

  • Sterilization of product-contact equipment

  • Sterilization of utensils

  • Filling-isolator decontamination

  • Environmental monitoring of the isolator environment

  • Water for injection systems at API, and fill–finish facility (i.e., endotoxin control)

  • Cleaning of API equipment

  • Cleaning of fill–finish equipment

  • Cleaning of empty bulk containers

  • Cleaning of container or closure

  • Bulk-container integrity

  • Final product container-closure integrity

  • Shipping studies

  • Validation of API drying.

Product purity requires attention to:

  • Impurity profiles

  • API process validation

  • API equipment cleaning

  • Foreign-matter removal

  • Absence of cross-contamination from prior products

  • Cleaning validation for API

  • Cleaning validation for fill–finish equipment

  • Bulk-container preparation

  • Container preparation

  • Stopper washing

  • Vial washing.

Efficacy mandates attention to:

  • Particle size (i.e., crystallization process)

  • Crystal morphology

  • API process validation

  • Suitability with filling equipment

  • Weight control

  • Filling equipment qualification

  • Shipping studies

  • Effect of pressure, temperature, and relative humidity

  • Bulk-powder stability (pre and poststerilization)

  • Filled-container stability.

Identity addresses:

  • Chemical structure

  • API synthesis

  • Bulk labeling

  • Primary-container label

  • Product name

  • Dosage

  • Lot number

  • Expiration date

  • Barcode

  • Secondary-container labeling

  • Product name

  • Product insert.

Strength includes consideration of:

  • Potency

  • API synthesis

  • Bulk-package integrity

  • Final-package integrity

  • Storage conditions

  • Shipping conditions

  • Stability

  • Bulk material

  • Presterilization

  • Poststerilization

  • Finished goods.

Other concerns

The previous lists include the primary concerns. Others considerations include:

  • Stopper coreability

  • Stopper and glass siliconization

  • Stopper moisture content

  • Intermediate-package cleaning

  • Intermediate-package integrity

  • API facility environmental conditions

  • Fill-isolator integrity.

Analytical support to validation. To properly evaluate critical quality attributes, validated analytical methods are required. Validating a pharmaceutical process or product before the test methods used to evaluate it are validated severely limits the quality of the data and thus jeopardizes the entire effort. It is pointless to perform any analysis without being confident that the results can be considered reliable.

Sampling for microbial and foreign matter. Sampling methods can also play a major role in perceived and actual quality, especially as related to microbial and particulate (absence of foreign matter) quality. Taking a sample in these instances can harm the very property the sample is intended to evaluate. Sample procedures must be designed to avoid incidental contamination of the production materials and samples. Microbiological and foreign-matter test methods should incorporate appropriate controls to ensure the results are indicative of the material and not the test method itself.

System-performance qualifications. In addition to the product-quality attributes described above, the validation of other essential systems is necessary. The most important of these are water and environmental-control systems that have a significant albeit indirect effect on the product-quality attributes. Other systems with a less clear effect on end-product quality may be assessed in a less comprehensive manner. Utilities such as steam, compressed air, and jacket services, ordinarily do not have a direct effect on the key quality concerns and can be placed into service by commissioning rather than formal qualification. The American Society for Testing and Materials has developed an expanded analysis of risk-based qualification for pharmaceutical systems (7).

What is PQ?

The term "performance qualification" (PQ) was developed to clarify the distinction between the process and product efforts and those related to equipment. It was a way to distinguish between the equipment-focused activities (e.g., installation, operational, or equipment qualification) and those related to the product or process (i.e., PQ). Certain firms call the product and process effort "process validation," but this term is by no means universal. Coincidently, PQ can also stand for "process qualification" or "product qualification." Fortunately, though these terms have been expressed, neither has seen widespread use. It might be advisable to consider yet another definition of the acronym PQ: "product quality." The author believes it best to use the term "performance qualification" for activity that focuses on the essential quality attributes of the product as delivered by the process. It must be recognized that the process and product cannot be separated. One is the result of the other, and knowledge of their interaction is critical to success.

The PQ of a pharmaceutical process must demonstrate how the process ensures product quality. The completed effort must demonstrate how the independent variables of the process (i.e., temperature measurement, addition rate, mix speed, and mix time) result in a product that meets its defined quality attributes (i.e., content uniformity, viscosity, and color).

The recommended approach to PQ considers process parameters, product attributes, and their interrelationship. Only in combination can a process or product validation be properly addressed.

The link between process parameters and quality attributes should be established during the developmental process and documented in technology-transfer reports. The development must determine the relationship between the important process parameters and product attributes such as:

  • Drying time and moisture content

  • Mixing time and content uniformity

  • Reaction conditions and impurity levels.

Establishing the link between parameters and attributes during the developmental process facilitates the execution of the process on the commercial scale. Kenneth Chapman's classic article, "The PAR Approach to Validation," provides an excellent example of the need to link the independent process parameters and the resulting dependent quality attributes (8). Independent variables are established by the pharmaceutical manufacturer as necessary for successful process operation and include aspects such as equipment operating set points, operating instructions, material and equipment specifications, required in-process tests, mole ratios, and addition rates. Each of these can be chosen to realize the desired outcome as defined by the dependent variables. The dependent variables are product attributes that are the result of applying the selected independent variables. The goal of the development is to determine the relationship between the independent and dependent variables and use that knowledge to ensure an acceptable outcome. The more that is known about that relationship, the more robust the process and the more likely that the performance qualification will be a success.

Successful performance qualification is a largely a result of sound development and adherence to CGMP on the commercial scale. To accomplish this, it is critical that firms understand the importance of a development effort that increases their process knowledge. A trendy term for this information is the "design space," and the overall effort has been termed "quality by design." Much of these ideas were embodied in FDA's recent initiative on risk-based compliance, which declared the attainment of process knowledge to be essential (9). That this effort and new terminology are necessary only indicates how misguided validation efforts have become in recent years. The following modest paraphrase of an early definition of validation is an appropriate way to consider process development efforts: "The goal of development (validation) is to identify the process variables necessary to ensure the consistent production of a product or intermediate (10)."

Development is not about great science; it's about robust processes that make quality products consistently.

The product- and process-qualification activities should be the centerpiece of the any firm's validation effort. Any loss of focus wastes resources and risks patient safety. We must maintain a clear link between what we are doing and what we are trying to achieve.

Validation doesn't replace any of the required CGMP activities, it merely confirms their appropriateness. There is no substitute for sound process design and development, and of course CGMP compliance in all activities. Validation failures are not a consequence of the validation, but rather of poor designs, inadequate development, or CGMP problems in operations. In essence, validation only serves to keep score.

The inability to validate a process or product is usually associated with one or more of the following causes:

  • Inadequate development (poor science)

  • Poor process control (inferior equipment or poor maintenance)

  • Inadequate instructions (poor documents or sloppy development)

  • Lack of knowledge (poor science or engineering)

  • Poor validation practice (inadequate know-how).

Examples of top-down application

The following examples are drawn from real-life situations where the validation and quality focus was misdirected because the firm had lost sight of the objectives they were striving for. In each case, end-product quality was placed at risk because of inappropriate priorities in the validation or control of other processes

Environmental worries trump sterilization. One firm was experiencing a significant failure rate in its bioreactors (close to 20%), which was greatly reducing its ability to support product sales. Investigation into the problem revealed that steaming-in-place of the system was being hampered by faulty steam traps and back pressure in the condensate line. When pressed to allow the traps to discharge into the surrounding ISO-8 room, the firm's environmental-quality unit objected that the condensate would degrade the environmental conditions in the room. The ability to sterilize the bioreactors and produce contamination-free products was compromised to protect an environment without product contact.

Pursuit of sterilization effectiveness risks microbial contamination. Parts for aseptic compounding and filling were sterilized as individual components to ensure maximum exposure during the steam-sterilization process. After sterilization, the individual parts were assembled aseptically into the final fluid-handling system. The risk of contamination during the assembly was ignored in pursuit of better sterilization. The firm relied on media fills to support the efficacy of this process.

The effect of the top-down approach

The top-down approach focuses the validation on the key quality attributes of the product rather than on less critical concerns. The products manufactured in this industry are intended to serve the patient, whose needs must be paramount in the development of any validation effort. Validation began as a means to ensure sterility and protect patient welfare. It is essential that as the industry maintain a connection between what it is endeavoring to do and whom it is doing it for. The patients deserve the safest and most efficacious products possible, and the cost to provide them should be realistic as well. Misplaced efforts that fail to support patient needs are anathema.

The approach described in this article is inherently risk-based because the validation activities that directly affect critical product-quality attributes are given the greatest emphasis and priority over potentially conflicting, but certainly less important indirect concerns. Validation efforts must focus on patient needs. Risk-based validation is a significant step in the right direction. Remember, "If a thousand people do a foolish thing, it is still a foolish thing."

James Agalloco is the president of Agalloco and Associates, PO Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, He is also a member of Pharmaceutical Technology's Editorial Advisory Board.

Submitted: Feb. 6, 2008. Accepted: Feb. 12, 2008.

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1. FDA, "Proposed Current Good Manufacturing Practices in the Manufacture, Processing, Packing or Holding of Large Volume Parenterals," Fed. Regist. 41 (106), 22202–22219 (June 1, 1976; Rescinded-Dec. 31, 1993).

2. FDA, "Preapproval Inspections/Investigations" CPGM 7346.832,, accessed June 9, 2008.

3. ISPE, Commissioning and Qualification, Baseline Guide, (Tampa, FL, 2001).

4. American Society for Testing and Materials, E2500-07—Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment (West Conshohocken, PA, 2007).

5. FDA, "Guideline on Sterile Drug Products Produced by Aseptic Processing," 2004,, accessed June 9, 2008.

6. FDA, "21 CFR 210.1 (a)," Fed. Regist. 43 (45076), (Rockville, MD, 1978).

7. ASTM, E2500-07—Standard Guide for Specification, Design and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment (West Conshohocken, PA, 2007).

8. K. Chapman, "The PAR Approach to Process Validation," Pharm. Technol. 8 (12), 22–36, 1984.

9. FDA, "Guidance for Industry, PAT—A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance" (Rockville, MD, 2004).

10. B. Spiller, "Process Validation of Solid Dosage Forms," in proceedings of Manufacturing Controls Seminar (The Proprietary Association, Cherry Hill, NJ, 1979), pp. 17–31.