In recent years, the Food and Drug Administration (FDA)-regulated industry has been listening to agency representatives and consultants talking about the need to implement a risk-based approach to decision-making processes. I totally agree with the need to implement this "common-sense" approach, but my question is this: Is this actually a new approach?

Industry personnel have been considering risk in everyday decisions, but have not realized or documented these decisions properly. I think that the key issue here is formal documentation. In the future, the industry must focus on and devote more time to pursuing and completing risk-related documentation. Firms must develop procedures to adequately document risk-based decisions, estimate their criticality, and evaluate their impact. The FDA is even implementing this approach internally for its inspection plans.

Another statement with which I totally concur reads: "Risk management is nothing more than resource management." Risk management is the process of identifying the critical areas on which each entity within the industry must focus its resources rather than stubbornly applying effort on the less critical aspects of operations. This is especially true for operations such as the typical cosmetic, or Over the Counter (OTC) drug site that manufactures hundreds of different products in fully flexible facility equipment set-ups with minimum resources, which permits them to compete in their selected markets.

SCOPE

In this article, I will describe a practical approach to applying impact and risk concepts to the processes and documentation related to facility systems and processing equipment qualifications within the cosmetic and OTC drug (topical and oral) manufacturing segments. In addition, I will describe the procedural requirements and the documentation needed to use impact and risk concepts during the definition of the systems and equipment qualification requirements. The article is not intended to describe the "Risk Assessment" tools in detail, but to provide a guide for the application of these tools.

Within the article, I will make reference to the International Society for Pharmaceutical Engineering's (ISPE) impact concepts from their "Baseline Engineering Guides" - specifically to Volume #5 on Commissioning and Qualification (see Reference 2). There are three different levels of impact: direct, indirect, and no-impact. Following are their basic definitions:

- Direct Impact System - equipment or system that will have focused and immediate impact on product quality - Indirect Impact System - equipment or system expected to have incidental or secondary impact on product quality - No-Impact - no impact, direct or indirect, on product quality

For the purpose of this article, I will focus on the first two categories having direct and indirect impact on product quality. In addition, the article will focus on the Installation Qualification (IQ) and Operational Qualification (OQ) sections of the qualification process. Performance Qualification (PQ) should be conducted exclusively on critical, direct impact systems. Test requirements should be specific to the system and its application.

A typical example of a direct impact system would include a purified water system that produces processed water for formulations; a product-filler being tested for different volumes, weights, and counts, is an example of a system that would have indirect product impact.

As discussed in the introduction, manufacturers of oral and topical products should focus their qualification efforts on critical, direct impact systems. There is no requirement to conduct a PQ for every system or piece of equipment in the facility. Specific process or product steps, functions, and parameters will be tested during the process validation for each individual process being challenged.

Policy and Procedure

The first thing that a facility requires is a policy and procedure document that defines the implementation of the chosen approach. The policy will include the scope and objective of the program, the personnel responsible for its implementation, the steps in determining test requirements based on impact or risk, and the documentation to be generated as a result of the analysis (including the protocol testing requirements). The procedure will establish the steps to determine an adequate level of testing using the impact assessment concepts and a risk criteria developed by the management team. Some of the decisions that can be based on impact or risk include:

Which Sections of a System Need to be Qualified?  Throughout my years of experience, I have often heard industry experts discussing the need to qualify individual components of a system versus qualifying only the critical components, for example, a pump within a water system. In a critical operation, such as an aseptic manufacturing area whose water source is a Water for Injection (WFI) system, qualifying every component may make sense. However, a topical product manufacturer that does not have the resources to qualify every pump, assuming a direct impact system, must focus on the critical components.

Which Pieces of Equipment within a Processing or Compounding Area or on a Packaging Line Require Qualification?  Does an OTC drug or cosmetic facility need to qualify storage tanks (no mixing capability) or just the mixing tanks and kettles? Do they need to qualify every component of a packaging line? I have seen industry consultants require an OTC manufacturer to qualify the line conveyors. This is neither practical nor effective, especially for the typical cosmetic or OTC drug manufacturer making topical products with no dosage limits.

Typically, I will recommend that these manufacturers focus their efforts on those pieces of equipment that might have an effect on product quality such as the filler, capper, labeler, or any heating or shrink-wrapping equipment that could cause heat shock to the product.

Which Parameters Should be Tested and at What Level?  Does an OTC drug or cosmetic facility need to test all systems at "worst-case" or the extreme parameter limits? How many runs or tests should be completed? A manufacturer can select those parameters that are critical to the operation of the equipment or system rather than testing all parameters without determining their impact levels.  Manufacturers will also be expected to test for more critical parameters and for critical operations. There is no need to test at "worst-case" conditions for every parameter. If the system is a direct impact system, the manufacturer should test at worst-case or extreme conditions only those parameters that are most critical for the operation or that have a critical impact on the process results.

Decisions on Criteria and Equipment Specifications versus Process Needs  The user must decide whether the qualification will be tested against process-specific needs or equipment design specifications. There are advantages and disadvantages with each option. If focused on process needs, the qualification will be simpler, but the risk is that the equipment may be needed later for a different process and would require qualification for the new set of parameters.

I suggest the implementation of different levels of qualification based on categories (see Recommended Strategies below). The selection criteria I recommend for the different categories are a combination of the ISPE impact assessment and risk concepts. The specific requirements for each level of qualification must be determined and included in the procedure, which should include the steps required to categorize the different systems and equipment and the documentation requirements needed to justify the selection and present the rationale.

Included as attachments, the procedure contains suggested protocol templates that take into consideration the qualification levels previously described in the procedure. You may wish to maintain a template for each level. This will simplify the process of developing these protocols for the document's author or owner.

The documentation of any specific decision based on impact and risk concepts for a particular system or equipment must be included in the applicable protocol with its rationale. The document must use the data and evaluations completed during design and process development such as study reports, specifications, and drawings.

The policy or procedure must also describe the specific approach for equipment that is controlled through Programmable Logic Controllers (PLC), higher level or distributed control systems, and those requirements applicable to electronic signatures and records according to the Code of Federal Regulations (CFR) 21, Part11.

RECOMMENDED STRATEGIES

There are specific qualification protocol requirements for different impact and risk-level equipment or systems. Following are the suggested strategies for applying impact and risk concepts during the development of qualification protocols:

Impact Levels

Direct Impact System:

Product Failure, Risk, or Hazard Level

ƒæ Level I - Oral or Topical Product with Dosage Limits "« Installation "Ï Include more detail as defined in the internal policy and procedure requirements. "Ï Refer to specific recommendations for IQ protocols below. "« Operational Qualification "Ï Consider operational functions, sequences, controls, or alarms. "« Challenge Parameter Ranges, Worst-Cases, or Extremes "Ï Use with critical parameters only.

ľ Level II - Oral or Topical Products with No Dosage Indications

"« Installation "Ï Include less detail as defined in the internal policy and procedure requirements. "Ï Refer to specific recommendations for IQ protocols below. "« Operational Qualification "Ï Consider all operational functions or sequences. "Ï Controls exist on critical parameters. "Ï Challenge only the critical alarms.

Indirect Impact System

"« Installation "Ï Include minimum detail as defined in the internal policy and procedure requirements. "Ï Refer to specific recommendations for IQ protocols below. "« Operational Qualification "Ï Test only those operational functions that could impact product quality.

Specific Test Requirements

Included here are some specific areas within the protocols on which to use different levels of test requirements:

ƒæ Installation Qualification (IQ) "« Main Component Verification "Ï Use only critical components for indirect impact systems. "Ï Include only critical controls and instrumentation or components for direct impact systems. "« Calibration "Ï Reduced list of critical instruments for indirect impact systems and risk level II direct impact systems. "Ï Most instruments in direct-impact systems are at risk level I. "« Input and Output Verification "Ï Critical parameters for indirect impact systems only. "Ï Expanded list for direct impact systems.

ƒæ Operational Qualification (OQ) "« Select the Critical Parameters "Ï May use risk assessment or analysis "Ï Select number of tests for each "« Select the Responses or Resulting Characteristics to be Verified Based on Risk "Ï May use a formal risk assessment or analysis

Specific Operational Qualification requirements by Impact Level:

ƒæ Indirect Impact System Verify the basic operational functions - only those that could impact the product quality. "« Functional Testing "Ï Include critical parameters at nominal set-point values "Ï Verify only critical responses or characteristics "« Normal Variation of the Parameter Value around the Nominal Set-Point "Ï Controls verification "Ï Motor verification "Ï Sequence verification (if applicable)

ƒæ Direct Impact Systems - Risk Level II Verify the basic operational functions including critical alarms. "« Functional Testing "Ï Test parameters at operational limits or specifications (not necessarily extremes, but reasonable operational limits) "Ï Verify critical responses or characteristics "« Use lower and upper set-point values while trying to meet the overall operational limit range considering the normal variation. "Ï Controls verification "Ï Motor verification "Ï Sequence verification (if applicable) "Ï Critical alarms verification and reporting.

Note: Define the list of critical alarms to be challenged during the development of the specific protocol. Not all alarms need to be challenged because the system is not a Risk Level I (critical) direct impact system. Only include the "out of limits/specifications" alarms in the critical operational parameters.

ƒæ Direct Impact Systems - Risk Level I Verify the basic operational functions including the alarms that could impact product quality. Challenge parameter ranges and worst-cases or extremes only for critical parameters. "« Functional Tests "Ï Test parameters at operational extreme limits "Ï Verify critical responses or characteristics "Ï Test minimum and maximum parameter set-point levels without using the actual operational limits as the set points.

Note: If the normal or expected parameter variation is considered, this will create a different process and the parameters values will be out of limits most of the time.

"X Controls verification - more detailed "X Motor verification "X Sequence verification (if applicable) "X Most system alarms verification and reporting. Test all alarms within the parameters and under the conditions that could have an impact on product quality, not necessarily all of them. Need to define the list of alarms to be challenged during the development of the specific protocol.

ľ No Impact Systems Systems, components, or equipment that does not fall within any of the categories above will be described as having "no-impact" or limited risk.

Legacy Systems and Equipment

IQ documentation requirements for legacy systems and equipment will be established using the same analysis as noted above. Special considerations may be required with legacy systems. For example:  Some documents may not be available. The need for these documents must be evaluated in terms of impact on equipment operation and maintenance.  Documents, such as drawings and specifications, may have to be developed "as is" or "as built."  Data required for risk assessment may be taken from historical data, such as product failures or complaints, instead of from designs.  Operational requirements must be similar to new systems or equipment.

Change Control

The approach to change control is similar to that already discussed, for example:  Apply the same approach used for qualifying equipment to determine requirements after change implementation.  Utilize direct and indirect impact concepts to determine the need for qualification testing and the required level for that testing.  Make the evaluation part of the change control procedure and documentation. Include the rationale for the decision in the procedure.  Ensure that the evaluation includes a determination that the changes implemented did not create new hazards or risks.

CONCLUSION

Using a practical approach to determine qualification requirements is detrimental for manufacturers in the cosmetic or OTC drug market. Resource management is their basic mode of operation. To remain competitive, these manufacturers must be selective in terms of the level of qualification testing and the equipment to be qualified. This article has offered a guide to making those decisions in a procedural, documented process to provide manufacturers with a means of remaining in compliance while using their resources in an effective manner.

Acronym Listing CFR Code of Federal Regulations cGMP Current Good Manufacturing Practice FDA Food and Drug Administration IQ Installation Qualification ISPE International Society for Pharmaceutical Engineering OQ Operational Qualification OTC Over the Counter PLC Programmable Logic Controllers PQ Performance Qualification

REFERENCES:

1. "FDA Guidance on Quality Systems Approach to Pharmaceutical cGMP Regulations," September 2006. 2. ISPE Baseline Engineering Guides - Volume #5, "Commissioning and Qualification," 2001. 3. ISO Standards - "ISO-14971 on Risk Management" 4. ICH Q9 Guideline on Quality Risk Management 5. FDA webpage on Efficient Risk Management (www.fda.gov/oc/mcclellan/strategic_risk.html) posted 8/2003 and updated 4/2004. This was included on the FDA Strategic Action Plan developed by the agency in August 2003.