Risk-Based Strategies for Determining Cleaning Validation Effort and Approach

Agenda

Interpreting Regulatory Requirements and GuidelinesOptimizing and Prioritizing Cleaning Validation (CV) EffortCV Risk Assessment (RA) Grouping StrategiesCVRA Worst-Case Scenarios identificationCVRA Life CycleHow Much CV is Adequate?

Regulatory Requirements and Guidelines

Regulations– cGMP Regulations, (FDA and HPFBI)

Principal Regulatory Guidelines– HPFBI, Cleaning Validation Guidelines, 2001– FDA, Guide to Inspections of Validation of Cleaning Processes,

1993

Some Key Reference Material– FDA, Pharmaceutical cGMP’s for the 21st Century – A Risk-Based

Approach, Fall 2004– PDA, Technical Report No. 29, Points to Consider for Cleaning

Validation, 1998, Supplement Vol. 52, No. 6– Hall, W. E., Validation of Cleaning Processes for Bulk

Pharmaceutical Chemical Processes

Selected Quotes from Reliable Sources

“It is considered acceptable to select a representative range of similar products and processes…A single validation study under consideration of the worst case can then be carried out which takes into account all of the relevant criteria”, HPFBI

“There has been a tendency for companies to stretch the concept of worst case beyond what regulatory officials will accept. Indeed, several companies have received FDA483 citations or warning letters for overdoing the grouping concept”, Hall, W.E.

“Once the product groups have been established, the next step is to determine the so-called “worst case” representative for each group”, PDA

Interpreting Regulatory / Industry Publications

Significant industry practice and regulatory guidance exists supporting selection of worst-case cleaning scenarios that bracket lesser-risk scenariosNo guidance exists that establish numeric limitations for CV effort reduction strategiesThere have been regulatory reprisals issued to firms for “too aggressive” CV effort reduction strategies

Risk-based strategies for determining the approach and effort for cleaning validation are common industry

practice How aggressive this approach is applied is a subject of

debate and confusion in the industry and regulators

Seminar Objectives

Discuss the structure and parameters that are available for use in a cleaning validation risk-assessmentNot to convince the group that a particular risk-based strategy is best Provide ideas for the development of a strategy that best suits the needs of your facility, processes, equipment and products

There are many different strategies that are effective and cGMP compliant

Seminar Scope

To be discussed in this seminar:– CVRA strategies related to chemical residues:

• Product ingredients• Cleaning agents

To be discussed in future CV seminars:– Risk-based approach for evaluating:

• Sterilization processes• Microbial contamination• Endotoxin contamination etc.

– Other CV program elements:• Cleaning validation master planning• Residue limits computation• Trace analytical method validation and coupon recovery• Cleaning validation protocol and approach

Agenda

Interpreting Regulatory Requirements and GuidelinesOptimizing and Prioritizing Cleaning Validation (CV) EffortCV Risk Assessment (RA) Grouping StrategiesCVRA Worst-Case Scenarios IdentificationCVRA Life CycleHow Much CV is Adequate?

Optimizing the Cleaning Validation Effort

All cleaning processes on all equipment for all product challenges cannot be validated

CVRA features that optimize validation effort:– Forms a complete matrix of all cleaning scenarios– Outlines numeric rules for grouping/ranking strategies– Identifies matrix extremes (boundaries) that become “worst-case scenarios”– Shows the scenarios that are lesser risks assured by the boundaries– Total effort becomes a strategically determined fraction of the maximum

Cleaning validation program axiom is that if scientifically-determined worst-case (extreme) scenarios are validated, then (generally)

the lesser-risk scenarios within the boundaries are assured

Prioritizing the Cleaning Validation Effort

All CV worst-case scenarios cannot be validated at once, where do you position your resources?

CVRA features that prioritize validation effort:– Even the most aggressive CVRA’s yield numerous worst-case scenarios– Numeric ranking methodologies for risk factors offer guidance for

identifying the high risk scenarios that should be validated first– Certain risk factors and scores are used as alarms for prioritizing effort– Critical tool for assessing new product additions to equipment trains and the

risk of contaminating the existing products in the production stream

CVRA information is a key element in establishing a diligent approach in positioning validation resources

to reduce potential contamination risks

Agenda

Interpreting Regulatory Requirements and GuidelinesOptimizing and Prioritizing Cleaning Validation (CV) EffortCV Risk Assessment (RA) Grouping StrategiesCVRA Worst-Case Scenarios IdentificationCVRA Life CycleHow Much CV is Adequate?

CVRA General Features and Controls

Grouping strategies are to be supported by engineering evaluations of equipment features and scientific assessments of formulations and ingredient chemistryArithmetic risk assessments of products and ingredients is to be objective and consistent across the entire product lineScoring in risk matrices is to be quickly traceable to reference information distinctly stored in library format within the departmentSubjective diversions for individual products that could be interpreted as risk manipulation is to be avoidedSkewing of risk factor ranking and scoring to influence the outcome in favour of selective worst-case scenario selections is to be avoided

Equipment Grouping Strategy

Catalogue all manufacturing equipment having product contactFactors influencing formation of equipment groups:– Similar manufacturing purpose:

• Tanks, mixers, piping, fillers, blenders, dryers, presses, coaters, etc.– Similar construction features:

• Tank shape, existence of spray balls, materials of construction, impeller types, pump types, hopper shape, filler types, etc.

Attempt to form the fewest number of groups possible

The aim is to have equipment members in a group thatshare similar cleaning procedure approaches

Cleaning SOP Grouping Strategy

Catalogue all equipment cleaning SOPsCompare to equipment groups and look for distinctly different cleaning approaches within an equipment group and verify correctness of cleaning approach– This activity usually results in a re-alignment of cleaning strategies resulting from

historic SOP diversity that may not be appropriateFactors influencing formation of cleaning SOP groups:– Similar physical cleaning operations:

• CIP, COP, Manual, etc.– Similar cleaning agents and order of operations:

• Example: Hot water, cleaning agent, hot water, purified water (or WFI), SIP Attempt to align the cleaning SOPs with the equipment groups formed

Any different cleaning SOP approaches within an equipment group must be further divided into separate groups – REMEMBER THAT

YOU ARE VALIDATING PROCEDURES NOT EQUIPMENT

Mfg Process / Product Grouping Strategy

Form a list of all unit processes:– Blending/compounding, transfer, hold, filling, granulation, drying,

compression, encapsulation, coating, etc– Relate the unit processes to the equipment groups

Attempt to form the fewest number of groups possible The aim is to understand how each piece of

equipment is cleaned and what are the product challenges for each cleaning SOP

This activity MUST reflect current reality, NOT desired facility optimization plans in order that it is defensible to a regulator

CVRA Selection Matrix Background

This is one recommended approach, there are others that are acceptableIntegrate all grouping strategiesForm a background cross-hatch of:– Equipment across the x-axis (appropriately grouped)– Product down the y-axis (appropriately grouped)

Complete the matrix by identifying which products come in contact with which equipment – “X” in the matrix boxes– Ensure that processing flexibility is considered (eg, alternate equipment and

batch sizes)– Ensure that equipment dedicated to a single product is identified

The goal at this stage is to possess accurate knowledge of where your products are made in the facility

Agenda

Interpreting Regulatory Requirements and GuidelinesOptimizing and Prioritizing Cleaning Validation (CV) EffortCV Risk Assessment (RA) Grouping StrategiesCVRA Worst-Case Scenarios IdentificationCVRA Life CycleHow Much CV is Adequate?

Product Risk Scoring Strategy

This is a recommended approach, there are others that are acceptableThree (3) different strategies:– Considering API score only:

• Most liberal approach• Recommended (rarely and) only for facilities producing low risk products

– Considering API and excipient scores individually:• Most conservative approach• Considers all ingredients as potential contamination sources• Recommended for facilities producing high risk products

– Considering an overall product score• Common approach• Considers all formula ingredients• Normalized based on formula contribution of each product ingredient• Still need to select a target analyte from worst-case formulas• Recommended for most facilities

Product Ingredient Risk Scoring Strategy

This is a recommended approach, there are others that are acceptable

A risk score for each ingredient is computed using the followingformula:

For each RF, [RL x DoI] = Individual RF scoreFor each ingredient, [Σ RF scores] = Ingredient risk score

CVRA defines many risk factorsCVRA defines risk levels and degree of impact for each risk factor

LegendRF: Risk factorRL: Risk LevelDoI: Degree of Impact

Product and Ingredient Risk Factors

This is a recommended approach, there are others that are acceptable

Risk factors are selected for the product line based on an objective criteria of applicability from the reference list below, not all apply to every product:Risk factors address issues relating to clean ability or contamination riskIngredient RF’s Product RF’sSolubility (aqueous usually) Operator Cleaning ExperienceToxicity (LD50, oral rat) High Product Residue PotentialTherapeutic Activity Presence of Grit

Process TemperatureProduct ComplexityFoaming PotentialBatch Size

Risk Levels and Degree of Impact

This is a recommended approach, there are others that are acceptableRisk Levels (RL)– Established (multiple) for each factor are established that predict either the level of

challenge to the clean ability of the ingredient or the potential contamination hazard.– The higher the risk level, the higher the risk

Degree of Impact (DoI)– Established (single) for each risk factor that ranks the relative importance of the risk

factor in relation to other ingredient or product risk factors– Some risk factors are more important contributors in evaluating cleaning validation risk

than others

Product Ingredient Risk Scoring Example

This is a recommended approach, there are others that are acceptableAn example of potential product ingredient risk scoring for the “Aqueous Solubility” risk factor is presented below:

Aqueous Solubility (Descriptive) (Abbrev.)

Degree of Impact (DoI)

Risk Levels

(RL)

Risk Factor Scores

Insoluble Insol. 5 50 Practically Insoluble Pr. Ins 5 50 Very Slightly Soluble V. Sl. Sol. 4 40 Slightly Soluble Sl. Sol. 3 30 Sparingly Soluble Sp. Sol. 2 20 Soluble Sol. 1 10 Freely Soluble Fr. Sol. 0 0 Very Soluble V. Sol.

10

0 0

Worst-Case Scenarios Selection

This is a recommended approach, there are others that are acceptableIngredient and/or product risk scores are computed and added to the selection matrix containing the product and equipment grouping informationWorst-case scenarios are identified using the following criteria:– Highest total ingredient or normalized product risk score (based on scoring method)– Presence of extreme (high) embedded individual risk factor scores for major risk factors

such as solubility, toxicity, therapeutics, operator experience– Other procedural or discretionary criteria that are applicable for the facility

Adequate risk assessment is assured when:– Worst-case scenario(s) have been selected for each equipment/process/cleaning SOP

group established in the matrix– All extremes are selected

It is prudent to examine this matrix at this point as a map to ensure that the worst-case scenario selections appear to encompass the

entire facility, its products and cleaning strategies

Agenda

Interpreting Regulatory Requirements and GuidelinesOptimizing and Prioritizing Cleaning Validation (CV) EffortCV Risk Assessment (RA) Grouping StrategiesCVRA Worst-Case Scenarios IdentificationCVRA Life CycleHow Much CV is Adequate?

Establishing and Maintaining the “Living”CVRA

This is a recommended approach, there are others that are acceptable

A CVRA is a large set of documents requiring much thought and resource to prepareA typical CVRA is composed of:– Governing text outlining the overall strategy and specific numeric approach to

evaluating cleaning validation risk scoring and grouping approaches– Appended product/ingredient risk score data tables– Appended worst-case scenario selection matrix for the entire facility– Supporting reference information consisting of equipment lists, facility and

equipment schematics, product formulas, processing masters and ingredient technical and safety information sheets

A CVRA becomes and remains living by:– Implementation, support and governance by the firm’s quality system and SOPs– Rendering applicable within the firm’s change management review loop for

example, new product additions to the facility or equipment changes for products– Care, feeding and periodic review by qualified personnel

Agenda

Interpreting Regulatory Requirements and GuidelinesOptimizing and Prioritizing Cleaning Validation (CV) EffortCV Risk Assessment (RA) Grouping StrategiesCVRA Worst-Case Scenarios IdentificationCVRA Life CycleHow Much CV is Adequate?

How Much CV is Adequate?

QuestionHow many worst-case scenarios should be selected as distinct cleaning

validation projects?AnswerSomewhere between one (1) worst-case scenario for each group established

and all possible product/process/equipment permutationsHow to establish an adequate cleaning validation effort:

Depends on product risk (public health) categories– Parenterals are higher risk than oral vitamins

Depends on nature and perceived effectiveness of the firm’s equipment cleaning program

– New or drastically changed cleaning program requires more validation– Historically ineffective or unproven (not validated) equipment cleaning program requires more

validation– Existence of historic cleaning validation failures requires additional validation

A well planned and documented risk-based tool that established a good understanding of cleaning issues will help reduce the perceived need for excessive CV effort

Thank You

About the Author

Tracy Davis B.Sc.Sr. Project ManagerInvensys Validation Technologies (IVT)(416) 727-2515tracy.davis@invensys.com

Experience17+ years in pharma industry11 years in generic industry : GenPharm Inc., TorPharmManagement positions held in: MRP, Formula Development, Production,

Regulatory Compliance and Validation6+ years in domestic and international pharma consulting: IVTDirect experience in preparation and inspectional approval of numerous

SNDS’s and ANDA’sMultidisciplinary experience in process development, CGMP compliance,

process/ cleaning validation strategies and PAT