Compliance Risk Management Using a Top-Down Validation Approach - Pharmaceutical Technology

Latest Issue

Latest Issue
PharmTech Europe

Compliance Risk Management Using a Top-Down Validation Approach
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.

Pharmaceutical Technology

An example product applying the top-down approach

Figure 2
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.

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.


blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
| Weekly

FDASIA was signed into law two years ago. Where has the most progress been made in implementation?
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
View Results
Eric Langerr Outsourcing Outlook Eric LangerTargeting Different Off-Shore Destinations
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerAsymmetric Synthesis Continues to Advance
Jill Wechsler Regulatory Watch Jill Wechsler Data Integrity Key to GMP Compliance
Sean Milmo European Regulatory WatchSean MilmoExtending the Scope of Pharmacovigilance Comes at a Price
From Generics to Supergenerics
CMOs and the Track-and-Trace Race: Are You Engaged Yet?
Ebola Outbreak Raises Ethical Issues
Better Comms Means a Fitter Future for Pharma, Part 2: Realizing the Benefits of Unified Communications
Better Comms Means a Fitter Future for Pharma, Part 1: Challenges and Changes
Source: Pharmaceutical Technology,
Click here