Validation of API manufacturing operations

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Journal of Validation Technology , 02/01/2007 13 2
Validation of API manufacturing operations: impact of Q7A.(Active Pharmaceutical Ingredients) Fuge, Juanita *~|~*
COPYRIGHT 2007 Advanstar Communications, Inc.

During the annual Validation Week event (October 2006) hosted by the Institute of Validation Technology, Max S. Lazar, President of FDA Regulatory Compliance Consulting and an active, contributing member of the JVT Editorial Advisory Board, discussed the impact of the Q7A Guidance on the validation of API manufacturing operations from his perspective as a topic leader of the Expert Working Group (EWG) that developed and negotiated that guidance. As an attendee at that Validation Week discussion, it is my pleasure to share the highlights of Max's unique perspective and to include here, as an important addition to your library, the full text of the Q7A Guidance. INTRODUCTION
Although in theory, validation of Active Pharmaceutical Ingredients (APIs) may be the same as validation for dosage forms, in actual application they are not the same. The differences arise from the differences that exist between APIs and dosage forms in practicality. That is in their complexity, sheer size, robustness, and chemical or biological design. The difference lies in how and when to do the validation; that it must be done remains.
From the introduction section of the Q7A document to its final chapter, validation is noted more than 70 times in the guidance. Validation is noted in the following sections of the guideline:
<pre>
Q7A Guidance Sections

Analytical Methods
API for Use in Clinical Trials
Blending
Change Control
Computerized Systems
Containment
Documentation and Records
Introduction and Glossary
Laboratory Controls
Process and Cleaning Validation
Process Equipment/Cleaning
Product Quality Review
Production Activities
Production/In-process Controls
Purified Water
Quality Management
Stability Monitoring
Viral Removal </pre>
Validation, according to the Food and Drug Administration's (FDA) "Guideline on General Principles of Process Validation" (May 1987), includes:
<pre>
"Establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a
product meeting its pre-determined specifications and quality
attributes." </pre>
We will look at the most significant words in this definition to clarify and expand upon their meanings. The first significant word, documented, implies protocols and records and means these must be completed, available, and be the documents upon which the validation is based. The next word, evidence, requires that good science and extensive sampling be used. The use of the word, consistently, implies multiple batches produced by the same process, or more specifically, one process producing batches of similar quality. The final important word used in the definition is pre-determined. Pre-determined implies both a knowledge of the API to be validated and requires that the knowledge be applied to the process before the validation is actuated. In other words, the validation should be completed to prove a pre-determined result.
Therefore, process validation is not an/a:
** Experiment
** Optimization Study
** Process Improvement Program
** Process Capability Study
** "Worst-case" Test
Process validation is a means of confirming in an orderly and scientific way, what we already believe is true. We are trying to meet the "pre-determined quality specifications and attributes" mentioned in FDA's definition.
VALIDATION AND API'S
Why the concern with API validation? We look to control variables that are tested at three levels: high, medium, and low.
Where:
N = [3.sup.X]
N = Total number of experiments
X = Number of control variables
How many experiments may be needed?
If the number of control variables (X) equals 4, then N = 34 or 81 experiments.* API processes are far more complex than this so that the actual number of runs would be extremely large.
*Note: This is an impractical number of experiments and API manufacturers cannot and should not be expected to perform such a large number of validation runs. To make these experiments feasible, API manufacturers must use a fraction of this number when performing validations.
Difference between GMP and Q7A Expectations
There is a distinct difference between what is expected regarding validation of APIs under Q7A Guidance and from the Drug Product GMP.
*** Drug Product GMP Expectations:
** All Steps/Controls
** Analytical Methods
** GMP Computerized Systems
** Purified Water Systems
** All Cleaning Procedures
** All changes that can impact quality
** Do not accept retrospective validatiaon
*** Q7A Expectations:
** Only critical steps/processes
** Specifies that the annual Product Review should be used to determine whether re-validation is needed for API processes
** Specifies that GMP-related computerized systems should be validated
** Allows retrospective validation when proper documentation exists
** Q7A specifies more details about validation than does 21CFR 211
**** Documentation retention system of validation documents (Reports should exist.)
**** For critical physical attributes, validation of blending is expected to ensure homogeneity (these must be defended)
**** Validation of analytical procedures that are NOT compendial
**** Validation policy, including:
***** Intentions
***** Approach
***** Cleaning procedures
***** Analytical procedures
***** Computerized systems
***** Persons responsible for all phases from design to approval and documentation
**** Validation should extend to ... operations ... critical to ... quality and purity of the API
**** Validation protocol
**** Details validation process
**** Validation report
**** Documentation of variation from protocol
**** Appropriate qualification BEFORE validation
**** Accepts (under defined conditions)
***** Prospective validation (norm)
***** Concurrent validation
***** Retrospective validation
****** Critical attributes/parameters identified
****** In-process controls/criteria established
****** No significant process/process failures unless due to human or mechanical causes
****** Impurity profiles established
****** Defines conditions for use of this type of validation
** Establishes Guidance for number of lots to use for validation
**** Prospective -- minimum 3 lots or batches
**** Concurrent -- minimum 3, if possible
**** Retrospective -- 10 to 30 lots or batches
** Periodic review of validation
**** Does NOT mandate automatic re-validation
** Cleaning procedures normally validated, but not always required
**** Is there a risk to API Quality?
**** Analytical checking advised
**** Cleaning limits based upon Pharmacological or Toxicological data
**** Micro and Endotoxin testing where appropriate
** Analytical procedures validated unless from official compendia such as USP/NF
** Impact of change on need for validation should be determined
** Concurrent validation acceptable for reworked API
** Process validation NOT normally expected for API under development
Compliance Expectations for API Validation
The Q7A Guidance was written with intended flexibility so that it could apply in many situations. Regulators throughout the world are expected to use it with this built-in flexibility. Practitioners, understanding this flexibility, must recognize the intent of the writers and use Q7A according to its application in their circumstances.
Process Validation under Q7A
Here are important items to remember when considering process validation under the Q7A guidelines. Remember that the terms qualification and validation are not synonymous; qualification is the testing and review of a piece of equipment, refer above to the FDA's definition of validation. Q7A allows concurrent validation. Changes under retrospective validation are accepted when there is no impact on the quality of the API. Finally, process validation is not required during API development. For API under development, to be used in clinical trials, no validation is required.
CONCLUSION
Basic validation is the same for drug products and APIs. There are numerous differences identified in Q7A; greater detail is provided in the Q7A Guidance than in 21 CFR PART 211 Drug Product GMP. Flexibility is identified for API's under development and in concurrent and retrospective validations. It is most important to understand the intent of the Expert Work Group that wrote and negotiated the International Guidance.
PRESENTER CONTACT INFORMATION: Max S. Lazar, President, FDA Regulatory Compliance Consulting, Surprise, AZ, 85374 USA maxslazar@aol.com 623-556-0556. Member of the ICH Q7A EWG (EWG PhRMA Topic Leader) that developed and negotiated the Q7A Guidance.
Article Acronym Listing
<pre>
API Active Pharmaceutical Ingredient
EWG Expert Working Group
FDA Food and Drug Administration
GMP Good Manufacturing Practice
ICH International Conference on Harmonization
NF National Formulary
USP United States Pharmacopoeia </pre>
VALIDATION WEEK '06 PRESENTATION BY: MAX S. LAZAR
COMPILED BY: JUANITA FUGE, EDITOR

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