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COMMENTARY
Amgen, Inc., Longmont, CO, USA; 2PDA, Bethesda, MD, USA; 3Divison of Acquired Immunodeficiency Syndrome, National
Institutes of Health (NIH), Bethesda, MD, USA; 4Amgen (Europe) GmbH, Zug, Switzerland PDA, Inc. 2014
ABSTRACT: The purpose of this article is to share ideas on developing a risk-based model for the scheduling of audits
(both internal and external). Audits are a key element of a manufacturers quality system and provide an independent
means of evaluating the manufacturers or the supplier/vendors compliance status. Suggestions for risk-based
scheduling approaches are discussed in the article.
KEYWORDS: Audit, compliance, Quality systems, Risk assessment, Risk factors.
LAY ABSTRACT: Pharmaceutical manufacturers are required to establish and implement a quality system. The quality
system is an organizational structure defining responsibilities, procedures, processes, and resources that the manufacturer has established to ensure quality throughout the manufacturing process. Audits are a component of the
manufacturers quality system and provide a systematic and an independent means of evaluating the manufacturers
overall quality system and compliance status. Audits are performed at defined intervals for a specified duration. The
intention of the audit process is to focus on key areas within the quality system and may not cover all relevant areas
during each audit. In this article, the authors provide suggestions for risk-based scheduling approaches to aid
pharmaceutical manufacturers in identifying the key focus areas for an audit.
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Additionally, a company will have established processes for risk acceptance decisions for its operations
PDA Journal of Pharmaceutical Science and Technology
Suggestions for risk factors to be evaluated in a prioritization matrix include compliance inputs (prior
regulatory inspection/company audit, overall compliance history), operational inputs, and facility inputs.
Each of these risk factors should be weighted based
upon the perceived impact on compliance.
As every manufacturing site is different, it is impossible to list all the different risk factors to be considered. However, this article does discuss some of the
more common risk assessment inputs used for audit
schedule development. The risks factors discussed in
the following sections (sections 1.1 to 1.5) should be
used as points to consider when assigning a fixed risk
rank to a site/operation. Assigning a fixed risk rank to
a site/operation will aid in the audit scheduling process.
1.1 Risk Factors for Operations Performed
The operations at the site can be assigned a fixed risk
rank based on the risk associated with the operations
performed. As an example, high-risk operations usually include sterile manufacturing, packaging and labeling, final product release testing, and excipient
testing. The function of excipient testing is included
under high-risk operations because these raw materials
are a part of the final product formulation and do not
undergo further purification. These operations tend to
have a higher degree of regulatory oversight and are
therefore assigned a higher risk level. Additionally,
supply chain oversight including distribution and
transport practices are regarded as a high risk in todays environment. Medium-risk operations would include drug substance manufacturing and solid oral
dosage form manufacturing of drug (medicinal) products, while warehousing (e.g., storage areas for product and raw materials) would be considered low-risk
operations if appropriately controlled.
1.2 Site/Facility Risk Inputs
When assessing the risk profile of a manufacturing site
for clinical or commercial products (both drug substance and drug product) or a supplier/vendor for
materials or a contract laboratory for release testing,
several factors about the facility/site and the equipment should be considered. These factors include facility design (e.g., the age of the facility and compliance with current expectations on design should be
considered) and maintenance, equipment maintenance
and calibration, and if there have been major changes
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Figure 1
The elements of a typical audit program.
Other areas that may indirectly affect the compliance
status of a site and should be considered in the assessment include new product introduction to the site,
major changes in key GxP personnel and ownership
(i.e., company buy-out or merger), and, if applicable,
knowledge about sister sites compliance status and
the companys contract manufacturing quality monitoring visit results, and the outcomes of the site internal audit program (if available). The dates of the last
regulatory inspection/audit and the dates of the anticipated next regulatory inspection could be considered,
too.
1.5 Business Inputs
Business concerns are not a part of the GMP realm;
however, certain business criticality issues should be
considered as part of your risk ranking process. These
could include the volume of product manufactured or
tested or stored, if the site is single-sourced, and if
there is a licensed/approved back-up site available.
2. Risk-Based Approaches: From Planning
to Completion
The elements of a typical audit program are depicted
in Figure 1. The audit process can be divided in six
steps: scheduling, planning, preparation, conducting
the audit, report generation/issuance/response acceptance, and follow-up/closure. Each step is discussed
below.
2.1 Scheduling
A risk-based approach to scheduling audits is a useful
tool to determine the audit frequency for both internal
PDA Journal of Pharmaceutical Science and Technology
Table I
Points to Consider When Scheduling a Supplier Audit
Audit Type
Suppliers of materials and services
(calibration and maintenance
services, clean gowns,
transportation providers)
Raw material/solvents
Criticality and
Complexity
Criticality of equipment
calibrated/maintained
by the supplier
Criticality of operation
performed by the
supplier
Criticality of material
to process
Sourcingregulatory
maturity of country
of manufacture
Single source?
contract manufacturing operations and quality (including the QP) could provide information as to the compliance status of the individual contractors. In addition, laboratory and/or operations staff members who
are in contact with contract manufacturers/laboratories
may have information to contribute to the overall risk
assessment of a contract manufacturer. Participation
of the QP in the scheduling process is useful because
of his or her product knowledge and involvement in
specific quality functions such the lot release decision.
Including the QP may be of particular importance in
multinational companies where the audit program may
be operated remotely from the QPs site of responsibility.
Once the assessment has been performed, a risk level
with a rating can be assigned to the audit as a means
of determining frequency. Risk levels can be high,
medium, and low. Typical intervals for the audit frequency, unless specifically required by regulations,
include 1218 months (high risk), 18 24 months (medium risk), and 24 36 months (low risk).
Under the risk-based paradigm, new information acquired during the year could be considered. Changing
suppliers, regulatory issues, product complaints, and
so on may lead to a modification of the audit schedule
during the year. Rationales for these changes can be
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Table II
Points to Consider When Scheduling an Audit of a Drug Substance or Drug Product Manufacturing
Process
Audit Type
Drug substance (biotechnology &
small-molecule active
pharmaceutical ingredients)
Process controls
Sourcingregulatory maturity of
country of manufacture
Single source?
Drug (medicinal)
productgeneral
Process controls
Ability to clean
Intended use
Sourcingregulatory maturity of
country of manufacture
Single source?
2.2 Planning
edge of the auditee/auditors, the preliminary timeframe for the audit, the preliminary scope and objective of the audit, and the expected duration of the
audit.
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Table III
Risk Management Elements When Planning an Audit (5)
Element of Audit
Planning
Lead auditor
Traditional Approach
Risk-Based Approach
Objective
Preliminary scope
Expected duration
Product
25 days
Table IV
Example of Ratings for Audit Observations
Rating
Critical
Major
Minor
Recommendation
Observation Description
Observation describing a situation that is likely
to result in a noncompliant product, quality
defect, or a situation that may result in an
immediate or latent health risk and includes
any observation that involves fraud,
misrepresentation or falsification of products
or data.
Critical observations in an audit will
compromise the success of inspection(s) by
authorities.
Observation that may result in the production
of a drug (substance or product) not
consistently meeting its marketing
authorization.
Major observations may compromise the
success of inspection(s) by authorities.
Remedial action must be initiated in the short
to medium term.
Observation that is neither critical nor major
but represents a departure from the GMP.
There is a low risk of inspection(s) by
authorities being compromised.
A recommendation does not represent a
violation of the principles of the PQS in
terms of QMS and/or GMP rules. It outlines
areas of suggested improvement.
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and GxP requirements along the product life cycle. PDA J. Pharm. Sci. Technol. 2012, 66(5),
396 402.
3. PDA Technical Report No. 54 (TR 54) Implementation of Quality Risk Management for Pharmaceutical and Biotechnology Manufacturing Operations, 2012.
4. Rnninger, S.; Holmes, M. A risk-based approach
for scheduling audits. PDA J. Pharm. Sci. Technol. 2009, 63(6), 575588.
5. PIC/S. A Recommended Model for Risk Based
Inspection Planning in the GMP Environment. PI
037-1, January 1, 2012.
6. Health Canada. Health Products and Food Branch,
Risk Classification of Post-Market Reporting
Compliance Observations, Guide-0063, November 21, 2005.
7. European Medicines Agency. Compilation of
Community Procedures on Inspections and Exchange of Information, EMA/INS/GMP/321252/
2012/Rev. 15, July 16, 2012.
8. Rnninger, S.; Berberich, J.; Fischer, G.;
Persson, I.; Wandt, C.; Wall, L. How can we
balance value, effort and risk in foreign GMP
inspections? A future perspective. GMP Review, 2012, 10, 14 18.