Pharmaceutica

Mallu et al., Pharm Anal Acta 2014, 5:2

[Link]

Analytica Acta
Review Article

Open Access

Periodic or Skip Testing in Pharmaceutical Industry: Us and Europe

Perspective
Useni Reddy Mallu1*, Raman NVVSS2, Sachin RD1 and Anand K1
1
2

Department of Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India

Hetero Drugs Ltd. (RandD), Plot No. B. 80 and 81, APIE, Balanagar, Hyderabad 500018, Andhra Pradesh, India

Abstract
Periodic Testing (PT) or Skip Testing (ST) is an important and widely discussed concept for the purpose of cost
saving in the generic pharmaceutical industry where widespread expenditure is a necessity. As there is no particular/
appropriate/apropos guideline recommending the implementation of the PT or ST concept so pharmaceutical
companies implement it depends on their vendor qualification procedure and other aspects. All pharmaceutical
industries have their internal Standard Operating Procedure (SOP) for the implementation of periodic or skip testing.
These tests can be implemented for Active Pharmaceutical Ingredients (APIs), excipients, packing materials and inprocess testing of finished products analysis. Implementation of PT or ST for API, excipient and packaging material
can be approached according to SOPs which would be available for an audit by the regulatory agencies. However,
the implementation of PT for in-process testing of finished product can be undertaken only after seeking concurrence
from the agency either during the review of a marketing authorization application or after approval of the application.
A suitable supplement or variation needs to be submitted to the agency for its review if PT is to be implemented
for in-process testing. This article explains the periodic testing/skip testing approach for in-process samples, APIs,
excipients and packing materials.

Keywords: Periodic testing or skip testing; SUPAC (Scale Up and

Post Approval Changes); Pre-approval supplement; Variations; Filing
documentation; Routine analysis

material and in-process samples. PT/ST cannot be implemented for

finished product testing.

Introduction

Periodic testing or skip testing should be implemented after

performing sufficient risk evaluation and assessment of product
quality during drug product development. It should be implemented
at commercial level only after gaining sufficient confidence. Periodic or
skip testing approach and stages are represented in the Figure 1.

NPharmaceutical industry and regulatory agencies have acquired

significant knowledge about drug product development by utilizing
scientific approaches and automation. In the past drug product quality
was ensured by testing but now a new concept is being considered
which believes in building quality in the product by design. The critical
quality attributes for the drug product are controlled by building a
control space within a design space by implementing the scientific and
statistical approaches such as Quality by Design (QbD) and Process
Analytical Technology (PAT). Before the implementation of PT/
ST approaches for the testing of commercial products, the applicant
should have sufficient data on the control strategy which has been built
in the manufacturing process of the product to ensure product quality
[1-3].

Periodic Testing (PT) or Skip Testing (ST)

As per WHO, Performance of specified tests at release on preselected batches and/or at predetermined intervals, rather than on
a batch-by-batch basis, with the understanding that those batches
not being tested still meet all acceptance criteria established for that
product. This presents a less than full schedule of testing should
therefore be justified and presented to and approved by the regulatory
authority prior to implementation.
PT or ST frequency, criteria, stage and material on which it has to be
implemented are usually defined by the companys written procedure
after taking in to consideration vendor qualification information and
other available data. The frequency for the implementation of Periodic
testing (PT) or Skip testing (ST) may be one batch per twenty batches or
the first batch manufactured every year (whichever is earlier) and it may
vary from one company to another. PT or ST can be implemented for
the testing of Active Pharmaceutical Ingredients, Excipients Packaging
Pharm Anal Acta
ISSN: 2153-2435 PAA, an open access journal

Where We Can Apply

Periodic (Pt) or
Considerations

Skip

Testing

(St)

Selection

PT or ST can be selected and implemented for the testing of

regular commercial batches. For selecting the periodic or skip tests, the
following points should be considered,
1. Whether materials are received from the approved supplier.
2. A documented history of satisfactory results for material supplied
and performance of supplier is available.
3. A documented history of satisfactory performance for the
process and product is available.

*Corresponding author: Useni Reddy Mallu, Sri Krishnadevaraya University

Chemistry, Anantapur, anantapur, AP 500072, India, Tel: 9490310239; E-mail:
drusenireddymallu@[Link]
Received December 16, 2013; Accepted January 17, 2014; Published January
23, 2014
Citation: Mallu UR, Raman NVVSS, Sachin RD, Anand K (2014) Periodic or Skip
Testing in Pharmaceutical Industry: Us and Europe Perspective. Pharm Anal Acta
5: 283. doi: 10.4172/2153-2435.1000283
Copyright: 2014 Mallu UR, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.

Volume 5 Issue 2 1000283

Citation: Mallu UR, Raman NVVSS, Sachin RD, Anand K (2014) Periodic or Skip Testing in Pharmaceutical Industry: Us and Europe Perspective.
Pharm Anal Acta 5: 283. doi: 10.4172/2153-2435.1000283

Page 2 of 5

Step-1

Product
Development
stage

Step-2

Step-3

Application
Submission

Application
Approved

Step-4

Request
for
Periodic or
Skip test

Step-5

Request
Approved/
Rejected

Step-6

Implementa
tion of
Periodic or
Skip test

Product Life Cycle

Analytical test
procedures
should be
developed.

All test
items need
to perform.

Periodic or
skip test
Strategy
approach/
protocol
preparation

All test
items
should be
included in
the FP spec.

If no
recommend
ations from
the reviewer
then we can
follow as per
the internal
SOP

If any test
item
needs to
skip from
the spec.
list then
applicant
should
request
the
agency.
Preapproval
suppleme
nt/
SUPAC/
Variation

If
approved
Implemen
t the
Periodic
or Skip
test.
If not
approved
Stop the
implemen
tation
immediat
ely

Applicant
can
implement
the agency
approved
test items as
periodic or
skip tests

Figure 1: Periodic or Skip test life cycle.

4. Compliance with specific regulatory requirements of testing is

ensured.

API

5. Sufficient development data for the specified tests is available.

Description (DS), Identification (ID), Loss on Drying

(LOD), water content, particle size, bulk density,
assay, purity test and microbial test.

Excipients

6. Scientific justification can be provided.

DS, ID, particle size, bulk density, powder fineness

and microbial test

Packing materials

7. To be implemented for tests which are not critical to assess the

product quality.
8. Batch to batch retesting to be stored in the event of failure and it
should be properly investigated and closed.
9. An impact assessment of the PT or ST should be undertaken.
10. Does the specification or method provide information about
the purity or potency of the finished product? If not, the specification
or method should be reconsidered.
11. Analytical method should predict or prevent the compliance
issue.
12. What would be the regulatory impact of eliminating or reducing
the test?
Risk assessment must be carried out for all suppliers of the material
being assessed. Where there is more than one supplier for a particular
material, then each supplier must be assessed individually. A periodic
review must be conducted to ensure that the risk assessment and PT
or ST schemes remain valid. Where an assessment has identified a
significant risk it must be appropriately mitigated.
Implementation of the PT or ST concept for the important test
Pharm Anal Acta
ISSN: 2153-2435 PAA, an open access journal

Al foil paper back

DS, ID*, Total grammage and width

Al foils plain

DS, ID* and width

Al foils printed

DS, ID*, width, printing matter and shade

Ampoules

DS, dimensions and weight*

Closures

Type of closure, dimensions, heat seal and pulp lines

Cold formable foil

DS, ID*, width and shade

Laminated Al foil pouch

DS, ID*, dimensions and printing

Molecular sieves

DS and adsorption capacity

Plastic containers

DS and physical parameters

Poly Bag

DS and dimensions

Purified cotton/Rayon filter DS, ID, water content

PVC and PVDC

DS, ID, width and shade*

PVC Aclar

DS, ID*, width, total grammage

Rubber stopper

DS, dimensions and absorbance

Silica gel bag

DS and weight

Silica gel canister

DS, dimension and adsorption capacity

Vials

DS, dimensions, weight*

Carton

DS, printing matter and shade

Leaflets

DS and printing

Self-adhesive label

DS, Text and Color

*If applicable this test can be recommended

Note: Key identification test only required.
Table 1: Mandatory test items for API, excipients and packing materials.

Volume 5 Issue 2 1000283

Citation: Mallu UR, Raman NVVSS, Sachin RD, Anand K (2014) Periodic or Skip Testing in Pharmaceutical Industry: Us and Europe Perspective.
Pharm Anal Acta 5: 283. doi: 10.4172/2153-2435.1000283

Page 3 of 5
items such as description, loss on drying, purity test and microbial
testing etc. The list of recommended test items are represented in the
below table for active ingredients, excipients and packing materials
(Table 1).

Periodic or Skip Testing for in-Process Samples

Skip testing approach can be implemented for in-process samples
of all categories of finished drug products such as tablets, capsules, semi
solids and liquids. This can be implemented after review of data for
20 to 30 consecutive batches which have been manufactured without
any change in process, formula, equipment or specification. PT/ST can
be implemented after approval from the respective regulatory agency.
After implementation of PT or ST if the process, formula, equipment
etc. is changed then the skip testing procedure should be reevaluated.
If any OOS/incident is encountered due to process quality and the
Root Cause Analysis indicates in-process testing or a change in the
process, specification or test procedures, then complete testing needs
to be performed on few consecutive batches without any change. The
internal quality assurance team will be responsible to perform the risk
assessment (Figure 2) [4-7].

Periodic or Skip Testing for Api, Excipients and Packing

Materials
Generally, after analyzing 30 to 40 batches, periodic testing or skip
testing may be implemented if data is found satisfactory and without
much variation. If any OOS/incident is encountered then complete
testing of few consecutive batches is to be performed and the quality
assurance team needs to perform the risk assessment. Different
companies may follow different PT or ST procedures (Figure 3).

Regulatory Authorization
PT or ST may be implemented for APIs, excipients and packaging
material after a favorable review of sufficient batch data and by
preparing SOPs which would be available for an audit by the regulatory
agencies. However, for implementation of PT for in-process testing of
finished product concurrence from the agency during the review of an
application or after approval is necessary. A suitable supplement or
variation needs to be submitted to the regulatory agency for its review
if PT is to be implemented for in-process testing of finished product
post approval.

Skip Testing approach for In-Process samples

ANDA submission and approval
st

th

th

1 Commercial Batch

20 /30 Commercial Batches* (Consecutive batches without any

change in process, formula, equipment and speciications)
Skip testing proposal through change control procedure (1batch in every 20 batches of 1batch per
year whichever is earlier)
Approval of change control/ concerned regulatory agency
Not Approved

Approved

Implementation as per the approval (1batch in every 20 batches of 1batch per year whichever is earlier)
If any OOS/incident in the FP (process quality issue)

3 consecutive batches without any change

Any process or speciication or test

Quality Assurance (Risk assessment)

If crossed the hold time duration then

retest can be performed

Skip testing Implementation (1batch in every 20 batches of 1batch per year whichever is earlier)
*The number of batches may vary from one applicant to another applicant
Figure 2: Periodic or Skip testing approach for In-process samples.

Pharm Anal Acta

ISSN: 2153-2435 PAA, an open access journal

Volume 5 Issue 2 1000283

Citation: Mallu UR, Raman NVVSS, Sachin RD, Anand K (2014) Periodic or Skip Testing in Pharmaceutical Industry: Us and Europe Perspective.
Pharm Anal Acta 5: 283. doi: 10.4172/2153-2435.1000283

Page 4 of 5

Skip Testing approach for API, Excipients and Packing Materials

Vendor selection and Qualiication
st

th

1 Batch from the vendor

th

30 /50 Received Batches* (Consecutive batches without any change in process and
speciications)

Skip testing proposal (1batch in every 20 /30 batches of 1batch per year whichever is earlier)
Approval of skip testing or periodic or reduced testing
Approved

Not Approved

Implementation as per the approval (1B in every 20/30 B of 1batch per year whichever is earlier)
If any OOS/incident in the FP (process quality issue)

5 consecutive batches without any change

Any process or spec or test procedure change

Quality Assurance (Risk assessment)

Skip testing Implementation (1batch in every 20/30 batches of 1batch per year whichever is earlier)
*The number of batches may vary from one applicant to another applicant

Figure 3: Periodic/Skip testing approach for API, Excipients and Packing materials.

USFDA Prospective [8]

As per the USFDA recommendations, PT or ST implementation
has to be submitted as a supplement to an approved application,. Some
changes may not require approval before implementation and some
changes may require an approval before implementation. Figure 4
represents the PT or ST items classification as per the USFDA.

notification to the FDA that a change will be implemented in the

process, analytical techniques/technologies. The Agency has 30 days
from the day of receipt to respond to the applicant. This is usually a
minor change which does not impact final product quality. The FDA
has 30 days to respond as to whether the changes are satisfactory. If the
manufacturer does not receive any response within the 30-day period,
it may be assumed that the change is acceptable.

Major-Prior Approval Supplement (PAS)

Minor (Annual Report)

PAS submission is required for implementation of PT or ST for

in-process testing of the finished product. We cannot implement PT or
ST for in-process testing of the drug product unless agency approves
the supplement.

For DS/DP, the addition or revision of an alternative analytical

procedure that provides the same or increased assurance of the quality
being tested as the analytical procedure described in the approved
product or deletion of an alternative analytical procedure.

Moderate-Changes Being Effected 30 Days (CBE-30)

Annual report: For the above change, applicant should provide the
sufficient data in the annual report.

Relaxing an acceptance criterion or deleting a test for raw materials

used in the manufacture of the drug substance, in-process materials
prior to the final intermediate, starting materials introduced prior to
the final drug substance intermediate, or drug substance intermediates
(excluding final intermediate) Relaxing an acceptance criterion or
deleting a test to comply with an official compendium that is consistent
with FDA statutory and regulatory requirements.

CBE 30 days
The CBE (Changes being effected) 30 supplement serves as a
Pharm Anal Acta
ISSN: 2153-2435 PAA, an open access journal

EU Variations (Type-IA) [9]

Implementation of PT or ST is categorized as a type-IA variation
and the applicant can proceed with annual report submission. As per
EMA recommendations, Type IA variations do not require approval
by the authorities before their implementation by the holder. However,
within 12 months from the date of implementation, the holder must
submit simultaneously to all national competent authorities. It needs
to be highlighted that if the variation is to be rejected by the competent

Volume 5 Issue 2 1000283

Citation: Mallu UR, Raman NVVSS, Sachin RD, Anand K (2014) Periodic or Skip Testing in Pharmaceutical Industry: Us and Europe Perspective.
Pharm Anal Acta 5: 283. doi: 10.4172/2153-2435.1000283

Page 5 of 5

Periodic or Skip Test: USFDA Prospective

MAJOR

Addition or Deletion or
Revision of an alternative
analytical procedure that
provides the same or
increased assurance for high
impact test items

Documentation
Approach:
Prior Approval
Supplement

MODERATE
Relaxing an acceptance criterion
or deleting a test for raw
materials used in drug substance
manufacturing, in-process
materials prior to the inal
intermediate, starting materials
introduced prior to the inal
drug substance intermediate, or
drug substance intermediates

Documentation
Approach: Changes
Being Effected
30days

MINOR
Addition or Deletion or
Revision of an alternative
analytical procedure that
provides the same or
increased assurance for
minute impact test items

Documentation
Approach:
Annual Report

Figure 4: PT or ST classification as per USFDA.

authority then the holder would immediately stop to implement the

concerned variations. Figure 4 represents the PT or ST implementation
as per the EMA regulations.

References

The specification parameter does not concern a critical parameter,

for example any of the following: assay, impurities (unless a particular
solvent is definitely not used in the manufacture of the active substance),
any critical physical characteristics e.g. particle size, bulk or tapped
density, identity test, water, any request for skip testing.

2. ICH q6a Guideline Specifications: Test procedures and Acceptance criteria for
New Drug Substances and New Drug Products. Comments for its application.

The specification parameter or proposal for the specific dosage form

does not concern a critical parameter for example: assay, impurities
(unless a particular solvent is definitely not used in the manufacture of
the finished product) any critical physical characteristics (hardness or
friability for uncoated tablets, dimensions) a test that is required for
the particular dosage form in accordance with the general notices of the
Ph. Eur.; any request for skip testing.

1. EMEA_ICH topic Q6A specifications: Test Procedures and Acceptance Criteria

for New Drug Substances and New Drug Products: Chemical Substances.

3. The Complete Stability Testing for a Successful Application Based on a

(Strategies, Requirements, Basic Principles Performance, Documents) 2.
Basic principles of stability testing.
4. Joint position paper from excipient manufacturers, drug product manufacturers
and USP on pharmaceutical excipient testing and control strategies; Based on
a PQRI survey and workshop.
5. Specifications and Control Tests on the Finished Product.
6. Lyon RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS (2006) Stability
Profiles of Drug Products Extended beyond labeled Expiration Dates. J Pharm
Sci 95: 1549-1560.
7. USFDA Guidelines (2004) Changes to an Approved NDA or ANDA;
Specifications-Use of Enforcement Discretion for Compendial Changes.

Conclusion

8. IRISH Medicines Board (2009) Quality Assessment and GMP Similarities and
Differences, EMEA.

Periodic Testing or Skip Testing can be implemented for testing

of products which are intended for commercialization. Generally, the
industry has to assess the possibility of acceptance of the parameters
by the regulatory agency. Generally parameters are proposed for PT or
ST for a minimum of 20 and 30 lots/batches of packaging material and
excipient etc. If the change is accepted by the agency then the company
should follow the internal SOP on PT/ST for the implementation of PT/
ST. As per USFDA, these changes are addressed under PAS, CBE-30 or
annual reportable category..As per EMA, these changes come under
type-IA (annual reporting) variation. As per USFDA, if the change is
major then the applicant should submit the prior approval supplement,
if the change is moderate then the applicant should follow the CBE
30days procedure and if the change is minor then the applicant can
include the change in the annual report. If the variation is accepted
then PT/ST may be implemented. But if the variation is rejected by the
agency then the sponsor should immediately stop the implementation.

9. EDQM: Topic 7_Certificate of Pharmaceutical Substances.

Pharm Anal Acta

ISSN: 2153-2435 PAA, an open access journal

Citation: Mallu UR, Raman NVVSS, Sachin RD, Anand K (2014) Periodic or Skip Testing
in Pharmaceutical Industry: Us and Europe Perspective. Pharm Anal Acta 5: 283. doi:
10.4172/2153-2435.1000283

Volume 5 Issue 2 1000283