The document discusses issues with the Drug Regulatory Authority of Pakistan's (DRAP) recommendations for batch sizes in product development and stability studies, which contradict international regulatory science norms. Specifically, DRAP recommends a batch size of only 2,500 tablets for lab-scale trials and stability testing every 1-2 weeks, rather than the accepted standards of at least 25% of pilot-scale batch size and testing every 3-6 months. The author argues this approach is not supported by any scientific reference and could compromise drug quality, safety and efficacy. The document advocates for DRAP to align its practices with international guidelines from organizations like the International Council for Harmonization to strengthen regulatory systems in Pakistan and better serve patients and industry.

1. BURDEN OF
HOLLOW TOOLS & APPROACHES
in
Product Development & Stability Studies
Roohi B. Obaid
Civil Service Officer/Deputy Director
At Drug Regulatory Authority of Pakistan
March 2017
Disclaimer:
It is written and judged in the best of author's professional knowledge, experience and education.
It has nothing to do with the organization or societies to which author is associated, so there is
no obligation to the author's organization or societies on the document. It represents current
thinking of the author on the subject. Within the boundary of good science, critical thinking and
comment with reference will always be respected
Narrowing the Confusions and Promoting Discussions based on Science

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Table of Contents
S. No Title Page No.
A Problem Statement 3
A-1 DRAP Recommendation 3
B Clarification 4
C Generic Drug Applications Assessment 4
D Stability Studies and Determination of Shelf Life 4
E Product Development 5
F Lab and Pilot Scale Batch Manufacturing 5
F-1 Batch Size 5
G Stability of Batches 6
G-1 Selection of Batches 6
G-2 Testing Frequency 6
H Conclusion 6
I Way Forward 6
J Project Designing & Regulatory Initiatives 7
K Reference 8
L Key Words 8

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A. Problem Statement:
Drug Regulatory Authority of Pakistan (DRAP) is the responsible and authorized organization
for the drug applications assessment to judge to judge the claim and promise of applicant for the
safety, quality and efficacy of the drug products. It also conducts inspection of manufacturing
facilities to monitor the state of control during the manufacturing process for integrity, quality
including consistency of the product units within a batch, batch after batch and time after time.
This role of authority has evolved in last decades for post-marketing evaluation to keep an eye on
quality surveillance and on detection of potential signals of unknown harms. Emerged safety
issues in recent past with some generics demand placement of generic drugs under surveillance
and vigilance for safety reasons. It is regrettable that DRAP has flexibility since decades for the
requirement of bioavailability/bioequivalence studies as well as in vitro dissolution studies, not
only in case of pre-registration requirements but also in case of renewal of market authorization.
The requisite support and inevitable attributes deserved to be respected for the conclusive
interest of patients are unfortunately kept unattended till date. Beside the flexible practice,
disregard to science and norms of regulatory science within DRAP have left the country and
patients on the mercy of manufacturers. It generates a perception that prevailing regulatory
procedures of DRAP are below the line and standards of competitive age. A simple example of
such practice is discussed here to clarify the situation. Development of a product is a lengthy
scientific process that requires sufficient knowledge management to generate data from trial
manufacturing. In this way, product is developed and demonstrates its overall required
performance and collects evidence that supports prediction of insignificant difference upon scale
up. Different environmental factors including immediate packaging, temperature, humidity and
light are studied for their impact on the quality of drug product. This helps in determining the
storage condition and shelf life of the product. Modern science has determined the principal to
select the sizes of batches and study protocol for determination of shelf life that prevails all
around the world and receives respect like all other scientific principle and theories.
A-1 DRAP Recommendation:
DRAP came up with their own idea that is contrary with the international norms and
standards of Regulatory Sciences for the size of batches in Product Development and
frequency of testing in Stability Studies.

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a) Batch size for Product Development and Stability Studies
2500 tablets for lab scale (represented as pilot scale in between lines)
b) Frequency of testing for stability studies
Week (01 to 26) intervals will be used to complete the number of tests at
both accelerated and real time conditions.
B. Clarification:
This practice of DRAP is not supported by any international reference and is not qualified yet to
demonstrate any meaningful support in determining the safety, efficacy and quality of drugs.
This is an abuse of math and a wrong approach for the foundation of product development and
stability studies on which future product quality and performance will be based.
C. Generic Drug Applications Assessment:
Generic product applications contain a set of dossier explaining mainly its Chemistry,
Manufacturing and Controls. This application is assessed to see the capability in the entire
manufacturing process of a particular formulation claiming equivalent Quality, Safety and
Efficacy with the innovator product. Its Material Quality, Manufacturing Process, Control
Strategies, Container Closure System, Comparative Dissolution Profile (CDP), Bioavailability
(BA), Bioequivalence (BE) studies etc. are the fundamental target of the Regulatory Agency to
gain reasonable trust through uniform tools for examining the claims. This assessment requires
multidisciplinary approach to make the process meaningful and navigate the decision based on
the inputs of different experts of their area of expertise. Approval or rejection of any application
principally require detailed report and its summary covering every critical aspect of the product.
D. Stability Studies and Determination of Shelf Life:
Product's stability studies are one of the subjects of paramount importance. It gives support to
understand the impact of temperature, moisture, light during the product storage determining the
shelf life of the product. In the field of life saving product manufacturing nothing can be
assumed. Every formulation requires stability studies to prove its shelf life even in case of any
change in manufacturing process or material etc. that may impact on its quality attributes.

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E. Product Development:
A decade old but an agreed active document of International Council of Harmonization (ICH) on
Pharmaceutical Development ICHQ8 provide an opportunity to change the approaches, from
empirical data driven to systematic knowledge driven, from retrospective to perspective, from
acceptance criteria based on limited batch data to acceptance criteria based on patient needs. It
emphasis more on science and risk based approach instead of test (document quality) that help
to understand and explore variability.
To provide a product that consistently meets patient needs, it is required to be manufactured by a
process that is well understood, robust and adaptable to the variability of input materials.
F. Lab and Pilot Scale Batch Manufacturing:
The lab scale trial batches are manufactured to understand product quality and performance. This
evolving information is used to justify the relevance of the lab scale developed manufacturing
process with relatively larger i.e. pilot scale in terms of critical processing parameters and critical
attributes to explore and strengthen the understanding of the product performance and its
manufacturing process capacity. The same way pilot scale batches are used to see potential
behavior upon scale up of commercial batch size.
F-1 Batch Sizes:
a) For Lab Scale batch, following sizes for different dosage forms are reported in
documents of the leading regulatory agencies of the world. Here it is tried to be
narrated in simple and clear words.
• For oral solid dosage forms: NLT 25% of the pilot scale batch
• Powders/solutions/suspensions: NLT 25% of the pilot scale batch
• Parenterals: NLT 25% of the pilot scale batch (50 Litre if unit is >2 ml),
(30 Litre if unit is up to 2 ml).
• Creams/Ointments: NLT 40% of the pilot scale batch
• Transdermal Patches: NLT 60% of the pilot scale batch

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b) For Pilot Scale batch at least one tenth of the full production scale batch or 100,
000 units (tablets or capsules), whichever is larger.
G. Stability of Batches:
G-1 Selection of Batches:
Three primary batches (one lab scale and two pilot scale) are required to generate data
with regard to stability studies. Similarity in formulation and packaging material with the
proposed commercial batches is compulsory. Moreover, the manufacturing process of
these primary batches should simulate to the proposed commercial batches capable to
promise the same quality meeting the pre-defined and studied specifications. It would be
worthy if different batches of drug substance are used to manufacture these primary
batches.
G-2 Testing Frequency:
For long term stability studies, the stability testing is required to be performed every 3
months in first year, every 6 months in the second year and then annually for the
proposed shelf life.
For 6 month accelerated stability studies, the stability testing is required to be performed
at least on 3 time points including initial and the final time point.
H. Conclusion:
Prevailing misconception (within DRAP & industry) and cross pollination of this misconception
may not favor to Patient, Regulatory System, Safety, Efficacy and Quality of the product but has
potential to perform otherwise. Respect to science for patient interest, country reputation and
industry promotion requires to keep DRAP aligned with principle of science and agreed
scientific requirements.
I. Way Forward:
Harmonization is expanding worldwide with focus to ensure the safety, efficacy and high quality
of medicines in a resource efficient way. The International Conference on Harmonization (ICH)

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now transformed into International Council for Harmonization is the key player in bringing
together the Regulatory Authorities and Pharmaceutical Industry of the developed world for
discussion on technical and scientific aspects. This resulted in the development of various
guidance documents on Quality, Safety, Efficacy and Multidisciplinary issues that are respected
and followed by the developed world and even the least developing world. The transformation
from Conference to Council has made it a truly global initiative expanding beyond the previous
ICH members (USA, EU and Japan) and Observers (Heath Canada and WHO), welcoming the
regulators from around the world to be involved in ICH. Efforts have been done to reduce the
regulatory burden and benefit from the experience of regulatory counterparts but without
compromising good science through confidence building exercise via memorandum of
understanding, mutual recognition agreements, joint inspection programs etc. An International
Generic Drug Regulators Program (IGDRP) has also been started to develop collaboration and
convergence in generic drug regulatory programs to address the challenges faced by increasing
workloads, globalization and complexity of scientific issues. IGDRP was initially started as a 3
year pilot (2011-2014) and is renamed as a program in 2014. It involves several countries.
Pakistan has to respect science and walk in line with the international norms of the developed
world in order to strengthen its fragile regulatory system and practices. This will not only
improve the safety, efficacy and quality of medicines available to the citizens but will also
reduce the gulf between the prevailing standards, tools and approaches compared to the rest of
the world. It will help to pull up our system at par with the international norms and to develop a
progressive strategy for regional and global harmonization. This is the only way to bring the
dream into reality of both protecting and promoting the health of citizens and pharmaceutical
industry i.e. creating a way for access of Pakistan's pharmaceutical products in the developed
world and to gain respect in the field of pharmaceutical regulation.
J. Project Designing and Regulatory Initiatives:
A balanced approach and efficient tools may be identified and designed to move in a trustworthy,
transparent, result oriented, knowledge based manner.

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K: Reference:
 International Council on Harmonization (ICH) Guidance on Stability Testing of New
Drug Substances and Products-Q1 A(R2)
 Compiled from the knowledge gained during scientific discussions, regulatory practice
and extensive reading of materials on the subject.
 Frequently asked Questions and Answers on US-FDA website
L. Key Words:
Generic Drug, Product Development, Stability Studies, Shelf Life, Batch Size, Frequency of
Testing, Lab Scale, Pilot Scale, ICH, Harmonization, Comparative Dissolution Profile (CDP),
Bioavailability (BA), Bioequivalence (BE) studies.