The draft guidance on “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials”

The draft guidance on “Pregnant Women: Scientific and Ethical Considerations for Inclusion in Clinical Trials” has issued today and is available at:

This draft guidance discusses the ethical and scientific issues when considering the inclusion of pregnant women in clinical trials of drugs and biological products. This draft guidance is intended to advance scientific research in pregnant women, and discusses issues that should be considered within the framework of human subject protection regulations.

amendments to certain Drugs and Cosmetics Rules, 1945

To prevent the indiscriminate sale of topical preparations containing steroids and antibiotics without prescription, the Health Ministry has banned over-the-counter sale of around 14 such creams.

In a notification issued on March 23, the ministry has put 14 steroid-based creams and ointments under the Schedule H category by making amendments to certain Drugs and Cosmetics Rules, 1945.

The decision was taken following consultation with the Drugs Technical Advisory Board (DTAB) which had recommended a ban on the sale of such creams without prescription and had also submitted their recommendations to the Central Drugs Standards Control Organisation (CDSCO).

The move come after dermatologists complained that pharmaceutical companies were selling steroid- based creams and ointments to patients who use them without medical guidance.

The revised rules will apply to skin creams that contain steroids or other prescription drugs and not for ordinary face-cleansing and moisturisers.

The creams which have been banned are alclometasone, beclomethasone, desonide, desoximetasone and flucinonide among others.

IPC has announced to organize the “IPC-EDQM Symposium on Drug Standards and Regulatory Updates” from April 26 & 27, 2018 in Mumbai.

Subsequent to Indian Pharmacopoeia Commission (IPC) having been awarded the status of “Observer” for participation in the activities of the European Directorate for the Quality of Medicine and Healthcare (EDQM), IPC has announced to organize the “IPC-EDQM Symposium on Drug Standards and Regulatory Updates” from April 26 & 27, 2018 in Mumbai.

The programme shall offer a unique opportunity for the organizers to present jointly their work and roles in taking forward the activities through active participation of stakeholders which include professionals from pharma industry, API manufacturers, associations, academicians, individuals, regulators, etc.

The participants will have the opportunity to hear key speakers from IPC, EDQM and regulatory bodies and attend interactive sessions.

What is data integrity in Pharmaceutical industry?

FDA suggests that adherence to the data integrity is must to ensure the cGMP compliance. GMP is a system for ensuring that products are consistently produced and controlled according to quality standards.

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The data integrity issues have been frontrunners for the USFDA to hammer pharma companies. The data integrity-related CGMP violations have led to several regulatory actions, including warning letters, import alerts, and consent decrees. A few years ago, Ranbaxy signed a consent decree with USFDA and also paid $500mn in civil and criminal fines.

Plants of Wockhardt, IPCA laboratories remain under the warning letter/import alerts for long now. Dr. Reddy had received a warning letter in 2015 over data integrity issues, along with others. Over the last two years, Indian companies like USV, Hetero and Sri Krishna Pharmaceuticals (all unlisted), Agila Specialties (Mylan’s subsidiary), etc. have received warning letters over data integrity, which USFDA gives a very high importance.

Recently, Sun Pharma, Aurobindo, Biocon, etc. received form 483 observations, but there was no data integrity related observations, hence stocks did not tank heavily. In case of Sun Pharma, the stock moved up. This makes it interesting to understand data integrity, from the eyes of USFDA.

USFDA suggests that data integrity refers to the completeness, consistency, and accuracy of data, which should be attributable, legible, contemporaneously recorded, original or a true copy, and accurate. USFDA suggests that adherence to the data integrity is must to ensure the cGMP compliance. GMP is a system for ensuring that products are consistently produced and controlled according to quality standards.

FDA’s minimum data integrity requirements are:

Data should be secure from alteration, inadvertent erasures, or loss. Backup data should be exact and complete.

Data should be stored to prevent deterioration or loss.

Certain activities should be documented at the time of performance and that laboratory controls should be scientifically sound.

The records should be retained as original records, true copies, or other accurate reproductions of the original records.

FDA requires data to record complete information, a complete record of all data from all the tests performed, and no test or data should be failed to record.

FDA also requires metadata to be stored throughout the record’s retention period.

Other guidance that USFDA suggests when it comes to data integrity includes:

The data to be auditable for reconstruction of the past events relating to the creation, modification, or deletion of the records.

The manufacturing companies should enable appropriate controls over the data/records so that change in the records can only be made only by authorized personnel restricting of the alteration of the records.

The system administrator role for computers (having rights to alter files and settings) be assigned to personnel independent from those who are responsible for recording the content.

The systems controls, including documentation controls, should be designed to follow CGMP to assure product quality.

Companies must keep the incomplete or the erroneous forms as part of the permanent record along with written justification for their replacement.

All changes in the critical data to be audit trailed.

The processes should be designed so that quality data to be created and maintained cannot be modified.

USFDA prohibits followings:

Recording of the data on pieces of paper that can be discarded.

Storing of the data in temporary memory.

Sampling and testing with the goal of achieving a specific result or to overcome an unacceptable result as this is not as per the CGMP standards.

Use of actual samples to perform system suitability (system suitability tests should be done by using written procedures and data should be recorded for scientific justification for exclusion).

USFDA suggests that drug shall be deemed adulterated if the methods or facilities or controls used to manufacture, process, pack, or hold the drug does not conform to adherence to the current good manufacturing practice. The adherence to the cGMP is required to assure that the drug has safety, identity and strength that meets the on the quality and purity characteristics.

(Source for this is USFDA website: Data Integrity and Compliance With CGMP Guidance for Industry)

Revised ICH (International Conference on Hormonisation) Quality Guidelines in pharmaceuticals are given below

Q1A (R2) – Stability Testing of New Drug Substances and Products

Q1 B – Stability Testing : Photo Stability Testing of New Drug Substances and Products

Q1C – Stability Testing for New Dosage Forms

Q1D – Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

Q1E – Evaluation of Stability Data

Q1F – Stability Data Package for Registration Application in Climatic Zones III and IV

Q2 (R1) – Validation of Analytical Procedures : Text and Methodology

Q3A (R2) – Impurities in New Drug Substances

Q3B (R2) – Impurities in New Drug Products

Q3C (R5) – Impurities : Guideline for Residual Solvents

Q3D – Impurities : Guideline for Elemental Impurities

Q4 – Pharmacopoeias

Q4A – Pharmacopoeial Harmonisation

Q4B – Evaluation and Recommendation of Pharmacopoeial Text for use in the ICH Regions

Q4B Annex 1(R1) – Residue on Ignition /Sulphated Ash General Chapter

Q4B Annex 2(R1) – Test for Extractable Volume of Parenteral Preparation General Chapter

Q4B – Annex 3(R1) – Test for Particulate Contamination : Sub-Visibal Particales General Chapter

Q4B – Annex 4A(R1) – Microbiological Examination of Non-Sterile Products : Microbial Enumeration Tests General Chapter

Q4B – Annex 4B(R1) – Microbiological Examination of Non-Sterile Products : Test for Specified Micro-Organism General Chapter

Q4B – Annex 4C(R1) – Microbiological Examination of Non-Sterile Products : Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical use General Chapter

Q4B – Annex 5(R1) – Disintegration Test General Chapter

Q4B Annex 6 (R1) – Uniformity of Dosage Units General Chapter

Q4B Annex 7(R2) – Dissolution Test General Chapter

Q4B Annex 8(R1) – Stability Test General Chapter

Q4B Annex 9(R1) – Tablet Friability General Chapter

Q4B Annex 10(R1) – Polyacrylamide Gel Electrophoresis General Chapter

Q4B Annex 11 – Capillary Electrophoresis General Chapter

Q4B Annex 12 – Analytical Sieving General Chapter

Q4B Annex 13 – Bulk Density and Tapped Density of Powders General Chapter

Q4B Annex 14 – Bacterial Endotoxin Test General Chapter

Q5A(R1) – Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin

Q5B – Quality of Biotechnology Products :

Q5C – Quality of Biotechnology Products :Quality of Biotechnological

Q5D – Derivation and Characterisation of Cell Substrates used for Production of Biotechnological/Biological Products

Q5E – Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process

Q6A – Specifications : Test Procedure and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances

Q6B – Specifications : Test Procedure and Acceptance Criteria for Biotechnological/Biological

Q7 – Good Manufacturing Guide for Active Pharmaceutical Ingredients

Q8(R2) – Pharmaceutical Development

Q9 – Quality Risk Management

Q10 – Pharmaceutical Quality System

Q11 – Development and Manufacture of Drug Substances (Chemical Entities Biotechnological/Biological Entities)

Q12 – Life Cycle Management

Data Integrity Considerations for Conventional and Rapid Microbiological Methods

Data integrity refers to maintaining and assuring the accuracy and consistency of data over its entire life-cycle, and is a critical aspect to the design, implementation and usage of any system which stores, processes, or retrieves data. Data integrity is a key regulatory concern and to aid those working in pharmaceuticals and healthcare guidance documents have been produced by the U.S. Food and Drug Administration (FDA) and the MHRA (1, 2). These call on the ALCOA approach to be followed: data must be attributable, legible (permanent), contemporaneous, original and accurate.

Data integrity applies to all production processes and laboratories, including microbiology. That microbiological practices are a potential concern is evidenced in several FDA warning letters, especially in relation to sample handling and reading. These concerns extend to both conventional methods of testing and to rapid methods, methods reliant upon paper documentation and computerized systems, paper documentation (3).

Even with the growing adoption of rapid methods, microbiology laboratories handle a lot of data. Unlike analytical laboratories, however, the data is more often an even mix of quantitative and qualitative data. Examples of data include the result of a settle plate exposed during the environmental monitoring of a cleanroom; the endotoxin content in a sample of water; the weight result from the weighing of a raw material for use in the pharmacopeia Microbial Limits Test and so on.

Despite the current high profile, the subject of data integrity in the pharmaceutical microbiology laboratory has not been afforded very much attention in terms of regulatory guidance. This article looks at two data integrity concerns within the microbiology laboratory, one relating to conventional methods and one to rapid methods, and considers some of the steps that can be taken to address identified weaknesses.

Conventional Methods
Environmental monitoring using conventional methods, such as air-sampling, settle plates and contact plates contributes to a cohesive assessment in the assurance of finished product quality. However, traditional culture-based microbiological methods typically possess inherent and unavoidable variability and as such these might result in erroneous conclusions (4). These concerns have been raised in FDA warning letters. Two take two examples: “plate counting, where colony forming units are miscounted” and “missing samples, such as environmental monitoring samples not being taken or dropped on transit to an incubator.” While the latter is careless, colony counting errors can occur where confluent growth occurs.

Some regulators have requested secondary checks for plate reading. This is an erroneous demand and unnecessary – personnel are either good at plate reading or they are not. Solutions to correct colony counting include rapid methods; good training in testing (to ensure that colony numbers fall within the countable range for the plate size); and effective training for reading plates, spotting phenomena like merged colonies, spreading organisms, and diminutive colonies that require reading under magnification and with white light.

Rapid Microbiological Methods
There are an array of different rapid microbiological methods, each with their own technologies and testing protocols. Data integrity concerns arise at the design, validation and operation stages. Taking validation, samples need to be representative of what will be tested using the instrument and tested multiple times and by different technicians in order to build in repeatability and robustness. Aspects that give validity to the result, such as limit of detection and limit of quantification (either directly in relation to microorganisms or indirectly through monitoring biological events) need to be introduced.

In terms of operations, data integrity extends to data capture, retention, archiving, and processing. Most rapid methods use computerized systems and here systems should be designed in a way that encourages compliance with the principles of data integrity. Examples include multi-level password control; user access rights which prevent (or audit trail) data amendments; measures to prevent user access to clocks; having automated data capture; ensuring systems have data backup.

When carrying out reviews of rapid microbiological methods five general and important data integrity questions are:

Is electronic data available?Is electronic data reviewed?Is meta data (audit trails) reviewed regularly?Are there clear segregation of duties?Has the system been validated for its intended use?

A satisfactory answer should be available for each of these five key questions.

Data integrity is applicable to microbiology, both conventional and rapid methods, as with every other part of the pharmaceutical operation. This short article has highlighted two areas that microbiologists need to be mindful of in terms of plate counting and computerized systems. Data integrity is an important subject and a regulatory ‘hot topic’; the ideas presented here and wider issues require careful attention by the microbiologist.


1. FDA (2016) Data Integrity and Compliance With CGMP, Draft Guidance for Industry, April 2016, U.S. Department of Health and Human Services, Food and Drug Administration, Washington

2. MHRA (2015) MHRA GMP Data Integrity Definitions and Guidance for Industry March 2015, Medicines Healthcare products and Regulatory Agency, London, UK

3. Sandle, T. (2016) Data Integrity Considerations for the Pharmaceutical Microbiology Laboratory, Journal of GXP Compliance, 20 (6): 1-12

4. Tidswell, E. C. and Sandle, T. (2017) Microbiological Test Data – Assuring Data Integrity, PDA Journal of Pharmaceutical Science and Technology, doi:10.5731/pdajpst.2017.008151