Accessed from 10.6.1.

1 by mvpstn3kts on Sun Feb 19 08:26:56 EST 2017

892 1027 Flow Cytometry / General Information USP 40

Low Event Rate

Cell clumping, low final sample cell densities, blockages in the instrument fluidics, or improper gating can often result in
abnormally low event detection. Proper cleaning, maintenance, and setup of the instrument, as well as consistent staining pro-
tocols, can help achieve consistent results with sufficient sensitivity.

High Fluorescence Intensity

As in the case for high fluorescence background, high mean cell fluorescence can result from too much labeled antibody,
inadequate or inconsistent cell washing, or inadequate blocking. Including detergent in the wash buffer, especially during in-
tracellular staining, can help prevent nonspecific antibody binding.

Weak Fluorescence Intensity

Many factors can result in weak fluorescence intensity. Instrument parameters such as poor laser alignment, improper com-
pensation, improper setup, inconsistent gain settings, and weak laser output can all negatively affect fluorescence intensity. In
addition, cell physiology or reagent preparation issues, such as insufficient antibody concentration, labile or secreted target
antigen, poor-quality or improperly stored reagents (resulting in fluorochrome fading), or inaccessible target antigen, can all
result in a weak signal. Adequate assay development, proper instrument maintenance, and adherence to qualified protocols
can all improve the fluorescence signal intensity.
General Chapters

Flow cytometry enables investigators to analyze cells for many different applications. Types of immunophenotypic and func-
tional assays are increasing in number and in scope. The presence of proteins and cellular processes and detection of rare or
abnormal cell populations can be studied. The reader is referred to the technical literature for application and method details.

REFERENCES

Coligan JE, Kruisbeek AM, Margulies DH, Shevach EM, Strober W. Current Protocols in Immunology. Fourth ed. Hoboken, NJ:
John Wiley and Sons; 1994.
Shapiro HM. Practical Flow Cytometry. Fourth ed. Hoboken, NJ; John Wiley and Sons; 2003.

1029 GOOD DOCUMENTATION GUIDELINES

INTRODUCTION

Purpose

Documentation can be viewed as the foundation of all quality systems because clear, complete, accurate records are essen-
tial to all operations and procedures. This general chapter provides guidelines on good documentation practices for the Good
Manufacturing Practice (GMP)-regulated industries, to be used in the production and control of pharmaceutical products, ac-
tive pharmaceutical ingredients (APIs), excipients, dietary supplements, food ingredients, and medical devices. This chapter
describes the underlying principles of proper documentation for GMP operations to assist the user while working with GMP
activities. These guidelines should be helpful for building the basic foundation of a quality system that will ensure proper docu-
mentation as well as record integrity and control.

Scope

This chapter covers different levels and types of documentation, including paper and electronic records that consist of raw
data, reports, protocols, and procedures related to manufacturing controls and analytical data. The chapter also includes rec-
ommendations on information that should be recorded for various types of GMP documents. Electronic systems should be de-
veloped to meet guidelines described in this chapter.
This chapter does not provide information about all applicable current legal requirements, nor does it affect any applicable
current requirements under GMP regulations.

Official from May 1, 2017

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 10.6.1.1 by mvpstn3kts on Sun Feb 19 08:26:56 EST 2017
USP 40 General Information / 1029 Good Documentation Guidelines 893

PRINCIPLES OF GOOD DOCUMENTATION

All steps related to the manufacturing, testing, packing, or holding of pharmaceutical products, APIs, excipients, dietary sup-
plements, food ingredients, and medical devices should be documented.
Good documentation principles for manual or electronic records include the following, as applicable:
Records should be clear, concise, accurate, and legible.
Data entries should be recorded promptly when actions are performed.
Backdating and postdating are not allowed.
All corrections to the original entries should be initialed and dated (or captured within an electronic audit trail), with an
explanation included in cases where the reason for the change is not obvious.
Data entries should be traceable to the person who made the entry.
Uncommon abbreviations and acronyms should be defined.
Controls should be in place to protect the integrity of the records.
In the event that ink may have faded over time (e.g., thermal paper), a copy can be used with verification of its accuracy;
the copy should be initialed and dated.
Notebooks, data sheets, and worksheets should be traceable.
An adequate documentation system is needed to ensure data integrity and availability of current and archived records.
Records should be retained per regulatory requirements and be readable during the retention period.
All pages should be paginated. Attachments (supporting documents) should be paginated with a reference to the parent
document.

General Chapters
DATA COLLECTION AND RECORDING

Formats for data collection and recording include, but are not limited to, the following:
Paper forms, data sheets, and worksheets
Notebooks and logbooks
Instrument printouts
Electronic data obtained with a system such as an electronic data system, laboratory information management system
(LIMS), or electronic laboratory notebook (ELN)
All data should be permanently recorded directly and legibly when the activity is performed. If it is paper record, then it
should be recorded in indelible ink. All data entries should be traceable to who made the entry and when. Additionally, elec-
tronic records must meet the requirements of the Code of Federal Regulations Title 21 (21 CFR), Part 11.
Any change to an entry should be made in a way that does not obscure the original entry, with an explanation in cases
where the reason for the change is not obvious. Changes should be traceable to who made the change and when the change
was made. For clarity, predefined correction codes may be used, for example, WD = wrong date.
Notebook pages and worksheets should be used consecutively, and information should be recorded chronologically. GMP
records such as batch records, test methods, and specifications should be given unique identifiers and use version control for
the documents.
All data entry fields should be completed. A single line and/or N/A should be drawn through portion(s) of a page that are
not used. If the record is in an electronic system and the system provides traceability of who filled each field and when, the
field can be left blank.
Decimals less than one should be preceded by a zero. Rounding rules and guidelines on significant figures are described in
USPNF General Notices and Requirements.
All dates should be expressed in a format that clearly indicates the day, month, and year.
All GMP records for data collection should undergo appropriate review and signature by a second person to confirm the
accuracy, compliance, and completeness of the entries. Additional signatures may be required on the basis of local Standard
Operating Procedures (SOPs) for different levels of review (e.g., performed by, verified by, checked by, reviewed by, approved
by) as accountability steps.
An official record of signature and initials should exist for each employee or can be contained within the document. Controls
should be in place for assigning signature approval requirements and delegation of signature authority, when needed.
In the event that verified copies of raw data have been prepared, the verified copy may be substituted for the original source
as raw data.
All multiple-page data sheets or instrument printouts in paper form should be signed/initialed on the first or last page with a
note indicating the total number of pages. The first page and all subsequent pages should be uniquely identified to the activity
being performed, such as the notebook reference, study number, or worksheet reference.

DIFFERENT TYPES OF GMP DOCUMENTS

The following or similar documents should include the following information, but are not limited to these items.

Official from May 1, 2017

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
 Accessed from 10.6.1.1 by mvpstn3kts on Sun Feb 19 08:26:56 EST 2017
894 1029 Good Documentation Guidelines / General Information USP 40

Laboratory Records

Laboratory records should be organized to ensure that the records are concise, clear, legible, and accurate, and detail the
following:
Description of materials, such as reagents. This information typically includes the material name, manufacturer and lot
number, titer or concentration, expiration date, grade (if known), and a reference to the lab notebook if prepared in the
lab
Identification of equipment used. This information typically includes equipment name, unique control number, and cali-
bration expiration date, as applicable
Procedures used
Measurements
Formulae and calculations
Results and conclusions

Equipment-Related Documentation

All equipment used in manufacturing, testing, packing, or holding of a raw material, component, API, finished product, or
other similar item should be maintained and qualified for its intended use. The documentation related to equipment includes:
Policies and procedures for operation and maintenance
Equipment use
General Chapters

Maintenance records
Calibration or qualification records
Instrument labeling

Deviations and Investigations

All aberrations, anomalies, and exceptions related to manufacturing, testing, packing, or holding of a raw material, compo-
nent, API, finished product, or other similar item should be documented. Once documented, the deviation should be evalu-
ated and investigated, as appropriate. Procedures should be in place for documenting, evaluating, and investigating such
events. Documentation of the investigation should include the following:
Description of the event
Root-cause investigation
Evaluation of data trend
Responsibilities of people involved in the investigation or deviations
Impact assessment
Corrective Action and Preventive Action (CAPA) with timelines
Review and approval

Batch Records

A Master Batch Record (MBR) is created as a template for the manufacture of a specific product. An Executed Batch Record,
based on the MBR, is used to document the steps and materials involved in the production of a specific batch of a raw materi-
al, component, API, finished product, or other similar item. Typically, the following sections are included in a Batch Record,
and should be approved by an appropriate representative from the manufacturing site or packaging site:
Header information (e.g., product name, batch number, manufacturing site)
Unit of operation (e.g., blending, coating, filling)
Manufacturing process
Target weights (raw materials)
Conditions (time, temperature)
Deviations and investigations
In-process sampling or testing
Other critical information, as applicable
Sampling plan for release, stability, and retention
Review and approval

Certificate of Analysis

The purpose of the Certificate of Analysis (C of A or CoA) is to report analytical results for a specific batch of a raw materi-
al, component, API, finished product, or other similar item. Typically, the following sections are included on a C of A and
should be approved by an appropriate representative from the testing site:

Official from May 1, 2017

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
Accessed from 10.6.1.1 by mvpstn3kts on Sun Feb 19 08:26:56 EST 2017
USP 40 General Information / 1029 Good Documentation Guidelines 895

Vendor, supplier, or manufacturer information (as applicable)

Product information (name and strength)
Results for the specific batch, with name of test, acceptance criteria, and result for each test
Conformance statement or equivalent
Reference to procedure and specification document
Reference of data source
Approval and date
Expiration date or retest information

Standard Operating Procedures

The purpose of an SOP is to provide directions to trained personnel regarding a given set of activities. SOPs should be clear
and concise. The following sections are typically included in an SOP:
Purpose and scope
Instructions and procedure
Responsibilities and roles
Materials or equipment, as appropriate
Definitions or references, as needed
Review and approval
Revision history

General Chapters
Protocols and Reports

Many tasks and activities are executed on the basis of a predefined, preapproved protocol. The results of these activities are
then documented in a final report with conclusions. Examples of such activities are as follows:
Equipment qualification
Analytical method validation or verification
Manufacturing process validation
Analytical method or manufacturing technology transfer
Cleaning validation
Stability study or testing
Comparability study
Both the protocol and the report should typically include the following sections:
Purpose
Plan or instructions
Predetermined acceptance criteria
Deviations or investigations, or a reference to (for report only)
Assessment or evaluation (for report only)
Data reference (for report only)
Review and approval
Revision history

Analytical Procedures

Analytical procedures provide direction to an operator on how to perform a given analytical test. The following sections will
typically be included in the analytical procedure:
Purpose
Test information
Product information
Safety information, if applicable
Materials and equipment
Procedure, as applicable
System suitability
Preparation of solutions and reagents
Preparation of standards and samples
Instrument parameters
Calculations and reporting
Review and approval with approval dates
Revision history

Official from May 1, 2017

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.
 Accessed from 10.6.1.1 by mvpstn3kts on Sun Feb 19 08:26:56 EST 2017
896 1029 Good Documentation Guidelines / General Information USP 40

Training Documentation

Personnel should be trained to perform their assigned tasks. The training should be documented, and the training records
should be retained and kept readily accessible. In general, training documentation should include:
Training description including name of training, version, and mode (self-training or instructor led)
Completion date
Information on the trainer, as applicable

Retention of Documents

An adequate policy for record retention and archiving should be established for the above records. The required length of
time depends on the regulatory requirements or company procedures; however, it should be at least 1 year after the batch
expiration date.

1030 BIOLOGICAL ASSAY CHAPTERSOVERVIEW AND GLOSSARY

USPNF contains four general chapters regarding the development, validation, and analysis of bioassays (biological assays):
General Chapters

Design and Analysis of Biological Assays 111, Design and Development of Biological Assays 1032, Biological Assay Validation
1033, and Analysis of Biological Assays 1034. This proposed new chapter, Biological Assay ChaptersOverview and Glossary
1030, provides an overview and some material common to chapters 1032, 1033, and 1034, including a glossary of bio-
assay-related terms.
The suite of USP bioassay chapters focuses on relative potency assays. These assays recognize the inherent variability in bio-
logical test systems (whether animals or cells) that may be seen from laboratory to laboratory and from day to day. That inher-
ent variability compromises the reliability of an absolute measure of potency. In relative potency assays, the biological activity
of a Test material is compared to the activity of a Standard in an assay system wherein the use of a Standard reduces the influ-
ence of the inherent variability of the system on the estimation of relative potency. Relative potency assays also provide focus
on important variability in response because of differences between the Test and Standard materials (if such a difference ex-
ists). The Test is expected to behave as a dilution or concentration of the Standard and should exhibit the property of similari-
ty. Although they are intended for relative potency bioassays, the principles and practices developed in these chapters may
have wider applicationfor example, to immunoassays and receptor-ligandbinding assays used to determine relative poten-
cy.
Chapter 1032 provides information for scientists developing a new biological assay. As seen in Table 1, the chapter covers
a range of activities across the life cycle of the assay, with emphasis on development leading to validation, including the choice
of test system and design considerations (e.g., plate layout). It also addresses data analysis strategies that should be considered
during development (before validation) but that are not routinely addressed later. Among these strategies are the choice of
weighting scheme, data transformation, if any, and choice of statistical model. Statistical details in support of these sections of
chapter 1032 are found in chapter 1034.
Table 1. Primary Sections of Design and Development of Biological Assays 1032
Section Section Title
1 Introduction
1.1 Purpose and Scope
1.2 Audience
2 Bioassay Fitness for Use
2.1 Process Development
2.2 Process Characterization
2.3 Product Release
2.4 Process Intermediates
2.5 Stability
2.6 Qualification of Reagents
2.7 Product Integrity
3 Bioassay Fundamentals
3.1 In Vivo Bioassays
3.2 Ex Vivo Bioassays
3.3 In Vitro (Cell-Based) Bioassays
3.4 Standard

Official from May 1, 2017

Copyright (c) 2017 The United States Pharmacopeial Convention. All rights reserved.