Russell E. Madsen is the former senior vice-president of science and technology at PDA, and is a current member of Pharmaceutical Technology's editorial advisory board.

Russell E. Madsen Jr.

In this extended op-ed, aseptic processing consultants James Agalloco, Russell Madsen, and James Akers discuss the current regulatory emphasis on environmental monitoring requirements. Based on the mistaken belief that monitoring is an exact measurement of reality, many current requirements emphasize monitoring when the real focus should be on minimizing operator contact with the process, they write. 

Pharmaceutical Technology’s Biologics and Sterile Drug Manufacturing 2018

 Biologics and Sterile Drug Manufacturing 2018

	When referring to this article, please cite it as J. Agalloco, R. Madsen, and J. Akers," Lies That Environmental Monitoring Systems Tell," 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing 2018 

Articles

Environmental monitoring, which operates below the limit of detection, is little more than a rote exercise that provides limited real value. So why does it figure so prominently in current regulatory requirements for aseptic manufacturing?

Lies That Environmental Monitoring Systems Tell

Many new biological entities use unique processing flows and steps that can require non-traditional thinking about process validation. Large-molecule drug products and attendant manufacturing processes often involve complex syntheses and purification steps that differ substantially from those employed for small-molecule pharmaceutical products. In fact, it has been said that for biotechnology products, “The product is the process.” Traditional small-molecule drug products have well-defined chemical structures and can be analyzed to ensure conformance to specifications. Biopharmaceuticals are often complex molecules, or mixtures of molecules, produced in biological systems and it is not always possible to fully characterize these products in the laboratory. Therefore, the manufacturing and purification processes become critically important in ensuring the “sameness,” quality, efficacy, and safety of these products.
	
	Process validation is documented process understanding and control that begins when it is determined that a cell, molecule, or compound may have clinical significance and ends when the product is no longer viable in the marketplace. Each product and process may have different validation formats and structures and may not fit the traditional validation models. Validation requires careful thought and planning. It is not a stack of protocols and reports designed to satisfy regulatory expectations. It is not following by rote a series of “qualifications” such as design (DQ), installation (IQ), operational (OQ), and performance qualification (PQ) studies. It is not hiring a validation company to develop the protocols, perform the studies, and write the reports.   

	When referring to this article, please cite it as R. Madsen, "Understanding Validation and Technical Transfer," 

Pharmaceutical Technology Biologics and Sterile Drug Manufacturing

Validation ensures safe and effective biologic products that benefit the patients whose health and wellbeing depend on the therapies.

Understanding Validation and Technical Transfer

 presented difficulties with the revised European guidelines on sterile manufacturing (1).  The authors included a brief summary of the comments developed on the draft document.  This article expands upon that summary, outlines the authors’ rationale, and highlights the most difficult aspects of the revision draft.

Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use

, Annex 1, Manufacture of Sterile Medicinal Products (2), when finalized, will be legally binding. Non-compliance could result in regulatory action, refusal, or revocation of marketing authorizations, and civil and criminal penalties. Given the revised Annex 1’s legal standing, it is vital that the document delineates appropriate regulatory expectations and accepts contemporary manufacturing and control procedures and practices.

	The European Medicines Agency (EMA) has put forward Annex 1 for comment, but the document is so badly written that understanding it, much less commenting on it, is far more difficult than it should be. As it stands, this version of Annex 1 will inevitably generate thousands of comments that will be difficult for EMA to reconcile within the framework of the current document. Preliminary review of the document indicates that it is poorly worded, ambiguous, and technically incorrect in many areas. The following comments represent a fraction of those identified during the authors’ review. They are categorized by general areas of concern.

	1. The document is inconsistent in its use of references; they are present in some sections and absent in others. The document should include a comprehensive set of reference documents to support the points made in the text. The inclusion of appropriate references is especially important for those aspects of the draft that are most contentious.

	2. The document presents a view of sterile product manufacture inconsistent with that developed elsewhere, as codified in regulations, international standards, and pharmaceutical compendia, for example:

	a. US and Japanese guidance on sterile product manufacturing differ markedly from what is presented.

	b. The cleanroom content in the draft does not conform to International Organization for Standardization (ISO) 14644 and perpetuates the myths that cleanrooms can be classified microbiologically and that microbiological testing can enhance sterility assurance (3).

) chapters <1211>, <1228>, and <1229> provide more contemporary and appropriate guidance for sterile product preparation (4–6).

	d. There are also conflicts with current EMA guidance (e.g., the water for injection [WFI] Q&A paper and Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products) (7-8).

	3. The revised Annex 1 does not provide separate consideration of conventional cleanrooms, restricted access barrier systems (RABS), and isolators; they are demonstratively different in many ways, and considering them together denigrates isolator performance, elevates RABS capabilities, and does not consider the limitations of the far less capable barrier-equipped conventional cleanroom.

	4. EMA’s illogical and arbitrary insistence upon maintaining its Grade A/B/C/D system should be abandoned and the ISO 5 classification system used throughout the document. We have addressed these in some instances, but other citations to Grades A/B/C/D may remain as well as individual citations to Grade A, Grade B, and the unclear Grade A/B. Grades A, B, C, and D should be replaced with the corresponding classes of ISO 5, 6, 7, and 8.  All references to the arbitrary and confusing Grade B, and the totally undefined Grade A/B, should be removed.

	5. Classification of controlled environments is limited to non-viable particle monitoring as described in ISO 14644. There are no means to classify cleanrooms based upon the microbial enumeration. Any suggestion that classification includes a microbial population requirement should be removed from the document.

	6. The document has a perspective on microbial monitoring that is inconsistent with scientific reality. The limit of detection for microbial testing is substantially higher than one colony forming unit (CFU), a level which is used throughout the document. This erroneous belief leads to numerous misconceptions and overstatements regarding what value environmental monitoring has in the preparation of sterile medicinal products.

	7. The document frequently asks for testing of materials, containers, and surfaces, with the expectation that the testing can somehow assure quality. The founding principle of validation is that it can assure confidence in the reliability and appropriateness of the process in ways that testing can never provide.

	8. The document needs better organization to place related content together (e.g., environmental monitoring, terminal sterilization, barrier system, and lyophilization content can be found in multiple locations). In addition, there is non-exact redundancy of the content (i.e., environmental monitoring, terminal sterilization), which only causes additional confusion.

	The use and application of barrier systems, isolation technology, and environmental and personnel monitoring are incorrectly described or applied, as follows:

	m) Monitoring systems-including an assessment of the feasibility of the introduction of scientifically sound, modern methods that optimize the detection of environmental contamination.

 This bullet item suggests that there are available means to demonstrate ‘sterility’ or ‘asepsis’ through the use of expanded monitoring. While these methods can be of value, expanding the application of these methods to enable detection of contaminants not currently found is scientifically incorrect because of the analytical and statistical limitations inherent in them. The environments used for sterile (aseptic) operations need not be, and by in large cannot be, ‘sterile’. The conflation of the condition of asepsis with the concept of sterility is both semantically and scientifically erroneous. It is impossible to test sterility in a product environment using any analytical technology. In addition, monitoring must never be invasive to the production processes in a manner that increases risk by adding activity in the critical zone. The increased interventional frequency that would result from the undefined practice of continuous monitoring (entails excessive risk for no additional useful information gained.

 Monitoring activities must not increase the risk of contamination ingress due to their proximity to critical activities.

	This monitoring should take place immediately after completion of a critical intervention and upon each exit from the cleanroom.

 Monitoring of personnel after each “critical intervention” increases risk of contamination by allowing personnel to reenter the critical zone after monitoring. Furthermore, there is no description provided in the document as to what constitutes a “critical intervention,” which would be required to interpret this statement. Monitoring after interventions attempts to do the impossible, which is to link contamination to specific interventions, and it implies that detection of contamination means sterile products will be contaminated. Neither of these objectives is analytically possible. Monitoring is an intervention subject to microbial contamination independent of any process-related interventional activity. Environmental monitoring in aseptic processing is already done far more intensely than is analytically or statistically warranted. Additional monitoring is not justifiable, as the actual limit of detection of the method is in the range of 10–100 CFU. Industry is already operating below the limit of detection of the method, and additional environmental monitoring is unwarranted as it has no quantitative or qualitative meaning.

  Grade A personnel monitoring should be performed in Grade B adjacent to the Grade A environment. For personnel working exclusively in Grade B, monitoring should be performed upon exit from the aseptic core.

	Normally, such conditions are provided by a localized air flow protection, such as laminar air flow work stations or isolators.

The use of unidirectional air flow in isolators provides no operational advantage over turbulent air. Years of experience in sterility test isolators where extensive manual activity is required have not demonstrated any contamination problem that could be resolved by the use of unidirectional air flow. Laminar air flow is a misnomer, as truly laminar air flow does not exist in any cleanroom or separative technology environment. The authors are establishing expectations that cannot be objectively evaluated or established.

 Normally, such conditions are provided by a localized air flow protection, such as provided in unidirectional air flow work stations.

	Unidirectional air flow systems should provide a homogeneous air speed in a range of 0.36–0.54 m/s (guidance value), the point at which the air speed measurement is taken should be clearly justified in the protocol. During initial qualification and requalification air speeds may be measured either close to the terminal air filter face or at the working height.

There are no reliable and reproducible means to measure air velocity at work height. The most appropriate means is to measure the air velocity proximate to the filter face. Airflow near the work surface is typically impeded by the presence of equipment or machines oriented perpendicular to the general direction of air movement. These conditions render air velocity measurements close to the work surface non-reproducible and thus meaningless. See Mason, W., et al, “Working Height Velocity Measurement in Conventional Cleanrooms, 

. Isolators because of the completeness of their separation do not require the same air velocities as conventional cleanrooms or RABS designs. Air velocities in isolators can be substantially less and non-unidirectional.

 Unidirectional air flow systems should provide a homogeneous air flow over exposed sterile materials. Air velocity measurements should be taken to define the operating condition, however in isolator enclosures or other low volume work areas air velocities can be considerably lower than is customary for manned clean rooms. Unidirectional air is not required in isolators.

	5. Premises–Barrier Technologies, Line 433 (and elsewhere)

 The document uses the term barrier in a manner that fails to distinguish between highly capable technologies such as isolators, which are among the most capable of current aseptic processing technologies, and less capable designs such as open RABS and simple curtain/partial barriers designs. Open RABS systems allow similar intervention strategies to those found in cleanrooms and are substantially less effective in achieving full personnel separation as compared to isolators or closed RABS. To identify these varying capability systems together as is done throughout the document is to equate their performance, which is substantially different. The text could be substantially improved by separate treatment of isolation technology and RABS (open and closed) technologies and by making a distinction between those designs and ordinary manned cleaned rooms, the majority of which rely on some form of minimally effective barrier.

 Provide separate consideration of conventional cleanrooms, RABS, and isolators because they are demonstratively different in many ways and considering them together denigrates isolator performance, elevates RABS capabilities (especially for open RABS designs), and implies that the far less capable barrier designs used in conventional cleanrooms are their equal.

	5. Premises–Clean Room and Clean Air Device Classification–Note, Lines 493-495 

	Note: Classification is a method of assessing the level of air cleanliness against a specification for a cleanroom or clean area device by measuring the airborne particle concentration. The classification is part of the qualification of a clean area.

The content is correct; however, its placement immediately after content that discusses ‘environmental cleanliness level in the operational state’ suggests that classification can be accomplished in the operational state. Classification of environments is restricted to ‘at rest’ or static conditions as stated in ISO 14644. It is not scientifically possible to classify an environment microbiologically; the growth-based methods used for such purposes have a limit of detection between 10–100 CFU and are statistically and analytically incapable of classifying an environment.

 Relocate this content to follow lines 497-499.

	Note: Classification is a method of assessing the level of air cleanliness against a specification for a cleanroom by measuring the airborne particle concentration. The classification is part of the qualification of a clean area and is performed under ‘at rest’ or static conditions.

	Section 9–Viable and non-viable environment & process monitoring–Section 9.13–Note 2, Line 1659–1662

	Note 2: With regards to the monitoring of 5.0 μm, the limit of 20 is selected due to the limitations of monitoring equipment. It should be noted that alert limits should also be set based on historical and qualification data, such that frequent sustained recoveries below the action limit should also trigger an investigation.

 The inability to accurately count low numbers of non-viable particles with current technology precludes the imposition of limits for 5 μm particles in ISO 5. This objection has been raised innumerable times by numerous individuals and organizations since the first issue of Annex 1 in 1999. Maintaining the façade that this is a statistically meaningful measurement is inappropriate as it perpetuates a technical fallacy. There is no scientific justification for retaining a monitoring requirement for 5 μm particles in this guidance.

 Delete the columns relating to 5 μm particles in Table 5 and Note 2.

	Delete content relating to 5 μm particles from the document.

	Technical errors dot the pages of the document. The following are some of the most egregious:

	5. Premises–Section 5.8, Line 357–359

	Floor drains in lower grade rooms should be fitted with traps or water seals to prevent back flow and should be regularly cleaned and disinfected.

 “Traps”, which are intended to allow air and condensate exit from a system while retaining steam, cannot prevent back flow.

 Floor drains in lower-grade rooms should be designed to prevent back flow and should be regularly cleaned and disinfected.

	Materials liable to generate fibers should not be permitted in clean areas.

 This sentence would essentially eliminate the presence of gowned personnel, who, studies have shown, continuously shed particles and fibers. Also, there are almost no aseptic gowns that are not made of fibers.

	8. Production and specific technologies–Section 8.26, Lines 931–932

	Critical defects should not be identified during any subsequent sampling of acceptable containers as it indicates a failure of the original inspection process.

 Inspection of containers for defects is not an absolute process even if automated. The potential for a defective unit to be accepted is always present.

: Critical defects should not be identified during any subsequent sampling of acceptable containers as it indicates a possible failure of the original inspection process.

	8. Production and specific technologies–Section 8.30, Lines 957–960

	Where it is not possible for a product to undergo a sterilization, consideration should be given to using terminal bioburden reduction steps, such as heat treatments (pasteurization), combined with aseptic processing to give improved sterility assurance.

 This sentence adds no value to the document. The included and correct definition of terminal sterilization embraces a wide range of processes when it is understood that the target of the sterilization process is the bioburden present and not the biological indicator (see 

 <1229>). Sterilization processes are intended to destroy the bioburden present (as opposed to reducing its population) and thus, the conditions necessary can be less rigorous than those previously utilized, which are fixated on killing high populations of a resistant biological indicator. The false expectation that mandates biological indicator destruction reduces the use of terminal sterilization rather than increasing it. Reduction of biological indicator population actually supports extremely safe terminal processes for the substantially less resistant bioburden.

	8. Production and specific technologies–Section 8.51, Lines 1086–1087

	Chemical or biological indicators may also be used, but should not take the place of physical measurements.

 Physical measurements rely upon mathematical models from microbiological data, which estimate the lethal effect a process asserts on microorganisms. As such, physical measurements are substantially less reliable (though easier to acquire) than the biological results they attempt to mimic. They should never be given preference over the results of a microbiological challenge study. Additionally, there are locations within items requiring sterilization where physical measurements are taken so remotely that their ability to “demonstrate” lethality is either extremely limited or non-existent.

The results from biological indicators and physical measurements must be considered in validation activities.

	8. Production and specific technologies–Section 8.78, Lines 1251–1253

	If a liquid product cannot be terminally sterilized by a microbiocidal process, it should be sterilized by filtration through a sterile, sterilizing grade filter …

The draft expects that a liquid product is to be “terminally sterilized by a microbiocidal process” an undefined process instead of simply stating that “a terminal sterilization process” be used.

If a liquid product cannot be terminally sterilized, it should be sterilized by filtration through a sterile, sterilizing grade filter …

	8. Production and specific technologies–Section 8.78, Lines 1287–1289

	f) Permit in-place integrity testing, preferably as a closed system, prior to filtration as necessary. In-place integrity testing methods should be selected to avoid any adverse impact on the quality of the product.

 Pre-use post-sterilization integrity tests (PUPSIT) of sterilizing filters should only be performed where a closed system is present throughout. Requiring PUPSIT where the system is not closed creates a greater risk than any value the integrity test can provide. This same expectation is repeated at lines 1331–1340. At the very least, content on the same subject should be together in the document.

	9. Viable and non-viable environment & process monitoring

	Although monitoring of â§ 5.0 μm particles are not required for room qualification and classification purposes, it is required for routine monitoring purposes as they are an important diagnostic tool for early detection of machine, equipment, and HVAC failure.

 See the earlier comment on lines 1659-1662. Further, the suggestion that larger particles would serve as a superior “important diagnostic tool” than smaller particles, which are more accurately counted, is not supported by documented evidence. Persistence in including this “requirement” in the face of objective scientific evidence to the contrary is completely without justification. 

  Delete all content relating to 5 μm particles from the document.

	There is a misdirected focus toward factors and suggested activities that do not increase patient safety or relate to the safety, identity, strength, quality, or purity of a drug product beyond the official or other established requirement.  In some cases, the recommendations add to patient risk.

	4. Personnel–Section 4.4, Lines 205–206

The location of the monitoring is not specified at this point in the document. Table 6 includes expected levels for Grades A/B with different values for each. This implies that Grade A monitoring of personnel take place in Grade A. This is both impractical for the sites identified (see lines 199–200) and excessively risky. Monitoring of personnel in Grade A increases the potential for contamination ingress into that environment because a) personnel (the major source of contamination) are present in Grade A for longer periods, b) monitoring in Grade A increases activity in close proximity to sterile materials, and c) added activity in Grade A increases contamination risk. Monitoring cannot confirm “sterility” or “asepsis” in any event, but there is no benefit to having this sampling being performed in Grade A. Insistence on the Grade A personnel monitoring and consideration of risk should allow for that sampling to occur in Grade B adjacent to the Grade A environment with the Table 6 limits. For personnel working exclusively in Grade B, that monitoring can be performed upon exit from the aseptic core. Personnel monitoring should never be performed in close proximity to sterilized materials.

 Grade A personnel monitoring should be performed in Grade B adjacent to the Grade A environment. For personnel working exclusively in Grade B, monitoring should be performed upon exit from the aseptic core.

	8. Production and specific Technologies–Section 8.18, Lines 883–886

	Containers closed by fusion (e.g., form-fill-seal small volume parenteral (SVP) and large volume parenteral (LVP) bags, glass or plastic ampoules) should be subject to 100% integrity testing.

This is nothing more than testing quality into the product as opposed to validating the sealing process and running confirmatory process checks.  Annex 1 references quality by design, statistical process control, and process validation approaches and then undercuts the asserted value of these well-recognized quality management tools with a poorly considered focus on end-product testing.

	8. Production and specific Technologies–Section 8.18, Lines 1331–1334

	The integrity of the sterilized filter assembly should be verified by testing before use, in case of damage and loss of integrity caused by processing, and should be verified by on-line testing immediately after use by an appropriate method such as a bubble point, diffusive flow, water intrusion, or pressure hold test.

 The document incorrectly applies risk analysis (e.g., integrity testing of a sterilized filter assembly before use [PUPSIT] and on-line integrity testing immediately after use).  PUPSIT adds risk by potentially requiring manipulations downstream of sterilized filters.

A previously published article presented difficulties with the revised European guidelines on sterile manufacturing.  The authors included a brief summary of the comments developed on the draft document.  This article expands upon that summary, outlines the authors' rationale, and highlights the most difficult aspects of the revision draft. 

Annex 1 Misses the Mark–Expanded Version

, Annex 1, Manufacture of Sterile Medicinal Products (1), when finalized, will be legally binding. Non-compliance could result in regulatory action, refusal, or revocation of marketing authorizations and civil and criminal penalties. Given the revised Annex 1’s legal standing, it is vital that the document delineates appropriate regulatory expectations and accepts contemporary manufacturing and control procedures and practices.

	The European Medicines Agency (EMA) has put forward Annex 1 for comment, but the document is so badly written that understanding it, much less commenting on it, is far more difficult than it should be. As it stands, this version of Annex 1 will inevitably generate thousands of comments that will be difficult for EMA to reconcile within the framework of the current document. Preliminary review of the document indicates that it is poorly worded, ambiguous, and technically incorrect in many areas. The following comments represent a fraction of those identified during our review. They are categorized by general areas of concern.

	Inconsistent use of and undefined terminology

	There are many instances where inconsistent use of terms or wording results in ambiguity and the inability to determine or demonstrate compliance, such as listed in the following:

		The terms “medicines” and “medicinal products” are used interchangeably and neither is defined.

		Line 188 instructs that “All personnel . . . in such areas should receive regular training,” but it is unclear to which areas this refers.

		Line 207 mentions a “continuous monitoring program for personnel” without explaining what this is, or how continuous personnel monitoring is feasible, useful, or even safe.

		Line 230 instructs that “Staff who have been engaged in the processing of human or animal tissue materials” should not enter “sterile product areas,” but none of these terms are defined.

		“Grade A/B” used throughout the document is undefined.

		At line 861, “time between the start of the preparation of a solution and its sterilization,” the word “solution” does not reflect the full range of medicinal products that should be subject to pre-sterilization time limits.

	The use and application of airlocks, barrier systems, isolation technology, and environmental and personnel monitoring systems are incorrectly described or applied, such as:

		Airlocks and pass-throughs vary in sophistication and design, but the document limits flexibility and informs at line 365 that “the final stage of the airlock should . . . be the same grade as the area into which it leads,” which is inappropriate for exit airlocks.

		Barrier technologies, other than true closed restricted-access barrier systems (RABS), are substantially less capable than isolators, yet the document considers them near equal in performance.

		Monitoring of large particles (≥ 5 µm) lacks accuracy and is inherently less sensitive than monitoring of smaller particles. Also, the prevalence of such particles in grade A/B areas is too low to make sampling for them statistically useful. And there is no evidence particles of this size range predict microbial risk. EMA should harmonize with International Organization for Standardization (ISO) 14644.

		Personnel monitoring should never be performed in grade A as instructed at line 205.  Such monitoring increases the biological load in critical environments with no product safety benefit.

	The following technical errors dot the pages of the document:

		At line 1251, a liquid product is to be “terminally sterilized by a microbiocidal process” instead of “terminally sterilized.”

		The use of traps for back flow prevention is specified at line 358, even though “traps” do not prevent back flow.

		At line 351, “Materials liable to generate fibres should not be permitted in clean areas,” which would eliminate gowned personnel, who, studies have shown, continuously shed particles and fibers.

		At line 839, the document instructs “The transfer of partially closed containers to a lyophilizer, should be done under grade A conditions (e.g., HEPA filtered positive pressure) at all times . . .” which is contradictory because grade A requires unidirectional airflow.

	There is a misdirected focus toward factors that do not increase patient safety or relate to the safety, identity, strength, quality, or purity of a drug product beyond the official or other established requirement:

		The document incorrectly applies risk analysis (e.g., line 1331, integrity testing of a sterilized filter assembly before use [pre-use post-sterilization integrity testing, PUPSIT] and on-line integrity testing immediately after use).  PUPSIT adds risk by potentially requiring manipulations downstream of sterilized filters.

		Routine and intervention-related monitoring of personnel in grade A adds activity and increases contamination risk, line 205.

		At line 883, “Containers closed by fusion, e.g., Form-Fill-Seal Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP) bags, glass or plastic ampoules, should be subject to 100% integrity testing.”  This is akin to testing quality into the product as opposed to validating the sealing process and running confirmatory process checks.  Annex 1 references quality by design, statistical process control, and process validation approaches and then undercuts the asserted value of these well-recognized quality management tools with a poorly considered focus on end-product testing. 

	Unusual concept of sterile product manufacture

	The document presents a view of sterile product manufacture inconsistent with that developed elsewhere, as codified in regulations, international standards, and pharmaceutical compendia, such as:

		US and Japanese guidance on sterile product manufacturing differ markedly from what is presented.

		The cleanroom content in the draft does not conform to ISO 14644 and perpetuates the myths that cleanrooms can be classified microbiologically and that microbiological testing can enhance sterility assurance.

) chapters <1211>, <1228>, and <1229> provide more contemporary and appropriate guidance for sterile product preparation (2–4).

		There are also conflicts with current EMA guidance (e.g., the water for injections Q&A paper and 

Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products).

	EMA should withdraw this draft of Annex 1. It should be significantly revised to include more contemporary and global content on sterile product manufacture and control and reissued for comment once its many faults have been corrected.

	The cited examples represent only a fraction of the more than 130 issues we identified in the document and we plan to submit a comprehensive response to EMA by the comment deadline of March 20, 2018 in the event that the draft is not withdrawn.

, Annex 1, Manufacture of Sterile Medicinal Products, December 2017.

<1211> Sterilization and Sterility Assurance of Compendial Articles

<1229> Sterilization of Compendial Articles

	Russell Madsen is president of the The Williamsburg Group, LLC,  James Agalloco is president of Agalloco and Associates, and Jim Akers is president of Akers Kennedy & Associates.

The revised Annex 1 on sterile manufacturing includes incorrect and ambiguous statements that must be fixed before implementation. 

Annex 1 Misses the Mark

How many samples should I take? Is the assay method validated? Is this result really out of specification? Should I adjust the tablet weight? Is this process under control? Should I reject the batch? The pharmaceutical industry has always faced questions such as these, and they may be answered best from a statistical perspective. 

 Validation by Design, Lynn Torbeck, PDA Books, Bethesda, MD, 2010, 200 pp., ISBN: 193372238X			

Unfortunately, many quality-assurance workers and production managers charged with answering these types of questions do not have an adequate working knowledge of statistics. They find it difficult to answer these questions and to understand answers that statisticians provide. 

Validation By Design: The Statistical Handbook for Pharmaceutical Process Validation, 

's Editorial Advisory Board, contains information useful to people who are new to statistics and to employees responsible for implementing statistical techniques that monitor and control pharmaceutical production processes and quality-assurance activities. The book was written specifically to address the statistical issues contained in the US Food and Drug Administration's November 2008 draft guidance for industry titled 

Process Validation: General Principles and Practices, 

which is reproduced in its entirety in an appendix. Torbeck's book can form the basis for interdepartmental discussions and for an understanding of the statistical techniques that are consistent with the intent of the guidance. 

An important feature of the book is its interpretation of the guidance's statistical implications. The author rewrote the guidance's statistical content as a series of self-audit questions that cite specific lines in the guidance document. For example, lines 27–29 of the guidance state, "The lifecycle concept links the product and process development, qualification of the commercial manufacturing process, and the maintenance of the process in a state of control during routine commercial production." The associated self-audit question asks, "Is the process in a state of control during routine commercial production?" The question is followed 

by a brief explanation of the term "state of control" and a reference to the chapter of the book that describes the concept. This self-audit format leads the reader through the various statistical techniques that enable compliance with various sections of the guidance. 

A second important feature of the book is the chapters that elucidate statistical methods and concepts. Each of these chapters is written in a standard format that contains subtopics such as "Other Names," "Acronyms," "Definition," "Related Topics," "Calculation," "Illustration," "Cautions," "Advice," and "References." This consistent categorization enables the reader to understand the statistical concepts and decide whether their use is appropriate in a particular situation. The chapters explain simple statistical concepts such as average and relative standard deviation, as well as complicated ones such as control charts, root-cause analysis, process mapping, interquartile range, and Plackett–Burman designs. 

The book should prove useful to employees charged with developing a self-audit program to measure the company's level of compliance with the process-validation guidance. It also would be a solid basis for writing validation protocols. 

The book cannot be considered an introductory text about statistics because the topics are not presented in depth. Still, its references provide necessary information for readers who wish to delve further into any of the subjects. According to the author's preface, the book is for "those engaged in meeting the requirements of the FDA process-validation guidance." The questions that interpret the guidance, the author's explanations, and the chapters about statistical methods and techniques should do much to help personnel meet those requirements. 

 is president of The Williamsburg Group, 18907 Lindenhouse Rd., Gaithersburg, MD 20879, tel. 301.938.4266, fax 301.869.5016, 

A book helps statistics novices prepare to comply with the US Food and Drug Administration's draft guidance on process validation.

Validation by Numbers

 is intended to provide practical information and examples to help pharmaceutical professionals comply with current good manufacturing practice (CGMP) requirements. The book is written from a European perspective and compares the US Food and Drug Administration's regulations and inspection practices with their European equivalents. 

The book's first chapters provide practical do's and don'ts to help regulatory-affairs professionals prepare for FDA inspections. The section offers tips about escorting and interacting with inspectors. For example, the book suggests restricting the number of participants in an inspection to optimize efficiency. It also warns against endless philosophical discussions once the company's point of view has been clearly communicated to the inspector. 

The chapter titled "Complaints and Notifications of Deficiency by the FDA" contains excellent information about FDA's investigational procedures. It briefly describes the agency's "Regulatory Procedures Manual" and "Investigations Operations Manual" and includes website links to these and other documents. 

FDA Requirements for CGMP Compliance, Author: Concept Heidelberg, Publisher: Editio Cantor Verlag, Aulendorf, Germany, 2007, 144 pp., ISBN 978-3-87193-363-9. 

Risk analysis has recently been a topic of interest to the pharmaceutical industry, largely as a result of FDA's CGMPs for the 21st Century initiative and International Conference on Harmonization's (ICH) 

 examines hazard analysis and critical control points (HACCP). This technique helps identify and control, or eliminate, processing steps that can jeopardize product quality. A particular highlight of that chapter is a practical example of applying HACCP analysis to an aseptic-filling operation for sterile-powder finished product. The section also describes FDA's risk-based approach to validation. 

The chapter about risk analysis and mitigation focuses on computer systems used in the pharmaceutical industry. It shows how the risk analysis and validation of those systems should comply with the CGMPs for the 21st Century initiative and ICH Q9. Useful flow charts demonstrate process and subprocess validation. The chapter also includes a handy illustration of subprocess failure mode and effect analysis. 

The final section of the book looks at quality control-related FDA requirements. A chapter about validating analytical methods compares FDA and ICH guidance documents. It also explores the relative importance of accuracy, precision, repeatability, specificity, detection limit, and linearity difference for identity, impurity, assay, and dissolution tests. The chapter contains an excellent review of how FDA regulations affect the validation of analytical methods. 

A subsequent chapter provides guidance for selecting a valid sampling plan that conforms with 21 

 211 regulations. The chapter discusses several sampling methods and tools for various types of containers and materials. It concludes with a discussion of statistical sampling. 

The book ends on the topic of handling out-of-specification (OOS) results, including a detailed flow chart that shows how to conduct an investigation when an OOS result is obtained in the laboratory. It also discusses how an OOS investigation should complement a corrective and preventive action program and an overall quality system. 

 would be useful to anyone in the pharmaceutical industry who is responsible for regulatory inspections. The book would be particularly valuable to employees who must understand US and European regulations and inspection practices. The book's greatest assets are its excellent references and regulatory document source information.  

's editorial advisory board and president of The Williamsburg Group, 18907 Lindenhouse Rd., Gaithersburg, MD 20879, tel. 301.938.4266, fax 301.869.5016, 

How do you answer an inspector's questions? How do you validate analytical methods? One book has answers for compliance professionals.